2012 Annual Meeting - American Neurological Association

ONSITE PROGRAM 

AMERICAN 

NEUROLOGICAL 

ASSOCIATION 

IN PARTNERSHIP WITH 

ASSOCIATION 

OF BRITISH 

NEUROLOGISTS 

EXPAND 

YOUR NEURAL 

NETWORKS 

2012 Annual Meeting 

OCTOBER 7-9 | BOSTON 

www.aneuroa.org/ANA2012

AMERICAN 

NEUROLOGICAL 

ASSOCIATION 

Officers & Councilors 

OFFICERS 

President: Eva L. Feldman, 2011-2013 

President-Elect: Robert H. Brown, Jr., 2011-2013 

1st Vice President: Justin C. McArthur, 2010-2012 

2nd Vice President: Karl Kieburtz, 2010-2012 

Secretary: Nina F. Schor, 2010-2013 

Treasurer: Steven P. Ringel, 2010-2014 

Past President: Robert L. Macdonald, 2011-2013 

COUNCILORS 

Robert D. Brown, Jr., 2009-2012 

Henry J. Kaminski, 2009-2012 

Daniel H. Geschwind, 2010-2012 

Amy R. Brooks-Kayal, 2010-2013 

Barbara G. Vickrey, 2010-2013 

Anthony J. Windebank, 2010-2013 

Allan I. Levey, 2011-2014 

Kenneth L. Tyler, 2011-2014 

Allison Brashear, 2011-2014 

LOCAL ARRANGEMENTS COMMITTEE 

Martin Samuels ‘12 

Anne Louise Oaklander ‘12 

SCIENTIFIC PROGRAM COMMITTEE 

William Mobley, Chair ‘13 J. Tim Greenamyre ‘13 

David Fink ‘12 

Frances Jensen ‘13 

Jaideep Kapur ‘12 Jack Parent ‘13 

Alan Pestronk ‘12 

James Meschia ‘13 

Richard Ransohoff ‘12 Joel Perlmutter ‘13 

Ralph Gregory ‘12 Steven Scherer ‘14 

Martin Rossor ‘12 Samuel Pleasure ‘14 

Hadi Manji ‘12 

Ahmet Hoke ‘14 

WELCOME REMARKS 

Dear Colleagues, 

Welcome to Boston and the American Neurological Association’s 

2012 Annual Meeting! There is plenty to be excited about this year, and we 

hope you’ll agree. 

First of all we would like to welcome our colleagues from the Association of 

British Neurologists, who bring with them an extraordinary level of scholarship 

and expertise that have helped us craft superb scientific programs on genetics, 

Alzheimer’s disease and more. 

We also hope you’ll take full advantage of our newer offerings as well, including 

daily faculty development courses designed to build the real-world skills that 

academic neurologists need to advance their careers, at every level. We’ve 

also added daily interactive lunch programs that will put attendees into lively 

conversations on common and controversial issues in neurology, as well as 

provide outstanding networking opportunities with neurology’s thought leaders, 

journal editors and NIH representatives, among others. 

And we’re bringing cutting-edge technology into the ANA Annual Meeting as 

well! This year’s onsite program will be available as an app for all mobile devices, 

including iPhone, iPad, Android and Blackberry. And the entire Annual Meeting 

space will be Wi-Fi enabled! 

So please take advantage of all the exciting offerings you’ll find at the 2012 

Annual Meeting, and be sure to meet and talk to as many colleagues as you 

can. You’ll see once again why the ANA has been The Home of Academic 

Neurology since 1875. 

Warm regards, 

TABLE OF CONTENTS 

Schedule at a Glance .............. 3 

Hotel Floorplan .................. 4 

General Information ............... 5 

Saturday Program Schedule ......... 6 

Sunday Program Schedule .......... 6 

Monday Program Schedule ......... 12 

Tuesday Program Schedule ......... 18 

Special Events. ................. 23 

Sunday Symposia Speaker Abstracts . . 24 

Monday Symposia Speaker Abstracts . . 29 

Tuesday Symposia Speaker Abstracts . . 34 

Eva L. Feldman, MD, PhD, FAAN 

ANA President 2011-2013 

William C. Mobley, MD, PhD 

Chair, ANA Scientific Program Advisory Committee 2011-2013

PROGRAM AT A GLANCE 

Saturday, October 6, 2012 

3:00 – 8:00 pm 

Registration Hours 

Monday, October 8, 2012 

6:30 am – 5:45 pm 


Tuesday, October 9, 2012 

6:30 am – 5:45 pm 


6:00 – 8:00 pm 

AUPN Leadership Lecture & Business Meeting 

Salon H-J (4th Floor) 

Junior Faculty 

Development 

Course 

Session I 

Salon F 

(4th Floor) 

Sunday, October 7, 2012 

6:00 am – 5:45 pm 


7:00 – 9:00 am 7:00 – 9:00 am 7:00 – 9:00 am 

Mid/Senior 

Level Faculty 

Development 

Course 

Session I 

Salon CD 

(4th Floor) 

AUPN: 

Neurology 

Chair 

Development 

Course 

Session I 

Salon AB 

(4th Floor) 

9:00 – 11:30 am 

SYMPOSIUM: New Tools to Define the 

Genetics of Neurological Disorders 

Salon E (4th Floor) 

11:45 am – 1:00 pm 

Interactive Lunch Workshops 

Meet the Symposia Presenters – Salon F (4th Floor) 

Meet the Editors – Wellesley (3rd Floor) 

Meet the Chairs – Dartmouth (3rd Floor) 

Meet the Professors – Simmons (3rd Floor) 

Meet NIH Institutes – Berkeley/Clarendon (3rd Floor) 

Being Heard Clearly – Harvard (3rd Floor) 

1:15 – 3:15 pm 

SYMPOSIUM: Imaging to Explore Neural Network 

Structure and Function 


3:30 – 5:30 pm 

Special Interest Group Symposia 

Cerebrovascular Disease – Salon F (4th Floor) 

Sleep Disorders and Circadian Rhythm – 

Salon CD (4th Floor) 

Education – Provincetown (4th Floor) 

Neuro-oncology – Salon B (4th Floor) 

Health Services Research – Salon A (4th Floor) 

5:30 – 7:00 pm 

Poster Stand-by Wine & Cheese Reception 

Back Bay Hall: Gloucester and Arlington (3rd Floor) 

7:00 – 9:00 am 


Development 

Course 

Session II 

Salon F 

(4th Floor) 

7:00 – 9:00 am 

Mid/Senior 

Level Faculty 

Development 

Course 

Session III 

Salon CD 

(4th Floor) 

7:00 – 9:00 am 

AUPN: 

Neurology Chair 

Development 

Course Session II 

Salon AB 

(4th Floor) 

9:00 – 11:30 am 

PRESIDENT’S SYMPOSIUM: Alzheimer’s Disease: 

New Perspectives on an Old Disease 


11:45 am – 1:00 pm 


MOC for Board-Certified Neurologists – 

Berkeley (3rd Floor) 

Pharma/Clinical Trials – 

Fairfield/Exeter (3rd Floor) 

Contemporary Clinical Issues in 

Neuromuscular Disease – 

Regis (3rd Floor) 

Headache & Pain Role of Imaging – 

Suffolk (3rd Floor) 

Concussion/Trauma/TBI – 

Simmons (3rd Floor) 

NeuroNEXT – 

Clarendon (3rd Floor) 

Career Challenges – 

Dartmouth (3rd Floor) 

11:45 am – 1:00 pm 

Women of the 

ANA Program 

Salon F 

(4th Floor) 

1:15 – 3:30 pm 

SYMPOSIUM: Results of Immune-Based 

Trials in Neurological Disorders 


3:30 – 5:30 pm 


Dementia and Aging – Salon F (4th Floor) 

Neurocritical Care – Salon D (4th Floor) 

Epilepsy – Provincetown (4th Floor) 

Neuromuscular Disease – Salon BC (4th Floor) 

Case Studies – Salon A (4th Floor) 

5:30 – 6:30 pm 



6:30 – 8:00 pm 

President’s Reception 

Boston Public Library 

7:00 – 9:00 am 


Development 

Course 

Session III 

Salon F 

(4th Floor) 

7:00 – 9:00 am 

Mid/Senior 

Level Faculty 

Development 

Course 

Session III 

Salon CD 

(4th Floor) 

7:00 – 9:00 am 

AUPN: 

Neurology 

Chair 

Development 

Course 

Session III 

Salon AB 

(4th Floor) 

9:00 – 11:05 am 

SYMPOSIUM: Derek-Denny Brown 

New Member Symposium 


11:05 am – 12:00 pm 

Introduction of New Members and 

Executive Session of Membership 


12:00 – 1:15 pm 


Decompressive Craniectomy for 

Trauma – Dartmouth (3rd Floor) 

Continuous EEG Monitoring in the 

ICU –Suffolk (3rd Floor) 

Neuro-oncology – Berkeley 

(3rd Floor) 

The Role of Amyloid PET 

Imaging in Early Diagnosis of 

Alzheimer Disease – 

Salon F (4th Floor) 

Managing Conflict – 


12:15 – 1:30 pm 

Orientation for 

New Members 

Salon CD 

(4th Floor) 

1:30 – 3:15 pm 

SYMPOSIUM: Advances in Headache and 

Pain Research and Treatment 


3:30 – 5:30 pm 


Behavioral Neurology – Salon AB (4th Floor) 

Autoimmune Neurology – Salon F (4th Floor) 

Movement Disorders – Salon CD (4th Floor) 

Regulatory Science – Provincetown (4th Floor) 

5:30 – 7:00 pm 



3

FLOOR PLANS 

3rd Floor 

4th Floor 

PROVINCE- 

TOWN 

ATRIUM 

AREA 

FREIGHT ELEVATORS 

SALON K 

SALON J 

SALON I 

SALON H 

SALON G 

SALON F 

SALON E 

SALON A 

SALON B 

SALON C 

SALON D 

NANTUCKET 

HYANNIS YARMOUTH VINEYARD 

ORLEANS 

FALMOUTH 

4

GENERAL INFORMATION 

Hotel Information 

Boston Marriott Copley Place 

110 Huntington Avenue 

Boston, Massachusetts 02116 

Phone: 1-617-236-5800 

Conference Website 

www.aneuroa.org/ANA2012 


4th Floor Registration Area 

Saturday, October 6: 3:00 pm – 8:00 pm 

Sunday, October 7: 6:00 am – 5:45 pm 

Monday, October 8: 6:30 am – 5:45 pm 

Tuesday, October 9: 6:30 am – 5:45 pm 

Poster Hours 


Sunday, October 7: 11:30 am – 7:00 pm 

(Poster Stand-by 5:30 – 7:00 pm) 

Monday, October 8: 11:30 am – 6:30 pm 


Tuesday, October 9: 11:30 am – 7:00 pm 


Speaker Ready Room 

Falmouth (4th Floor) 

Saturday, October 6: 6:00 am – 8:00 pm 

Sunday, October 7: 6:00 am - 5:30 pm 

Monday, October 8: 6:00 am - 5:30 pm 

Tuesday, October 9: 6:00 am - 5:00 pm 

Wireless Connection 

A wireless connection is available for ANA attendees. To connect, join the 

wireless network American Neurological Assoc. When prompted, 

you can enter the code 1134ana to access the internet. 

Mobile App 

The ANA is pleased to announce a new mobile application for the 2012 

Annual Meeting. The Mobile app, powered by Eventlink and created by 

Core-apps LLC, is a native application for smartphones (iPhone and 

Android), a hybrid web-based app for Blackberry, and there’s also a webbased 

version of the application for all other web browser-enabled phones. 

Evaluations Online! 

Evaluations will be available online only this year. Evaluations can be found 

at www.aneuroa.org/2012Evaluations. Attendees will also receive 

an email with links to the evaluations. Your input is very important to us 

in helping plan future Annual Meetings, and we urge you to complete the 

evaluations on a timely basis. 

Accreditation 

This live activity has been planned and implemented in accordance with 

the Essential Areas and Policies of the Accreditation Council for Continuing 

Medical Education (ACCME) through sponsorship of the American 

Neurological Association. The ANA is accredited by the ACCME to provide 

continuing medical education for physicians. The American Neurological 

Association designates this educational activity for a maximum of 37.25 

hours AMA PRA Category 1 Credit. Each physician should claim only 

those hours of credit that he/she actually spent in the educational activity. 

The 2012 Certificate of Attendance was mailed to U.S. attendees in their 

registration packets. 

Dress Code 

Business Casual 

iPosters 

ANA is excited to announce that we will again offer iPosters, an online 

access to poster presentations found at the Annual Meeting. Poster 

presenters will have the option of uploading their posters to the iPoster 

website so attendees can view their posters in advance. Attendees can 

search by topic or category, and view research and interact directly with the 

presenters online. Computer kiosks will be made available at the Annual 

Meeting specifically for viewing iPosters. iPosters are also available 

online throughout the year. To view the Annual Meeting iPosters, please 

visit ana.posterview.com. 

2012 New Members 

Please go to www.aneuroa.org/2012NewMembers for information 

on the new active, corresponding, and honorary members of the ANA. 

Information on New Members can also be viewed in the Atrium (3rd Floor). 

2012 Award Recipients 

Please go to www.aneuroa.org/2012Awards to view the 2012 ANA 

Award Recipients. Information on Award Recipients can also be viewed in 

the Atrium (3rd Floor). 

How to Download: for iPhone (plus iPod Touch & iPad) and Android 

phones: Visit the App Store or Android Market on your phone and search 

for ANA 2012. For all other phone types (including Blackberry and other 

web browser-enabled phones): While on your smartphone, point your 

mobile browser to m.core-apps.com/ana_annual2012. From there 

you will be directed to download the proper version of the app for your 

particular device, or, on some phones, you simply bookmark the page for 

future reference. We hope this new mobile application makes it even easier 

for you to make the most out of your Annual Meeting experience! 

5

SATURDAY, OCTOBER 6 SUNDAY, OCTOBER 7 

6:00 – 8:00 pm 

Salon H-J (4th Floor) 

3:00 – 8:00 pm 

Registration 


AUPN: Neurology Chair Development Course 

Leadership Course Kickoff: 

Coming Challenges in Health Care: 

How Does Leadership Respond 

Chair: Henry J. Kaminski, MD, George Washington University, 

Washington, DC 

Marc J. Roberts, PhD, Harvard University, Boston 

The AUPN is pleased to be able to tap into Harvard’s School of Public 

Health’s expertise to provide this course on such a timely subject. 

The lecture is open to all and is of particular interest to Chairs of 

Neurology to assist in strategic decision making. 

Marc Roberts is Professor of Political Economy at the Harvard School 

of Public Health and is an active consultant in helping organizations 

adjusting to changing market conditions. He played a leading role in 

the World Bank’s training efforts on health sector reform around 

world-having taught courses for senior government officials in nearly 

thirty countries. He will apply his knowledge to advise leaders in 

neurology what to expect in the coming years from health care reform. 

The Leadership Lecture will be preceded by the AUPN Business 

Meeting and include a reception with wine and appetizers. 

7:00 – 9:00 am 


6:00 am – 5:45 pm 

Registration 


6:00 – 7:00 am 

Coffee and Rolls 

Coffee will be available until 10:30 am 

Junior Faculty Development Course: Establishing 

Yourself in the World of Academic Neurology 

Session I: Getting Funded/Grant Writing 

Chair: Daniel H. Lowenstein, MD, University of California, San Francisco 

Frances E. Jensen, MD, Children’s Hospital, Boston 

Randall R. Steward, PhD, NIH/NINDS, Bethesda, Md. 

Vicky Holets Whittemore, PhD, NIH/NINDS, Bethesda, Md. 

This session will focus on a core need required of everyone who is 

pursuing academic neurology with an emphasis on research: getting 

funded. Regardless of the funding source, getting funded requires 

convincing others that you have the ideas, skills, capacity and track record 

to use a research grant in a way that will lead to important discoveries, and 

this is accomplished by writing outstanding grant proposals. The session 

will focus on the entire process of getting funded, including timelines for 

generating a proposal, idea generation, organization of the research plan 

(including special tips on effectively conveying your plan), the nature of the 

review process, and how to respond to reviewers’ critiques. 

7:00 – 9:00 am 


Mid/Senior Level Faculty Development Course: 

Negotiations & Conflict Resolution 

Session I: Being Heard Clearly 

Chair: Lisa M. DeAngelis, MD, Memorial Sloan-Kettering Cancer Center, 

New York 

Susan Miller, PhD, CCC-SLP, Voice Trainer, LLC, Washington, DC 

Whether conversing with patients, presenting to your faculty or delivering a 

paper at a national meeting, you want to be heard clearly. In this workshop, 

we will investigate how your eye contact, gestures and movement affect the 

quality of your daily communications and how to read your listener’s body 

language. You will learn how to modulate your vocal tone, breath control, 

speaking rate and anxiety to assure pleasant, vocal production. You will 

master the basics of developing a clear succinct message about yourself 

of a project and delivering it powerfully. In this highly interactive workshop 

you will discover the keys to being heard clearly. 

6

7:00 – 9:00 am 

Salon AB (4th Floor) 


Session I: Challenges of Faculty Development 

and Managing K Awardees 

Moderator: Karen C. Johnston, MD, University of Virginia, Charlottesville 

Stephen L. Hauser, MD, University of California, San Francisco 

This session will focus on the challenges of faculty development and more 

specifically on managing K08/K23 and related awards. We hope to have a 

vigorous discussion to address the question of how Chairs and Departments 

can better support the careers of clinician scientists and help to ensure 

their success whenever possible. Although the specific challenges will vary 

between institutions, one common area is the management of cost sharing 

requirements assumed by departments for recipients of K awards. 

This session is not available for AMA PRA Category 1 Credit. 

9:00 – 11:30 am 


SYMPOSIUM: New Tools to Define the Genetics of 

Neurological Disorders 

Chair: Patrick F. Chinnery, PhD, FRCPath, FRCP, FMedSci, 

Newcastle University, Newcastle upon Tyne, UK 

Co-Chair: Robert H. Brown, Jr., MD, DPhil, University of 

Massachusetts, Worcester 

This symposium will describe the current state-of-the-art in neurogenetics, 

highlighting key recent findings that influence our understanding of 

neurological disease mechanisms, and have a direct role in clinical 

neurological practice. Topics covered will include: (i) the role of genomewide 

association studies to advance our understanding of common 

neurological disorders; (ii) Using next-generation whole exome and whole 

genome sequencing to diagnose single-gene disorders, (iii) epigenetic 

mechanisms and RNA-regulation in neurological disease; and (iv) 

diagnosing mitochondrial DNA diseases. By the end of the symposium, 

the attendee will have a broad understanding of current genetic and 

epigenetic approaches to understand neurological disease, and new 

diagnostic tools for neurogenetic diagnostics. 

Learning Objectives: Having completed this symposium, participants 

will be able to: 

1. Understand the methodological approach, strengths, weaknesses, 

successes and failures of GWAS in neurology, and what can we expect 

in the future 

2. Understand the methodological approach (targeted exon capture vs 

whole exome and genome approaches), strengths and weaknesses 

(including the “hit rate”), recently identified neurogenetics, and the role 

in clinical diagnostics. 

3. Understand what epigenetics, dissect epigenetic mechanisms, and 

epigenetic mechanisms in neurological disease. 

4. Understand what RNA regulation is, how RNA-mediated mechanisms 

are studied, and what the implications for understanding neurological 

and neurodegenerative disorders are. 

5. Understand the genetic basis of mitochondrial disease, principles 

of molecular diagnosis in mitochondrial disorders, and diagnostic 

algorithm for mitochondrial diseases. 

9:00 – 9:05 am 

Wolfe Award Presentation 

Thomas E. Lloyd, MD, PhD, Johns Hopkins University, Baltimore, Md. 

Annals of Neurology Prize Presentation 

Michael G. Schlossmacher, MD, FRCPC, Brigham and Women’s Hospital, 

Harvard Medical School, Boston and University of Ottawa, Ontario, Canada 

9:05 – 9:30 am 

Genome-Wide Association Studies: Have They Delivered 

for Neurology 

Stephen Sawcer, PhD, University of Cambridge, Cambridge, UK 

9:30 – 10:00 am 

Next-Generation Whole Exome and Whole Genome 

Sequencing to Diagnose Single-Gene Disorders 

Andrew Singleton, PhD, National Institutes of Health, Bethesda, Md. 

