Belden, Christine M.

Abstract The objective of this study was to determine the prevalence, incidence, and clinical diagnostic accuracy for neuropathologically diagnosed progressive supranuclear palsy (PSP) with data from a longitudinal clinicopathological study using Rainwater criteria to define neuropathological PSP. Of 954 autopsy cases, 101 met Rainwater criteria for the neuropathologic diagnosis of PSP. Of these, 87 were termed clinicopathological PSP as they also had either dementia or parkinsonism or both. The prevalence of clinicopathologically defined PSP subjects in the entire autopsy dataset was 9.1%, while the incidence rate was estimated at 780 per 100 000 persons per year, roughly 50-fold greater than most previous clinically determined PSP incidence estimates. A clinical diagnosis of PSP was 99.6% specific but only 9.2% sensitive based on first examination, and 99.3% specific and 20.7% sensitive based on the final clinical exam. Of the clinicopathologically defined PSP cases, 35/87 (∼40%) had no form of parkinsonism at first assessment, while this decreased to 18/83 (21.7%) at final assessment. Our study confirms a high specificity but low sensitivity for the clinical diagnosis of PSP. The low clinical sensitivity for PSP is likely primarily responsible for previous underestimates of the PSP population incidence rate.

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.

Abstract Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 4/20 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 8/21 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 2/42 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results; these involved immune response, neuronal constituents, and olfactory/taste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation.

Abstract The Alzheimer disease (AD) neuropathological hallmarks amyloid β (Aβ) and tau neurofibrillary (NF) pathology have been reported in the olfactory bulb (OB) in aging and in different neurodegenerative diseases, which coincides with frequently reported olfactory dysfunction in these conditions. To better understand when the OB is affected in relation to the hierarchical progression of Aβ throughout the brain and whether OB pathology might be an indicator of AD severity, we assessed the presence of OB Aβ and tau NF pathology in an autopsy cohort of 158 non demented control and 173 AD dementia cases. OB Aβ was found in less than 5% of cases in lower Thal phases 0 and 1, in 20% of cases in phase 2, in 60% of cases in phase 3 and in more than 80% of cases in higher Thal phases 4 and 5. OB Aβ and tau pathology significantly predicted a Thal phase greater than 3, a Braak NF stage greater than 4, and an MMSE score lower than 24. While OB tau pathology is almost universal in the elderly and therefore is not a good predictor of AD severity, OB Aβ pathology coincides with clinically-manifest AD and might prove to be a useful biomarker of the extent of brain spread of both amyloid and tau pathology.

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.

Background: Imaging biomarkers have the potential to distinguish between different brain pathologies based on the type of ligand used with PET. AV-45 PET (florbetapir, Amyvid™) is selective for the neuritic plaque amyloid of Alzheimer’s disease (AD), while AV-133 PET (florbenazine) is selective for VMAT2, which is a dopaminergic marker. Objective: To report the clinical, AV-133 PET, AV-45 PET, and neuropathological findings of three clinically diagnosed dementia patients who were part of the Avid Radiopharmaceuticals AV133-B03 study as well as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Methods: Three subjects who had PET imaging with both AV-133 and AV-45 as well as a standardized neuropathological assessment were included. The final clinical, PET scan, and neuropathological diagnoses were compared. Results: The clinical and neuropathological diagnoses were made blinded to PET scan results. The first subject had a clinical diagnosis of dementia with Lewy bodies (DLB); AV-133 PET showed bilateral striatal dopaminergic degeneration, and AV-45 PET was positive for amyloid. The final clinicopathological diagnosis was DLB and AD. The second subject was diagnosed clinically with probable AD; AV-45 PET was positive for amyloid, while striatal AV-133 PET was normal. The final clinicopathological diagnosis was DLB and AD. The third subject had a clinical diagnosis of DLB. Her AV-45 PET was positive for amyloid and striatal AV-133 showed dopaminergic degeneration. The final clinicopathological diagnosis was multiple system atrophy and AD. Conclusion: PET imaging using AV-133 for the assessment of striatal VMAT2 density may help distinguish between AD and DLB. However, some cases of DLB with less-pronounced nigrostriatal dopaminergic neuronal loss may be missed.

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 Comorbid Lewy body pathology is very common in Alzheimer’s disease and may confound clinical trial design, yet there is no in vivo test to identify patients with this. Tissue (and/or radioligand imaging) studies have shown cardiac sympathetic denervation in Parkinson’s disease and dementia with Lewy bodies, but this has not been explored in Alzheimer’s subjects with Lewy bodies not meeting dementia with Lewy bodies clinicopathological criteria. To determine if Alzheimer’s disease with Lewy bodies subjects show sympathetic cardiac denervation, we analysed epicardial and myocardial tissue from autopsy-confirmed cases using tyrosine hydroxylase and neurofilament immunostaining. Comparison of tyrosine hydroxylase fibre density in 19 subjects with Alzheimer’s disease/dementia with Lewy bodies, 20 Alzheimer’s disease with Lewy bodies, 12 Alzheimer’s disease subjects without Lewy body disease, 19 Parkinson’s disease, 30 incidental Lewy body disease and 22 cognitively normal without Alzheimer’s disease or Lewy body disease indicated a significant group difference (P &lt; 0.01; Kruskal–Wallis analysis of variance) and subsequent pair-wise Mann–Whitney U tests showed that Parkinson’s disease (P &lt; 0.05) and Alzheimer’s disease/dementia with Lewy bodies (P &lt; 0.01) subjects, but not Alzheimer’s disease with Lewy bodies subjects, had significantly reduced tyrosine hydroxylase fibre density as compared with cognitively normal. Both Parkinson’s disease and Alzheimer’s disease/dementia with Lewy bodies subjects also showed significant epicardial losses of neurofilament protein-immunoreactive nerve fibre densities within the fibre bundles as compared with cognitively normal subjects (P &lt; 0.01) and both groups showed high pathologic alpha-synuclein densities (P &lt; 0.0001). Cardiac alpha-synuclein densities correlated significantly with brain alpha-synuclein (P &lt; 0.001), while cardiac tyrosine hydroxylase and neurofilament immunoreactive nerve fibre densities were negatively correlated with the densities of both brain and cardiac alpha-synuclein, as well as Unified Parkinson’s Disease Rating Scale scores (P &lt; 0.05). The clear separation of Alzheimer’s disease/dementia with Lewy bodies subjects from Alzheimer’s disease and cognitively normal, based on cardiac tyrosine hydroxylase fibre density, is the first report of a statistically significant difference between these groups. Our data do not show significant sympathetic cardiac denervation in Alzheimer’s disease with Lewy bodies, but strongly confirm that cardiac nuclear imaging with a noradrenergic radioligand is worthy of further study as a potential means to separate Alzheimer’s disease from Alzheimer’s disease/dementia with Lewy bodies during life.