Adler, C H

Background Neuropsychiatric symptoms (NPS) are frequent in Alzheimer's disease (AD) dementia, but a higher NPS burden is found in dementia with Lewy bodies (DLB). Lewy body (LB) pathology frequently co-occurs with AD pathology and may not meet neuropathological criteria for DLB (ADLB). NPS trajectories over disease course in these subgroups is not well understood. Objective We investigated changes in NPS severity over time, at two time points, comparing clinicopathologically defined cohorts of AD (without LB), ADLB, DLB, and controls. Methods Cases with two available Neuropsychiatric Inventory-Questionnaire (NPIQ), at the time of enrollment and within 2.5 years of death, were selected from the Arizona Study of Aging and Neurodegenerative Disorders. Differences and rate of change in NPIQ scores were compared between AD (n = 75), ADLB (n = 48) DLB (n = 65), and controls (n = 32) with covariates for age, sex, and cognition. Results First NPIQ scores were highest in ADLB when compared to AD (p = 0.04) and controls (p = 0.01) but not different from DLB. A significant increase in NPS severity was observed in DLB and AD (p < 0.001) over a mean follow up time of 4.9 ± 3.0 years, and the rate of change was significantly greater in DLB when compared to other groups. Final NPIQ scores were highest in DLB when compared to AD (p = 0.03) but not ADLB, and in DLB, ADLB, and AD than controls ( all p < 0.001). Conclusions Early NPS burden as well as NPS severity progression rate, independently of cognitive status, might be useful clinical metrics and may help predict underlying pathological diagnoses.

Abstract Former American football players are at risk for developing traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE). The objective of this study was to determine whether hyposmia is present in traumatic encephalopathy syndrome. The study included 119 former professional American football players, 60 former college football players, and 58 same-age asymptomatic unexposed men from the DIAGNOSE CTE Research Project. All subjects included in the analysis had completed the Brief Smell Identification Test (B-SIT). Traumatic encephalopathy syndrome and the level of CTE certainty were diagnosed using the 2021 NINDS consensus diagnostic criteria. TES is categorized antemortem by provisional levels of increasing CTE certainty: Suggestive, Possible, and Probable. Former players who had traumatic encephalopathy syndrome and Probable CTE had lower B-SIT scores than those with TES and Suggestive CTE. Hyposmia was more likely in the former players with TES who were either CTE Possible or Probable than in those who did not have TES or had TES but were less likely to have CTE, or CTE Suggestive. There was no difference in B-SIT scores between all former players versus unexposed men nor overall between the football players with and without TES. We conclude that lower B-SIT scores may be a clinical biomarker for underlying CTE in former American football players.

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.

AbstractBackgroundThe G2019S leucine‐rich repeat kinase 2 (LRRK2) gene mutation is an important and commonly found genetic determinant of Parkinson's disease (PD). The neuropathological findings associated with this mutation have thus far been varied but are most often associated with Lewy body (LB) pathology.ObjectiveDescribe a case of clinical Parkinson's disease with levodopa responsiveness found to have LRRK2 mutations and the absence of Lewy bodies.MethodWe present an 89‐year‐old man with a 10‐year history of slowly progressive parkinsonism suspected to be secondary to Parkinson's disease.ResultsNeuropathological evaluation revealed nigral degeneration without Lewy bodies or Lewy neurites, but there were frequent tau‐immunopositive neurites and astrocytes in the putamen and substantia nigra, neocortical glial tau positive astrocytes associated with aging‐related tau astrogliopathy (ARTAG), as well as neurofibrillary tangles, beta amyloid plaques, and amyloid angiopathy typical of advanced Alzheimer's disease. G2019S LRRK2 homozygous mutations were found.ConclusionThis case illustrates that levodopa‐responsive clinical PD caused by G2019S LRRK2 mutations can occur without Lewy bodies.

AbstractBackgroundWhile preclinical studies have shown that alpha‐synuclein can spread through cell‐to‐cell transmission whether it can be transmitted between humans is unknown.ObjectivesThe aim was to assess the presence of a synucleinopathy in autopsied conjugal couples.MethodsNeuropathological findings in conjugal couples were categorized as Parkinson's disease (PD), dementia with Lewy bodies (DLB), Alzheimer's disease with Lewy bodies (ADLB), incidental Lewy body disease (ILBD), or no Lewy bodies.ResultsNinety conjugal couples were included; the mean age of death was 88.3 years; 32 couples had no Lewy bodies; 42 couples had 1 spouse with a synucleinopathy: 10 PD, 3 DLB, 13 ADLB, and 16 ILBD; 16 couples had both spouses with a synucleinopathy: in 4 couples both spouses had PD, 1 couple had PD and DLB, 4 couples had PD and ADLB, 2 couples had PD and ILBD, 1 couple had DLB and ADLB, in 3 couples both had ADLB, and 1 couple had ADLB and ILBD. No couples had both spouses with ILBD.ConclusionsThis large series of 90 autopsied conjugal couples found 16 conjugal couples with synucleinopathies, suggesting transmission of synucleinopathy between spouses is unlikely. © 2024 International Parkinson and Movement Disorder Society.