10:00 – 10:15 am 

Coffee Break 

10:15 – 10:40 am 

Epigenetics and Disorders of the Nervous System: 

An Evolving Synthesis 

Mark F. Mehler, MD, Albert Einstein College of Medicine, Bronx, N.Y. 

10:40 – 11:05 am 

Regulatory RNAs in Neurological Disease 

Claes Wahlestedt, MD, PhD, University of Miami 

11:05 – 11:30 am 

New Tools to Define the Genetics of Neurological Disorders: 

Mitochondrial Disorders 

Patrick F. Chinnery, PhD, FRCPath, FRCP, FMedSci, Newcastle University, 

Newcastle upon Tyne, UK 

11:30 am – 7:00 pm 


All Day Poster Presentations 

Poster Stand-by time will be from 5:30 – 7:00 pm 

11:30 am – 1:00 pm 

Lunch 

Pick up your lunch in the 4th Floor Foyer. 

7

SUNDAY, OCTOBER 7 

11:45 am – 1:00 pm 

Interactive Lunch Workshops: 

Networking Roundtables 

Sunday’s Interactive Lunch Workshops are designed to connect attendees 

with experts in the field in a fast-paced series of informal discussions. 

The room will be set up with five to six round tables – each assigned to one 

expert in the identified topic and each allowing for 15-20 attendees per table. 

Because of this informal format, attendees are encouraged to move between 

experts, tables and workshops as they wish. 

Meet the Symposia Presenters 


Speakers from the New Tools to Define the Genetics of Neurological 

Disorders symposium will be available to further discuss their 

symposium presentations. 

Faculty: Andrew Singleton, PhD, National Institutes of Health, 

Bethesda, Md. 

Stephen Sawcer, PhD, University of Cambridge, UK 





Meet the Editors 

Wellesley (3rd Floor) 

Editors from the Annals of Neurology, Brain, Archives of Neurology, 

Neurology, Stroke and the New England Journal of Medicine will be 

available to discuss the submission process, publishing tips and other 

key topics of interest. 

Moderator: Nilufer Ertekin-Taner, MD, PhD, Mayo Clinic, 

Jacksonville, Fla. 

Faculty: Stephen L. Hauser, MD, University of California, San Francisco 

Alastair Compston, MBBS, PhD, FmedSci, University of Cambridge, UK 

Allan H. Ropper, MD, Brigham and Women’s Hospital, Boston 

Roger N. Rosenberg, MD, University of Texas Southwestern, Dallas 

Karen L. Furie, MD, MPH, Rhode Island Hospital and Brown Medical 

School, Providence 

David S. Knopman, MD, Mayo Clinic, Rochester, Minn. 

Moderator: Joachim Baehring, MD, DSc, Yale School of Medicine, 

New Haven, Conn. 

Faculty: Justin C. McArthur, MBBS, MPH, FAAN, 

Johns Hopkins University, Baltimore, Md. 

Richard P. Mayeux, MD, MSc, Columbia University, New York 

Martin A. Samuels, MD, DSc(hon), FAAN, MACP, FRCP, Brigham and 

Women’s Hospital, Boston 

David A. Hafler, MD, Yale University, New Haven, Conn. 

Robert H. Brown Jr., MD, DPhil, University of Massachusetts, Worcester 

Merit E. Cudkowicz, MD, Massachusetts General Hospital, Boston 

Meet the Professors 


This is a place to connect with seasoned academic neurology professors to 

discuss tried and true practices for teaching and a free exchange of ideas. 

Moderator: Rebecca F. Gottesman, MD, PhD, Johns Hopkins University, 

Baltimore, Md. 

Faculty: David A. Drachman, MD, University of Massachusetts, Worcester 

J.P. Mohr, MD, Columbia University, New York 

William M. Landau, MD, Washington University, St. Louis, Mo. 

Anne B. Young, MD, PhD, Massachusetts General Hospital, Boston 

Guy M. McKhann, MD, Johns Hopkins University, Baltimore, Md. 

Meet NIH Institutes 

Berkeley/Clarendon (3rd Floor) 

This is your chance to get your questions answered by representatives from 

the National Institute of Neurological Disorders and Stroke (NINDS). 

Moderator: Anne Louise Oaklander, MD, PhD, Massachusetts General 

Hospital, Boston 

Faculty: Story C. Landis, PhD, NINDS, Bethesda, Md. 

Stephen Korn, PhD, NINDS, Bethesda, Md. 

Walter J. Koroshetz, MD, NINDS, Bethesda, Md. 

Being Heard Clearly: A Follow-up Discussion 

Harvard (3rd Floor) 

Continue the conversation on using the power of voice and body language 

to get your message heard with Susan Miller following her Mid/Senior Level 

Faculty Development Course talk. 

Faculty: Susan Miller, PhD, Voicetrainer LLC, Washington, DC 

Meet the Chairs 


Prominent Chairs of neurology will discuss how they have handled their 

position, what’s involved with being a Chair, what is the process for attaining 

their position, how to interact with Chairs, etc. 

8

1:15 – 3:15 pm 


SYMPOSIUM: Imaging to Explore 

Neural Network Structure and Function 

Chair: Kirk A. Frey, MD, PhD, University of Michigan, Ann Arbor 

Co-Chair: James B. Brewer, MD, PhD, University of California, San Diego 

This symposium will discuss ways in which the structure and function 

of the network of biological neurons or neural networks can be explored 

using different imaging practices. Much research is currently centered 

on detecting pre-disease or molecular states that occur before typical 

symptoms of a disease are detected using molecular imaging. Due to its 

increasing popularity, a large number of investigators are also collecting 

imaging data from healthy and clinical subjects during rest. Diffusion 

tensor imaging (DTI) uses MR imaging to map the brain’s white matter 

tracts and perform fiber-tracking. By the end of this symposium, attendees 

will have a broad understanding of how molecular imaging, resting state 

connectivity and diffusion tensor imaging (DTI) can be used to explore 

neural network structure and function. 



1. Understand the basic underpinnings of the BOLD signal and what it 

means in functional MRI. 

2. Understand the application of MR-based resting state functional 

connectivity and how this can be applied to investigate the 

pathophysiology of neurologic disorders. 

3. Understand how MR-based diffusion weighted imaging can be used 

to measure regional diffusivity and reveal neural connections via tract 

tracing methods. 

4. Understand the ability of molecular imaging approaches to investigate 

brain pathways, the importance of validation of these methods and the 

integration of these methods with MR-based methods. 

1:15 – 1:20 pm 

Distinguished Neurology Teacher Award Presentation 

Carl E. Stafstrom, MD, PhD, University of Wisconsin, Madison 

1:20 – 1:45 pm 

Decoding the BOLD Signal in Functional MR Imaging 

Anna Devor, PhD, University of California, San Diego 

1:45 – 2:10 pm 

Resting State Connectivity 

Michael D. Greicius, MD, MPH, Stanford University, Stanford, Calif. 

2:10 – 2:35 pm 

Diffusion Tensor Imaging (DTI) 

Lawrence L. Wald, PhD, Massachusetts General Hospital, Boston 

2:35 – 3:00 pm 

Molecular Imaging 

Joel S. Perlmutter, MD, Washington University, St. Louis, Mo 

3:00 – 3:15 pm 

Question and Answer 

3:30 – 5:30 pm 

3:15 – 3:45 pm 

Coffee Break 

Special Interest Group Symposia (SIG) 

Please note the color of your SIG’s signage, as they have been color 

coded to match the posters related to the SIG topic. 

Cerebrovascular Disease 


Co-Chairs: Argye E. Hillis, MD, MA, Johns Hopkins University, 

Baltimore 

E. Steve Roach, MD, Ohio State University, Columbus 

Leaders in the Field Presentations: 

Early to Middle Phase Trial Designs in Acute Stroke: 

One Size Does Not Fit All 

Elliott Clarke Haley, MD, University of Virginia, Charlottesville 

Wake Up, Little Susie: Extending the Window of IV Thrombolysis 

Lee H. Schwamm, MD, FAHA, Massachusetts General Hospital, Boston 

Populations at Risk: Stroke and Diabetes 

Kerstin Bettermann, MD, PhD, Penn State University, Hershey, Pa. 

Applying the Lessons from 20 Years of Sickle Cell 

Stroke Research 

E. Steve Roach, MD, Ohio State University, Columbus 

Data Blitz Presentations: 

Lipid Measurements and Risk of Ischemic Vascular Events: 

Framingham Study 

Aleksandra Pikula, MD, Boston University, Boston 

Genetic Risk in Cerebral Small Vessel Disease (SVD): 

17q25 Locus Associates with White Matter Lesions but 

Not Lacunar Stroke 

Poneh Adib-Samii, MBBS, St. George’s University, London, UK 

Quality of Life after Lacunar Stroke: The Secondary 

Prevention of Small Subcortical Strokes (SPS3) 

Mandip Dhamoon, MD, MPH, Mount Sinai School of Medicine, 

New York 

Q&A/Wrap Up/Adjourn 

9

SUNDAY, OCTOBER 7 

Sleep Disorders and Circadian Rhythm 


Co-Chairs: Clifford B. Saper, MD, PhD, Beth Israel Deaconess 

Medical Center, Boston 

Phyllis C. Zee, MD, PhD, Northwestern University, Chicago 

Leader in the Field Presentation: 

Molecular Dissection of Narcolepsy Signs and Symptoms 

Thomas Scammell, MD, Harvard Medical School, Beth Israel 

Deaconess Medical Center, Boston 


Sleep and Circadian Rhythm Disruption in Parkinson’s Disease 

David Breen, MD, University of Cambridge, Cambridge, UK 

Rest-Activity Fragmentation and Risk of Alzheimer’s Disease 

Andrew Lim, MD, University of Toronto, Canada 

TSC-mTOR Pathway and Circadian Rhythms 

Jonathan Lipton, MD, PhD, Children’s Hospital, Boston 

Medical and Psychiatric Conditions Associated with Narcolepsy 

Maurice Ohayon, MD, DSc, PhD, Stanford University, Palo Alto, Calif. 

REM Sleep without Atonia and Freezing Gait in 

Parkinson’s Disease 

Aleksandar Videnovic, MD, MSc, Northwestern University, Chicago 

Sleep Research Society Reception 

Education: The ACGME Milestones Project: 

The Next Step in Program Accreditation 

Sponsored by the AUPN 

Provincetown (4th Floor) 

Moderator and Chair: Ralph F Józefowicz, MD, University of 

Rochester, N.Y. 

Co-Moderator: Steven L. Lewis, MD, Rush University, Chicago 

The Neurology Milestones: What They Are and What 

They Are Not 

Steven L. Lewis, MD, Rush University, Chicago 

The Program Director’s Perspective: The Devil is in the Details 

Ralph F Józefowicz, MD, University of Rochester, N.Y. 

The Chair’s Perspective: Getting Faculty on Board 

David Lee Gordon, MD, University of Oklahoma, Oklahoma City 

The Resident’s Perspective: Views from the Trenches 

Sarah Wahlster, MD, Harvard University, Boston 

The ABPN Perspective: Strengthening the Credentialing 

Process for Board Certification 

Larry Faulkner, MD, American Board of Psychiatry and Neurology, Chicago 

The International Perspective: Credentialing Neurologists 

in the UK 

Geraint Fuller, MD, Association of British Neurologists, London, UK 

Panel – Audience Discussion 

Neuro-oncology 

Salon B (4th Floor) 

Co-Chairs: Jeremy N. Rich, MD, Cleveland Clinic, Cleveland, Oh. 

Benjamin W. Purow, MD, University of Virginia, Charlottesville 


Targeted Molecular Therapies for GBM; Lessons Learned 

and Future Directions 

Patrick Wen, MD, Harvard Medical School, Brigham and Women’s 


An Update on the Benefits and Limitations of Anti-Angiogenic 

Therapy for Glioblastoma 

David Reardon, MD, Dana-Farber Cancer Institute, Boston 

The Search for Predictive Markers for Glioblastoma Response 

Versus Resistance to Anti-Angiogenic Therapies 

Tracy Batchelor, MD, Dana-Farber Cancer Institute, Boston 

Current Challenges in Primary CNS Lymphoma 

Lisa DeAngelis, MD, Memorial Sloan-Kettering Cancer Center, New York 


Genetic Modifiers Affecting Neurofibromatosis (GMAN): 

Cutaneous Tumor Burden in Neurofibromatosis Type 1 

Fawn Leigh, MD, Massachusetts General Hospital, Boston 

Bevacizumab for NF2-related Vestibular Schwannoma 

Scott Plotkin, MD, PhD, Massachusetts General Hospital, Boston 

Leveraging Expression of the GABA-A Receptor, alpha 5 in 

Medulloblastoma as a Novel Therapeutic Target 

Soma Sengupta, MD, Children’s Hospital, Boston 

Cerebrospinal Fluid and MRI Analysis in Leptomeningeal 

Carcinomatosis 

Joachim Baehring, MD, DSc, Yale School of Medicine, New Haven, Conn. 

Ataxia, Ophthalmoplegia and Areflexia: What Would You Think 

Nazia Karsan, MBBS, BSc, MRCP, St. George’s Hospital, London, UK 

Question and Answer 

10

Health Services Research — NEW! 

Salon A (4th Floor) 

Chair: Barbara G. Vickrey, MD, MPH, University of California, Los Angeles 


Community Partnered Research to Improve Outcomes & 

Eliminate Disparities in Neurological Care 

Barbara G. Vickrey, MD, MPH, University of California, Los Angeles 

Can Corporate America Solve Health Disparities 

Lewis B. Morgenstern, MD, University of Michigan, Ann Arbor 


What Patient Factors Associate with Inaccuracies in Reporting 

of Parkinsonian Signs 

Nabila Dahodwala, MD, MS, University of Pennsylvania, Philadelphia 

The Association of Non-Clinical Factors with Head CT 

Use in Emergency Department Dizziness Visits: 

A Population-Based Study 

Kevin Kerber, MD, University of Michigan, Ann Arbor 

5:30 – 7:00 pm 



Poster Categories 

Cerebrovascular Disease 

Education 

Neuro-oncology 

Sleep Disorders and Circadian Rhythm 

Neurogenetics 

Neuroinfectious Disease 

Neuro-ophthalmology 

Pediatric Neurology 

Rehabilitation and Regeneration 

Trauma/Injury 

HEALS (Healthy Eating And Lifestyle after Stroke): A Pilot Trial 

of a Multidisciplinary Lifestyle Intervention Program 

Amytis Towfighi, MD, University of Southern California and Rancho Los 

Amigos National Rehabilitation Center, Los Angeles 

Racial and Ethnic Differences in Post-Stroke Depression among 

Community Dwelling Adults 

Lesli Skolarus, MD, University of Michigan, Ann Arbor 

Improving Stroke Symptom Recognition and Response in 

Elderly Korean-Americans 

Sarah Song, MD, MPH, Rush University, Chicago 

Wrap-up/Summary/Implications for Neurology 

11

MONDAY, OCTOBER 8 

7:00 – 9:00 am 


6:30 am – 5:45 pm 

Registration 


6:30 – 7:30 am 





Session II: Where Does All the Money Go 


Clifford B. Saper, MD, PhD, Beth Israel Deaconess Medical Center, Boston 

Justin C. McArthur, MBBS, MPH, FAAN, Johns Hopkins University, 


This course will provide an overview of financial management as it affects 

a typical faculty member within an academically oriented neurology 

department. Specific topics will include: funds flow, clinical revenues and 

expenses, construction and implementation of compensation and bonus 

plans, philanthropy, and research budgets, indirect costs of research, and 

grants management. Case studies (examples) will be used to illustrate best 

practices, and lessons learned. 

7:00 – 9:00 am 




Session II: Negotiations 


New York 

Career Challenges for Mid/Senior Level Physicians 

Ranna I. Parekh, MD, MPH, Massachusetts General Hospital and McLean 


This course is designed for mid-senior level faculty interested in 

collaborative negotiations. For most successful people at this point in 

their careers, they are already skilled at negotiations. Hence, one hope of 

this course is to build confidence that many us already employ important 

negotiations strategies and to perhaps explain some of the theories why 

they have been effective. 

At the core of collaborative negotiations is achieving the best outcome for 

oneself and others while building trusting relationships. 

There are 5 major objectives for participants: 

1. Describe major work/life situations and the appropriate negotiation 

strategies to employ 

2. Define interest based or win:win or Collaborative Negotiations. 

3. Understand the five stages of Collaborative Negotiations and how each 

stage predicts effective outcomes and longterm partnerships 

4. Guide participants through the most challenging stage of negotiations: 

the brainstorming or creative problem stage 

5. Learn to build trust and rapport during the negotiations process. 

Throughout the course, there will be many work and interpersonal examples 

and the audience will be encouraged to bring their own negotiation “cases” 

for small group discussion. 

7:00 – 9:00 am 



Session II: Avoiding Senior Faculty and Chair Burnout 

Steven T. DeKosky, MD, University of Virginia, Charlottesville 

Sharon L. Hostler, MD, University of Virginia, Charlottesville 

Chairs of Departments of Neurology and senior faculty who have been 

working for several decades are at risk of fatigue and burnout with the 

changes in medical care, pressures regarding NIH grants, and requirements 

for increased productivity. In contrast to most departments’ experience 

with orienting and mentoring young faculty, efforts to provide development 

and resilience in older faculty are much less, and the faculty themselves 

are reluctant to “ask for help” to appear needy, inadequate, or be seen 

as no longer being independent, “triple threats,” or able to “do it all.” 

In this session we will discuss the phenomenon as well as programs and 

techniques to identify and characterize burnout, and methods to prevent 

or combat it. 


9:00 – 11:30 am 


President’s Symposium: Alzheimer’s Disease: 


Chair: Alastair Compston, MBBS, PhD, FmedSci, University of 

Cambridge, UK 

Co-Chair: Karen Ashe, MD, PhD, University of Minnesota, Minneapolis 

The symposium will highlight development in the genetics of Alzheimer’s 

disease, the identification of biomarkers for the molecular neuropathology 

and its serial impact on regional brain structure and function, and emerging 

concepts on the initiation and evolution of the disease processes. 

12

Steady progress has been made in identifying Mendelian genes for familial 

Alzheimer’s disease but less is known about risk factors for sporadic 

disease although genome wide association studies have now prioritized 

several possible new genes implicating novel disease pathways. Improved 

understanding of the genetic basis for Alzheimer’s disease is expected to 

expand our understanding of mechanisms involved early in the disease 

process; and to provide guidelines for cost-effective genetic screening in 

clinical practice. 

The current focus is on early detection of Alzheimer’s disease through 

the recognition of mild cognitive impairment; but there is a need to 

identify individuals without symptoms in whom the disease process of 

Alzheimer’s disease is nevertheless present, at a stage when brain structure 

and function are minimally impaired and interventions are likely to be 

most effective. 

This pre-supposes that work on the mechanisms of tissue injury will 

progress beyond understanding the accumulation of plaques and tangles 

to provide an account of propagation and dissemination of the molecular 

pathology, or its multiple sites of origin so that mechanism-based 

therapeutic strategies are used to improve on the existing limited efficacy 

of Aricept, memantine and vitamin E. 



1. Compare the clinical features and mechanisms of familial and sporadic 

Alzheimer’s disease. 

2. Understand the mechanisms whereby the risk allele for ApoE confers 

susceptibility to Alzheimer’s disease. 

3. Explore current ideas on the extent to which knowledge of prion disease 

informs ideas on the possibility of transmission and propagation of the 

molecular pathology of Alzheimer’s disease. 

4. Provide insights into early disease mechanisms from detecting 

biomarkers for the neuropathology in blood and cerebrospinal fluid. 

5. Provide insights into disease mechanisms from correlating alteration 

in the structure and function of brain regions early and throughout the 

course of Alzheimer’s disease. 

