Beach, Thomas G.

AbstractBackgroundPost‐mortem assessment remains the only option and a gold standard for a definitive diagnosis of Parkinson’s disease (PD). The antemortem diagnosis is challenging due to a variable clinical presentation and the abundance of mimicking conditions, obscuring the clinical picture and delaying the treatment. It is well established that while PD pathologically manifests in central nervous system with aggregation of α‐synuclein as Lewy bodies and Lewy neurites, this pathology is also found in the peripheral nervous system. Peripheral Lewy‐type synucleinopathy (LTS) is present in early PD, suggesting its utility as a diagnostic and prognostic biomarker. We have previously confirmed that detection of LTS in submandibular gland (SMG) biopsies is sensitive (.75) and specific (.90) for early PD. However, the assessment by a neuropathologist of multiple levels of such biopsy is laborious and time‐consuming.MethodHere work we applied two Convolutional Neural Networks (CNN) for detection of LTS on 283 digital whole slide images (WSI) from 95 unique SMG biopsies. A total number of 8,386 LTS were annotated following the interrater reliability study with kappa=.7. We used transfer learning to train a CNN model to classify image patches (40‐by‐40 pixels at 20x) with and without presence of LTS objects.ResultThe trained CNNs showed the following performance on image patches: sensitivity: .982/.988, specificity: .998/.999, precision: .852/.950, accuracy: .995/.998, and F‐1 score .912/.968 for ResNet30/InceptionV4 respectively. On test WSI the sensitivity in detecting LTS was .963/.971 respectively.ConclusionThis work is first to demonstrate the practical utility of an CNN for screening for LTS, which can further translate into a practical screening tool facilitating the antemortem diagnosis of PD. We further plan to develop neural networks for accurate and precise detection and quantification of LTS in antemortem SMG biopsies. This, altogether, would offer a screening, confirmatory, prognostic, and quantitative tool for clinical assessment of early PD.

AbstractBackgroundOur understanding of the biological changes in the brain associated with Alzheimer’s disease (AD) pathology and cognitive impairment remains incomplete. Unbiased discovery proteomic analysis of AD brain can help to increase our understanding of these changes.MethodWe analyzed dorsolateral prefrontal cortex, precuneus, and temporal cortex of control, asymptomatic AD, and AD brains from multiple different centers by label‐free quantitative mass spectrometry and weighted protein co‐expression analysis to obtain a consensus protein co‐expression network of AD brain. We also analyzed cerebrospinal fluid to investigate potential biomarkers related to this network.ResultThe network consisted of 13 protein co‐expression modules. Six of these modules correlated with amyloid‐β plaque burden, tau neurofibrillary tangle burden, cognitive function, and clinical functional status, and were altered in asymptomatic AD, AD, or in both disease states. These six modules reflected synaptic, mitochondrial, sugar metabolism, extracellular matrix, cytoskeletal, and RNA binding/splicing biological functions. The identified protein network modules were preserved in a community‐based cohort analyzed by a different quantitative mass spectrometry approach. They were also preserved in temporal lobe and precuneus brain regions. Some of the modules were influenced by aging, and showed changes in other neurodegenerative diseases such as frontotemporal dementia and corticobasal degeneration. The module most strongly associated with AD pathology and cognitive impairment was the sugar metabolism module. This module was enriched in AD genetic risk factors, and was also highly enriched in microglia and astrocyte protein markers associated with an anti‐inflammatory state, suggesting that the biological functions it represents may serve a protective role in AD. Proteins from the sugar metabolism module were increased in cerebrospinal fluid from asymptomatic AD and AD cases, highlighting their potential as biomarkers of the altered brain network.ConclusionIn this study of >2000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brain that may serve as therapeutic targets and fluid biomarkers for the disease.