AbstractBackgroundYoung‐onset multiple system atrophy (YOMSA) is defined as the onset of multiple system atrophy (MSA) before the age of 40 years old. YOMSA is rare and there is much uncertainty of the phenotype and natural history in patients with YOMSA.ObjectiveThe objective is to evaluate the characteristics and disease course of patients with YOMSA.MethodsWe retrospectively reviewed medical records of patients with MSA who were evaluated at all Mayo Clinic sites from 1998 to 2021. We identified patients with YOMSA and evaluated clinical characteristics, autonomic function testing results, and disease course.ResultsOf 1496 patients with a diagnosis of clinically probable or clinically established MSA, 20 patients had YOMSA. The median age of onset was 39.1 (interquartile range [IQR] = 37.1, 40.1) years; 13 patients (65%) were male. MSA‐parkinsonism was the most common subtype (65%). The median duration of symptom onset to YOMSA diagnosis was 4.9 (IQR = 3.7, 9) years. At the time of medical record review, 17 patients were deceased with a median survival of 8.3 (IQR = 7, 10.9) years. Univariate analysis showed that initial onset of autonomic failure predicted unfavorable survival (hazard ratio = 2.89, P = 0.04) compared to those who presented with motor impairment only at onset. At the time of YOMSA diagnosis, composite autonomic severity score was available in 19 patients with a median of 5 (IQR = 4, 6.5).ConclusionsYOMSA resembles MSA in most aspects including phenotype and prognosis, although the diagnosis is usually delayed. The presence of autonomic failure at symptom onset may be a poor predictor for survival.

Abstract Cerebral white matter rarefaction (CWMR) was considered by Binswanger and Alzheimer to be due to cerebral arteriolosclerosis. Renewed attention came with CT and MR brain imaging, and neuropathological studies finding a high rate of CWMR in Alzheimer disease (AD). The relative contributions of cerebrovascular disease and AD to CWMR are still uncertain. In 1181 autopsies by the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), large-format brain sections were used to grade CWMR and determine its vascular and neurodegenerative correlates. Almost all neurodegenerative diseases had more severe CWMR than the normal control group. Multivariable logistic regression models indicated that Braak neurofibrillary stage was the strongest predictor of CWMR, with additional independently significant predictors including age, cortical and diencephalic lacunar and microinfarcts, body mass index, and female sex. It appears that while AD and cerebrovascular pathology may be additive in causing CWMR, both may be solely capable of this. The typical periventricular pattern suggests that CWMR is primarily a distal axonopathy caused by dysfunction of the cell bodies of long-association corticocortical projection neurons. A consequence of these findings is that CWMR should not be viewed simply as “small vessel disease” or as a pathognomonic indicator of vascular cognitive impairment or vascular dementia.

ABSTRACTBackgroundThe criteria for PD‐MCI allow the use of global cognitive tests. Their predictive value for conversion from PD‐MCI to PDD, especially compared to comprehensive neuropsychological assessment, is unknown.MethodsThe MDS PD‐MCI Study Group combined four datasets containing global cognitive tests as well as a comprehensive neuropsychological assessment to define PD‐MCI (n = 467). Risk for developing PDD was examined using a Cox model. Global cognitive tests were compared to neuropsychological test batteries (Level I&II) in determining risk for PDD.ResultsPD‐MCI based on a global cognitive test (MMSE or MoCA) increases the hazard for developing PDD (respectively HR = 2.57, P = 0.001; HR = 4.14, P = <0.001). The C‐statistics for MMSE (0.72) and MoCA (0.70) were lower than those based on neuropsychological tests (Level I = 0.82; Level II = 0.81). Sensitivity, specificity and diagnostic accuracy balance was best in Level II.ConclusionMMSE and MoCA predict conversion to PDD. However, Level II neuropsychological assessment seems the preferred assessment for PD‐MCI.