9:00 – 9:05 am 

Welcome from the President; Presentation to the Association of 

British Neurologists 

Eva L. Feldman, MD, PhD, FAAN, ANA President, University of Michigan 

9:05 – 9:25 am 

Lessons for Alzheimer’s Disease from Early Detection of 

Familial Cases 

Martin N. Rossor, MD, Institute of Neurology, University College 

London, UK 

10:00 – 10:15 am 

Coffee Break 

10:15 – 10:40 am 

Mechanisms of Neurodegeneration: Lessons from Prion Disease 

John Collinge, MD, Institute of Neurology, University College London, UK 

10:40 – 11:05 am 

Biomarkers for the Diagnosis and Course of Alzheimer’s Disease 

Randall J. Bateman, MD, Washington University, St. Louis, Mo. 

11:05 – 11:30 am 

Imaging Structure and Function in Alzheimer’s Disease 

William J. Jagust, MD, University of California, Berkeley 

11:30 am – 6:30 pm 




11:45 am – 1:00 pm 


11:30 am – 1:00 pm 

Lunch 


12th Annual Women of the ANA Lunch Program: 

34 Years in Academic Neurology 

Co-Chairs: Kathleen B. Digre, MD, University of Utah, Salt Lake City 

Shirley H. Wray, MD, PhD, Massachusetts General Hospital, Boston 

Faculty: Anne B. Young, MD, PhD, Massachusetts General 


Dr. Young will reflect on her life, including her scientific contributions and 

years leading a neurology department. She will share advice for others 

following a similar path. 

The Women of the ANA program is tailored to address the concerns and 

view of women. Lunch will be provided. 

9:25 – 10:00 am 

Presentation of Raymond D. Adams Lectureship Award and 

Neurobiology of APOE and its Impact on Alzheimer’s Disease 

David M. Holtzman, MD, Washington University, St. Louis, Mo. 

13


11:45 am – 1:00 pm 

Interactive Lunch Workshops: 

Common Neurological Issues 

Monday’s Interactive Lunch Workshops are designed to offer information and 

informal discussions on key issues facing academic neurology. Because of 

the informal format, attendees are encouraged to move between workshops if 

they wish. 

Maintenance of Certification (MOC) for Board-Certified 

Neurologists 


This session will provide an overview of the ABPN MOC Program. 

The background and rationale for MOC will be discussed. The specific 

requirements for the four parts of MOC will be presented and the new 

Continuous MOC Program will be described. Participants will learn how 

to establish their own ABPN folios for identifying their personalized MOC 

requirements and for recording their progress in MOC. 

Moderator: Ralph F. Józefowicz, MD, University of Rochester, 

Rochester, N.Y. 

Faculty: Janice Massey, MD, Duke University, Durham, N. Car. 

Larry R. Faulkner, MD, Buffalo Grove, Ill. 

Pharma/Clinical Trials 

Fairfield/Exeter (3rd Floor) 

Despite intensive efforts, success in clinical trials for neurodegenerative 

disorders has been elusive. Panelists will discuss the challenges, progress, 

and promising new approaches to clinical development in Alzheimer’s 

disease, Parkinson’s disease, and ALS. 


Moderator: Volney Sheen, MD, PhD, Beth Israel Deaconess 

Medical Center, Boston 

Faculty: Eric Siemers, MD, Eli Lilly and Co., Indianapolis, Ind. 

Genevieve A. Laforet, MD, PhD, Biogen Idec, Boston 

Bernard Ravina, MD, Biogen Idec, Cambridge, Mass. 

Contemporary Clinical Issues in Neuromuscular Disease: 

Role of Genetic Testing 

Regis (3rd Floor) 

This symposium will include a discussion of the utility of genetic testing in 

the evaluation of suspected inherited peripheral neuropathies and muscle 

disorders. The discussants will present an overview of indications for genetic 

testing coupled with testing strategies, against a backdrop of the need to 

provide cost effective health care. Controversies and the uses and abuses 

of genetic testing will be covered. Advances in genetic techniques that may 

change the landscape and approach to genetic diagnosis in neuromuscular 

disorders will be addressed. Brief presentations by Dr. David Herrmann 

(genetic testing in suspected inherited neuropathies) and Dr. Anthony Amato 

(genetic testing in muscle disorders) will be followed by an interactive 

discussion encouraging audience participation. 

Moderator: Juliann M. Paolicchi, MD, Weill Cornell Medical Center, 

New York 

Faculty: David N. Herrmann, MBBCh, University of Rochester, New York 

Anthony A. Amato, MD, Brigham and Women’s Hospital, Boston 

Headache & Pain Role of Imaging 


What is the role of neuroimaging and funcitional MRI in migraine What does 

it tell us about migriane chronification, drug effects, and the effect of gender 

on migraine When is neuroimaging absolutely required Which modality 

should be used 

Faculty: Stephen D. Silberstein, MD, Thomas Jefferson University, 

Philadelphia 

David Borsook, PhD, MBBCh, Children’s Hospital Boston 

Concussion/Trauma/TBI 


Traumatic brain injury (TBI) is associated with a variety of pathophysiologic 

events and clinical consequences that are typically labeled on a continuum 

ranging from mild to severe. The preponderance of cases of TBI is on the mild 

side of the continuum and mild TBI has been receiving increasing attention 

in part because of a recent focus on sports concussion and blast injury. 

The other extreme on the continuum, those with very severe TBI causing 

prolonged disorders of consciousness (DOC), has also received increasing 

attention. Interest in this group of patients is largely related to concerns about 

distinguishing patients who are unconscious, in a vegetative state (VS), from 

those who have small, inconsistent signs of consciousness, recently defined 

as the minimally conscious state (MCS). It has also been a fertile area of 

investigation because it contributes to our understanding of one of the key 

questions in neuroscience, the nature of consciousness. In the last decade, 

investigations of patients with DOC after severe TBI have probed differences in 

brain network activity using fMRI and other physiologic modalities in patients 

in a VS, MCS and higher levels of consciousness, have demonstrated better 

than expected outcomes in patients with prolonged DOC, and have established 

potentially effective treatments such as deep brain stimulation of the thalamus 

to improve purposeful behavior and pharmacological agents (i.e., amantadine) 

to speed the pace of recovery. This workshop will include discussions of the 

problems of DOC after severe TBI and recent studies on assessment, outcome 

and treatment. 

Moderator: Thomas P. Bleck, MD, Rush Medical College, Chicago 

Faculty: Ann C. McKee, MD, Boston University, Boston 

Doug I. Katz, MD, Boston University, Boston 

14

NeuroNEXT 


The Network for Excellence in Neuroscience Clinical Trials, or 

NeuroNEXT, was created by NINDS to conduct studies of treatments 

for neurological diseases through partnerships with academia, private 

foundations, and industry. This session will feature the NeuroNEXT 

Scientific Program Director and the Clinical and Data Coordinating 

Center’s Principal Investigator. 

Moderator: Anne Louise Oaklander, MD, PhD, Massachusetts General 


Faculty: Elizabeth McNeil, MD, MSc, NINDS, Bethesda, Md. 

Merit E. Cudkowicz, MD, Massachusetts General Hospital, Boston 

Christopher Coffey, PhD, University of Iowa, Iowa City 

Career Challenges: A Follow-up Discussion 


Continue the conversation on the principles of negotiation with Rana Parekh 

following her Mid/Senior Level Faculty Development Course talk. 

Faculty: Ranna I. Parekh, MD, MPH, Massachusetts General Hospital, 

Boston 

1:15 – 3:30 pm 


SYMPOSIUM: Results of Immune-Based Trials in 


Chair: Edward H. Koo, MD, University of California, San Diego 

Co-Chair: Kevin Talbot, DPhil, FRCP, University of Oxford, UK 

This symposium will discuss the knowledge of theoretical and mechanistic 

basis for Alzheimer ’s disease. Attendees will learn about the science of 

immunotherapy in the context of neurological disorders. Lastly, attendees 

will gain a new awareness of current trials, designs and findings so that 

they are updated on the most recent scientific discoveries surrounding the 

identified disorders. The program will include talks on the pathogenetic 

context for immunotherapy, a Phase III Study of Solaneuzumab for 

Alzheimer’s disease, two Phase III Study Results of Bapineuzumab for 

Alzheimer’s Disease, and a Phase II Study of Immunotherapy in Multiple 

Sclerosis followed by a panel discussion with audience participation. 

1:15 – 1:25 pm 

The Pathogenetic Context for Immunotherapy & 

ACCME Overview 

Edward H. Koo, MD, University of California, San Diego 

1:25 – 1:50 pm 

Phase 3 Studies of Solanezumab for Mild to Moderate 

Alzheimer’s Disease 

Rachelle S. Doody, MD, PhD, Baylor College of Medicine, Houston 

1:50 – 2:15 pm 

Phase III Studies of Bapineuzumab for Mild to 

Moderate Alzheimer’s Disease Dementia 

Reisa A. Sperling, MD, Brigham and Women’s Hospital, Boston 

2:15 – 2:40 pm 

Panel Discussion of Immunotherapeutic Trials in 

Alzheimer Disease 

2:40 – 3:10 pm 

Soriano Lectureship: Phase III Trials of Alemtuzumab in 

Relapsing-Remitting Multiple Sclerosis 


3:10 – 3:20 pm 

Panel Discussion MS 

Panelists: Carole Ho, MD, Genentech, San Francisco 

Susanne Ostrowitzki, MD, F. Hoffmann-La Roche, Ltd., Basel, Switzerland 

Norman R. Relkin MD, PhD, Weill Cornell Medical College, New York 

John C. Morris MD, Washington University, St. Louis, Mo. 

Jody Corey-Bloom, MD, PhD, University of California, San Diego 

Robert O. Messing, MD, University of California, San Francisco 

Stephen Salloway, MD, MS, Brown University, Providence, R.I. 

3:20 – 3:30 pm 

General Discussion of Symposium 

3:15 – 3:45 pm 

Coffee Break 



1. Understand the biological basis for immunotherapy use in neurological 

disorders. 

2. Convey most recent findings on this trial: A Phase III Study of 

Solaneuzumab for Alzheimer disease. 

3. Convey most recent finding on this trial: A Phase III Study of 

Immunotherapy in Multiple Sclerosis. 

4. Convey most recent finding on this trial: A Phase III Study of 

Bapineuzumab. 

15


3:30 – 5:30 pm 


Please note the color of your SIG’s signage, as they 

have been color coded to match the posters related to the SIG topic. 

Dementia and Aging 


Chair: Richard P. Mayeux, MD, MSc, Columbia University, New York 


Parkinson’s Disease with Dementia and Lewy 

Body Dementia: Genetics and Biomarkers 

Karen Marder, MD, MPH, Columbia University, New York 

Alzheimer’s Disease: Implications from GWAS 

Christiane Reitz, MD, PhD, Columbia University, New York 


Gephyrin Plaques Identified in Frontal Cortex of Alzheimer’s 

Disease Brains 

Chadwick Hales, MD, PhD, Emory University, Atlanta 

Relationship between Beta-Amyloid Retention and Ischemia in 

the Patients with Subcortical Vascular Cognitive Impairment 

Young Noh, MD, Sungkyunkwan University School of Medicine, 

Samsung Medical Center, Seoul, Republic of Korea 

Brain Imaging and Cognitive Predictors of Incident Stroke, 

Dementia and Alzheimer’s Disease 

Galit Weinstein, PhD, Boston University, Framingham, Mass. 

Genetic Susceptibility for Amyloid Pathology in 


Joshua Shulman, MD, PhD, Baylor College of Medicine, Houston 

Retinal Degeneration in FTLD Patients and PGRN-Deficient 

Mice Preceded by TDP-43 Mislocalization 

Ari Green, MD, MCR, University of California, San Francisco 

Question & Answer/Discussion 

Neurocritical Care — NEW! 

Salon D (4th Floor) 

Chair: Thomas P. Bleck, MD, Rush University, Chicago 


Refractory Status Epilepticus 

Thomas Bleck, MD, Rush University University, Chicago 

Intracerebral Hemorrhage 

Jonathan Rosand, MD, MSc, Massachusetts General Hospital Center for 

Human Genetic Research, Boston 

Infectious Causes of Encephalitis 

Alan Aksamit, Jr., MD, Mayo Clinic, Rochester, Minn. 


Fatal Hyperammonemic Brain Injury from Valproic Acid Exposure 

Danny Bega, MD, Brigham and Women’s Hospital, Boston 

Rapid High Volume CSF Loss – A New Cause of Coma 

Minjee Kim, MD, Brigham and Women’s Hospital, Boston 

A Population-Based Study of Aetiology and Outcome in 

Acute Neuromuscular Respiratory Failure 

Aisling Carr, MD, PhD, Royal Victoria Hospital, Belfast, Northern Ireland, UK 

Risk Factors for Intracranial Haemorrhage in Acute 

Ischaemic Stroke Patients Treated with rtPA 

Peter Fernandes, MRCP, University of Edinburgh, UK 

Incidence and Impact of Medical and Neurological ICU 

Complications on Moderate-Severe Traumatic Brain Injury 

Susanne Muehlschlegel, MD, MPH, University of Massachusetts Medical 

School, Worcester 

Question & Answer/Discussion 

Epilepsy 


Co-Chairs: Kevin J. Staley, MD, Massachusetts General Hospital, Boston 

Sydney S. Cash, MD, PhD, Massachusetts General Hospital, Boston 


Using Dravet Syndrome Patient-Derived Cells to Study 

Epilepsy and SUDEP Mechanisms 

Jack Parent, MD, University of Michigan, Ann Arbor 

Optogenetic Treatment of Focal Epilepsy 

Laura Mantoan Ritter, MD, Institute of Neurology, University College 

London, UK 

16

Identification of the Gene for Paroxysmal Kinesigenic 

Dyskinesia with Infantile Convulsions 

Louis Ptacek, MD, University of California, San Francisco 

Ketamine Use in Refractory Status Epilepticus 

Andrea Synowiec, DO, Allegheny General Hospital, Pittsburgh, Pa. 

EEG Based Functional Networks: A Robust Biomarker 

Across Time 

Catherine Chu, MD, Massachusetts General Hospital, Boston 

Monogenic and “Polygenic” Epilepsy Mutations Alter 

GABAA Receptor Biogenesis and Function 

Robert Macdonald, MD, PhD, Vanderbilt University, Nashville, Tenn. 

Neuromuscular Disease 

Salon BC (4th Floor) 

Chair: Jon Ravits, MD, FAAN, University of California, San Diego 

Co-chair: Tahseen Mozaffar, MD FAAN, University of California, Irvine 


Updates on ALS 

Pamela Shaw, MBBS, MD, FRCP, University of Sheffield, UK 

Using Antisense Oligonucleotides in Neuromuscular Disease 

Charles Thornton, MD, University of Rochester, N.Y. 

Updates on Neuropathies 

Jun Li, MD, PhD, Vanderbilt University, Nashville, Tenn. 


Infections in Myasthenia Gravis 

Raghav Govindarajan, MD, Cleveland Clinic, Weston, Fla. 

The Survival Motor Neuron (SMN) Gene as a Therapeutic Target 

in Amyotrophic Lateral Sclerosis 

Kevin Talbot, MBBS, DPhil, University of Oxford, UK 

Case Studies — NEW! 

Salon A (4th Floor) 

Two Weeks on the Consult Service: An Experience in 

Medical Neurology 

Chair/Presenter: Martin A. Samuels, MD, DSc(hon), FAAN, MACP, FRCP, 

Brigham and Women’s Hospital, Boston 

An important aspect of neurology involves the neurological aspects of 

general medical diseases. This session will review some real recent cases 

from two weeks on the consult service in July 2012. Selected aspects of 

the interface between neurology and general medicine will be addressed. 

Audience participation will be encouraged. 

5:30 – 6:30 pm 



Poster Categories: 

Dementia and Aging 

Epilepsy 

Neurocritical Care 

Neuromuscular Disease 

6:30 – 8:30 pm 

President’s Reception at the Boston Public Library 

Boston Public Library | Central Library | McKim Building 

700 Boylston St., Boston, MA 02116 

See page 23 for details and directions. 

Blockade of Matrix Metalloproteinase-3 after Traumatic Nerve 

Injury Preserves the Motor End Plate 

Ranjan Gupta, MD, University of California, Irvine 

A Multicenter Phase II Open-Label Trial of Valproic Acid and 

L-Carnitine in Infants with SMA Type I 

Kathryn Swoboda, MD, University of Utah, Salt Lake City 

Peripheral Nerve Function Following Treatment with Tanezumab 

Mark Brown, Pfizer, Inc., Groton, Conn. 

Question and Answer/Discussion 

17

TUESDAY, OCTOBER 9 

7:00 – 9:00 am 


6:30 am – 5:45 pm 

Registration 


6:30 – 7:30 am 





Session III: Getting Published 


Getting Published and Increasing Your Visibility 

Stephen Hauser, MD, University of California, San Francisco, 


Conveying your ideas and discoveries in writing, and getting these out 

in the public domain so they can be scrutinized and valued as important 

contributions to the field, constitute yet another essential skillset in 

academics. This session, led by two of the most eminent editors in neurology 

today, will focus on how to be successful in getting papers published. 

The discussion will include a review of the essential characteristics of 

outstanding papers, as well as an inside look into the review process, 

including the initial “in-house” assessment of manuscripts, the selection of 

reviewers, the editors’ consideration of the reviews, and best approaches for 

addressing editorial decisions on your manuscript. 

7:00 – 9:00 am 




Session III: Managing Conflict: How to Talk About the Tough Stuff 


New York 

Catherine J. Morrison, JD, Johns Hopkins Carey Business School, 


The environment in which research and clinical faculty practice is one in 

which the need for negotiation and conflict management abounds. The ability 

to foster agreements and manage conflict within and between workgroups 

can strengthen relationships, transform ideas into initiatives, and move 

parties beyond stuck places. This interactive workshop is designed to help 

participants understand and apply an effective framework when engaging in 

conflict conversations. 

7:00 – 9:00 am 



Session III: Tricks to Financial Success 

Martin A. Samuels, MD, DSc(hon), FAAN, MACP, FRCP, Brigham and 

Women’s Hospital, Boston 

Neurology departments are traditionally strong in the research arena, but 

have faced challenges from hospital and medical school leadership with 

regard to financial performance. This session is meant to examine some of 

the possible approaches that serve to mitigate this chronic problem. Major 

topics include: creating an incentive system that balances academic and 

clinical requirements, handling cross-subsidy among divisions, maintaining 

adequate compensation to encourage recruitment and retention, dealing with 

increasing disparities in salary for procedural neurologists, collaborating 

with neurosurgery, neuroradiology and psychiatry and maintaining academic 

strength in the face of fiscal challenges. 


9:00 – 11:05 am 


SYMPOSIUM: Derek Denny-Brown 

New Member Symposium 

Chair: William C. Mobley, MD, PhD, FRCP, University of California, 

San Diego 

This symposium will include a presentation by the ANA’s Derek 

Denny-Brown Neurological Award recipients, along with seven additional 

new members of the ANA. Their talks will highlight their work – either 

clinical or lab-based investigation. New Member Induction and the Annual 

Business Meeting will follow this session. 

9:00 – 9:20 am 

Presentation of Derek Denny-Brown Neurological Scholar 

Award: Clinical Science and Temporal Trends in Acute 

Stroke Management 

Dawn Kleindorfer, MD, University of Cincinnati, Oh. 

9:20 – 9:35 am 

Presentation of Derek Denny-Brown Neurological Scholar Award: 

Basic Science and A Large Repeat Expansion in the C9ORF72 

Gene is a Common Cause of ALS and FTD 

Bryan J. Traynor, MB, MD, PhD, MMSc, MRCPI, 

National Institute on Aging, National Institutes of Health, Bethesda, Md. 

9:35 – 9:50 am 

Pilot Clinical Trial of Eculizumab in AQP4-IgG-Positive NMO 

Sean J. Pittock, MD, Mayo Clinic, Rochester, Minn. 

18


9:50 – 10:05 am 

Iatrogenic Mitochondrial Disease Emerging Years after 

Stopping Anti-HIV Treatment: The Tip of the Iceberg in 2012 



10:05 – 10:20 am 

SMN Controlled MiR-183 Regulates Neuronal Morphology 

Via mTOR and Akt1 

Mustafa Sahin, MD, PhD, Children’s Hospital Boston 

10:20 – 10:35 am 

Presentation of The Grass Foundation – ANA Award in 

Neuroscience Award and Multiscale Investigations of Epilepsy, 

Sleep and Cognition 


10:35 – 10:50 am 

Congenital Myasthenic Syndrome (CMS), Autophagic Myopathy, 

and Cognitive Dysfunction Caused by Mutations in DPAGT1 

Duygu Selcen, MD, Mayo Clinic, Rochester, Minn. 

