Mehta, Shyamal

AbstractBackgroundIdiopathic rapid eye movement sleep behavior disorder (RBD) is a strong known predictor of a final clinicopathological diagnosis of a Lewy type α‐synucleinopathy (LTS). Olfactory dysfunction is an early symptom of synucleinopathies and has been repeatedly associated with the presence of post‐mortem LTS.ObjectiveTo assess the combined value of a clinician diagnosis of probable RBD (PRBD) and hyposmia in predicting the post‐mortem presence of LTS in a broader, less‐selected, volunteer elderly population.MethodsWe studied 652 autopsied subjects from the Arizona Study of Aging and Neurodegenerative Disorders, which were evaluated for PRBD, had completed annual movement and cognitive assessments, and had at least one the University of Pennsylvania Smell Identification Test (UPSIT) olfactory test.ResultsHistological evidence of LTS was significantly more frequent in those who had PRBD (112/152: 73.7%) than those without (177/494: 35.8%) (P < 0.001). LTS was more frequent in cases with PRBD and a low UPSIT score (90.8%) compared to cases with PRBD only (73.7%) (P < 0.001) or cases with a low UPSIT score only (69.4%) (P < 0.001). Sensitivity of PRBD diagnosis for predicting LTS was 38.8% and specificity 88.8%, whereas sensitivity of a low UPSIT score was 74.4% and specificity 73.4% (Youden's index = 0.276 for PRBD, 0.478 for UPSIT). When combining both measures, sensitivity was 34.3% and specificity increased to 97.2%.ConclusionPRBD, diagnosed without sleep study confirmation, combined with a reduced olfactory performance is highly specific for predicting post‐mortem presence of LTS. The combination of both measures may provide a cost‐effective means of predicting LTS in a broader community.

AbstractBackgroundWe previously reported that in our autopsy‐confirmed cohort of Dementia with Lewy Bodies (DLB), Parkinson’s Disease Dementia (PDD) and Alzheimer’s Disease (AD), DLB with parkinsonism (DLB+Park) predicted faster progression of UPDRS‐III scores compared to PDD, DLB without parkinsonism (DLB‐Park), and AD. This study examined annualized rate of change of UPDRS‐III subscales in our cohort.MethodsData included were from participants in Arizona Study of Aging and Neurodegenerative Diseases (AZSAND) with clinicopathologic diagnosis of DLB (n = 48), PDD (n = 98) or pure AD (n = 48), and longitudinal movement exams. Mixed effects model (accounting for age, education, and sex) was used to determine predicted mean UPDRS‐III and subscale scores (0‐4) for all groups. Individual UPDRS‐III subscale scores were derived for: Body Bradykinesia, Limb Bradykinesia, Gait, Postural Instability, Limb Rest Tremor, Neck Rigidity and Limb Rigidity. Where applicable, scores for multiple limbs involved were averaged.ResultsLongitudinal data was analyzed for over 1430‐participant years. Parkinsonism was present in 65.6% of DLB participants. PDD participants were more likely to be treated with dopaminergic agents (87.8%) compared to (p<0.001) DLB+Park (57.6%), DLB‐park (0%) and AD (2.1%). Frequency (29.4% vs. 29.0%) and severity (mean±SE = 0.4±0.07 and 0.4±0.12) of Limb Rest Tremor was similar for PDD and DLB+park. Limb Bradykinesia frequency and severity were PDD: 100%, 2.4±0.11, DLB+Park: 96.8%, 2.1±0.18, DLB‐Park: 20%, 0.4±0.23, and AD: 62%, 1.1±0.16. Frequency of gait abnormality was 98.5% in PDD, 90.3% in DLB+park, 60% in DLB‐Park and 57.8% in AD. Rigidity was most frequent in the PDD group (88.2%), followed by DLB+Park (71%), AD (19.6%), and none DLB‐park (0%). Over 8 years trajectories for limb bradykinesia and gait were greater for DLB+park than PDD (Figure 1, Cohen’s d range 0.89‐2.18 and 0.63‐1.99 over 8 years, p<0.001).ConclusionOur results suggest that DLB+Park group have faster motor progression predominantly related to gait abnormalities and limb bradykinesia. Future analyses will explore more convergent data, integrated effects of various measures and their differential contributions in this cohort.

