Dugger, Brittany N.

AbstractBackgroundDigital pathology and machine learning (ML) workflows have paradigm shifting potential especially in the field of Alzheimer’s disease and related disorders. However, many institutions/centers may not have access to these technologies. To provide benchmark data, a survey was developed and distributed to National Institutes of Health’s Alzheimer’s Disease Centers (ADCs) in the United States.MethodSurvey questions covered topics such as: infrastructure (i.e. type of digital slide scanners used), funding sources (i.e. how the scanner was funded), and data management/storage (i.e. size of digital files). After development, review, and approval by the ADC digital pathology working group, the survey was distributed via email to 35 past and current ADC directors and/or ADC neuropathology core leaders. Participation in the survey was completely voluntary and answers did not contain any personal data.ResultThe survey generated over a 90% response rate, and the majority of those who completed the survey were neuropathology core leaders; 81% stated their ADC had access to a digital slide scanner, most common brand being Aperio/Leica. One third of respondents stated there was a fee for service to utilize the scanner. For digital pathology and/or ML resources, 40% of respondents stated none are supported in any way by their ADC. To cover the purchase and operation of the scanner, 50% stated they had institutional support. Many were unsure of the approximate average scanned file size of digital images (37%) and total amount of storage space that files occupied (50%). Many (75%) were aware of other departments at their institution working with digital pathology and/or ML, but a similar percentage was unaware of multi‐university or industry partnerships.ConclusionThese results demonstrate many ADCs have access to a digital slide scanner and had institutional support to cover the purchase. However, further investigation is needed to understand hurdles and barriers for implementing both digital pathology and ML workflows aiding in standardized methods across ADCs.

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

Dementia is a frequent complication of Parkinson's disease (PD). About half of PD dementia (PDD) is hypothesized to be due to progression of the underlying Lewy body pathology into limbic regions and the cerebral cortex while the other half is thought to be due to coexistent Alzheimer's disease (AD). Clinically, however, these are indistinguishable. The spread of amyloid plaques to the striatum has been reported to be a sensitive and specific indicator of dementia due to AD. The purpose of the present study was to determine if the presence of striatal plaques might also be a useful indicator of the presence of diagnostic levels of AD pathology within PD subjects. We analyzed neuropathologically-confirmed cases of PD without dementia (PDND, N = 31), PDD without AD (PDD, N = 31) and PD with dementia meeting clinicopathological criteria for AD (PDAD, N = 40). The minimum diagnostic criterion for AD was defined as including a clinical history of dementia, moderate or frequent CERAD cortical neuritic plaque density and Braak neurofibrillary stage III-VI. Striatal amyloid plaque densities were determined using Campbell-Switzer and Thioflavine S stains. Striatal plaque densities were significantly higher in PDAD compared to PDD (p < 0.001). The presence of striatal plaques was approximately 80% sensitive and 80% specific for predicting AD. In comparison, the presence of cerebral cortex plaques alone was highly sensitive (100%) but had poor specificity (48% to 55%). The results suggest that striatal amyloid imaging may be clinically useful for making the distinction between PDD and PDAD.

Abstract This study was designed to correlate clinical findings with the extent of pathologic a-synuclein (aSyn) in the brain using the Unified Staging System for Lewy Body disorders (USSLB). Data from 280 cases from the Arizona Study of Aging and Neurodegenerative Disorders are presented. Each case had a complete USSLB staging and at least 1 full research clinical assessment, including subspecialty neurologist-administered movement and cognitive evaluation. Of the 280, 25.7% were cognitively normal, 8.6% had mild cognitive impairment, and 65.7% had dementia. All cases could be categorized into 1 of 5 USSLB stages (8.6% stage I—olfactory bulb only; 15.4% IIa—brainstem predominant; 13.6% IIb—limbic predominant; 31.8% III—brainstem and limbic; and 30.7% IV—neocortical) yet using the Braak staging system 70 cases (25.3%) could not be classified. Those with USSLB stages III and IV died at a younger age. Multiple measures of motor parkinsonism, cognitive impairment, hyposmia, and probable RBD were significantly correlated with increasing USSLB stage. We conclude that the USSLB is the most comprehensive staging system for all Lewy body disorders and allows for categorization and ranking of all brains with significant correlations to many motor and nonmotor clinical signs and symptoms.

