Memory & Aging Project

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Memory & Aging Project

Reno-Cerebrovascular Disease:

Potential Pathophysiologic Mechanisms

Aron S. Buchman, MD

Rush University Medical Center

Chicago, IL

International Stroke Conference AHA/ASA

New Orleans, LA

February 2, 2012


Rush University Medical Center

Neelum Aggarwal, MD

Konstantinos Arfanakis, PhD

Zoe Arvanitakis, MD, MS

Lisa Barnes, PhD

David A. Bennett, MD

Patricia Boyle, PhD

Bob Dawe, PhD

Denis Evans, MD

Debra Fleischman, PhD

Bryan James, PhD

Sue Leurgans, PhD

Sukriti Nag, MD, PhD

Philippa Norman, MD, MPH

Julie Schneider, MD, MS

Eisuke Segawa, PhD

Raj Shah, MD

Chunhui Yang, PhD

Lei Yu, PhD

Robert Wilson, PhD

Rush Alzheimer’s Disease Center Staff

ACKNOWLEDGMENTS

Harvard, Broad Institute, Brigham & Women’s

Philip De Jager, MD, PhD

Lori Chibnik, PhD

Joshua Shulman, MD, PhD

Harvard-MIT, Broad Institute

Alex Meissner, PhD

Harvard, Beth Israel Deaconess

Clif Saper, MD, PhD

State University of New York (SUNY)

Steven R. Levine, MD

Tel Aviv University

Jeffrey M. Hausdorff, PhD

Translational Genomics Research Institute

Eric Reiman, MD

Matt Huentelman, PhD

University of Pennsylvania

Steven Arnold, MD

University of British Columbia

William Honer, MD

University of Toronto

Andrew S.P. Lim, MD


Funding

National Institute on Aging

National Heart Lung and Blood Institute

Alzheimer’s Association

Illinois Department Public Health

Elsie Heller Brain Bank Endowment Fund

Robert C. Borwell Endowment Fund

Study Participants

Religious Orders Study

Rush Memory and Aging Project


Chronic

Macroinfarcts

Cerebrovascular Disease

Is Comprised of Different Pathologies

Dyslipidemia

Large Vessel

Atherosclerosis

Acute

Macroinfarcts

Diabetes Hypertension

Small Vessel

Arteriolosclerosis Cerebral Amyloid Angiopathy

White Matter

Microinfarcts Microbleeds

Disease


OBJECTIVES

1. Describe 2 clinical-pathologic studies of aging and

cerebrovascular pathologies collected

2. Examine whether kidney function is associated with

cerebrovascular pathologies

3. Examine whether kidney function modifies the

association of cerebrovascular pathologies and

cognitive function

4. Additional potential mechanisms


OBJECTIVES

1. Describe 2 clinical-pathologic studies of aging and

cerebrovascular pathologies collected

2. Examine whether kidney function is associated with

cerebrovascular pathologies.

3. Examine whether kidney function modifies the

association of cerebrovascular pathologies and

cognitive function.

4. Additional Potential Mechanisms


Religious Order Study

> 1,150 residents

> 95% follow-up of survivors

> 275 persons have developed incident AD

> 90% autopsy rate with > 530 autopsies

Memory & Aging Project

> 1,400 residents

> 90% follow-up of survivors

> 240 persons have developed incident AD

> 80% autopsy rate with > 425 autopsies


Overall Study Design

Bennett DA, et al. Neuroepidemiology 2005;25:163–175.


Cerebrovascular Pathologies Collected

Chronic

Macroinfarcts

Large Vessel

Atherosclerosis

Acute

Macroinfarcts


Cerebrovascular Pathologies Collected

Small Vessel

Arteriolosclerosis Cerebral Amyloid Angiopathy

White Matter

Microinfarcts Microbleeds

Disease


Frequency of Cerebrovascular Disease

in the Memory and Aging Project (N=381)

Chronic Infarcts

N=135 (35.4%)

Dyslipidemia

Large Vessel

Atherosclerosis

N=173 (45.1%)

Acute Infarcts

N=56 (14.7%)

Diabetes

N=73 (19.2%)

Arteriolosclerosis

N=164 (42.1%)

Microinfarcts

N=101 (26.5%)

Small Vessel

White Matter

Disease

Hypertension

N=244 (64.0%)

Cerebral Amyloid Angiopathy

N=72 (18.9%)

Microbleeds


SUMMARY 1

1. Cerebrovascular pathologies are common being

observed in up to 75% older adults

2. Microvascular pathology is present in >60% of cases

3. Microvascular pathology is found in >35% of older

adults without macroinfarcts


OBJECTIVES

1. Describe 2 clinical-pathologic studies of aging and

cerebrovascular pathologies collected.