10:50 – 11:05 am 

Anti-NMDA Receptor Encephalitis, a Series of 212 Children 

Maarten Titulaer, MD, PhD, IDIBAPS/University of Barcelona 

11:05 – 11:30 am 


Introduction of New Members 

11:30 am – 12:00 pm 


Executive Session of Membership 

12:00 – 7:00 pm 




12:00 – 1:15 pm 

Lunch 


12:15 – 1:30 pm 


Orientation for New Members 

For new ANA members only. 

12:00 – 1:15 pm 

Interactive Lunch Workshops: Controversies 

in Neurology 

Tuesday’s Interactive Lunch Workshops are designed to offer information 

and informal discussions on key issues facing academic neurology. 

Because of the informal format, attendees are encouraged to move between 

workshops if they wish. 

Decompressive Craniectomy for Trauma 


Decompressive craniectomy has become more common in the past 

decade in circumstances of threatened herniation or increased intracranial 

pressure. The recently published DECRA trial raises questions about the 

utility of at least one form of this procedure. The speakers, a neurologist 

and a neurosurgeon who are both neurointensivists, will discuss the 

controversy. 

Moderator: Thomas P. Bleck, MD, Rush University, Chicago 

Faculty: Allan H. Ropper, MD, Brigham and Women’s Hospital, Boston 

William B. Gormley, MD, MPH, Brigham and Women’s Hospital, Boston 

Continuous EEG Monitoring in the ICU: When and Why is it 

Needed and How Much is Enough 


Dr. Herman and Dr. Hirsch will discuss and debate controversies in the 

use of continuous EEG monitoring in the ICU, including indications for 

monitoring, optimal duration of monitoring, impact on clinical care and 

outcome, and models for staffing and technology. They will outline 

current recommendations for monitoring, gaps in current knowledge, 

and directions for future research. 

Moderator: Nathan Crone, MD, Johns Hopkins, Baltimore, Md. 

Faculty: Lawrence J. Hirsch, MD, Yale University, New Haven, Conn. 

Susan T. Herman, MD, Beth Israel Deaconess Medical Center, Boston 

Neuro-oncology: Treatment of Low-Grade Gliomas 


Low-grade infiltrative astrocytoma, oligodendroglioma and mixed 

astrocytic-oligodendroglial tumors (World Health Organization grade II) 

account for approximately 10 % of neuroepithelial tumors and 3 % of all 

primary nervous system neoplasms. With only about 2,000 cases per year, 

they are outnumbered by their malignant counterparts (anaplastic glioma, 

glioblastoma multiforme). Recent discoveries as part of the Cancer Genome 

Atlas project and other whole genome analyses and gene expression 

profiling studies have refined the multistep paradigm of gliomagenesis. 

As a result, new diagnostic and prognostic markers have been established 

(for example, somatic mutations of isocitrate dehydrogenase, translocation 

between chromosome 1p and 19q). Technological advances including 

magnetic resonance spectroscopy, functional MRI and fiber tractography 

have led to our ability to diagnose these tumors earlier and determine their 

spatial relationship to important cortical structures and white matter tracts. 

Traditional management strategies have been challenged in prospective 

clinical trials. Novel multidisciplinary protocols incorporating surgery, 

19


radiation, and chemotherapy have been developed to treat gliomas more 

effectively and with reduced morbidity. This workshop aims to provide 

an up-to-date and concise review of the molecular pathogenesis, 

diagnostic strategies, current standards of care, and novel therapies of 

low-grade gliomas. In an interactive format, remaining controversies, 

mainly with respect to timing of diagnostic and therapeutic interventions, 

will be discussed. 

Faculty: Joachim M. Baehring, MD, MSc, Yale University, 

New Haven, Conn. 

Helen A. Shih, MD, Massachusetts General Hospital, Boston 

The Role of Amyloid PET Imaging in Early Diagnosis of 

Alzheimer Disease 


Amyloid PET imaging is emerging as a preclinical marker of AD that may 

be valuable for early (prodromal and pre-symptomatic) diagnosis and 

thus for targeting appropriate candidates for prevention drug trials. It may 

also prove useful for judging the efficacy of certain AD disease-modifying 

therapies. This session will discuss both the exciting possibilities and the 

potential for misuse of this emerging modality. 

Prof. Sperling will briefly highlight the history of and evidence for this 

imaging biomarker, current recommendations and practice in research and 

clinical settings within the US. She will also discuss the role of amyloid 

PET in risk prognostication and for improving accuracy of differential 

diagnosis in certain clinical situations. Prof. Breteler will present the 

caveats that need to be considered in the interpretation of amyloid PET 

imaging and its use in clinical settings, drug trials and population-based 

epidemiological research. For instance that a biomarker needs to be 

validated in the same clinical or population setting in which it will be 

utilized. She will discuss the use of this imaging in Europe, the required 

bayesian perspective of pre-test probabilities modifying the interpretation 

of results, and the uncertainties regarding the significance of a positive 

PET in a population setting. She will discuss limitations in assuming that 

deposition of amyloid on PET is equivalent to a diagnosis of AD and the 

need for additional evidence to ascertain the time line and significance of 

various imaging and laboratory biomarkers in the course of development 

of early AD. The integration of amyloid PET with the other imaging and 

laboratory markers and the relative advantages, risks and disadvantages 

of the various amyloid tracers such as Pittsburgh Compound-B (PiB) and 

florbetapir as well as all other questions raised by the audience will be 

discussed by both speakers. 

Moderator: Sudha Seshadri, MD, Boston University, Boston 

Faculty: Reisa A. Sperling, MD, Brigham and Women’s Hospital, Boston 

Monique M.B. Breteler, MD, PhD, German Center for Neurodegenerative 

Disease, Bonn, Germany 

Managing Conflict: A Follow-up Discussion 


Continue the conversation on resolving conflict and creating effective 

change with Catherine Morrison following her Mid/Senior Level Faculty 

Development Course talk. 

Faculty: Catherine J. Morrison, JD, Johns Hopkins University, 


1:30 – 3:15 pm 


SYMPOSIUM: Advances in Headache and Pain 

Research and Treatment 

Chair: Robert O. Messing, MD, University of California, San Francisco 

Co-Chair: Clifford Woolf, MB, BCh, PhD, Children’s Hospital, Boston 

This symposium will highlight new developments in the pathogenesis 

of migraine headache and chronic neuropathic pain that inform new 

approaches to treatment. 

Migraine is a recurring, episodic, often unilateral headache. It can be 

preceded by abnormal visual, sensory, motor and/or speech functions 

(migraine with aura), perceived as throbbing, and be associated with 

nausea and vomiting, hypersensitivity to light (photophobia), noise 

(phonophobia) and smell (osmophobia), as well as muscle tenderness and 

cephalic and extracephalic cutaneous allodynia. This lecture will summarize 

current understanding of (a) the mechanism by which aura activates 

peripheral nociceptors in the cranial meninges, (b) the mechanisms by 

which repeated activation of meningeal nociceptors produces central 

sensitization and renders migraineurs allodynic, (c) the mechanisms 

by which light exacerbates the headache, (d) the mechanisms by which 

thalamo-cortico-thalamic circuits produce many of the migraine-specific 

associated symptoms, and (e) the implications of our current understanding 

to therapeutic choices of the individual patient. 

The development of neuropathic pain therapeutics faces several 

challenges. Less than 50% of patients have 50% pain relief with the 

most effective agents and many patients experience intolerable side 

effects. Therefore, there is great need for the development of new 

treatments. Peripheral nerve injury results in profound changes in gene 

expression in sensory neurons resulting both in adaptive responses, like 

regeneration, and maladaptive ones that contribute to neuropathic pain. Use 

of model organisms like Drosophila and rodents has identified candidate 

“pain genes” which have been validated in patient cohorts both as pain 

biomarkers and as targets for novel therapeutics. Studies of pain signaling 

in peripheral sensory neurons have identified specific ion channels and 

kinases as additional targets for developing new therapeutic agents. 

Animal models of neuropathic pain, while providing substantial insight 

into neuropathic pain mechanisms, have not been reliable predictors of 

therapeutic effectiveness in people. These clinical trials are frequently 

negative due to a large positive therapeutic response in the placebo group, 

which presents challenges for clinical investigators. Recent experience 

in novel approaches to therapy will be highlighted by discussion of 

20

preclinical justification and results of ongoing trials testing the effectiveness 

of anti-NGF antibodies in chronic pain, including risk of adverse effects and 

their management. 



1. Understand the unique relationship between visual aura and the delayed 

onset of migraine headache, the progression of disease and the impact 

of early treatment, how light can make the headache worse. Participants 

will also be able to recognize signs of peripheral and central sensitization 

during migraine and they will learn about thalamocortical pathways that 

modulate cortical activity relevant to migraine headache. 

2. Provide insights into maladaptive responses in the CNS that provide 

targets for new therapeutics to treat chronic pain. 

3. Understand how studies of pain signaling in peripheral sensory neurons 

can reveal novel therapeutic targets. 

4. Understand limitations of current medications and clinical trials design 

issues in developing pain therapeutics. 

5. Provide an update on the Tanezumab trial. 

1:35 – 1:50 pm 

The Pathophysiology of Migraine Headache and its 

Modulation by Light 

Rami Burstein, PhD, Beth Israel Deaconess Medical Center, Boston 

1:50 – 2:15 pm 

F.E. Bennett Memorial Lectureship: Finding and Exploiting 

Neuropathic Pain Genes 

Clifford Woolf, MD, PhD, Children’s Hospital of Boston 

2:15 – 2:35 pm 

Mining Nociceptor Signaling for Pain Therapeutics 


2:35 – 2:55 pm 

The Bench to Bedside Challenges in Neuropathic Pain 

Therapeutics 

Roy L. Freeman, MD, Beth Israel Deaconess Medical Center, Boston 

2:55 – 3:10 pm 

Anti-NGF: A Saga in Drug Development 

David R. Cornblath, MD, Johns Hopkins University, Baltimore, Md. 

3:10 – 3:15 pm 

Questions and Answers 

3:15 – 3:45 pm 

Coffee Break 

3:30 – 5:30 pm 


Please note the color of your SIG’s signage, as they have been color 

coded to match the posters realated to the SIG topic. 

Behavioral Neurology 


Chair: Bruce L. Miller, MD, University of California, San Francisco 


Understanding the Nature and Neuroanatomy of Consciousness 

Prof. Adam Zeman, University of Exeter, UK 

Chronic Traumatic Encephalopathy 

Ann McKee, MD, Boston University, Bedford, Mass. 

Executive Control and the Frontal Lobes 

Kirk R. Daffner, MD, Harvard Medical School, Boston 

Misdiagnosis in Dementia 

Bruce L. Miller, MD, University of California, San Francisco 


Evolution of Psychiatric Co-Morbidity in the Transition Phase 

in a Cohort of Patients with Neurological Perinatal Disability 

Andrea Martinuzzi, MD, PhD, E. Medea Scientific Institute, 

Conegliano, Italy 

Inflammation and Cognitive Decline in Normal Elderly 

Joel Kramer, PsyD, University of California, San Francisco 

Changes in Cortical Functional Connectivity Introduced 

with Intermittent Theta Burst TMS to the Cerebellum 

Assessed with fMRI 

Mark Halko, PhD, Harvard Medical School, Boston 

Modulation and Assessment of the Cerebello-Cortical 

Connectivity through Transcranial Magnetic Stimulation (TMS) 

Combined with Electroencephalography (EEG) 

Faranak Farzan, PhD, Harvard Medical School, Boston 

Effects of the Dopamine Agonist Rotigotine on Hemispatial 

Neglect Following Stroke 

Masud Husain, DPhil, FMedSci, UCL Institute of Neurology, London, UK 

Increased Phosphorylation of the MAPK/ERK Pathway Is 

Associated with Social Impairment in BTBR Mice 

Aliereza Faridar, MD, PhD, University of California, San Francisco 

Discussion 

21


Autoimmune Neurology 


Chair: Vanda A. Lennon, MD, PhD, Mayo Clinic, Rochester, Minn. 


Autoimmune Encephalitis: The Antigens and Guidelines 

to Interpretation 

Josep Dalmau, MD, PhD, University of Pennsylvania, Philadelphia 

Neurological Autoimmunity: From Cortex to Colon 


Pathogentic Insights from Comparisons of NMO and Multiple 

Sclerosis Lesions 

Bogdan Popescu, MD, PhD, University of Saskatchewan, Saskatoon, 

Canada 

Autoimmune Pain 

Christopher Klein, MD, Mayo Clinic, Rochester, Minn. 


Faciobracial Dystonic Seizures are Immunotherapy-Responsive 

and Treatment may Prevent Amnesia 

Sarosh R. Irani, DPhil, MRCP, University of Oxford, UK 

Clinical Information of Four Men with Anti-N-Methyl D-Aspartate 

Receptor Encephalitis 

Hirano Makito, MD, Kinki University, Osaka, Japan 

Unusual Presentation of Paraneoplastic Stiff-Person Syndrome 

with Underlying Breast Cancer 

Alvin Shrestha, MBChB, University Hospitals Birmingham, UK 

Myositis with Autoantibodies to / Sarcoglycan: A New Disease 

Russell Lane, MBBS, Imperial College, Healthcare NHS Trust, London, UK 

Discussion 

Movement Disorders 


Co-Chairs: William T. Dauer, MD, University of Michigan, Ann Arbor 

Ming Guo, MD, PhD, University of California, Los Angeles 


Update on Spinocerebellar Ataxias (SCAs) 

Stefan Pulst, MD, University of Utah, Salt Lake City 

Basal Ganglia Dysfunction in a Model of Cerebellar-induced 

Dystonia 

Kamran Khodakhah, PhD, Albert Einstein College of Medicine, Yeshiva 

University, Bronx, New York 

22 

Common Pathways in Neurodegeneration: Focus 

on Lysosomal Dysfunction in Parkinson’s Disease 

Dimitri Krainc, MD, PhD, Harvard Medical School, Boston 


What Issues Face Parkinson’s Patients at Ten Years 

and Beyond 

Anhar Hassan, MBBCh, FRACP, University of Florida, Gainesville, Fla. 

Predictors of Cognitive Performance Following Bilateral 

Subthalamic Nucleus Deep Brain Stimulation 

Angela Costello, D ClinPsych, King’s College Hospital, 

NHS Foundation Trust, London, UK 

Inhibitory Neurons in the Ventral Medial Medulla Modulate 

Gait and Tone 

Veronique VanderHorst, MD, PhD, Harvard Medical School, Boston 

Discussion 

Regulatory Science — NEW! 


Chair: Ira Shoulson, MD, Georgetown University, Washington, DC 

Regulatory Science Informing the Review and Approval of 

Innovative Neurology Products 

Russell Katz, MD, US Food & Drug Administration (FDA), 

Silver Spring, Md. 

Translational and Clinical Neuroscience Contributions to 

Regulatory Science 

D. Elizabeth McNeil, MD, National Institute of Neurological Disorders 

and Stroke (NINDS), National Institutes of Health, Bethesda, Md. 

How Industry and Translational Neurology Can Contribute 

to and Benefit from Regulatory Science 

Bernard Ravina, MD, Biogen Idec, Cambridge, Mass. 

Centers of Excellence in Regulatory Science & Innovation 

and Applications to Academic Neurology 

Ira Shoulson, MD, and Erin Wilhelm MPH, Center of Excellence in 

Regulatory Science and Innovation (CERSI), Georgetown University, 

Washington, DC 

Panel and General Discussion 

5:30 – 7:00 pm 



Poster Categories 

Behavioral Neurology 

Headache and Pain/Neuro-otology 

Movement Disorders 

Neuroimmunology

SPECIAL EVENTS 

President’s Reception at the Boston Public Library 

Monday, October 8, 2012, 6:30 – 8:30 pm 

Boston Public Library 

Central Library, McKim Building, 700 Boylston St., Boston, MA 02116 

Everyone is invited to attend the President’s Wine and Cheese Reception at the Boston Public Library’s McKim 

Building. The Boston Public Library is within walking distance of the Boston Marriott Copley Place, but shuttles will 

be provided for those who wish to use them. The Boston Public Library’s McKim Building was built in 1895 and is 

on the National Register of Historic Buildings and is a National Historic Landmark. Light hors d’oeuvre selections, 

along with wine and beer, will be served at the library. The President’s Reception is complimentary for paid meeting 

attendees, but a name badge is required for entry. Guests may purchase a ticket for $50 at the registration desk. 

Walking Directions 

From the Marriott Copley Place Hotel lobby, go Northeast on Huntington Avenue (take a right out of the lobby) 

Take a sharp left to stay on Huntington Avenue (Westin Copley will be on your right hand side) 

Turn left on Dartmouth Street 

Enter the Boston Public Library (McKim Building) 

Please Note: Use the entrance on Dartmouth Street and not Boylston St. 

Poster Stand-by Wine & Cheese Receptions 


Sunday, October 7, 2012, 5:30 – 7:00 pm 

Monday, October 8, 2012, 5:30 – 6:30 pm 

Tuesday, October 9, 2012, 5:30 – 7:00 pm 

What would the best 

of medicine look like 

A heritage built upon helping protect and preserve vision. 

A commitment to advancing the Science of Rejuvenation. 

A resolve to confront the global obesity epidemic head-on. 

A devotion to help improve patients’ lives through urologics. 

Helping people with skin conditions face the world. 

A dedication to enabling patients to live life without compromise and to their fullest potential. 

It would look like Allergan. 

Allergan is a multi-specialty health care company established more than 60 years ago with a commitment to 

uncover the best of science and develop and deliver innovative and meaningful treatments to help people 

reach their life’s potential. Today, we have approximately 10,000 highly dedicated and talented employees, 

global marketing and sales capabilities with a presence in more than 100 countries, a rich and ever-evolving 

portfolio of pharmaceuticals, biologics, medical devices and over-the-counter consumer products, and stateof-the-art 

resources in R&D, manufacturing and safety surveillance that help millions of patients see more 

clearly, move more freely and express themselves more fully. From our beginnings as an eye care company to 

our focus today on several medical specialties, including eye care, neurosciences, medical aesthetics, medical 

dermatology, breast aesthetics, obesity intervention and urologics, Allergan is proud to celebrate 60 years 

of medical advances and proud to support the patients and physicians who rely on our products and the 

employees and communities in which we live and work. 

To find out more about Allergan, visit www.allergan.com 

Copyright 2011 Allergan, Inc. Irvine, CA 92612. TM and ® marks owned by Allergan, Inc. APC16NB10 

23

SUNDAY SPEAKER ABSTRACTS 

SYMPOSIUM: New Tools to Define the Genetics 

of Neurological Disorders 

Genome-Wide Association Studies: Have They Delivered 

for Neurology 

Stephen Sawcer, PhD, University of Cambridge, Cambridge, UK 

Genome-Wide Association Studies (GWAS) have resulted in a veritable 

explosion in knowledge about all manner of complex traits (http://www. 

genome.gov/gwastudies/), 1 and have revolutionised the genetic analysis of 

multiple sclerosis. 2,3 Each robustly associated variant provides the potential 

for a novel insight into aetiology and thereby improves the prospects for 

the development of rational therapy. However, for many of these loci the 

potential insights and benefits are not immediately obvious and seem 

set to require extensive fine mapping and functional analysis before they 

are revealed. In most cases associated variants are neither necessary nor 

sufficient and effects measured in the context of mathematical models are 

not expected to reflect underlying biology or to indicate the importance of 

implicated genes. 

In considering the differences between this type of complex genetics and 

the more familiar Mendelian genetics we might draw an analogy with the 

difference between quantum theory and Classical mechanics; in each 

case seemingly incontrovertible determinism is replaced by mathematical 

descriptions of uncertainty and counterintuitive behaviour is common 

place. In this probabilistic environment purely mathematical issues can 

profoundly influence the perception of results and need to be properly 

considered if interpretation is not to be misleading. 4 In my talk, as well as 

describing what has been discovered, I will also try and describe some of 

the relevant mathematical issues in the hope of aiding in the interpretation 

of these exciting new data. 

