Annexin A11 aggregation in FTLD-TDP type C and related neurodegenerative disease proteinopathies.

TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein found within ribonucleoprotein granules tethered to lysosomes via annexin A11. TDP-43 protein forms inclusions in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Annexin A11 is also known to form aggregates in ALS cases with pathogenic variants in ANXA11.

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.

Whole Clinic Research Enrollment in Parkinson's Disease: The Molecular Integration in Neurological Diagnosis (MIND) Study.

Background: Observational studies in Parkinson's disease (PD) have focused on relatively small numbers of research participants who are studied extensively. The Molecular Integration in Neurological Diagnosis Initiative at the University of Pennsylvania aims to characterize molecular and clinical features of PD in every patient in a large academic center.

Objective: To determine the feasibility and interest in a global-capture biomarker research protocol.

Hippocampal subfield pathologic burden in Lewy body diseases vs. Alzheimer's disease.

Aims: Lewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but comorbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here we use digital histological methods to test the association between hippocampal SYN pathology and the distribution of tau and amyloid-beta (Aβ) pathology in LBD and contrast with AD subjects. We also correlate pathologic burden with antemortem episodic memory testing.

ADNC-RS, a clinical-genetic risk score, predicts Alzheimer's pathology in autopsy-confirmed Parkinson's disease and Dementia with Lewy bodies.

Growing evidence suggests overlap between Alzheimer's disease (AD) and Parkinson's disease (PD) pathophysiology in a subset of patients. Indeed, 50-80% of autopsy cases with a primary clinicopathological diagnosis of Lewy body disease (LBD)-most commonly manifesting during life as PD-have concomitant amyloid-beta and tau pathology, the defining pathologies of AD. Here we evaluated common genetic variants in genome-wide association with AD as predictors of concomitant AD pathology in the brains of people with a primary clinicopathological diagnosis of PD or Dementia with Lewy Bodies (DLB), diseases both characterized by neuronal Lewy bodies.

The Many Faces of Parkinson's Disease.

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Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases.

PD, PD with dementia, and dementia with Lewy bodies are clinical syndromes characterized by the neuropathological accumulation of alpha-synuclein in the CNS that represent a clinicopathological spectrum known as Lewy body disorders. These clinical entities have marked heterogeneity of motor and nonmotor symptoms with highly variable disease progression. The biological basis for this clinical heterogeneity remains poorly understood.

Cognitive and Pathological Influences of Tau Pathology in Lewy Body Disorders.

Objective: To use digital histology in a large autopsy cohort of Lewy body disorder (LBD) patients with dementia to test the hypotheses that co-occurring Alzheimer disease (AD) pathology impacts the anatomic distribution of α-synuclein (SYN) pathology and that co-occurring neocortical tau pathology in LBDs associates with worse cognitive performance and occurs in a pattern differing from AD.

Methods: Fifty-five autopsy-confirmed LBD (Parkinson disease with dementia, n = 36; dementia with Lewy bodies, n = 19) patients and 25 AD patients were studied. LBD patients were categorized as having moderate/severe AD copathology (SYN + AD = 20) or little/no AD copathology (SYN-AD = 35).

The Contribution of Tau, Amyloid-Beta and Alpha-Synuclein Pathology to Dementia in Lewy Body Disorders.

Parkinson's Disease (PD) and the closely related Dementia with Lewy Bodies (DLB) are due to the accumulation of pathogenic alpha-synuclein protein in brain cells manifest by heterogeneous motor and non-motor symptoms, including cognitive impairment and dementia. The majority of patients with Parkinson's Disease develop Dementia (PDD) in late stages of the disease and have widespread neocortical distribution of alpha-synuclein pathology at autopsy, compared with PD without dementia, in which neocortical synuclein pathology is less prevalent. These three entities PD, DLB and PDD comprise a clinical spectrum, collectively known as Lewy Body Disorders (LBD).

Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated.

Lewy bodies commonly occur in Alzheimer's disease, and Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across neurodegenerative diseases is unknown. We assessed the extent of tau, amyloid-β, α-synuclein and TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical neurodegenerative disease. We interrogated pathological Alzheimer's disease (n = 247); other tauopathies (n = 95) including Pick's disease, corticobasal disease and progressive supranuclear palsy; the synucleinopathies (n = 164) including multiple system atrophy and Lewy body disease; the TDP-43 proteinopathies (n = 188) including frontotemporal lobar degeneration with TDP-43 inclusions and amyotrophic lateral sclerosis; and a minimal pathology group (n = 72).

CSF tau and β-amyloid predict cerebral synucleinopathy in autopsied Lewy body disorders.

Objective: To test the association of antemortem CSF biomarkers with postmortem pathology in Lewy body disorders (LBD).

