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    Home » Thinking Outside of the ‘Alpha-Synuclein Box’: A Critical Role of Tau in Lewy Body Disorders
    ABSTRACT & COMMENTARY

    Thinking Outside of the ‘Alpha-Synuclein Box’: A Critical Role of Tau in Lewy Body Disorders

    February 1, 2019
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    Keywords

    Dementia

    alpha-synuclein

    By Claire Henchcliffe, MD, DPhil

    Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College

    Dr. Henchcliffe reports she is a consultant for Amneal Pharmaceuticals, Prevail Therapeutics, and US WorldMeds, and receives grant/research support from Biogen.

    SYNOPSIS: Neocortical tau pathology was associated with worse antemortem cognition in this large study of Parkinson’s disease dementia and dementia with Lewy bodies. Regional brain variations correlated with specific cognitive domains.

    SOURCE: Coughlin D, Xie SX, Liang M, et al. Cognitive and pathological influences of tau pathology in Lewy body disorders. Ann Neurol 2018; Dec. 14. doi: 10.1002/ana.25392. [Epub ahead of print].

    This sophisticated analysis of alpha-synuclein and tau pathology in Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), often termed “alpha-synucleinopathies,” suggests an important role for tau protein as a contributor to cognitive deficits. Tissue was characterized histologically from 55 brains of individuals with PDD or DLB from the Penn LBD autopsy cohort. Cases were categorized as medium-to-high AD pathology (SYN+AD, n = 20) or no to low-level AD pathology (SYN-AD, n = 35) according to ABC scoring (Aβ amyloid Thal phase; Braak tau phase; CERAD plaque score). In examining antemortem clinical characteristics of the two groups, later age at onset with faster progression to clinical dementia and death was seen in the SYN+AD group (onset 69 ± 6.2 years; dementia 73.2 ± 6.7 years; death 77 ± 8.7 years) compared with the SYN-AD group (onset 61.8 ± 9.8 years; dementia 72.5 ± 6.3 years; death 78 ± 6.1 years). DLB was more common than PDD in the SYN+AD group compared with the SYN-AD group (60% vs. 20%).

    Coughlin et al used digitized histology methods to generate scores on tissue sections for percent area occupied of immunoreactivity for tau, Aβ, and alpha-synuclein. The authors analyzed more than 900 slides comprising tissue from neocortical areas chosen for their roles in cognition (mid-frontal gyrus, superior temporal gyrus, angular gyrus), in addition to entorhinal cortex and putamen. In the SYN+AD group, greater tau and Aβ burden was found in neocortical regions when compared with the SYN-AD group.

    Interestingly, greater alpha-synuclein burden also was demonstrated in neocortical regions (but not entorhinal cortex nor putamen) in the SYN+AD group compared with the SYN-AD group. Moreover, the alpha-synuclein neocortex:putamen ratio was higher in the SYN+AD group compared with the SYN-AD group. SYN and tau pathology independently associated with temporal cortex, in contrast with a relatively higher burden in the mid-frontal gyrus in AD. Antemortem neuropsychological testing comprised the Mini-Mental Status Exam, the Dementia Rating Scale-2, semantic category fluency testing, and the Boston Naming Test. The SYN+AD group performed worse on the Boston Naming Test, but not significantly on other measures. However, there were a number of interesting correlations of regional tau measures of percent area occupied with specific testing, including category fluency with the midfrontal gyrus (r = -0.45; P < 0.001) and the Boston Naming Test with the superior temporal gyrus (r = -0.45; r = -0.68; P < 0.001). This did not hold for alpha-synuclein or β amyloid pathology.

    COMMENTARY

    This important report once again highlights the heterogeneity of PDD and DLB, two of the so-called alpha-synucleinopathies. The authors nicely suggested how non-alpha-synuclein pathology can go some way toward explaining differences between individual patients in terms of symptoms, signs elicited in clinical testing, and clinical trajectory. This study is highly innovative, leveraging a great amount of data collected and using digital pathology to demonstrate the association of specific cognitive deficits with tau pathology in specific and relevant brain regions. In contrast, β amyloid did not show regional associations. The regional deposition of tau in PDD and DLB also seemed to differ with that in AD samples studied for comparison, raising questions about what processes cause this difference. In the cases defined as SYN+AD, not only was there more neocortical tau, there also was more neocortical alpha-synuclein (and at a higher level relative to alpha-synuclein pathology in the putamen). Could this simply be a reflection of “overall worse” pathology in these cases, or could pathophysiological processes be in place that mean one protein could drive damage and deposition in the other? Although this speculation is interesting, an important consideration now is how to make this information actionable and clinically useful. Getting outside of the “alpha-synuclein box” may trigger broader consideration in the debate on diagnosis. Importantly, it also could stimulate improved clinical trials and new therapeutic development for the devastating consequences of these categories of dementia.

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    Neurology Alert

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    Neurology Alert (Vol. 38, No. 6) - February 2019
    February 1, 2019

    Table Of Contents

    Continuous EEG Monitoring in Critically Ill Patients Is Associated With Reduced Hospital Mortality

    Rituximab for CIDP Associated With Systemic Immune Disorders

    Amyloid-ß Pathology Induced by Contaminated Cadaver-Derived Growth Hormone

    Predicting the Risk of Mild Cognitive Impairment Using Imaging Biomarkers

    Thinking Outside of the ‘Alpha-Synuclein Box’: A Critical Role of Tau in Lewy Body Disorders

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    Financial Disclosure: Neurology Alert’s Editor in Chief Matthew Fink, MD; Peer Reviewer M. Flint Beal, MD; Executive Editor Leslie Coplin; Editor Jonathan Springston; and Editorial Group Manager Terrey L. Hatcher report no financial relationships relevant to this field of study.

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