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Phenotypic Heterogeneity in Dementia: A Challenge for Epidemiology and Biomarker Studies

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      Abstract

      Dementia can result from a number of distinct diseases with differing etiology and pathophysiology. Even within the same disease, there is considerable phenotypic heterogeneity with varying symptoms and disease trajectories. Dementia diagnosis is thus very complex, time-consuming, and expensive and can only be made definitively post-mortem with histopathological confirmation. These inherent difficulties combined with the overlap of some symptoms and even neuropathological features, present a challenging problem for research in the field. This has likely hampered progress in epidemiological studies of risk factors and preventative interventions, as well as genetic and biomarker research. Resource limitations in large epidemiologically studies mean that limited diagnostic criteria are often used, which can result in phenotypically heterogeneous disease states being grouped together, potentially resulting in misclassification bias. When biomarkers are identified for etiologically heterogeneous diseases, they will have low specificity for any utility in clinical practice, even if their sensitivity is high. We highlight several challenges in in the field which must be addressed for the success of future genetic and biomarker studies, and may be key to the development of the most effective treatments. As a step toward achieving this goal, defining the dementia as a biological construct based on the presence of specific pathological features, rather than clinical symptoms, will enable more precise predictive models. It has the potential to lead to the discovery of novel genetic variants, as well as the identification of individuals at heightened risk of the disease, even prior to the appearance of clinical symptoms.

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          Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.

          The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.
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            Author and article information

            Affiliations
            Department of Epidemiology and Preventive Medicine, Monash University , Melbourne, VIC, Australia
            Author notes

            Edited by: Charles B. Hall, Albert Einstein College of Medicine, United States

            Reviewed by: Terri Kang Johnson, Dexcom, Inc., United States; Charalampos Socrates Siristatidis, National and Kapodistrian University of Athens, Greece

            *Correspondence: Joanne Ryan joanne.ryan@ 123456monash.edu

            This article was submitted to Epidemiology, a section of the journal Frontiers in Public Health

            Contributors
            Journal
            Front Public Health
            Front Public Health
            Front. Public Health
            Frontiers in Public Health
            Frontiers Media S.A.
            2296-2565
            19 June 2018
            2018
            : 6
            6018385 10.3389/fpubh.2018.00181
            Copyright © 2018 Ryan, Fransquet, Wrigglesworth and Lacaze.

            This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

            Counts
            Figures: 0, Tables: 1, Equations: 0, References: 61, Pages: 6, Words: 5327
            Funding
            Funded by: National Health and Medical Research Council 10.13039/501100000925
            Award ID: APP1135727
            Funded by: Monash University 10.13039/501100001779
            Categories
            Public Health
            Perspective

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