AbstractBackgroundClinical diagnostic criteria for PD rely on rest tremor, bradykinesia, and rigidity. These features are non‐specific and neuropathological confirmation remains the gold standard for diagnosis. This study presents data on clinical certainty ratings in autopsy‐proven PD.MethodsSubjects were assessed annually by a movement disorders specialist and assigned to a clinical certainty group for PD based on multiple clinical features before autopsy. The three groups considered for analysis are as follows: Group I 0–49% certainty, Group II 50‐89% certainty, and Group III 90–100% certainty. All subjects were autopsied and had a standardized neuropathological assessment.Results275 subjects were assigned a PD certainty at their last visit before death. Group I had 80 subjects, Group II 56 subjects, and Group III 139 subjects. The clinical features recorded in Group I, II, and III, were as follows: rest tremor, bradykinesia, rigidity, postural instability, asymmetric onset, persistent asymmetry, current response to dopaminergic treatment, motor fluctuations, and dyskinesia. Rigidity, postural instability, asymmetric onset, current response to dopaminergic treatment, motor fluctuation, and dyskinesia were more likely to be present in the group which was rated with higher certainty. The final diagnosis of PD was confirmed by neuropathological assessment in 85% of the patients in Group III as compared to 30% in Group II and 5% in Group I.ConclusionsHigh certainty (90–100%) had strong positive predictive value (85%) for autopsy‐proven PD as compared to either lower certainty groups (0–49% and 50–89%) which had lower predictive value (5% and 30% respectively).

AbstractObjectiveTo assess the predictive potential of the complete response pattern from the University of Pennsylvania Smell Identification Test for the diagnosis of Parkinson's disease.MethodsWe analyzed a large dataset from the Arizona Study of Aging and Neurodegenerative Disorders, a longitudinal clinicopathological study of health and disease in elderly volunteers. Using the complete pattern of responses to all 40 items in each subject's test, we built predictive models of neurodegenerative disease, and we validated these models out of sample by comparing model predictions against postmortem pathological diagnosis.ResultsConsistent with anatomical considerations, we found that the specific test response pattern had additional predictive power compared with a conventional measure – total test score – in Parkinson's disease, but not Alzheimer's disease. We also identified specific test questions that carry the greatest predictive power for disease diagnosis.InterpretationOlfactory ability has typically been assessed with either self‐report or total score on a multiple choice test. We showed that a more accurate clinical diagnosis can be made using the pattern of responses to all the test questions, and validated this against the “gold standard” of pathological diagnosis. Information in the response pattern also suggests specific modifications to the standard test that may optimize predictive power under the typical clinical constraint of limited time. We recommend that future studies retain the individual item responses for each subject, and not just the total score, both to enable more accurate diagnosis and to enable additional future insights.

Background and purpose Mutations in the glucocerebrosidase ( GBA ) gene are known to be a risk factor for Parkinson's disease ( PD ). Data on clinicopathological correlation are limited. The purpose of this study was to determine the clinicopathological findings that might distinguish PD cases with and without mutations in the GBA gene. Methods Data from the Arizona Study of Aging and Neurodegenerative Disorders were used to identify autopsied PD cases that did or did not have a GBA gene mutation. Clinical and neuropathological data were compared. Results Twelve PD cases had a GBA mutation and 102 did not. The GBA mutation cases died younger (76 vs. 81 years of age) but there was no difference in disease duration or clinical examination findings. No neuropathological differences were found in total or regional semi‐quantitative scores for Lewy‐type synucleinopathy, senile plaques, neurofibrillary tangles, white matter rarefaction or cerebral amyloid angiopathy scores. Conclusions In longitudinally assessed, autopsied PD cases, those with GBA mutations had a younger age at death but there was no evidence for clinical or neuropathological differences compared to cases without GBA mutations. Due to the small GBA group size, small differences cannot be excluded.