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NEUROLOGY In summary, research in 2011 conveyed new findings to help us to understand, treat and prevent disease progression in patients with MS. Better imaging of cortical lesions could provide insights into the patho biology of MS and may yield new outcome measures for MS clinical trials. Advances in understanding the environmental factors that are associated with disease progression in MS could facilitate the development of better therapies and personalized management for patients with this disabling disease. Jacobs Neurological Institute, Buffalo General Hospital, University at Buffalo, State University of New York, Building E, 2nd Floor, 100 High Street, Buffalo, NY 14203, USA (B. Weinstock‑Guttman). Department of Pharmaceutical Sciences and Neurology, State University of New York, 427 Cooke Hall, Buffalo, NY 14260, USA (M. Ramanathan). Correspondence to: B. Weinstock–Guttman bguttman@thejni.org Acknowledgments The authors would like to thank the Department of Defense, the Jog for The Jake Foundation, National Multiple Sclerosis Society, National Science Foundation and NIH for providing financial support for their research activities. Competing interests B. Weinstock–Guttman declares associations with the following companies and organizations: Acorda, Biogen Idec, Cyberonics, EMD Serono, Novartis, Pfizer, Teva Neuroscience. M. Ramanathan declares associations with the following companies and organizations: Allergan, the American Association of Pharmaceutical Scientists, Biogen Idec, EMD Serono, Netezza, Novartis, Pfizer. See the article online for full details of the relationships. 1. O’Connor, P. et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N. Engl. J. Med. 365, 1293–1303 (2011). 2. Sormani, M. P. et al. Modeling the distribution of new MRI cortical lesions in multiple sclerosis longitudinal studies. PLoS ONE 6, e26712 (2011). 3. Weinstock‑Guttman, B. et al. Serum lipid profiles are associated with disability and MRI outcomes in multiple sclerosis. J. Neuroinflammation 8, 127 (2011). 4. Weinstock‑Guttman, B., Zivadinov, R. & Ramanathan, M. Inter‑dependence of vitamin D levels with serum lipid profiles in multiple sclerosis. J. Neurol. Sci. 311, 86–91 (2011). 5. Kappos, L. et al. A placebo‑controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 362, 387–401 (2010). 6. Calabrese, M., Filippi, M. & Gallo, P. Cortical lesions in multiple sclerosis. Nat. Rev. Neurol. 6, 438–444 (2010). DEMENTIA IN 2011 Microbleeds in dementia —singing a different ARIA Philip Scheltens and Jeroen D. C. Goos In 2011, researchers used imaging techniques to investigate brain microbleeds in patients with dementia and highlighted how lobar microbleeds could be used as a marker for amyloid pathology and for predicting mortality. New guidelines on the inclusion and exclusion of participants with microbleeds in anti-amyloid clinical trials were also published. Scheltens, P. & Goos, J. D. C. Nat. Rev. Neurol. 8, 68–70 (2012); published online 10 January 2012; doi:10.1038/nrneurol.2011.222 Following initial reports of small dotlike lesions on gradient-echo MRI in the brains of patients with dementia (Figure 1), many investigators set out to describe the prevalence and incidence of these lesions—later designated as micro bleeds or microhemorrhages—in both healthy people and individuals with this condition. Prevalence rates varied from 10% in healthy elderly individuals to 60% in patients with vascular dementia. 1 Interest in these lesions peaked when the first cases of incident micro bleeds along with increased signal inten sity on fluid-attenuated inversion recovery imaging, thought to represent vaso genic edema, were reported in patients receiving amyloid-lowering therapy. During the 2010 Inter national Conference on Alzheimer Disease (AD), turmoil ensued over a cautionary letter from the FDA, which suggested drastic cut-offs in randomized clinical trials of amyloid-lowering drugs, both in terms of excluding patients with a single microbleed and terminating the participation of patients who developed a new microbleed during the study. In response, a series of important papers regarding the detection, prevalence and clinical relevance of microbleeds in patients with dementia-related disease appeared in 2011, includ ing a consensus statement from an inter national working group that introduced new terminology. At the beginning of 2011, Cordonnier and van der Flier reviewed the available litera ture on brain microbleeds