Davis, Kathryn

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

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.

Background: Some epidemiology studies suggest that atherosclerotic cardiovascular disease (ASCVD) risk factors increase the risk of developing Parkinson’s disease (PD). However, conflicting data suggest lower rates of ASCVD in PD. Objective: The objective of this study is to determine, with data from a longitudinal clinicopathological study, whether ASCVD risk factors are associated with a PD diagnosis and/or increased brain or peripheral load of Lewy-type synucleinopathy (LTS). Methods: All subjects were followed to autopsy and neuropathological examination in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Multivariable regression models, including age, gender, and smoking history, were used to investigate the association of a PD diagnosis or brain or submandibular gland LTS load with ASCVD risk factors. Results: 150 subjects were included (PD n = 60, controls n = 90). Univariable comparisons and regression models showed a general trend to inverse associations. The multivariable odds ratio (OR) of brain LTS load for carotid artery disease was 0.93 (95% CI: 0.86 to 0.98; p = 0.02), for anticoagulant use 0.95 (95% CI: 0.90 to 0.99; p = 0.04) and for abnormal heart weight 0.96 (95% CI: 0.92 to 0.99; p = 0.01). Composite clinical and overall (clinical + pathology composite risk scores) composite risk scores were also significantly lower in the PD subjects ( p = 0.0164 and 0.0187, respectively). Submandibular gland LTS load was not significantly related to ASCVD conditions. Conclusions: This study shows associations of higher brain LTS with lower prevalence of both clinical and pathological indices of ASCVD in PD subjects versus age-similar controls. We suggest that this is due to α-synuclein pathology-induced sympathetic denervation in PD.

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.