ABSTRACT Background An unmet clinical need in Parkinson's disease (PD) is to identify biomarkers for diagnosis, preferably in peripherally accessible tissues such as skin. Immunohistochemical studies have detected pathological α‐synuclein (αSyn) in skin biopsies from PD patients albeit sensitivity needs to be improved. Objective Our study provides the ultrasensitive detection of pathological αSyn present in the skin of PD patients, and thus, pathological αSyn in skin could be a potential biomarker for PD. Methods The real‐time quaking‐induced conversion assay was used to detect pathological αSyn present in human skin tissues. Further, we optimized this ultra‐sensitive and specific assay for both frozen and formalin‐fixed paraffin‐embedded sections of skin tissues. We determined the seeding kinetics of the αSyn present in the skin from autopsied subjects consisting of frozen skin tissues from 25 PD and 25 controls and formalin‐fixed paraffin‐embedded skin sections from 12 PD and 12 controls. Results In a blinded study of skin tissues from autopsied subjects, we correctly identified 24/25 PD and 24/25 controls using frozen skin tissues (96% sensitivity and 96% specificity) compared to 9/12 PD and 10/12 controls using formalin‐fixed paraffin‐embedded skin sections (75% sensitivity and 83% specificity). Conclusions Our blinded study results clearly demonstrate the feasibility of using skin tissues for clinical diagnosis of PD by detecting pathological αSyn. Moreover, this peripheral biomarker discovery study may have broader translational value in detecting misfolded proteins in skin samples as a longitudinal progression marker. © 2020 International Parkinson and Movement Disorder Society

Objective Considering the demonstrated implication of the retina in Parkinson disease (PD) pathology and the importance of dopaminergic cells in this tissue, we aimed to analyze the state of the dopaminergic amacrine cells and some of their main postsynaptic neurons in the retina of PD. Methods Using immunohistochemistry and confocal microscopy, we evaluated morphology, number, and synaptic connections of dopaminergic cells and their postsynaptic cells, AII amacrine and melanopsin‐containing retinal ganglion cells, in control and PD eyes from human donors. Results In PD, dopaminergic amacrine cell number was reduced between 58% and 26% in different retinal regions, involving a decline in the number of synaptic contacts with AII amacrine cells (by 60%) and melanopsin cells (by 35%). Despite losing their main synaptic input, AII cells were not reduced in number, but they showed cellular alterations compromising their adequate function: (1) a loss of mitochondria inside their lobular appendages, which may indicate an energetic failure; and (2) a loss of connexin 36, suggesting alterations in the AII coupling and in visual signal transmission from the rod pathway. Interpretation The dopaminergic system impairment and the affection of the rod pathway through the AII cells may explain and be partially responsible for the reduced contrast sensitivity or electroretinographic response described in PD. Also, dopamine reduction and the loss of synaptic contacts with melanopsin cells may contribute to the melanopsin retinal ganglion cell loss previously described and to the disturbances in circadian rhythm and sleep reported in PD patients. These data support the idea that the retina reproduces brain neurodegeneration and is highly involved in PD pathology. ANN NEUROL 2020;88:893–906