in patients with AD. 1 The authors suggested that these lesions were associated with amyloid pathology and may have a crucial role in the pathophysiology of AD. Microbleeds were proposed to represent a link between the amyloid cascade hypo thesis and the vascular hypothesis—both popular explanatory models for the pathogenesis of AD. Furthermore, the location of the microbleeds was suggested to indicate their underlying etiology: lobar microbleeds would presumably be associated with cerebral amyloid angiopathy (CAA), whereas microbleeds in deep brain regions would be associated with hypertensive vasculopathy and increased risk of vascular complications. The clinical implications of microbleeds in patients with dementia were also stressed. Besides an association with cognition, micro bleeds have been linked to mortality, especially in cases of multiple lesions, as described by Henneman et al. in a 2009 study. 2 These investigators did not, however, assess the cause of death in their patients. Throughout 2011—within months of publication of the review by Cordonnier and van der Flier 1 —reports were published on several studies that have substantially extended our knowledge on microbleeds in patients with dementia-associated diseases. The suggestion that micro bleeds were closely linked to amyloid pathology was supported by the findings of Yates et al. for the Australian Imaging, Bio markers and Lifestyle Study of Ageing Research Group. 3 They found that even in healthy con trols, lobar microbleeds (detected using 3T susceptibility-weighted imaging [SWI]) were associated with higher amyloid burden, as seen on 11 C-Pittsburgh compound B (PiB) PET imaging. Moreover, PiB-positive scans were more prevalent in participants with multiple lobar microbleeds (86%) than in those with only one lobar microbleed (67%). In agreement with these findings, results from a study by Goos et al., 4 in which cerebro spinal fluid amyloid biomarkers were used to assess amyloid burden, confirmed the relationship between lobar microbleeds and amyloid pathology. Altmann–Schneider and colleagues studied the relationship between microbleeds and mortality (with assessment of the cause of death) in a population of 435 elderly people with pre-existing vascular dis ease. 5 Individuals with more than one microbleed had a sixfold increase in the risk S60 | JANUARY 2012 www.nature.com/reviews
of stroke-related death compared with those with no lesions. The location of the lesions also affected the risk of poor clinical outcomes: compared with individuals without any lesions, patients with nonlobar microbleeds had a twofold increase in the risk of cardiovascular death, and indivi duals with probable CAA type (lobar) microbleeds had a sevenfold increase in the risk of strokerelated death. These findings support the hypothesis that microbleeds have separate etiologies depending on their location in the brain, 1 and may provide an indication for the use of anticoagulant treatment in patients with these lesions—in particular, those with lobar microbleeds. The importance of detecting microbleeds before and during clinical trials was underlined in an extensive review on amyloidrelated imaging abnormali ties (ARIA) by Sperling et al. for the Alzheimer’s Association Research Roundtable Work group. 6 These imaging abnormalities, seen on MRI, are thought to represent a spectrum of ‘leaky vessels’ that occur following anti- amyloid immunization therapy. The working hypothesis was that vasogenic edema (now called ARIA-E) caused leakage only of proteinaceous fluids from the vessels, whereas microbleeding—under the new umbrella term ARIA-H (for hemorrhage)—caused more-extensive leakiness of the vessels that allowed blood cells to cross the blood– brain barrier. For patients in clinical trials, the presence of microbleeds at baseline may be a risk factor for developing ARIA, Key advances ■ Lobar microbleeds in patients with dementia were found to be associated with high amyloid burden 3 ■ Microbleeds were shown to have different etiologies and associated risk of mortality on the basis of their location in the brain 5 ■ New terminology for amyloid‑related imaging abnormalties (ARIA) and a new cut‑off point for microbleeds in participants of amyloid‑modifying clinical trials were introduced 6 ■ Susceptibility‑weighted imaging showed enhanced sensitivity for detecting microbleeds compared with gradient‑ echo imaging, and may help in future for identifying associations between microbleeds and clinical outcomes 7 ■ Studies that compared imaging with histopathology of microbleeds suggest that further refinement of imaging techniques is required to accurately detect these lesions 8 as the number of lobar lesions is assumed to correlate with the presence and severity of CAA. Given the uncertainty regarding the risk of ARIA and concerns about CAA severity, Sperling et al. recommended a cut-off value for the exclusion of participants in trials of amyloid-modifying therapies for AD at four microbleeds. 