References: 

1. Hindorff et al. Potential etiologic and functional implications of 

genome-wide association loci for human diseases and traits. PNAS. 

2009 106: 9362-7 

2. IMSGC. Risk Alleles for Multiple Sclerosis Identified by a Genomewide 

Study. N Engl J Med. 2007;357(9):851-62. 

3. IMSGC and WTCCC2. Genetic risk and a primary role for 

cell-mediated immune mechanisms in multiple sclerosis. Nature. 

2011;476(7359):214-9. 

4. Sawcer and Wason. Risk in complex genetics: “All models are wrong 

but some are useful” Ann Neurol. 2012 ePub April. 

Next-Generation Whole Exome and Whole Genome 

Sequencing to Diagnose Single-Gene Disorders 

Andrew Singleton, PhD, National Institutes of Health, Bethesda, Md. 

Participants will be provided with an update on the use of second 

generation sequencing approaches in the identification of disease causing 

genetic variants. This will center on the strengths and weaknesses of 

these approaches, and in particular how such methods will facilitate 

the identification of disease-linked mutations that were resistant to 

identification using traditional linkage and positional cloning approaches. 

There will be a discussion of considerations such as family structure, 

sample collection, data handling, and data analysis, with an emphasis on 

when to use such methods, and a review of the problems and pitfalls that 

can lead to false positives. In addition there will be discussion of when this 

approach is most useful in identifying the genetic causes of disease in the 

context of genetic testing, particularly how this may be a time and resource 

efficient method in genetically heterogeneous disorders [1]. 

References: 

1. Singleton AB. Exome sequencing: a transformative technology. 

Lancet Neurol. 2011 Oct;10(10):942-6. 

Epigenetics and Disorders of the Nervous System: 

An Evolving Synthesis 


Epigenetics and epigenomic medicine encompass an evolving science 

of brain and behavior that are providing revolutionary insights into the 

mechanisms underlying brain development and evolution, neuronal and 

neural network homeostasis, plasticity connectivity, stress responses, 

bioenergetics, senescence, neuropsychiatric disease pathogenesis and 

dynamic tissue remodeling and cellular reprogramming. Epigenetic 

processes include DNA methylation, histone modifications, nucleosome 

repositioning, higher order chromatin remodeling events, deployment of 

non-protein-coding RNAs and RNA editing and DNA recoding. RNA is 

centrally involved in orchestrating these processes, thereby suggesting 

that the evolving transcriptional and post-transcriptional output of the cell 

is the primary determinant of epigenetic memory states. These contextspecific 

processes can be modulated by: (1) metabolic, homeostatic 

and environmental cues that control profiles of gene expression and 

post-transcriptional processing, (2) RNA/DNA editing events via activitydependent 

intracellular transport and regulation of RNA processing and 

RNA regulatory complexes, and (3) intricate intercellular neural, systemic 

and even germ line trafficking of diverse classes of RNAs and transposable 

elements with short- and long-range effector functions. These interrelated 

processes promote dynamic nuclear reorganization to continuously 

modulate individual gene expression profiles and functional gene networks 

with complex temporal and spatial trajectories. Such gene regulatory 

trajectories are required for enhancing the fidelity of neural signaling 

events linked to complex cognitive and behavioral repertoires. Epigenetics 

therefore represents the long sought after molecular interface mediating 

gene-environmental interactions along the entire neuraxis during critical 

periods throughout the lifecycle. The emerging field of environmental 

epigenomics has begun to identify combinatorial profiles of environmental 

stressors modulating the latent phase, time of initiation, and progression 

24

of neurological disease states, as well as defining novel biomarkers 

and molecular indicators of graded responses to therapeutic initiatives. 

Next-generation pharmacoepigenomic therapies will likely promote 

accelerated recovery of seemingly irrevocably lost cognitive, behavioral and 

sensorimotor functions, without exhibiting potentially deleterious off-target 

effects, through epigenetic reprogramming of endogenous neural stem cell 

fates, dynamic tissue remodeling and restoration of neural network integrity, 

plasticity and connectivity. 

References: 

1. Qureshi, IA, Mehler, MF. 2012. Emerging Roles of Non-Coding RNAs 

in Brain Evolution, Development, Plasticity and Disease. Nat Rev 

Neuroscience 13: 528-541. 

2. Qureshi, IA, Mehler, MF. 2011. Non-Coding RNA Networks 

Mediating Cognitive Disorders Across the Lifespan. Trends Mol Med 

17: 337-346. 

3. Abrajano, JJ, Quershi, IA, Gokhan, S, Molero, AE, Zheng, D, Bergman, 

A, Mehler, MF. 2010. Corepressor for Element-1-Silencing Factor 

Preferentially Mediates Gene Networks Underlying Neural Stem Cell 

Fate Decisions. Proc Natl Acad Sci USA 107: 16685-16690. 

4. Mehler, MF. 2008. Epigenetic Principles and Mechanisms Underlying 

Nervous System Functions in Health and Disease. Prog Neurobiol 

86: 305-341. 

Regulatory RNAs in Neurological Disease 


Much of the mammalian genome is transcribed (1) into non-coding 

RNAs of different categories which will be described. This lecture will be 

concerned with microRNAs (2) as well as natural antisense transcripts 

(NATs) most of which are long noncoding RNAs (3). NATs are found in 

most gene loci and regulate gene expression through several distinct 

mechanisms including chromatin modifications. Inhibition/perturbation of 

endogenous NATs by modified oligonucleotides called AntagoNATs (4), in 

vitro or in vivo, reveals concordant or discordant regulation and results in 

down- or up-regulation of conventional (protein-coding) gene expression, 

respectively. Evidence will be presented that AntagoNATs can potently 

induce locus-specific and reversible up-regulation of gene expression, 

such as BDNF, associated with alterations in chromatin marks (4). 

References: 

1. Carninci P, Wahlestedt C, et al. The transcriptional landscape of the 

mammalian genome. Science 309: 1559-1563, 2005. 

2. Miller, B.H., Zeier, Z., Xi, L., Deng, S., Strathmann , J., Willoughby, D., 

Kenny, P.J., Elsworth, J.D, Lawrence, M.S., Roth, R.R., Edbauer, D., 

Kleiman, R., Wahlestedt, C. MiR-132 dysregulation in schizophrenia 

has implications for both neurodevelopment and adult brain function. 

Proc Natl Acad Sci (USA) 109(8):3125-30, 2012. 

3. Katayama S … and Wahlestedt C. Antisense transcription in the 

mammalian transcriptome. Science 309:1564-1566, 2005. 

4. Modarresi F, Faghihi MA, Lopez-Toledano MA, Fatemi RP, Magistri 

M, Brothers SP, Van der Brug MP, Wahlestedt C. Natural antisense 

inhibition results in transcriptional de-repression and gene upregulation. 

Nature Biotechnology, doi: 10.1038/nbt.2158, 2012. 

New Tools to Define the Genetics of Neurological Disorders: 

Mitochondrial Disorders 



Clinical and genetic heterogeneity are the hallmark of mitochondrial 

disorders. Ultimately due to a biochemical defect of the respiratory chain, 

mitochondrial disorders can be caused by mutations in both the nuclear 

genome, and the maternally inherited 16.5Kb mitochondrial genome 

(mtDNA). As a result, mitochondrial disorders can be inherited maternally, 

or as an autosomal dominant, recessive, or X-chromosome-linked trait. 

On the one hand, the same clinical phenotype can be caused by mutations 

in mtDNA or an expanding array of different nuclear genes. On the other 

hand, the same genetic defect can cause a wide range of different clinical 

phenotypes. This presents a major diagnostic challenge in routine 

neurological practice. This is compounded by the fact that mitochondrial 

disease enters the differential diagnosis of many common diseases seen 

in the general neurology clinic. However, making a genetic diagnosis is 

important, because it can have a profound implications for the recurrence 

risks within the family, and because new therapies are emerging for 

specific genetic subgroups. 

The traditional clinical approach to the investigation of mitochondrial 

disease involves targeted molecular genetic testing in patients 

with “classical” mitochondrial syndromes, such as mitochondrial 

encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), 

or Leber hereditary optic neuropathy (LHON), but these form the minority. 

The next step involves a biopsy of an affected tissue, followed by highlyspecialised 

histochemical and biochemical studies, which are usually 

carried out in specialized laboratories, and are sometimes difficult to 

interpret. The results of these investigations guide further genetic analysis 

of the mitochondrial and nuclear genomes. Finally, despite an often 

protracted and costly series of investigations, in ~30% of patients it is not 

possible to reach a molecular diagnosis, even in a specialist centre. 

In principle, next generation sequencing provides an opportunity to side 

step much of this complexity. A growing number of new mitochondrial 

disease genes have been identified within the last 18 months using 

targeted and whole-exome capture systems, and mitochondrial DNA can 

be sequenced at great depth, potentially circumventing the problem of 

detecting low-level heteroplasmy levels in blood. Combing the two in a 

single “office-based” blood test is on the horizon, but there are potential 

pitfalls at present. This presentation will provide a guide to these pitfalls, 

and how they can be avoided. 

References: 

1. Koopman WJ, Willems PH, Smeitink JA. Monogenic mitochondrial 

disorders. N Engl J Med 2012;366:1132-41. 

2. Haack TB, Danhauser K, Haberberger B, et al. Exome sequencing 

identifies ACAD9 mutations as a cause of complex I deficiency. 

Nat Genet;42:1131-4. 

3. Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human 

disease. Nat Rev Genet 2005;6:389-402. 

4. Calvo SE, Compton AG, Hershman SG, et al. Molecular diagnosis 

of infantile mitochondrial disease with targeted next-generation 

sequencing. Science translational medicine 2012;4:118ra10. 

25


SYMPOSIUM: Imaging to Explore Neural Network 

Structure and Function 

Decoding the BOLD Signal in Functional MR Imaging 

Anna Devor, PhD, University of California, San Diego 

Understanding how neuronal activity drives changes in blood flow and 

energy metabolism is critical for laying a solid physiological foundation 

for interpreting functional neuroimaging studies in humans. In particular, 

functional magnetic resonance imaging (fMRI) based on the blood 

oxygenation level dependent (BOLD) response has become a widely 

used tool for exploring brain function, and yet the physiological basis 

of this technique is still poorly understood. The primary physiological 

phenomenon that leads to the BOLD effect is that cerebral blood flow (CBF) 

increases much more than the cerebral metabolic rate of oxygen (CMRO 2 

), 

increasing local blood oxygenation and causing a slight increase of the MRI 

signal due to different magnetic properties of oxy- and deoxyhemoglobin. 

Although the goal of fMRI studies is usually to assess changes in neuronal 

activity, the signal measured depends on the relative changes in CBF and 

CMRO 2 

. For this reason, it is difficult to interpret the magnitude of the 

BOLD response as a quantitative reflection of the magnitude of the change 

in neuronal activity without a deeper understanding of how neuronal 

activity, CBF and CMRO 2 

are connected. 

The simplest picture one could imagine for this physiological coupling is 

that changes in neuronal activity drive changes in energy metabolism which 

then drive changes in blood flow. However, a large body of work over the 

last decade indicates that this simple picture is almost certainly wrong. 

While molecules produced by increased energy metabolism (CO 2 

, lactate, 

etc.) do have a vasoactive effect, much of the acute CBF response under 

healthy conditions appears to be driven by molecules related to neuronal 

signaling. In short, rather than a linear chain of events, blood flow and 

energy metabolism appear to be driven in parallel by neuronal activity. 

With the growing recognition of the complexity of neurovascular coupling, 

research has focused on the “neurovascular unit”, a close association 

between neurons, astrocytes and blood vessels. A number of experimental 

tools have been developed for probing the neurovascular unit in animal 

models, providing the potential for a much deeper understanding of these 

fundamental physiological mechanisms. In this talk, we review recent 

advances in imaging technology with microscopic resolution applicable 

to in vivo animal studies, discuss our working hypotheses regarding the 

regulation of blood flow and neurophysiological correlates of fMRI signals, 

and provide an outlook for the future directions in neurovascular research. 

References: 

1. Devor A, Sakadzic S, Srinivasan VJ, Yaseen MA, Nizar K, Saisan PA, 

Tian P, Dale AM, Vinogradov SA, Franceschini MA, Boas DA. Frontiers 

in optical imaging of cerebral blood flow and metabolism. J Cereb 

Blood Flow Metab. 2012;32:1259-76. 

2. Tian P, Teng IC, May LD, Kurz R, Lu K, Scadeng M, Hillman EM, 

De Crespigny AJ, D’Arceuil HE, Mandeville JB, Marota JJ, Rosen 

BR, Liu TT, Boas DA, Buxton RB, Dale AM, Devor A. Cortical depthspecific 

microvascular dilation underlies laminar differences in blood 

oxygenation level-dependent functional MRI signal. Proc Natl Acad Sci 

U S A. 2010;107:15246-15251. 

3. Devor A, Tian P, Nishimura N, Teng IC, Hillman EM, Narayanan SN, 

Ulbert I, Boas DA, Kleinfeld D, Dale AM. Suppressed neuronal activity 

and concurrent arteriolar vasoconstriction may explain negative blood 

oxygenation level-dependent signal. J Neurosci. 2007;27:4452-4459. 

4. Cauli B, Hamel E. Revisiting the role of neurons in neurovascular 

coupling. Front Neuroenergetics. 2010;2:9. 

Resting State Connectivity 

Michael D. Greicius, MD, MPH, Stanford University, Stanford, CA 

Resting-state fMRI is a relatively novel imaging modality that allows 

for the detection and characterization of large-scale, distributed brain 

networks. Like standard task-activation fMRI the method relies on the 

intrinsic contrast provided by the blood oxygen level-dependent (BOLD) 

signal. During quiet rest, brain regions are characterized by low-frequency 

BOLD signal fluctuations. Resting-state fMRI leverages the fact that these 

low-frequency BOLD signal fluctuations are strongly correlated across 

brain regions known to constitute networks. The first demonstration of 

the neurobiological plausibility and potency of this method was by Biswal 

and colleagues at the Medical College of Wisconsin, who showed that 

the left motor cortex was functionally connected to the contralateral motor 

cortex, the bilateral sensory cortices, and the bilateral premotor cortices. 

Subsequent work has shown that a large array of networks, supporting 

a host of sensory, motor, and cognitive functions can be delineated with 

resting-state fMRI. 

Among the 15-20 networks that have been reliably demonstrated with 

resting-state fMRI one of them, known as the default-mode network (DMN), 

appears critical for episodic memory retrieval and has been strongly 

linked to Alzheimer’s disease (AD). In 2004, our group first demonstrated 

that the DMN shows reduced connectivity in AD patients compared to 

healthy controls. This finding has been replicated numerous times and 

advanced up the clinical spectrum. Sorg and colleagues showed in 

2007 that DMN connectivity is reduced in patients with mild cognitive 

impairment (MCI) compared to healthy controls. Two groups have shown 

that healthy older controls with positive amyloid PET scans have reduced 

DMN connectivity compared to older controls with negative amyloid PET 

scans. The APOE story is a bit murkier with some groups showing reduced 

DMN connectivity in healthy older E4 carriers compared to E3 carriers 

and some groups showing increased connectivity or no difference. Our 

group has demonstrated that the predicted reduction in DMN connectivity 

among healthy older E4 carriers is robust and detectable in women but 

not in men (in keeping with the often overlooked interaction between 

gender and APOE). Recent work from Sperling and colleagues in the 

Dominantly Inherited Alzheimer’s Network (DIAN) study has shown that 

DMN connectivity begins to decline in carriers of autosomal dominant AD 

mutations about 5-10 years before predicted symptom onset. 

DMN connectivity has substantial support, therefore, as a candidate 

imaging biomarker in AD. A number of critical questions and limitations 

remain before this approach can be reliably applied at the single subject 

level. At the group level, however, resting-state fMRI has already yielded 

some valuable new insights into AD. The hope is that with continued 

refinement in the acquisition and analysis parameters, resting-state fMRI 

26

will prove useful as a diagnostic aid in individual patients. For the time 

being, it has the potential to play a valuable role, at the group-level, as an 

early, objective marker of treatment response in clinical trials. 

References: 

1. Biswal B, Yetkin FZ, Haughton VM, Hyde JS. Functional connectivity 

in the motor cortex of resting human brain using echo-planar MRI. 

Magn Reson Med. 1995 Oct;34(4):537-41. 

2. Greicius MD, Srivastava G, Reiss AL, Menon V. Default-mode 

network activity distinguishes Alzheimer’s disease from healthy aging: 

evidence from functional MRI Proc Natl Acad Sci U S A. 2004 Mar 

30;101(13):4637-42. Epub 2004 Mar 15. 

3. Sorg C, Riedl V, Mühlau M, Calhoun VD, Eichele T, Läer L, Drzezga 

A, Förstl H, Kurz A, Zimmer C, Wohlschläger AM. Selective changes 

of resting-state networks in individuals at risk for Alzheimer’s disease. 

Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18760-5. Epub 2007 

Nov 14 

4. Damoiseaux JS, Seeley WW, Zhou J, Shirer WR, Coppola G, 

Karydas A, Rosen HJ, Miller BL, Kramer JH, Greicius MD; for the 

Alzheimer’s Disease Neuroimaging Initiative. Gender Modulates 

the APOE {varepsilon}4 Effect in Healthy Older Adults: Convergent 

Evidence from Functional Brain Connectivity and Spinal Fluid Tau 

Levels.J Neurosci. 2012 Jun 13;32(24):8254-8262. 

Diffusion Tensor Imaging (DTI) 

Lawrence L. Wald, PhD, Massachusetts General Hospital, Boston 

MRI diffusion imaging has emerged as our principle method for the study 

of anatomical connectivity in the living human brain (human connectome). 

It achieves this by utilizing the relatively free diffusion of endogenous 

brain water along the axon bundles compared to the restricted diffusion 

perpendicular to a fascicle. But, perhaps more than any other “-omics” 

endeavor, the accuracy and level of detail obtained from mapping the major 

whitematter pathways in the living human brain depends on the capabilities 

of the imaging technology used. The current tools are remarkable; for 

example allowing the formation of an “image” of the water diffusion 

probability distribution in regions of complex crossing fibers at each of half 

a million voxels in the brain. Nonetheless our ability to map the complex 

organization of connection pathways in vivo is acquisition limited. This talk 

will review the methods in use for studying fiber architecture with diffusion 

MRI as well as the limitations of the technique, which include sensitivity, 

image resolution, and efficiency of encoding the diffusion probability 

distribution for diffusion tractography. 

Fortunately, recent advances in MR technology have advanced the level 

of white matter structure that can be interrogated in the living human 

brain. These include High Angular Resolution Diffusion Imaging (HARDI) 

techniques as well as improved scanner hardware and more efficient 

acquisition sequences (by 3x). These tools have provided rich engineering 

challenges but are found to be enabling technology for improved structural 

connectomics with MRI. 

References: 

1. Wedeen VJ, Rosene DL, Wang R, Dai G, Mortazavi F, Hagmann P, 

Kaas JH, Tseng WY. The geometric structure of the brain fiber 

pathways. Science 2012; 335(6076);1628-34 

2. Hagmann P, Cammoun L, Gigandet X, Gerhard S, Grant PE, Wedeen V, 

Meuli R, Thiran JP, Honey CJ, Sporns O. MR connectomics: Principles 

and challenges. J. Neurosci Methods. 2010 194(1); 34-45. 

3. Schmahmann JD, Smith EE, Eichler FS, Filley CM. Cerebral white 

matter: neuroanatomy, clinical neurology, and neurobehavioral 

correlates. Ann N Y Acad Sci. 2008 1142: 266-309. 

4. Johansen-Berg H, and Behrens T.E.J. Diffusion MRI: from quantitative 

measurement to in-vivo neuroanatomy. Academnic Press 2009. 

Molecular Imaging 

Joel S. Perlmutter, MD, Washington University, St. Louis, Mo. 

Molecular imaging with either PET or SPECT agents has provided new 

insights into the function of brain networks. These methods have revealed 

surprising findings about the pathophysiology of Parkinson disease (PD), 

yet some imaging studies have raised more questions than answers. This 

talk will focus on several examples of how molecular imaging has revealed 

new findings about cognitive impairment in PD; describe the applications 

and limitations of imaging methods to quantify nigrostriatal pathways and 

finally discuss the integration of molecular imaging with other imaging 

modalities to investigate brain networks. 

