Feasibility, validity, and normative data for the remote Uniform Data Set neuropsychological battery at the University of Pennsylvania Alzheimer's Disease Research Center.

Introduction: We investigated the feasibility and validity of the remotely-administered neuropsychological battery from the National Alzheimer's Coordinating Center Uniform Data Set (UDS T-Cog).

Methods: Two hundred twenty Penn Alzheimer's Disease Research Center participants with unimpaired cognition, mild cognitive impairment, and dementia completed the T-Cog during their annual UDS evaluation. We assessed administration feasibility and diagnostic group differences cross-sectionally across telephone versus videoconference modalities, and compared T-Cog to prior in-person UDS scores longitudinally.

Posterior hippocampal sparing in Lewy body disorders with Alzheimer's copathology: An in vivo MRI study.

Background: Lewy body disorders (LBD), encompassing Parkinson disease (PD), PD dementia (PDD), and dementia with Lewy bodies (DLB), are characterized by alpha-synuclein pathology but often are accompanied by Alzheimer's disease (AD) neuropathological change (ADNC). The medial temporal lobe (MTL) is a primary locus of tau accumulation and associated neurodegeneration in AD. However, it is unclear the extent to which AD copathology in LBD (LBD/AD+) contributes to MTL-specific patterns of degeneration.

α-Synuclein Conformations in Plasma Distinguish Parkinson's Disease from Dementia with Lewy Bodies.

Aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Evidence exists for aSyn "strains" - conformations with distinct biological properties. However, biomarkers for PD vs.

α-Synuclein Conformations in Plasma Distinguish Parkinson's Disease from Dementia with Lewy Bodies.

Spread and aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). While evidence exists for multiple aSyn protein conformations, often termed "strains" for their distinct biological properties, it is unclear whether PD and DLB result from aSyn strain differences, and biomarkers that differentiate PD and DLB are lacking. Moreover, while pathological forms of aSyn have been detected outside the brain ( in skin, gut, blood), the functional significance of these peripheral aSyn species is unclear.

repeat expansions modify risk for secondary motor and cognitive-behavioral symptoms in behavioral-variant frontotemporal degeneration and amyotrophic lateral sclerosis.

In behavioral-variant frontotemporal degeneration (bvFTD) and amyotrophic lateral sclerosis (ALS), secondary motor or cognitive-behavioral symptoms, respectively, are associated with shorter survival. However, factors influencing secondary symptom development remain largely unexplored. We performed a retrospective evaluation of the entire disease course of individuals with ALS (n=172) and bvFTD (n=69).

Genetic and phenotypic characterization of Parkinson's disease at the clinic-wide level.

Observational studies in Parkinson's disease (PD) deeply characterize relatively small numbers of participants. The Molecular Integration in Neurological Diagnosis Initiative seeks to characterize molecular and clinical features of every PD patient at the University of Pennsylvania (UPenn). The objectives of this study are to determine the feasibility of genetic characterization in PD and assess clinical features by sex and GBA1/LRRK2 status on a clinic-wide scale.

Cytoarchitectonic gradients of laminar degeneration in behavioral variant frontotemporal dementia.

Behavioral variant frontotemporal dementia (bvFTD) is a clinical syndrome primarily caused by either tau (bvFTD-tau) or TDP-43 (bvFTD-TDP) proteinopathies. We previously found lower cortical layers and dorsolateral regions accumulate greater tau than TDP-43 pathology; however, patterns of laminar neurodegeneration across diverse cytoarchitecture in bvFTD is understudied. We hypothesized that bvFTD-tau and bvFTD-TDP have distinct laminar distributions of pyramidal neurodegeneration along cortical gradients, a topologic order of cytoarchitectonic subregions based on increasing pyramidal density and laminar differentiation.

Improving Regression Analysis with Imputation in a Longitudinal Study of Alzheimer's Disease.

Background: Missing data is prevalent in the Alzheimer's Disease Neuroimaging Initiative (ADNI). It is common to deal with missingness by removing subjects with missing entries prior to statistical analysis; however, this can lead to significant efficiency loss and sometimes bias. It has yet to be demonstrated that the imputation approach to handling this issue can be valuable in some longitudinal regression settings.

Neighborhood disadvantage reduces cognitive reserve independent of neuropathologic change.

Introduction: Individuals in socioeconomically disadvantaged neighborhoods exhibit increased risk for impaired cognitive function. Whether this association relates to the major dementia-related neuropathologies is unknown.

Methods: This cross-sectional study included 469 autopsy cases from 2011 to 2023.

Changes in Digital Speech Measures in Asymptomatic Carriers of Pathogenic Variants Associated With Frontotemporal Degeneration.

Background And Objectives: Clinical trials developing therapeutics for frontotemporal degeneration (FTD) focus on pathogenic variant carriers at preclinical stages. Objective, quantitative clinical assessment tools are needed to track stability and delayed disease onset. Natural speech can serve as an accessible, cost-effective assessment tool.

Tau-neurodegeneration mismatch reveals vulnerability and resilience to comorbidities in Alzheimer's continuum.

Introduction: Variability in relationship of tau-based neurofibrillary tangles (T) and neurodegeneration (N) in Alzheimer's disease (AD) arises from non-specific nature of N, modulated by non-AD co-pathologies, age-related changes, and resilience factors.