2. Examine whether kidney function is associated with

cerebrovascular pathologies

3. Examine whether kidney function modifies the

association of cerebrovascular pathologies and

cognitive function.

4. Additional Potential Mechanisms


Cerebrovascular Pathology Is Associated with

Level of Function Proximate to Death

Buchman et al, Stroke 2011; 42: 3183-9.

Arvanitakis et al. Stroke 2011;42:722-7

Motor Cognitive

Memory & Aging Project

Religious Order Study


Baseline Renal Function Predicts

(


Baseline Renal Function Predicts

Decline in Motor Function

Term Estimate (S.E, p-Value)

Time -0.015 (0.0055, p=0.009)

eGFRbaseline 0.001 (0.0005, p=0.058)

eGFRbaseline * Time 0.0002 (0.0001, p=0.010)

Memory & Aging Project


Does Impaired Kidney Function Cause

Cerebrovascular Pathology?

Impaired Kidney

Function

2

?

Motor Function

Cognitive Function

Cerebrovascular

Disease Pathology

1


Kidney Function Proximate to Death Is Not

Associated with Cerebrovascular Pathologies*

Pathology Estimate (S.E., p-Value)

Macroinfarcts -0.692 (0.679, p=0.309)

Atherosclerosis -0.772 (0.695, p=0.268)

Microinfarcts 0.004 (1.056, p=0.997)

CAA -0.178 (0.995, p=0.858)

Arteriolosclerosis -0.316 (0.281, p=0.805)

* Based on a series of regression models which all controlled

for age at death, sex, education

Memory & Aging Project


OBJECTIVES

1. Describe 2 clinical-pathologic studies of aging and

cerebrovascular pathologies collected.

2. Examine whether kidney function is associated with

cerebrovascular pathologies.

3. Examine whether kidney function modifies the

association of cerebrovascular pathologies and

cognitive function

4. Additional Potential Mechanisms


Does Kidney Function Modify the Association of

Cerebrovascular Pathology & Clinical Function?

Impaired Kidney

Function ?

Cerebrovascular

Disease Pathology

Cognition


Kidney Function Proximate to Death Does Not

Modify CVD Pathologies with Cognition*

eGFR x Pathology Estimate (S.E., p-Value)

eGFR x Macroinfarcts 0.094 (0.071, p=0.187)

eGFR x Atherosclerosis 0.0002 (0.012, p=0.885)

eGFR x Microinfarcts 0.003 (0.003, p=0.429)

eGFR x CAA 0.001 (0.003, p=0.607)

eGFR x Arteriolosclerosis 0.056 (0.132, p=0.672)

* Based on a series of regression models which included

terms for age at death, sex, education, eGFR and pathology

Memory & Aging Project


Concerns/Limitations

1. CVD pathology is heterogeneous may need

more cases?

2. Very old adults i.e. does the risk of CKD vary

across the lifespan?

3. What is best marker for kidney function in

older adults and timing: baseline, average,

change in function or proximate to death?


OBJECTIVES

1. Describe 2 clinical-pathologic studies of aging and

cerebrovascular pathologies collected.

2. Examine whether kidney function is associated with

cerebrovascular pathologies.

3. Examine whether kidney function modifies the

association of cerebrovascular pathologies and

cognitive function.

4. Additional potential mechanisms


Potential Mechanisms

Impaired Kidney

Function

?

?

Cerebrovascular

Disease Pathology

Motor Function

Cognitive Function


Is small vessel disease a systemic disorder of

aging affecting multiple organs?


Which Small Vessel Disease (SVD)?

Post-Mortem versus Brain Imaging

Other Measures

Inflammatory markers

Neuronal loss

Endothelial function

Other pathologies i.e. AD

Gouw et al. JNNP 2011;82:126-135


Are there regional differences in the clinical

phenotype of SVD within the CNS ?

A B

Memory & Aging Project


FUTURE STUDIES……

• Are the causal pathways initiated by vascular risk factors

similar in the kidney and brain?

• Even if eGFR is an appropriate measure of CKD, do the

consequences of kidney function vary over the lifespan?

• Histopathologic studies are needed to characterize the

specific microvascular pathologies underlying WMH as

well as other “invisible” pathologies.

• Are there regional differences with respect to the

consequences of small-vessel diseases within and

outside the CNS?


Thank You

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