Dementia associated with PD has been thought to be caused by a 

combination of underlying alpha-synuclein pathology in cortical area or 

co-existing Alzheimer’s disease. The development of the amyloid imaging 

agent Pittsburgh Compound B (PIB) has permitted in vivo measurement of 

brain deposition of ABeta42, which could reveal whether Alzheimer’s was 

a contributing factor. Initial studies revealed that a subset of people with 

PD and cognitive impairment, whether starting early in the course of PD 

or later, had positive PIB PET scans. Since PIB is based upon thioflavin T 

which binds to beta-pleated sheet structures such as ABeta42 or alphasynuclein, 

the first step in interpretation of these studies was to determine 

whether the PIB also bound to alpha-synuclein in vivo. Postmortem follow 

up of those PD patients with dementia that had PIB scans revealed that PIB 

did not mark alpha-synuclein. However, the surprise was that those with 

positive PIB scans had abnormal ABeta42 but only rarely had abnormal 

tau deposition, both of which are commonly associated with dementia due 

to Alzheimer’s disease. Thus, application of PIB PET to PD has different 

implications than to those with Alzheimer’s disease. Most importantly, this 

also demonstrates the importance of careful validation of a biomarker for 

each application. 

A similar lesson can be learned from application of several different 

molecular imaging methods to measure presynaptic nigrostriatal neurons. 

The basic approaches include fluorodopa (FD) that reflects decarboxylase 

and storage; dopamine transporter (DAT) ligands and radioligands that 

bind to vesicular monoamine transporter type 2 (VMAT2) on presynpatic 

vesicles. Striatal uptake of these tracers has been used to either indicate 

degenerative parkinsonism or measure its progression. Yet, studies using 

these tracers have found discordant results when compared to clinical 

27


measures of PD progression. Recent studies to validate these measures 

in nonhuman primates have revealed rather surprising findings. First, 

nigrostriatal reserve, the degree of loss of dopaminergic neurons needed 

to cause parkinsonism, is less than previously thought. Second, the degree 

of parkinsonism correlates with loss nigral neurons but not with striatal 

dopamine. All of the PET measures of striatal uptake correlate with striatal 

dopamine but only correlate with nigral neurons when loss of those neurons 

does not exceed 50%. All of the PET measures change in synch with each 

other providing no support for differential regulation, at least in this animal 

model. The striatal PET uptakes measures do correlate strongly with in vitro 

quantitatively autoradiography demonstrating that these findings are not 

likely due to specific characteristics of the PET tracers used. These findings 

may explain much of the discordant results in past studies. New approaches 

to these PET measures may reveal approaches that can directly measure 

nigral neurons and obviate some of the past limitations. 

Finally, molecular imaging studies can be used to drive analysis of other 

methods to investigate brain networks. For example, abnormalities found 

on PET can be used in conjuntion with resting state functional connectivity 

studies with MR to investigate the functional consequences of selected 

regional abnormalities. 

References: 

1. Burack M, Hartlein J, Flores H, Taylor-Reinwald L, Perlmutter JS, 

Cairns NE. In vivo amyloid imaging in autopsy confirmed Parkinson 

disease with dementia. Neurology, 74:77-84, 2010. 

2. Kotzbauer PT, Cairns NJ, Campbell MC, Willis AW, Racette BA, 

Tabbal S, Perlmutter JS. Pathological accumulation of -synuclein and 

A in Parkinson disease with dementia. Arch Neurol. 23:1-6, 2012 

[Epub ahead of print]. 

28

MONDAY SPEAKER ABSTRACTS 

President’s Symposium: Alzheimer’s Disease: 


Lessons for Alzheimer’s Disease from Early Detection of 

Familial Cases 

Martin N. Rossor, MD, Institute of Neurology, University College 

London, UK 

A major challenge in understanding the early natural history of Alzheimer’s 

disease (AD) has been that the disease is likely to be well established by the 

time patients present with memory complaints, even if they do not fulfill the 

criteria for a diagnosis of dementia. The identification of at risk individuals 

by virtue of age or mild symptoms are inevitably limited by either the 

numbers needed to study or by the late presentation. The elucidation of 

the genetics of autosomal dominant familial AD offers an opportunity of 

studying in detail the offspring of affected parents many years prior to the 

anticipated age at onset. The similarity of the clinical and pathological 

features of familial to sporadic AD suggests that the insights gained can be 

generalised to sporadic cases. Moreover, non-carrier siblings provide the 

ideal control group. Due to the relative rarity of autosomal dominant AD 

only small cohorts of APP and presenilin AD have previously been studied 

but have been able to show early changes in PiB binding and MRI atrophy 

before the onset of cognitive change. The analysis of longitudinal changes 

suggest a progression of tissue loss that starts in the medial temporal 

lobe and early cingulate cortex and spreads to involve association areas 

in a pattern similar to that in the Braak and Braak classification. Recently 

the multi-national study of dominantly inherited AD (DIAN: PI J. Morris) 

has provided the increased number of patients with cognitive imaging and 

CSF measures to establish a sequence of events in disease progression 

and to explore the heterogeneity across different mutations. DIAN also 

offers the prospect of prevention trials. The methodology of studying at 

risk familial dementias is also being applied to other disorders such as the 

frontotemporal dementias. 

References: 

1. Fox NC, Warrington EK, Seiffer AL, Agnew SK, Rossor MN. 

Presymptomatic cognitive deficits in individuals at risk of familial 

Alzheimer’s Disease. A longitudinal prospective study. Brain 

1998;121:1631-1639 

2. Scahill RI, Schott JM, Stevens JM, Rossor MN, Fox NC. Mapping the 

evolution of regional atrophy in Alzheimer’s disease: Unbiased analysis 

of fluid-registered serial MRI. Proceedings of the National Academy of 

Science 2002; 99(7): 4703-4707 

3. Klunk WE, Price JC, Mathis CA, Tsopelas ND, Lopresti BJ, Ziolko 

SK, Bi W, Hoge JA, Cohen AD, Ikonomovic MD, Saxton JA, Snitz BE, 

Pollen DA, Moonis M, Lippa CF, Swearer JM, Johnson KA, Rentz DM, 

Fischman AJ, Aizenstein HJ, DeKosky ST Amyloid deposition begins 

in the striatum of presenilin-1 mutation carriers from two unrelated 

pedigrees. J Neurosci. 2007 Jun 6;27(23):6174-84. 

4. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, 

Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, 

Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade 

E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, 

Schofield PR, Sperling RA, Salloway S, Morris JC; the Dominantly 

Inherited Alzheimer Network. Clinical and Biomarker Changes in 

Dominantly Inherited Alzheimer’s Disease N Engl J Med. 2012 Jul 11. 

[Epub ahead of print] 

Presentation of Raymond D. Adams Lectureship Award and 

Neurobiology of APOE and its Impact on Alzheimer’s Disease 

David M. Holtzman, MD, Washington University, St. Louis, Mo. 

The apolipoprotein E gene (APOE) is the strongest genetic risk factor for 

Alzheimer’s disease (AD) and also cerebral amyloid angiopathy (CAA). It 

also appears to play a role in outcome following head trauma and possibly 

other neurological disorders. APOE is located on chromosome 19 and in 

humans has 3 common isoforms APOE2, APOE3, and APOE4 which only 

differ from each other by a single amino acid (E2: cys 112, cys 158; E3 

cys 112, arg 158; E4 arg 112, arg 158). In regard to AD, relative to APOE3 

the most common allele, one copy of APOE4 increases risk for AD ~3.7 

fold while 2 copies increases risk by ~ 12-fold. Relative to APOE3, one 

allele of APOE2 decreases risk for AD by ~40%. APOE is an apolipoprotein 

expressed at highest levels in the liver but is also expressed at high levels 

in the CNS. In the periphery, APOE plays an important role in plasma 

cholesterol metabolism. It is the most abundant apolipoprotein expressed 

in the CNS where it secreted predominantly by astrocytes in high-density 

lipoprotein (HDL)-like particles. There are several ways that APOE has 

been proposed to influence the CNS both normally and in diseases states 

including effects on plasticity, inflammation, and cell signaling. However, 

there is abundant evidence that a major mechanism via which it influences 

both AD and CAA is by interacting with the amyloid- (A) peptide to 

affect both A clearance and aggregation. In humans, APOE4 results in a 

dose-dependent earlier onset of brain amyloid deposition and an increase 

in CAA while APOE2 results in a delay of amyloid deposition. A variety 

of transgenic mouse models that express human forms of the amyloid 

precursor protein (APP) develop amyloid deposition, neuritic plaques, and 

CAA with associated hemorrhages. APP transgenic mice in which apoE 

is knocked out develop very little to none of these changes. Expression 

of human APOE isoforms in APP transgenic mice results in restoration 

of amyloid deposition dose-dependently with the amount of amyloid 

pathology being in the order E4>E3>E2. In vivo microdialysis and other 

studies suggest that E4 slows soluble A clearance vs. E3 and E2 which 

may account for this differential effect. In some recent immunotherapy trials 

for AD involving passive administration of anti-A antibodies, E4-positive 

individuals have been found to have increased risk for development of 

amyloid related imaging abnormalities (ARIA) including vasogenic edema 

and cerebral microhemorrhages. The etiology of this complication is not 

completely clear but it is probably due to an interaction between anti-A 

antibodies and CAA which is present to a significantly greater extent in 

E4-positive individuals with AD. APOE may also be a therapeutic target for 

AD in that decreasing its levels in different ways results in less amyloid 

deposition and increasing its lipidation state also decreases amyloid 

deposition. Further studies are needed to better understand both the normal 

neurobiology of APOE, its exact role in neurological diseases, and its ability 

to be therapeutically targeted. 

References: 

1. Strittmatter, W.J., Saunders, A.M., Schmechel, D., Pericak-Vance, M., 

Enghild, J., Salvesen, G.S., and Roses, A.D. (1993). Apolipoprotein E: 

high avidity binding to ß-amyloid and increased frequency of type 4 

allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 

90, 1977-1981. 

2. Kim, J., Basak, J.M., and Holtzman, D.M. (2009). The role of 

apolipoprotein E in Alzheimer’s disease. Neuron 63, 287-303. 

29


3. Verghese, P.B., Castellano, J.M., and Holtzman, D.M. (2011). 

Apolipoprotein E in Alzheimer’s disease and other neurological 

disorders. Lancet Neurology 10, 241-252. 

4. Castellano, J.M., Kim, J., Stewart, F.R., Jiang, H., DeMattos, R.B., 

Patterson, B.W., Fagan, A.M., Morris, J.C., Mawuenyega, K.G., 

Cruchaga, C., et al. (2011). Human apoE isoforms differentially 

regulate brain amyloid-beta peptide clearance. Science Translational 

Medicine 3, 89ra57. 

Mechanisms of Neurodegeneration: Lessons from Prion Disease 

John Collinge, MD, Institute of Neurology, University College London, UK 

Prions are lethal pathogens causing neurodegenerative diseases such 

as Creutzfeldt-Jakob disease in humans but which also affect a range of 

other animals. They appear devoid of nucleic acid and composed of 

polymerised conformational isomers of host-encoded cellular prion protein 

(PrP) 1 . Their unique biology, allied with the risks to public health posed by 

prion zoonoses such as bovine spongiform encephalopathy (BSE), has 

focussed much attention on understanding the molecular basis of prion 

propagation and the “species barrier” which controls cross-species 

transmission. Both are intimately linked to understanding how multiple 

prion “strains” are encoded by a protein-only agent, a challenging question 

in molecular biology which raises intriguing questions in evolution. 

It is increasingly clear that the underlying mechanisms, involving 

aggregation of a misfolded host protein, may be of much wider significance 

in commoner neurodegenerative diseases and contribute to their aetiology 

or to the spreading of pathology. Recent advances suggest that prions 

themselves are not directly neurotoxic, but rather their propagation leads 

to production of toxic species which may be uncoupled from infectivity. 

A general protein-only model has been proposed for prion propagation 

and neurotoxicity which may also be relevant to mechanisms of 

neurotoxicity in other neurodegenerative diseases associated with 

accumulation of misfolded proteins 1,2 . Therapeutic proof of principle has 

been achieved 3 and the development of effective treatment for prion 

neurodegeneration appears realistic; fully humanised anti-PrP monoclonal 

antibodies have been produced for clinical trial. In addition to a wider role 

for the general protein-only model, the proposal that prion protein may 

have a direct role in mediating aspects of neurotoxicity in Alzheimer’s 

disease is being investigated which might allow common therapeutic 

approaches and development 4 . 

References: 

1. Collinge, J. & Clarke, A. A general model of prion strains and their 

pathogenicity. Science 318, 930-936 (2007). 

2. Sandberg, M. K., Al Doujaily, H., Sharps, B., Clarke, A. R., & Collinge, 

J. Prion propagation and toxicity in vivo occur in two distinct 

mechanistic phases. Nature 470, 540-542 (2011). 

3. Mallucci G et al. Depleting neuronal PrP in prion infection prevents 

disease and reverses spongiosis. Science 302, 871-874 (2003). 

4. Freir, D. B. et al. Interaction between prion protein and toxic amyloid 

beta assemblies can be therapeutically targeted at multiple sites. 

Nature Communications 2, 336 (2011). 

Biomarkers for the Diagnosis and Course of 


Randall J. Bateman, MD, Washington University, St. Louis, Mo. 

The order and magnitude of Alzheimer’s disease (AD) pathologic processes 

are not well understood, partly because AD develops over many years. 

Autosomal dominant Alzheimer’s disease (ADAD) has a predictable 

age at onset, and provides an opportunity to determine the sequence 

and magnitude of pathologic changes which culminate in symptomatic 

disease. Results of the in vivo metabolic production, exchange, and 

clearance of amyloid-beta isoforms in Presenilin mutation carriers 

will be presented. In addition, results from the Dominantly Inherited 

Alzheimer Network (DIAN) clinical, cognitive, MRI, FDG-PET, PIB-PET, 

CSF and blood tests will be reviewed and compared to sporadic AD. 

Cross sectional data analyzed using the estimated years to symptom 

onset will be reviewed to determine the relative order and magnitude of 

pathophysiological changes. Pathogenic mutations causing ADAD result in 

a series of changes beginning with systemic increased soluble amyloidbeta 

(A)42, followed by brain amyloidosis, increased CSF tau, decreased 

brain glucose metabolism, decreased brain volume, and subtle cognitive 

impairment before dementia is manifest. The sequence of events in AD 

pathophysiology offers the opportunity for predictive testing and secondary 

prevention trials. Because the clinical and pathological phenotypes of 

dominantly inherited AD are similar in many respects to those of the far 

more common late-onset AD, the nature and sequence of brain changes in 

ADAD are likely to be relevant for late-onset AD. (Clinicaltrials.gov number, 

NCT00869817) 

References: 

1. Bateman RJ, Xiong C, Benzinger TLS, Fagan AM, Goate A, Fox 

NC, et al. Clinical and Biomarker Changes in Dominantly Inherited 

Alzheimer’s Disease. New England Journal of Medicine.0(0):null. doi: 

doi:10.1056/NEJMoa1202753. 

2. Bateman RJ, Aisen PS, De Strooper B, Fox NC, Lemere CA, Ringman 

JM, et al. Autosomal-dominant Alzheimer’s disease: a review and 

proposal for the prevention of Alzheimer’s disease. Alzheimers Res 

Ther. 2011;3(1):1. Epub 2011/01/08. doi: alzrt59 [pii]10.1186/alzrt59. 

PubMed PMID: 21211070; PubMed Central PMCID: PMC3109410. 

3. Jack CR, Jr., Knopman DS, Jagust WJ, Shaw LM, Aisen PS, 

Weiner MW, et al. Hypothetical model of dynamic biomarkers of the 

Alzheimer’s pathological cascade. Lancet neurology. 2010;9(1):119-28. 

Epub 2010/01/20. doi: 10.1016/S1474-4422(09)70299-6. PubMed 

PMID: 20083042; PubMed Central PMCID: PMC2819840. 

4. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, 

et al. Toward defining the preclinical stages of Alzheimer’s disease: 

recommendations from the National Institute on Aging-Alzheimer’s 

Association workgroups on diagnostic guidelines for Alzheimer’s 

disease. Alzheimers Dement. 2011;7(3):280-92. Epub 2011/04/26. 

doi: 10.1016/j.jalz.2011.03.003. PubMed PMID: 21514248; PubMed 

Central PMCID: PMC3220946. 

30

Imaging Structure and Function in Alzheimer’s Disease 

William J. Jagust, MD, University of California, Berkeley 

Imaging studies of patients with Alzheimer’s disease (AD), as well as 

studies of patients with Mild Cognitive Impairment (MCI) and normal 

aging, have informed our understanding of the role of -amyloid (A) 

in the pathogenesis of dementia. A conceptual model of dementia 

development postulates an early effect of A on a variety of “downstream” 

processes that probably involve the microtubule-associated protein tau, 

as well as a number of phenomena that can be measured in vivo. These in 

vivo measures, or biomarkers, include regionally specific brain atrophy, 

alterations in the connectivity of large scale brain networks, and changes 

in brain glucose metabolism that all reflect neurodegeneraion. In theory, 

by imaging A and these other biomarkers of neurodegeneration, one 

may not only detect evidence of AD in individuals with manifest dementia 

symptoms, but also detect AD in individuals in pre-dementia and even 

presymptomatic stages. 

This talk will explore the current evidence for this disease model. In 

particular, data on the prevalence of A deposition in the brain in normal 

aging, MCI, and AD will be reviewed, along with evidence that this A 

is associated with alterations in neuronal structure and function. The 

prognostic implications of A deposition in normal aging and MCI will 

also be reviewed, as well as the implications of brain atrophy, resting 

state functional connectivity, and glucose hypometabolism. In particular, 

evidence for the concept that AD exists in presymptomatic stages with 

various degrees of neurodegeneration will be presented. The application 

of PET amyloid imaging to the evaluation of patients with dementia, 

particularly those with unusual presentations, will also be discussed, 

contrasting effects related to A and the brain-behavior associations 

revealed with glucose metabolism. The application of these imaging 

modalities permits the in vivo examination of the cascade of pathological 

events that occurs in the progression of AD from presymptomatic stages 

to overt dementia. These data will indicate the extensive damage present 

in those with dementia symptoms, and the possibilities for selecting and 

treating individuals at presymptomatic disease stages. 

References: 

1. Perrin RJ, Fagan AM, Holtzman DM. Multimodal techniques for 

diagnosis and prognosis of Alzheimer’s disease. Nature, 

461:916-922, 2009 

2. Jack CR, Knopman DS, Jagust WJ, Shaw 461: LM, Aisen PS, Weiner 

MW, Petersen RC, Trojanowski JQ. Hypothetical model of dynamic 

biomarkers of the Alzheimer’s pathological cascade. Lancet Neurology, 

9:119-128. 2010. 

3. Rabinovici GD, Rosen HJ, Alkalay A, Kornak, J, Furst AJ, Agarwal N, 

Mormino EC, O’Neil JP, Janabi M, Karydas A, Growdon ME, Jang, 

JY, Huang EJ, DeArmond SJ, Trojanowski JQ, Grinberg LT, Gorno- 

Tempini ML, Seeley, WW, Miller BL, Jagust WJ. Amyloid versus 

FDG-PET in the differential diagnosis of AD and FTLD. Neurology, 

77: 2034-2042, 2011. 

4. Reiman EM, Jagust WJ. Brain imaging in the study of Alzheimer’s 

Disease. Neuroimage 61:505-516, 2012. 

SYMPOSIUM: Results of Immune-Based Trials in 


Phase 3 Studies of Solanezumab for Mild to Moderate 


Rachelle S. Doody, MD, PhD, Baylor College of Medicine, Houston 

Immune-based therapies in Alzheimer’s disease were initiated after 

seminal studies showed that immunization with aggregated A42 reduced 

development of and stimulated clearance of amyloid plaques in amyloid 

precursor protein (APP) transgenic mice which overproduce beta amyloid 

in the brain (1). A trial of this approach (which also employed the adjuvant 

QS-21) in patients with mild to moderate AD was stopped early due to the 

adverse occurrence of meningoencephalitis in six percent of the immunized 

patients (2). Subsequently, both active and passive immunization strategies 

have been pursued, with the therapeutic agents differing in their methods of 

delivery, antigenic targets, binding properties, and the degree to which they 

enter the central nervous system. 