6 This new guideline allows for variability in imaging measurements and reflects the uncertainty regarding the clinical relevance of small numbers of microbleeds. The authors further stated that occurrence of new asymptomatic microbleeds in patients during trials should not auto matically disqualify them from receiving further treatment; however, owing to a lack of data, no exact cut-off for dis qualification could be given. As the authors stressed, counting of microbleeds is not an exact science, and the uncertainty is further complicated by the varying sensitivities of different MRI techniques for detecting these lesions. Reporting in Stroke in May 2011, Goos et al. 7 compared conventional gradient-echo imag ing with SWI to detect microbleeds in 140 patients from a memory clinic, and also to determine whether microbleeds were associated with patient and clinical characteristics. As expected, use of the more-advanced SWI technique enabled identi fication of patients with microbleeds with a greater sensitivity than could be achieved with gradient-echo imaging (40% versus 23%). SWI also detected a higher num ber of microbleeds per patient than did gradient-echo imaging. However, the corre lation between lesion numbers, clinical out comes and other radiological outcomes was limited. The clinical relevance of microbleeds will probably depend more on their location and size, than on the total number of lesions per se. The authors concluded, therefore, that although new imaging techniques can show a higher number of lesions, conventional imaging methods can already detect the majority of clinically relevant lesions. New imaging methods might help in identifying any associations between lesions and clinical and radiological outcomes; however, these new techniques are in urgent need of validation. De Reuck et al. 8 made an interesting attempt to validate MRI findings with patho logy, as reported in Cerebrovascular Disorders. The researchers investigated 20 post mortem brains from patients with AD with different cerebrovascular lesions. Images of 45 large sections of the cerebral hemi spheres, brainstem and cere bellum NEUROLOGY Figure 1 | Brain microbleeds on MRI. Numerous lobar microbleeds with sparing of the basal ganglia and thalamus, suggestive of severe cerebral amyloid angiopathy in a 71‑year‑old patient with dementia with Lewy bodies. Image obtained using susceptibility‑weighted imaging at 3T. obtained using 7.0T T2*-weighted MRI were paired with images showing histological detection of hematomas and microbleeds. In the cortico- subcortical regions, the sensitivity, specificity, and positive and negative predictive values of T2* imaging to detect microbleeds were excellent. How ever, analysis of MRI alone resulted in an over estimation of microbleeds in the stria tum due to the presence of iron de posits that were, in fact, not related to real hemor rhages. Furthermore, 31% of T2* hypo signals in the deep white matter were shown to be vessels filled with post mortem thrombi. Judging from these findings, more studies are needed before we can fully understand the correlations between MRI and pathology in patients with AD. From this selection of studies published in 2011, we can conclude that lobar microbleeds are a marker for underlying amyloid patho logy, are associated with strokerelated mortality, and should be adequately investi gated in patients participating in anti- amyloid clinical trials. Optimizaton of imaging methods to detect microbleeds will be of the utmost importance, and emerging techni ques will need to be evaluated and calibrated using clinical and pathological correlates. VU University Medical Center, Alzheimer Center, Department of Neurology, De Boelelaan, 1118 1081 HZ Amsterdam, The Netherlands (P. Scheltens, J. D. C. Goos). Correspondence to: P. Scheltens p.scheltens@vumc.nl KEY ADVANCES IN MEDICINE JANUARY 2012 | S61
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CARDIOLOGY ACUTE CORONARY SYNDROMES
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