Importance Positron emission tomography (PET) may increase the diagnostic accuracy and confirm the underlying neuropathologic changes of Alzheimer disease (AD). Objective To determine the accuracy of antemortem [ 18 F]flortaucipir PET images for predicting the presence of AD-type tau pathology at autopsy. Design, Setting, and Participants This diagnostic study (A16 primary cohort) was conducted from October 2015 to June 2018 at 28 study sites (27 in US sites and 1 in Australia). Individuals with a terminal illness who were older than 50 years and had a projected life expectancy of less than 6 months were enrolled. All participants underwent [ 18 F]flortaucipir PET imaging, and scans were interpreted by 5 independent nuclear medicine physicians or radiologists. Supplemental autopsy [ 18 F]flortaucipir images and pathological samples were also collected from 16 historically collected cases. A second study (FR01 validation study) was conducted from March 26 to April 26, 2019, in which 5 new readers assessed the original PET images for comparison to autopsy. Main Outcomes and Measures [ 18 F]flortaucipir PET images were visually assessed and compared with immunohistochemical tau pathology. An AD tau pattern of flortaucipir retention was assessed for correspondence with a postmortem B3-level (Braak stage V or VI) pathological pattern of tau accumulation and to the presence of amyloid-β plaques sufficient to meet the criteria for high levels of AD neuropathological change. Success was defined as having at least 3 of the 5 readers above the lower bounds of the 95% CI for both sensitivity and specificity of 50% or greater. Results A total of 156 patients were enrolled in the A16 study and underwent [ 18 F]flortaucipir PET imaging. Of these, 73 died during the study, and valid autopsies were performed for 67 of these patients. Three autopsies were evaluated as test cases and removed from the primary cohort (n = 64). Of the 64 primary cohort patients, 34 (53%) were women and 62 (97%) were white; mean (SD) age was 82.5 (9.6) years; and 49 (77%) had dementia, 1 (2%) had mild cognitive impairment, and 14 (22%) had normal cognition. Prespecified success criteria were met for the A16 primary cohort. The flortaucipir PET scans predicted a B3 level of tau pathology, with sensitivity ranging from 92.3% (95% CI, 79.7%-97.3%) to 100.0% (95% CI, 91.0%-100.0%) and specificity ranging from 52.0% (95% CI, 33.5%-70.0%) to 92.0% (95% CI, 75.0%-97.8%). A high level of AD neuropathological change was predicted with sensitivity of 94.7% (95% CI, 82.7%-98.5%) to 100.0% (95% CI, 90.8%-100.0%) and specificity of 50.0% (95% CI, 32.1%-67.9%) to 92.3% (95% CI, 75.9%-97.9%). The FR01 validation study also met prespecified success criteria. Addition of the supplemental autopsy data set and 3 test cases, which comprised a total of 82 patients and autopsies for both the A16 and FR01 studies, resulted in improved specificity and comparable overall accuracy. Among the 156 enrolled participants, 14 (9%) experienced at least 1 treatment-emergent adverse event. Conclusions and Relevance This study’s findings suggest that PET imaging with [ 18 F]flortaucipir could be used to identify the density and distribution of AD-type tau pathology and the presence of high levels of AD neuropathological change, supporting a neuropathological diagnosis of AD.

Twelve cases (6 M, 6F; mean age 87.9) with incidental Lewy bodies (no clinical diagnosis of parkinsonism or dementia) had medical histories of supraventricular arrhythmia (6/12), dysphagia (5/12), depression (5/12) and falls (4/12). Standardized movement disorder assessments were performed antemortem on 6 cases. The mean Part III UPDRS score was 7 (range 2–14). Motor findings included kinetic tremor (5/6), rest tremor (3/6), postural instability (3/6), postural tremor (2/6), and voice tremor (2/6). Of these 6 cases one was considered to have a normal movement exam, 2 were diagnosed as essential tremor, and 3 as nonspecific tremor disorder. Mean MMSE score in 7 cases was 26.6 (range 23–30). Medical records review revealed 4/12 cases had cognitive impairment not meeting criteria for dementia. Of these 12 cases, 5 had received standardized cognitive assessments: 3 were categorized as cognitively normal and 2 as mild cognitive impairment. Our series of incidental Lewy body disease cases reveal a range of neurologic findings including tremor and cognitive impairment. Antemortem standardized evaluations suggest there may be early clinical markers for Lewy body disorders. Supported by the State of AZ Department of Health Services, NIA P30 AG19610 and the Prescott Family Parkinson's Initiative: a Partnership of the Michael J. Fox Foundation and the Arizona Parkinson's Disease Consortium.

AbstractObjectiveThere are few neuropathological studies on Parkinson's disease with mild cognitive impairment (PD‐MCI). Those published reveal coexisting Lewy body and Alzheimer's disease pathology. Our objective is to determine the pathology that underlies PD‐MCI.MethodsWe used data from the Arizona Study of Aging and Neurodegenerative Disorders, a longitudinal clinicopathological study. Of 736 autopsied subjects with standardized movement and cognitive assessments, 25 had PD‐MCI. Neuropathological findings, including Lewy body and Alzheimer's disease pathology, were compared in PD subjects with amnestic MCI (A‐MCI) and nonamnestic MCI (NA‐MCI).ResultsSignificant pathological heterogeneity within PD‐MCI was found. This included varying Lewy body stages, Alzheimer's disease pathology, and cerebral amyloid angiopathy. There was a significant increase in the severity of Lewy body pathology (meeting The Unified Staging System for Lewy Body disorders neocortical stage) in nonamnestic MCI (7/1, 63%) when compared with amnestic MCI (3/14, 21%, P = 0.032).ConclusionAlthough a small study, distinct pathological changes may contribute to PD‐MCI phenotype. © 2020 International Parkinson and Movement Disorder Society