Solanezumab is a humanized anti--amyloid monoclonal antibody that 

binds to soluble A species and can foster its clearance from brain (3). 

The antigenic target for solanezumab is the mid-region (epitopes 16-23) or 

central domain of A, and it preferentially binds to the soluble forms of A 

(3). A pre-clinical study comparing passive A antibodies with N-terminal 

versus central domain antigenic targets suggested that solanezumab may 

be less likely to induce vasogenic edema compared to N-terminally directed 

antibodies (4). Phase 1 and phase 2 studies supported the safety of this 

agent for further testing in AD patients and showed changes in peripheral 

and central amyloid levels as a result of treatment (5,6). 

Eli Lilly and Company has completed two identical phase 3 studies of 

solanezumab in patients with mild to moderate AD (NINCDS-ADRDA 

criteria). A total of 2052 patients were randomized to receive 400 mg 

solanezumab IV or placebo every four weeks for 80 weeks. Co-primary 

outcomes were the Alzheimer’s Disease Assessment Scale-cognitive 

subscale (ADAS-cog11) and the Alzheimer’s Disease Cooperative 

Study-Activities of Daily Living Scale (ADCS-ADL). All subjects underwent 

magnetic resonance imaging at weeks 12, 28, 52, and 80; and subsets 

underwent Florbetapir PET imaging/lumbar puncture at baseline and 

endpoint. We will present results for the co-primary efficacy measures, 

safety, and some biological markers and will discuss how the results of 

these studies influence our understanding of the amyloid hypothesis and 

AD therapeutics. 

References: 

1. Schenk D, etal Nature 1999;400-173-177 (Letter) 

2. Gilman S, etal Neurology 2005;64:1553-1562 

3. Samadi H and Sultzer D Expert Opin Biol Ther 2011:1-12 

4. Racke M, etal Neurobiol Disease 2005;25(3):629-636 

5. Siemers E, etal Clin Neuropharm 2010;33(2):67-73 

6. Farlow M, etal Alzheimer’s & Dem 2012 do1:10.1016/j.jalz2011.09.224 

31


Phase III Studies of Bapineuzumab for Mild to 

Moderate Alzheimer’s Disease Dementia 

Reisa A. Sperling, MD, Brigham and Women’s Hospital, Boston 

Amyloid- accumulation is one of the hallmark pathologic processes 

that defines Alzheimer’s disease (AD). Bapineuzumab is an N-terminus, 

anti-amyloid- monoclonal antibody being evaluated in a Phase 3 clinical 

trial program for the treatment of AD. The Phase 3 studies enrolled AD 

patients with mild to moderate dementia severity (MMSE 16-26) into four 

78 week double-blind, placebo-controlled trials. Results of the first two of 

these studies are presented here. 

Separate Phase 3 trials, with differing dose levels of bapineuzumab, 

were designed for APOE 4 allele carriers and non-carriers as Phase 2 

data suggested possible differences between these populations. The 

non-carrier (301) study was initially designed to test 3 dose levels of 

bapineuzumab (0.5, 1.0, and 2.0 mg/kg) vs. placebo. The 2.0mg/kg dose 

was stopped approximately one year into the study due to the incidence 

of amyloid-related imaging abnormalities (ARIA) thought to represent 

vasogenic edema. The carrier (302) study tested only 1 dose level 

(0.5mg/kg) vs. placebo. 

Bapineuzumab or saline placebo was administered intravenously every 

13 weeks over the 78 week trial. Safety MRIs to monitor for ARIA were 

performed 6 weeks after each infusion. The co-primary clinical endpoints 

are change in the Alzheimer’s Disease Assessment Scale – Cognitive 

subscale (ADAS-Cog, a composite cognitive measure) and the Disability 

Assessment for Dementia (DAD, functional measure of activities of daily 

living). Biomarker substudies assessing effects of bapineuzumab on PiB- 

PET imaging estimates of brain amyloid burden, cerebrospinal fluid (CSF) 

phospho-tau, and brain volume on structural MRI, were included. Statistical 

analyses were performed to estimate treatment differences at study endpoint 

through mixed models for repeated measures and analysis of covariance. 

The APOE 4 non-carrier study enrolled and dosed 1,331 AD patients, 

and the APOE 4 carrier study randomized and dosed 1,121 AD patients, 

including 4 hetero- and homozygotes. The primary efficacy outcomes 

(ADAS-Cog and DAD) for both carrier and non-carrier studies will be 

presented. Biomarker endpoints (PiB PET, CSF phospho-tau, volumetric 

MRI) will also be presented, as well as safety data, including ARIA findings 

on MRI and other adverse events. 

These two Phase 3 clinical trials were designed to provide a robust 

evaluation of the efficacy and safety of bapineuzumab treatment in AD 

patients with mild-moderate dementia as a potential disease-modifying 

therapy, based on a combination of clinical and biomarker evidence. The 

implications of findings across the APOE 4 carrier and non-carrier studies 

will be discussed. The results will also be discussed in the context of the 

plans for earlier intervention studies with anti-amyloid immunotherapeutic 

agents, including secondary prevention trials in asymptomatic genetic atrisk 

and biomarker at-risk populations. 

Sperling R, Salloway S, Raskind M, Ferris S, Honig L, Porsteinsson A, 

Sabbagh M, Liu E, Yuen E, Lull J, Miloslavsky M, Reichert M, Ketter N, 

Lu Y, Wang D, Nejadnik B, Guenzler V, Grundman M, Black R, Brashear HR 

References: 

1. Black R, Sperling RA, Safirstein B, Motter RN, Pallay A, Nichols A, 

Grundman M. A single ascending dose study of bapineuzumab in 

patients with Alzheimer’s disease. Alzheimer’s Disease and Associated 

Disorders 2010 Apr-Jun; 24(2):198-203. PMID: 20505438 

2. Salloway SP, Sperling RA, Gilman S, Fox NC, Blennow K, Raskind M, 

Sabbagh M, Honig LS, Doody R, van Dyck CH, Mulnard R,Barakos J, 

Gregg K, Liu E, Lieberberg I, Schenk D, Black R and Grundman M. A 

Phase 2 multiple ascending dose trial of bapineuzumab in mild to 

moderate Alzheimer’s disease. Neurology 2009, Dec 15; 73(24):2061- 

70. PMCID: PMC2790221 

3. Sperling RA, Salloway S, Brooks, DJ, Tampieri D, Barakos J, Fox NC, 

Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Lieberburg I, 

Arrighi HM, Morris KA, Lu Y, Liu E, Gregg KM, Brashear RH, Kinney 

GG, Black R, Grundman M. Amyloid-related imaging abnormalities 

(ARIA) in Alzheimer’s disease patients treated with bapineuzumab: 

A retrospective analysis. Lancet Neurology 2012 Mar; 11(3):241-49 

PMID: 22305802 

Phase III Trials of Alemtuzumab in Relapsing-Remitting 

Multiple Sclerosis 


Lymphocyte depletion has been used over many years to treat multiple 

sclerosis. Campath-1H (alemtuzumab), the first humanized monoclonal 

antibody, targets CD52 and rapidly depletes circulating lymphocytes. It 

was first used in the context of multiple sclerosis in 1991. After it became 

clear that lymphocyte depletion is not clinically effective once patients have 

moved to the progressive phase of the disease, open-label studies and a 

phase 2 clinical trial with an active comparator, involving 334 previously 

untreated patients with early-stage relapsing-remitting multiple sclerosis, 

showed that alemtuzumab reduces the number of episodes by 74 per cent, 

and reduces the risk of sustained accumulation of disability by 71 per cent 

compared to interferon beta-1a. Many individuals receiving alemtuzumab 

were less disabled after three years than at the beginning of the study, in 

contrast to worsening disability in the interferon beta-1a treated patients. 

The main adverse effect of treatment was a 25% risk of developing another 

autoimmune disease as the immune system reconstitutes following 

exposure to alemtuzumab. A further period of observation, now extended 

to at least 5 years for all participants, confirms the superior efficacy of 

alemtuzumab in this study. Two phase 3 trials are also now completed. 

In CARE-MS1 treatment-naïve patients with relapsing-remitting multiple 

sclerosis were randomized to pulsed treatment with alemtuzumab (n=376) 

at baseline and 12 months, or continuous interferon beta-1a (n=187), and 

assessed at two years for clinical and MRI outcomes. CARE-MS2 used 

the same protocol but recruited patients with relapsing-remitting multiple 

sclerosis who had already experienced 1 relapse on interferon beta or 

glatiramer. In CARE-MS1, alemtuzumab reduced annualized relapse rate 

by 55% compared to interferon beta-1a; 8% of alemtuzumab patients 

experienced sustained accumulation of disability versus 11% of interferon 

beta-1a patients. Alemtuzumab reduced the proportions of patients with 

gadolinium-enhancing lesions and new or enlarging T2-hyperintense 

32

lesions and reduced brain volume loss by 40%, all compared to interferonbeta. 

In CARE-MS2, alemtuzumab reduced relapse rate by 49% compared 

to interferon beta-1a, risk of sustained accumulation of disability by 

42%, new gadolinium or T2 lesions by 60% and 32% respectively, and 

brain volume loss by 0.20%. Sustained reduction in disability was more 

likely after alemtuzumab. In both studies the frequency of secondary 

autoimmunity was c20%; no new safety signals were observed. 

Inflammation and axon degeneration are each involved in the pathogenesis 

of multiple sclerosis. The evaluation of alemtuzumab has revealed the 

relative contribution of inflammatory and neurodegenerative events 

underlying the natural history of multiple sclerosis as this evolves from the 

relapsing-remitting to progressive phase of the disease; identified novel 

mechanisms of symptom production reflecting altered axonal structure and 

function; provided a ‘human’ model of lymphocyte reconstitution that has 

explained general principles of autoimmunity; demonstrated the critical 

importance of timing in order to achieve high efficacy for immunological 

treatments in multiple sclerosis; shown that – at least over a period of 10 

years – lymphocyte depletion early in the course of relapsing-remitting 

multiple sclerosis stabilises the natural history of the disease; demonstrated 

that fixed disability in multiple sclerosis may recover; and provided 

evidence for the mechanisms and effect of protective autoimmunity in the 

human central nervous system. 

References: 

1. International CAMMS223 Trial Study Group. A randomized, raterblinded, 

trial of alemtuzumab versus interferon beta-1a in early, 

relapsing-remitting multiple sclerosis. New England Journal of 

Medicine 2008: 359; 1786-1801 

2. Coles AJ, Fox EJ, Vladic A, Gazda SK, Brinar VV, Selmay K, Skoromets 

AA, Stolyarov I, Bass A, Sullivan H, Margolin DH, Lake SL, Moran 

S, Palmer J, Smith MS, Compston DAS Alemtuzumab treatment 

of multiple sclerosis: five-year follow-up of the CAMMS223 trial. 

Neurology 2012: 78; 1069-78 

3. Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox E, 

Hartung H-P, Havrdova E, Selmaj K, Weiner HL, Miller T, Fisher E, 

Sandbrink R, Lake SL, Margolin DH, Oyuela P, Panzara MA, Compston 

DAS for the CARE-MS 2 investigators. Alemtuzumab in multiple 

sclerosis relapsing on disease-modifying therapy (submitted) 

4. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung H-P, 

Havrdova E, Selmaj KW, Weiner HL, Fisher E, Brinar VV, Giovannoni G, 

Stojanovic M, Ertik BI, Lake SL, Margolin DH, Panzara MA, Compston 

DAS for the CARE-MS I investigators. Alemtuzumab versus interferon 

beta as initial multiple sclerosis treatment (submitted). 

33

TUESDAY SPEAKER ABSTRACTS 

SYMPOSIUM: Derek Denny-Brown New 

Member Symposium 

Presentation of Derek Denny-Brown Neurological 

Scholar Award: Clinical Science and Temporal Trends in 

Acute Stroke Management 

Dawn Kleindorfer, MD, University of Cincinnati, Cincinnati, Oh. 

There is no doubt that the approval of rt-PA has revolutionized the field 

of stroke. However, it is not clear how often stroke patients are actually 

receiving rt-PA. This deceptively simple question is actually very difficult 

to answer. There is no perfect database to answer these types of questions. 

Administrative data lacks clinical detail, and represents a sampling of 

stroke patients. Clinical databases lack generalizability, and typically have 

significant referral biases. However, utilizing an administrative database 

with linked pharmacy data, we estimated that the rates of rt-PA utilization 

were initially very low and flat, but finally started increasing around 2004 1 . 

This timing of this coincided with the institution of primary stroke centers 

accreditation in 2004, and did not appear to be as influenced by changes 

in hospital reimbursement rates for rt-PA patients as we had hypothesized. 

In 2009, we estimate that 4.5% of hospitalized ischemic stroke patients 

received rt-PA. 

The next logical question becomes, “Why are the rates of rt-PA use so low”. 

To answer that, one must understand the eligibility of stroke patients for 

rt-PA, which requires more detailed clinical data from an entire population. It 

turns out that only 6-8% of ischemic stroke patients are eligible for rt rt-PA 

PA within a population 2 , mostly driven by delayed arrival times of patients 

to medical attention 3 . Recent attempts to expand the limited time window in 

which rt-PA can be given likely will not significantly improve treatment rates, 

as patients either arrive very early or very late. Other targets, such as treating 

infarcts with milder severity, may be better targets for improvement. 

We also began exploring the impact hospital-level factors and their impact 

on rates of rt-PA use. We were especially interested in the role of primary 

stroke centers and how they impacted hospitallevel rates of rt-PA utilization. 

Many had thought that those centers choosing to certify would already be at 

a high level of treatment, and the certification process would not change this, 

or that the effect would “wear off” over time. We found exactly the opposite, 

that centers seeking certification had dramatically increased rates of rt-PA 

use that was relatively constant for the three years pre- and post-certification. 

Finally, the Center for Medicare Services has become interested in measuring 

and publicly ranking hospitals regarding the quality of stroke care. By 

working with the incredibly productive Get With the Guidelines team, we were 

able to prove that comparisons between hospitals must account for initial 

stroke severity, or else those hospitals providing the highest quality care to 

the sickest patients will likely be unfairly portrayed. 4 

In order to improve our public’s health for stroke, the fourth leading cause 

of death, we should make every attempt to understand the true quality of 

care provided and the proportion of patients eligible for new therapeutic 

approaches. Without accurate and precise measurement of how often and to 

whom acute stroke treatments are given, we cannot measure our success nor 

advance the implementation of these proven therapies. 

References: 

1. Adeoye O, Hornung R, Khatri P, Kleindorfer D. Recombinant tissue-type 

plasminogen activator use for ischemic stroke in the united states: 

A doubling of treatment rates over the course of 5 years. Stroke. 2011 

2. Kleindorfer D, Kissela B, Schneider A, Woo D, Khoury J, Miller R, 

Alwell K, Gebel J, Szaflarski J, Pancioli A, Jauch E, Moomaw C, 

Shukla R, Broderick JP. Eligibility for recombinant tissue plasminogen 

activator in acute ischemic stroke: A population-based study. Stroke. 

2004;35:e27-29 

3. Kleindorfer D, Alwell, K, Khoury, J, Ewing, I, Schneider, A, Flaherty, 

ML, Moomaw, C, Khatri, P, Stettler, B, Broderick JP. Temporal trends in 

emergency department arrival times for acute ischemic stroke: 

A population-based study. Stroke. 2005;36:494 

4. Fonarow G PW, Saver JL, Smith EE, Reeves MJ, Broderick JP, Kleindorfer 

DO, Sacco RL, Olson DM, Hernandez AF, Peterson ED, Schwamm 

LH. Comparison of 30-day mortality models for proflining hospital 

performance in acute ischemic stroke with vs. Without adjustment 

for stroke severity. Journal of the American Medical Association. 

2012;308.:257-264 

Presentation of Derek Denny-Brown Neurological Scholar Award: 

Basic Science and A Large Repeat Expansion in the C9ORF72 

Gene is a Common Cause of ALS and FTD 

Bryan J. Traynor, MB, MD, PhD, MMSc, MRCPI, National Institute on Aging, 

National Institutes of Health, Bethesda, Md. 

Amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease) is a fatal 

neurodegenerative disorder that leads to rapidly progressive paralysis 

and respiratory failure. ALS is the third most common neurodegenerative 

disease in the Western world, and there are currently no effective therapies. 

Frontotemporal dementia (FTD) is the most common form of dementia in 

the population under the age of 65. An overlap between these two clinically 

distinct neurological diseases has long been recognized, but the molecular 

basis of this intersection was unknown. 

Recently, the Neuromuscular Diseases Research Unit (NDRU), a part of the 

Laboratory of Neurogenetics at the National Institute on Aging, identified the 

major genetic cause of both ALS and FTD. To do this, Dr. Traynor (chief of 

NDRU) organized a worldwide consortium, bringing together groups that 

had previously been competitors to focus their efforts towards identifying 

this gene. This was made possible by the next generation sequencing 

technologies available at the NIH. This innovative approach worked, and his 

group published the cause of chromosome 9-linked ALS/FTD in the journal 

Neuron in September 2011. 1,2 In these cases, the disease is caused by a six 

base pair segment of DNA that is pathologically repeated over and over again, 

up to several thousand times. This so-called large hexanucleotide repeat 

disrupts the C9ORF72 gene located on chromosome 9, and is the most 

common genetic cause of both ALS and FTD identified to date, accounting 

for approximately 40% of all familial cases of ALS and FTD in European and 

North American populations. Further, Dr. Traynor’s group has shown that 

this mutation underlies about 8% of cases of sporadically occurring ALS and 

FTD that lack a family history. 3 This represents the first time that a common 

genetic cause has been identified for the sporadic form of these diseases. In 

a separate publication in The New England Journal of Medicine, they have 

34

also shown that the same large hexanucleotide repeat expansion underlies 

~1% of cases clinically diagnosed with Alzheimer’s Disease. 4 A one percent 

reduction in the number of AD cases would represent approximately $1 

billion in healthcare cost savings annually. 

The discovery of the C9ORF72 hexanucleotide repeat expansion is a 

landmark discovery in our understanding of neurodegenerative disease. 

It has already greatly effected how these diseases are diagnosed, 

investigated and perceived, and provides a mechanistic link between 

two clinically distinct disorders, ALS and FTD. It also provides a distinct 

therapeutic target for gene therapy efforts aimed at ameliorating the disease, 

and such efforts are already well underway. 

References: 

1. Renton AE, et al. A hexanucleotide repeat expansion in C9ORF72 is 

the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011; 

72: 257–68. 

2. DeJesus-Hernandez M, et al. Expanded GGGGCC hexanucleotide 

repeat in noncoding region of c9orf72 causes chromosome 9p-linked 

FTD and ALS. Neuron 2011; 72: 245–56. 

3. Majounie E, et al. Frequency of the C9orf72 hexanucleotide repeat 

expansion in patients with amyotrophic lateral sclerosis and 

frontotemporal dementia: a cross-sectional study. Lancet Neurol. 2012; 

11:323–30 

4. Majounie E, et al. Repeat expansion in C9ORF72 in Alzheimer’s 

Disease. N Engl J Med. 2012; 366:283–4 

Pilot Clinical Trial of Eculizumab in AQP4-IgG-Positive NMO 


Objective: Investigate safety and efficacy of blocking terminal complement 

activation in reducing frequency of neuromyelitis optica (NMO) relapses. 

We conducted an open-label study of eculizumab, an inhibitor of C5 

cleavage, in patients with aggressive NMO. 

Methods: 14 adults with NMO spectrum disorder ( 2 relapses in the 

preceding 6 months or 3 in the preceding 12 months) were treated 

with eculizumab for 1 year. 7 had failed standard immunosuppressant 

treatments. 

Results: After 12 months treatment, 12 of 14 were relapse-free. The 

median annualized attack rate declined from 3 (pre-eculizumab) to 0 (oneculizumab; 

p


direct miR-183 binding to their 3’UTRs. Moreover, elevated levels of miR- 

183 can block Akt1 and mTOR translation in growing axons. Taken together, 

these observations suggest that microRNAs can regulate local translation of 

specific genes directly and control protein synthesis broadly by modulating 

the activity of mTORC1 and mTORC2 and highlight a new molecular 

mechanisms contributing to SMA pathology. 