Methods: We used regional T-N residual patterns to partition 184 patients within the Alzheimer's continuum into data-driven groups. These were compared with groups from 159 non-AD (amyloid "negative") patients partitioned using cortical thickness, and groups in 98 patients with ante mortem MRI and post mortem tissue for measuring N and T, respectively.

Epigenetic age and socioeconomic status contribute to racial disparities in cognitive and functional aging between Black and White older Americans.

Epigenetic age, a biological aging marker measured by DNA methylation, is a potential mechanism by which social factors drive disparities in age-related health. Epigenetic age gap is the residual between epigenetic age measures and chronological age. Previous studies showed associations between epigenetic age gap and age-related outcomes including cognitive capacity and performance on some functional measures, but whether epigenetic age gap contributes to disparities in these outcomes is unknown.

Validating virtual administration of neuropsychological testing in Parkinson disease: a pilot study.

COVID-19 has highlighted the need for remote cognitive testing, but the reliability and validity of virtual cognitive testing in Parkinson disease (PD) is unknown. Therefore, we assessed PD participants enrolled in an observational, cognition-focused study with an extensive cognitive battery completed both in-person and via video conference close in time. Data for 35 PD participants with normal cognition to mild dementia were analyzed.

Linked Patient and Provider Impressions of Outpatient Teleneurology Encounters.

Background And Objectives: Teleneurology is common in clinical practice partly due to the SARS CoV-2 pandemic. Impressions about teleneurology from patients and providers alike are generally favorable; some of the reported benefits include ease of access to specialized health care, savings of time and money, and similar quality of care as an in-person visit. However, comparisons between patient and provider impressions about the same teleneurology encounter have not been described.

Turning apathy into action in neurodegenerative disease: Development and pilot testing of a goal-directed behaviour app.

This study aims to design and pilot an empirically based mobile application () to increase daily activity in persons with apathy and ADRD and test its feasibility and preliminary efficacy. was developed to address impairments in goal-directed behaviour, including difficulty with initiation, planning, and motivation that contribute to apathy. Participants included patients with apathy and MCI, mild bvFTD, or mild AD and their caregivers.

Long-term epilepsy outcome dynamics revealed by natural language processing of clinic notes.

Objective: Electronic medical records allow for retrospective clinical research with large patient cohorts. However, epilepsy outcomes are often contained in free text notes that are difficult to mine. We recently developed and validated novel natural language processing (NLP) algorithms to automatically extract key epilepsy outcome measures from clinic notes.

Pathological combinations in neurodegenerative disease are heterogeneous and disease-associated.

Pathologies that are causative for neurodegenerative disease (ND) are also frequently present in unimpaired, older individuals. In this retrospective study of 1647 autopsied individuals, we report the incidence of 10 pathologies across ND and normal ageing in attempt to clarify which pathological combinations are disease-associated and which are ageing-related. Eight clinically defined groups were examined including unimpaired individuals and those with clinical Alzheimer's disease, mixed dementia, amyotrophic lateral sclerosis, frontotemporal degeneration, multiple system atrophy, probable Lewy body disease or probable tauopathies.

Tau-Neurodegeneration reveals vulnerability and resilience to comorbidities in Alzheimer's continuum.

Variability in the relationship of tau-based neurofibrillary tangles (T) and degree of neurodegeneration (N) in Alzheimer's Disease (AD) is likely attributable to the non-specific nature of N, which is also modulated by such factors as other co-pathologies, age-related changes, and developmental differences. We studied this variability by partitioning patients within the Alzheimer's continuum into data-driven groups based on their regional T-N dissociation, which reflects the residuals after the effect of tau pathology is "removed". We found six groups displaying distinct spatial T-N and thickness patterns despite similar tau burden.

Validating virtual administration of neuropsychological testing in Parkinson disease: a pilot study.

Background COVID-19 has highlighted the need for remote cognitive testing. Virtual testing may lessen burden and can reach a larger patient population. The reliability and validity of virtual cognitive testing in Parkinson disease (PD) is unknown.

Plasma phosphorylated tau181 predicts cognitive and functional decline.

Objective: To determine if plasma tau phosphorylated at threonine 181 (p-tau181) distinguishes pathology-confirmed Alzheimer's disease (AD) from normal cognition (NC) adults, to test if p-tau181 predicts cognitive and functional decline, and to validate findings in an external cohort.

Methods: Thirty-one neuropathology-confirmed AD cases, participants with clinical diagnoses of mild cognitive impairment (MCI, N = 91) or AD dementia (N = 64), and NC (N = 241) had plasma collected at study entry. The clinical diagnosis groups had annual cognitive (Mini-Mental State Examination, MMSE) and functional (Clinical Dementia Rating Scale, CDR) measures.

Associations of phosphorylated tau pathology with whole-hemisphere ex vivo morphometry in 7 tesla MRI.

Introduction: Neurodegenerative disorders are associated with different pathologies that often co-occur but cannot be measured specifically with in vivo methods.

Methods: Thirty-three brain hemispheres from donors with an Alzheimer's disease (AD) spectrum diagnosis underwent T2-weighted magnetic resonance imaging (MRI). Gray matter thickness was paired with histopathology from the closest anatomic region in the contralateral hemisphere.