AbstractBackgroundAlthough parkinsonism is a core feature of Parkinson’s Disease Dementia (PDD) and Dementia with Lewy bodies (DLB), its evolution is less delineated. We aimed to assess differences in severity and progression of parkinsonian motor symptoms and signs in a community autopsy cohort with clinicopathologic diagnosis of DLB, PDD or Alzheimer’s Disease (AD).MethodData included were from 194 participants in the Arizona study of Aging and Neurodegenerative Disorders with clinicopathologic diagnosis of DLB (n=48), PDD (n=98) (±AD co‐pathology) or pure AD (n=48), and at least two movement exams performed by movement disorders subspecialists who classified PD and parkinsonism according to MDS‐UPDRS criteria. DLB was subgrouped by presence or absence of parkinsonism at final exam (DLB+Park and DLB–Park). Between group trajectory of UPDRS‐II and UPDRS‐III scores were explored using piecewise‐linear and non‐linear MMRM multivariate analysis.ResultOver 1435 participant‐years of longitudinal data were included in the analyses (Figure 1). Mean±SD age at baseline movement exam and death were 76.0±7.5 and 83.4±6.8 years, respectively. At baseline, most participants did not have dementia or substantial motor abnormalities (except motor abnormalities in PDD). DLB (73.9%) and PDD (69.2%) groups had more males than AD (33.3%). Parkinsonism was present in 65.6% of DLB at last exam. Piecewise‐linear MMRM analysis showed baseline UPDRS‐II and UPDRS‐III scores were highest (p<0.001) for PDD (mean±SE: 14.3±0.78 and 27.4±1.64), followed by DLB+Park (5.0±1.05 and 17.4±3.10), DLB‐Park (3.7±2.54 and 3.8±1.35) and AD (3.2±0.88 and 8.0±1.94). Annual rate of increase in UPDRS‐II was greatest for DLB+Park (1.44±0.20) and PDD (1.04±0.08), followed by DLB‐Park (0.89±0.18) and AD (0.30±0.11). Annual rate of increase in UPDRS‐III was highest for PDD and DLB+Park (2.12±0.20 vs 2.64±0.42), followed by DLB‐Park and AD (1.31 ± 0.38 and 0.64 ± 0.22). Preliminary non‐linear MMRM models (Figure 2) further supported substantial between group/subgroup differences in motor trajectories, and progression in DLB‐Park.ConclusionThese preliminary results in a large, well‐characterized clinicopathological community‐based autopsy cohort support that DLB+Park experience comparable, or greater, parkinsonian motor progression to PDD. Future modeling/sensitivity analyses will better delineate expected trajectories of motor progression to add prognostication value in clinic and design of DLB clinical trials.

AbstractBackgroundHyposmia is characteristic of idiopathic Parkinson's disease (PD) and dementia with Lewy bodies (DLBs), whereas progressive supranuclear palsy (PSP) typically has normal sense of smell. However, there is a lack of pathologically confirmed data.ObjectiveThe objective is to study hyposmia in pathologically confirmed PSP patients and compare to PD patients and nondegenerative controls.MethodsWe studied autopsied subjects in the Arizona Study of Aging and Neurodegenerative Disorders who had antemortem olfactory testing and a neuropathological diagnosis of either PD, PSP, or control.Results: This study included 281 cases. Those with neuropathologically confirmed PSP (N = 24) and controls (N = 174) had significantly better sense of smell than those with PD (N = 76). Although most PSP patients had normal olfaction, there were some with hyposmia, resulting in an overall reduced sense of smell in PSP compared to controls. The sensitivity of having PSP pathologically in those presenting with parkinsonism and normosmia was 93.4% with a specificity of 64.7%. Cases with both PSP and PD pathologically had reduced sense of smell similar to PD alone (N = 7). Hyposmic PSP patients had significantly higher Lewy body burden not meeting criteria for additional PD/DLB diagnosis.ConclusionsPathologically confirmed PD had reduced olfaction compared with PSP or controls. In the setting of parkinsonism in this sample, the presence of normosmia had high sensitivity for PSP. Hyposmia in PSP suggests the presence of additional Lewy body pathology. © 2021 International Parkinson and Movement Disorder Society

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