Min J. Kye, PhD 1 , Mary H. Wertz 1 , Bikem Akten, PhD 1 , Pierre Neveu, PhD 2 , 

Kenneth S. Kosik, MD 3 and Mustafa Sahin, MD, PhD 1 . 1 Neurology, Boston 

Children’s Hospital, Boston, MA, 02115; 2 Cell Biology and Biophysics Unit, 

European Molecular Biology Laboratory, Heidelberg, Germany, 60117; 

3 

Neuroscience Research Institute, University of California at Santa Barbara, 

Santa Barbara, CA 93106. 

Presentation of The Grass Foundation – ANA Award in 

Neuroscience Award and Multiscale Investigations of Epilepsy, 

Sleep and Cognition 


Both normal and abnormal activity in the brain involves actions at 

multiple different scales. From ion channels, to individual neurons, to 

widespread neuronal interactions encompasses cortical and subcortical 

structures, activities at different levels interact to culminate in particular 

behaviors. Unraveling the mechanisms at these different scales, and the 

nature of interactions across scales remains a tremendous challenge in 

the neurosciences and neurology. Our group has focused on making use 

of the unprecedented spatiotemporal information obtainable from patients 

undergoing invasive physiological monitoring for epilepsy to explore the 

different scales of neuronal activity during normal cognitive processing, 

sleep and epileptic activity. We augment the already substantial capabilities 

of routine, clinical recordings with different forms of microelectrodes 

which record the activity from small groups of neurons and even 

individual neurons. 

In this brief talk we will start with a summary of the different techniques 

that we are currently using with an emphasis and the different scales of 

information that can be obtained from each system. These modalities include 

non-invasive approaches of EEG and MEG as well as routine invasive, 

intracranial recordings techniques. They also include microelectrodes 

which are either placed on the pial surface or within the parenchyma of 

the brain. These later devices include microgrids and microwires, laminar 

microelectrode arrays and the NeuroPort microelectrode array. 

Using these systems we have found that epileptic activity in the brain 

involves a complex interplay of inhibitory and excitatory neuronal activity 

which does not strictly demonstrate pure hypersynchrony or hyperexcitability 

[1-2]. Analysis of individual neuronal firing during both interictal discharges 

and seizures themselves reveals a wide variety of different neuronal firing 

patterns. Furthermore, there are hints that some neurons may change their 

firing activity well in advance of the event itself. Examination of larger scale 

dynamics, at the level of the cortex as a whole, also shows complex behavior 

of the entire network with periods of the seizure (primarily mid-seizure) 

in which there is less synchrony than might be expected [3]. From these 

combined, multi-scalar, data emerges a model of the seizure as a process 

which is heterogeneous in space and temporally dynamic. 

36 

Similar investigations of typical sleep activity also reveal more complexity in 

both space and time than is expected from early analysis of scalp EEG alone. 

Sleep spindles, for example, show a variety of different localizations across 

the brain during sleep. The combined microscale and macroscale data has 

led to revisions of existing models of thalamocortical interactions with a new 

emphasis on differences between core and matrix projections accounting for 

different aspects of the spindle and carrying implications for processing of 

information during sleep . 

Finally, multiscale analysis of language processing suggests widespread 

cortical involvement in even simple semantic tasks – even in areas outside 

traditional language cortex [4]. At the level of the single neuron this aspect 

is revealed in individual neuronal responses to particular word sounds in the 

superior temporal gyrus. 

Together, these studies exemplify the power and possibilities of detailed 

neurophysiological examination which takes into account and tries to 

understand the interplay of activity across scales. While in their early 

stages, these types of investigation will hopefully shed substantial light on 

both normal and abnormal processing in the brain in a way which can be 

leveraged for novel therapeutic benefit. 

References: 

1. Keller, C.J., et al., Heterogeneous neuronal firing patterns during 

interictal epileptiform discharges in the human cortex. Brain, 2010. 

133(Pt 6): p. 1668-81. 

2. Truccolo, W., et al., Single-neuron dynamics in human focal epilepsy. 

Nat Neurosci, 2011. 

3. Kramer, M.A., et al., Coalescence and fragmentation of cortical networks 

during focal seizures. J Neurosci, 2010. 30(30): p. 10076-85. 

4. Chan, A.M., et al., Decoding word and category-specific spatiotemporal 

representations from MEG and EEG. Neuroimage, 2011. 54(4): 

p. 3028-39. 

Congenital Myasthenic Syndrome (CMS), Autophagic Myopathy, 

and Cognitive Dysfunction Caused by Mutations in DPAGT1 

Duygu Selcen, MD, Mayo Clinic, Rochester, Minn. 

We recently identified two CMS patients with CNS involvement. Patient 1 

is a16-year-old mentally retarded girl with severe generalized CMS since 

infancy. One of her siblings is also affected and has autistic features. 

Patient 2 is a 14-year-old girl with mild cognitive deficits and progressive 

limb-girdle CMS since infancy. Both respond poorly to anti-AChE therapy. 

Intercostal muscle specimens in both show small tubular aggregates in 

type 2 fibers, type1 fiber atrophy, and a vacuolar myopathy with autophagic 

features. Endplate studies reveal that quantal release, postsynaptic response 

to acetylcholine quanta, and endplate AChR content are reduced to ~50% 

of normal. Quantitative EM of 65 endplate regions shows hypoplastic 

endplates, very small nerve terminals, and poorly differentiated postsynaptic 

regions. Neither patient harbors mutations in currently recognized CMS 

disease genes but exome sequencing in each identifies two heteroallelic 

mutations in DPAGT1 coding for dolichyl-phosphate N-acetylglucosamine 

phosphotransferase, an enzyme subserving protein N-glycosylation. 

Immunoblots of muscle extracts probed by two different antibodies 

demonstrates reduced to absent glycosylation of ~70 kDa proteins. We 

hypothesize that hypoglycosylation of synapse-specific proteins causes 

defects in motor as well as central synapses.

Duygu Selcen, MD1, XinMing Shen, PhD1, Ying Li, PhD2, Eric Wieben, 

PhD3 and Andrew G. Engel, MD1. 1Neurology, Mayo Clinic, Rochester, 

MN, 55905; 2Biomedical Statistics and Informatics, Mayo Clinic, Rochester 

and 3Biochemistry and Molecular Biology, Mayo Clinic, Rochester. 

Anti-NMDA Receptor Encephalitis, a Series of 212 Children 

Maarten Titulaer, MD, PhD, IDIBAPS/University of Barcelona 

Since its discovery in 2007, anti-NMDAR encephalitis has been 

recognized as one of the most frequent autoimmune encephalitis. We 

report a longitudinal cohort study of 212 children, focusing on symptom 

presentation, treatment, and outcome at 24 months, and provide 

treatment guidelines. 

73% of patients were girls. 41% of girls 12 years had ovarian teratoma(s) 

compared with 6%


3. Burstein R, Jakubowski M, Garcia-Nicas E, Kainz V, Bajwa Z, Hargreaves 

R, et al. Thalamic sensitization transforms localized pain into widespread 

allodynia. Ann Neurol. 2010;68(1):81-91. 

4. Burstein R, Jakubowski M, Collins B. Defeating migraine pain with 

triptans: A race against the development of cutaneous allodynia. Ann 

Neurol. 2004;55(1):19-26. 

5. Noseda R, Kainz V, Jakubowski M, Gooley JJ, Saper CB, Digre K, et al. 

A neural mechanism for exacerbation of headache by light. Nat Neurosci. 

2010;13(2):239-45. 

F.E. Bennett Memorial Lectureship: Finding and Exploiting 

Neuropathic Pain Genes 

Clifford Woolf, MD, PhD, Children’s Hospital of Boston 

Loss function recessive mutations in certain key “pain genes” like Nav1.7, can 

produce a large phenotype, such as congenital insensitivity to pain, but only in 

populations where consanguinity is present, and therefore, such probands are 

extremely rare. Both acute pain sensitivity and the risk of developing chronic 

pain are, however heritable, with an estimated ~50% genetic contribution. The 

challenge is identifying the common genetic polymorphisms responsible, which 

will require genome-wide screens in large, well phenotyped cohorts. In the 

meanwhile, candidate gene studies based on unbiased preclinical genome-wide 

profiling in Drosophila and rodents have revealed that the while the relative risk 

produced by each pain gene in most cases is likely to be small, cumulatively 

they will progressively help identify individuals at high risk. Furthermore, 

identifying pain-related genes provides a powerful means of validating in 

patients, targets for the development of novel analgesics. 

Costigan M, Belfer I, Griffin RS, Dai F, Barrett LB, Coppola G, Wu T, Kiselycznyk 

C, Poddar M, Lu Y, Diatchenko L, Smith S, Cobos EJ, Zaykin D, Allchorne A, 

Shen PH, Nikolajsen L, Karppinen J, Männikkö M, Kelempisioti A, Goldman D, 

Maixner W, Geschwind DH, Max MB, Seltzer Z, Woolf CJ. Multiple chronic pain 

states are associated with a common amino acid-changing allele in KCNS1. 

Brain. 2010 133:2519-27 

Neely GG, Hess A, Costigan M, Keene AC, Goulas S, Langeslag M, Griffin RS, 

Belfer I, Dai F, Smith SB, Diatchenko L, Gupta V, Xia CP, Amann S, Kreitz S, 

Heindl-Erdmann C, Wolz S, Ly CV, Arora S, Sarangi R, Dan D, Novatchkova 

M, Rosenzweig M, Gibson DG, Truong D, Schramek D, Zoranovic T, Cronin 

SJ, Angjeli B, Brune K, Dietzl G, Maixner W, Meixner A, Thomas W, Pospisilik 

JA, Alenius M, Kress M, Subramaniam S, Garrity PA, Bellen HJ, Woolf CJ, 

Penninger JM. A genome-wide Drosophila screen for heat nociception identifies 

23 as an evolutionarily conserved pain gene. Cell. 2010 143:628-38 

Sorge RE, Trang T, Dorfman R, Smith SB, Beggs S, Ritchie J, Austin JS, Zaykin 

DV, Meulen HV, Costigan M, Herbert TA, Yarkoni-Abitbul M, Tichauer D, 

Livneh J, Gershon E, Zheng M, Tan K, John SL, Slade GD, Jordan J, Woolf CJ, 

Peltz G, Maixner W, Diatchenko L, Seltzer Z, Salter MW, Mogil JS. Genetically 

determined P2X7 receptor pore formation regulates variability in chronic pain 

sensitivity. Nature Medicine. 2012 18:595-599 

Tegeder I, Costigan M, Griffin RS, Abele A, Belfer I, Schmidt H, Ehnert C, 

Nejim J, Marian C, Scholz J, Wu T, Allchorne A, Diatchenko L, Binshtok 

AM, Goldman D, Adolph J, Sama S, Atlas SJ, Carlezon WA, Parsegian 

A, Lotsch J, Fillingim RB, Maixner W, Geisslinger G, Max MB, Woolf CJ. 

GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and 

persistence. Nature Medicine. 2006 12:1269-1277. 

38 

Mining Nociceptor Signaling for Pain Therapeutics 


Recent evidence indicates that acute activation of pain pathways can provoke 

long-lasting changes in signal transduction within peripheral sensory 

pain neurons (nociceptors) that render these neurons hyper-responsive. 

This phenomenon, termed “hyperalgesic priming”, has been modeled in 

animals where inflammatory mediators, such as prostaglandin E2, which 

acutely signal via protein kinase A, acquire the capacity to activate additional 

signaling pathways that produce a prolonged hyperalgesic state. Critical to 

this process is activation of the enzyme protein kinase C epsilon (PKC). 

Studies in rats and mice have demonstrated that activation of PKC is 

important for hyperalgesia due to inflammation, to chemotherapeutic, 

alcoholic, or diabetic neuropathy, and to stress-induced generalized pain. 

Confirmed downstream targets of PKC that regulate the excitability of 

nociceptors include the polymodal receptor TRPV1 and the sodium channel 

Nav1.8; additional targets remain to be identified and validated. Given the 

apparent key role of PKC as a hub for nociceptor signaling, there has 

been growing interest in developing PKC inhibitors to treat inflammatory, 

neuropathic, and generalized pain disorders. Our recent work has identified 

a series of potent kinase inhibitors that are relatively selective for PKC over 

other PKC isozymes and cross the blood brain barrier. Additional animal 

studies indicate that PKC inhibition is likely to be anxiolytic and possibly 

anti-inflammatory, providing a favorable therapeutic profile for a new class of 

drugs to treat pain. 

References: 

1. Reichling DB, Levine JD. Critical role of nociceptor plasticity in chronic 

pain. Trends Neurosci. Dec 2009;32(12):611-618. 

2. Aley KO, Messing RO, Mochly-Rosen D, Levine JD. Chronic 

hypersensitivity for inflammatory nociceptor sensitization mediated 

by the epsilon isozyme of protein kinase C. J Neurosci. 

2000;20(12):4680-4685. 

3. Wu DF, Chandra D, McMahon T, et al. PKCepsilon phosphorylation 

of the sodium channel NaV1.8 increases channel function and produces 

mechanical hyperalgesia in mice. J Clin Invest. Apr 2 2012;122(4): 

1306-1315. 

4. Hodge CW, Raber J, McMahon T, et al. Decreased anxiety-like behavior, 

reduced stress hormones, and neurosteroid supersensitivity in mice 

lacking protein kinase C epsilon. J. Clin. Invest. Oct 2002;110(7): 

1003-1010. 

The Bench to Bedside Challenges in Neuropathic Pain 

Therapeutics 

Roy L. Freeman, MD, Beth Israel Deaconess Medical Center, Boston 

Neuropathic pain therapeutics faces several challenges. There are currently 

seven drugs approved by the FDA for the treatment of neuropathic pain: 

lidocaine delivered topically via a patch, gabapentin in three different 

formulations, pregabalin, duloxetine and topical capsaicin administered 

as an 8% concentration patch. Despite the availability of these drugs and 

the widespread use of numerous unapproved drugs from different classes, 

current pharmacological approaches do not provide satisfactory pain relief 

in many patients. In clinical trials, even the most effective of these agents 

provides less than a 50% improvement in less than 50% of subjects. 

Furthermore, many patients experience intolerable adverse events with

these therapies. Inarguably, the availability and widespread use of these 

agents has improved patient quality of life, but there remains a need for 

more potent agents with a superior adverse event profile. 

It is not yet known whether a response to one intervention is generalizable. 

Specifically, it is not known whether individuals who respond to one 

medication would also respond to a second medication with a different 

mechanism of action or whether response characteristics vary among 

patients. There is preliminary evidence that the pain phenotype and genotype 

may influence individual response characteristics. The rationale behind 

the role of the pain phenotype in determining therapeutic response is 

based on the hypothesis that the phenotype is a specific manifestation of 

the mechanism that underlies the pain and that, if so, the pain phenotype 

predicts responsiveness to a medication with a specific mechanism of action. 

Detailed phenotypic studies have been performed in multicenter clinical trials 

and by multinational academic consortia. These may provide the basis of 

studies to predict therapeutic responsiveness and a more rational approach 

to pain therapeutics. 

The animal models of neuropathic pain continue to provide insights into 

the molecular mechanisms whereby nerve injury results in chronic pain 

and all of the approved agents are effective in models of neuropathic pain. 

However, a successful response in these models is not a consistent predictor 

of success in clinical trials; many agents appear effective in preclinical pain 

models but fail in subsequent clinical trials. Further, none of the approved 

agents originated from preclinical studies. All showed initial clinical 

effectiveness and were subsequently tested in animal models, following a 

bedside-to-bench route. Yet success in the animal neuropathic pain model 

remains the gateway to the clinical arena. There are no data as to whether 

agents, ineffective or partially effective in the animal model show success in 

the clinic. As an alternative, several human models of neuropathic pain exist 

but the predictive value of these is not established. 

References: 

1. Freeman R. Pharmacotherapy of Neuropathic Pain. In: Simpson DM, 

McArthur JCM, Dworkin R, Editors. Neuropathic Pain: Mechanisms and 

Management. Oxford University Press. New York, NY. 2012 

2. Klein T, Magerl W, Rolke R, Treede RD. Human surrogate models of 

neuropathic pain. Pain. 2005 Jun;115:227-33. 

3. Maier C, Baron R, Tölle TR, Binder A Birbaumer N, Birklein F, 

Gierthmühlen J,et al. Quantitative sensory testing in the German 

Research Network on Neuropathic Pain (DFNS): somatosensory 

abnormalities in 1236 patients with different neuropathic pain 

syndromes. Pain. 2010;150:439-50. 

4. Mogil JS. Animal models of pain: progress and challenges. Nat Rev 

Neurosci. 2009;10:283-94. 

Anti-NGF: A Saga in Drug Development 

David R. Cornblath, MD, Johns Hopkins University, Baltimore, Md. 

Prof. Rita Levi-Montalcini and Prof. Stanley Cohen discovered nerve growth 

factor (NGF) in the 1950s while faculty members at Washington University 

in St Louis initially working in the laboratory of Prof. V. Hamburger. For this 

discovery, they won the Nobel Prize in Physiology or Medicine in 1986. 

NGF is a small secreted protein that is critical for the growth, survival and 

maintenance of sympathetic and sensory neurons during a critical period 

of development. Without it, these neurons undergo apoptosis during 

this critical period. NGF causes axonal growth and axonal branching. 

NGF prevents or reduces neuronal degeneration in animal models of 

neurodegenerative diseases. NGF has also been shown to promote peripheral 

nerve regeneration. The expression of NGF is increased in inflammatory 

diseases where it suppresses inflammation. NGF appears to promote myelin 

repair. These basic science results lead to the first-in-human clinical trials 

in humans (Petty et al. 1994). In that study, it was discovered that there was 

a dose-limiting toxicity: with systemic administration, subjects developed 

a myalgic syndrome while with local administration, subjects developed 

hypersensitivity at the site of injection. These observations lead to the idea 

that blocking NGF may block pain transmission. 

Several companies have now developed anti-NGF drugs. The initial 

concern from a safety perspective was that these would cause a peripheral 

neuropathy as NGF is known to be important in the maintenance of small 

sensory neurons. Thus, considerable thought was given to potential 

peripheral neurologic toxicity. Monitoring schemes were developed and 

implemented. Extensive neurologic review of possible toxicity was in place. 

Then the unexpected occurred. There appeared to be an excess of cases 

of osteonecrosis leading to total joint replacement. The company furthest 

along in development notified the DSMB and the FDA. Further review lead 

to the discovery of additional cases although expert adjudication opined that 

the adverse events were not ON but rather a rare condition called rapidly 

progressive osteoarthritis (RPOA). Prior to complete expert adjudication 

of the cases, the FDA placed the clinical trials on hold for one company 

and began close monitoring of the other companies clinical development 

programs. Later all clinical development programs were placed on hold. 

The mechanism of how anti-NGF drugs leads to this adverse event 

remains unknown. 

The clinical trials of the several anti-NGF drugs have suggested considerable 

clinical promise in the treatment of pain – from osteoarthritis to diabetic 

polyneuropathy to potentially visceral pain syndromes. One hopes that 

clinical development can resume so that we can learn about the full risk: 

benefit profile of these drugs. 

References: 

1. Levi-Montalcini R (2004). “The nerve growth factor and the neuroscience 

chess board”. Prog. Brain Res. 146: 525–7. 

2. The Nobel Prize in Physiology or Medicine 1986 Stanley Cohen, 

Rita Levi-Montalcini http://www.nobelprize.org/nobel_prizes/medicine/ 

laureates/1986/press.html 

3. Petty BP et al. The effect of systemically administered recombinant 

human nerve growth factor in healthy human subjects. Ann Neurol. 

1994;36:244-6. 

39

The 2012 ANA Annual Meeting is supported by generous educational grants from: 

 

 

 

 

 

 

 

This activity is supported by an educational grant from Lilly USA, LLC. 

For further information concerning Lilly grant funding visit www.lillygrantoffice.com. 

The American Neurological Association wishes to 

thank the following 2012 Annual Meeting sponsors: 

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138 th Annual Meeting 

New Orleans, LA | October 13-16, 2013

2012 Annual Meeting - American Neurological Association

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