Methods: Patients with autopsy-confirmed LBD (n = 24) and autopsy-confirmed Alzheimer disease (AD) (n = 23) and cognitively normal (n = 36) controls were studied. In LBD, neuropathologic criteria defined Lewy body α-synuclein (SYN) stages with medium/high AD copathology (SYN + AD = 10) and low/no AD copathology (SYN - AD = 14).

Circulating brain-enriched microRNAs as novel biomarkers for detection and differentiation of neurodegenerative diseases.

Background: Minimally invasive specific biomarkers of neurodegenerative diseases (NDs) would facilitate patient selection and disease progression monitoring. We describe the assessment of circulating brain-enriched microRNAs as potential biomarkers for Alzheimer's disease (AD), frontotemporal dementia (FTD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

Methods: In this case-control study, the plasma samples were collected from 250 research participants with a clinical diagnosis of AD, FTD, PD, and ALS, as well as from age- and sex-matched control subjects (n = 50 for each group), recruited from 2003 to 2015 at the University of Pennsylvania Health System, including the Alzheimer's Disease Center, the Parkinson's Disease and Movement Disorders Center, the Frontotemporal Degeneration Center, and the Amyotrophic Lateral Sclerosis Clinic.

Regional brain amyloid-β accumulation associates with domain-specific cognitive performance in Parkinson disease without dementia.

Parkinson disease patients develop clinically significant cognitive impairment at variable times over their disease course, which is often preceded by milder deficits in memory, visuo-spatial, and executive domains. The significance of amyloid-β accumulation to these problems is unclear. We hypothesized that amyloid-β PET imaging by 18F-florbetapir, a radiotracer that detects fibrillar amyloid-β plaque deposits, would identify subjects with global cognitive impairment or poor performance in individual cognitive domains in non-demented Parkinson disease patients.

Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis.

Background: Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies.

Methods: In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed α synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA.

Progression of alpha-synuclein pathology in multiple system atrophy of the cerebellar type.

Aims: The aim of this study was to identify early foci of α-synuclein (α-syn pathology) accumulation, subsequent progression and neurodegeneration in multiple system atrophy of the cerebellar type (MSA-C).

Methods: We analysed 70-μm-thick sections of 10 cases with MSA-C and 24 normal controls.

Results: MSA-C cases with the lowest burden of pathology showed α-syn glial cytoplasmic inclusions (GCIs) in the cerebellum as well as in medullary and pontine cerebellar projections.

Amyloid-Beta Positron Emission Tomography Imaging of Alzheimer's Pathology in Parkinson's Disease Dementia.

Background: Neuronal loss and α-synuclein (α-syn) pathology are diagnostic of PD in the appropriate clinical context. However, some PD patients have co-morbid Alzheimer's disease (AD) pathology on autopsy, including amyloid-β (Aβ) plaques and neurofibrillary tangles. Florbetapir(F) is a PET ligand that detects Aβ pathology.

Arguing against the proposed definition changes of PD.

As members of the Lewy Body Dementia Association Scientific Advisory Council, we aim to address some of the issues raised in the article titled "Time to Redefine PD? Introductory Statement of the MDS Task Force on the Definition of Parkinson's Disease." In particular, we suggest that the 1-year rule distinguishing Parkinson's disease dementia from dementia with Lewy bodies is worth maintaining because it serves an important purpose in clinical practice and clinical and basic science research and when helping the lay community understand the complexity of these different clinical phenotypes. Furthermore, we believe that adding an additional diagnostic label, "PD (dementia with Lewy bodies subtype)," will confuse rather than clarify the distinction between dementia with Lewy bodies and PD or PD dementia, and will not improve management or expedite therapeutic development.

Drug-induced phospholipidosis caused by combinations of common drugs in vitro.

Drug-induced phospholipidosis (DIPLD), characterized by the accumulation of phospholipids within lysosomes, is suspected to impair lysosomal function and considered an adverse side effect of the administered medication. The increasing use of polypharmacy and the resultant elevated risks of adverse drug reactions raise the need to explore the effects of drug combinations with respect to their influence on side effects, such as DIPLD. In this study, we utilized an in vitro assay to investigate DIPLD that was caused by 24 commonly used drugs applied alone and in binary combinations with each other.

The Penn Parkinson's Daily Activities Questionnaire-15: Psychometric properties of a brief assessment of cognitive instrumental activities of daily living in Parkinson's disease.

Introduction: To describe the psychometric properties of the Penn Parkinson's Daily Activities Questionnaire-15 (PDAQ-15), a 15-item measure of cognitive instrumental activities of daily living for Parkinson's disease (PD) patients derived from the original 50-item PDAQ.

Methods: PDAQ-15 items were chosen by expert consensus. Knowledgeable informants of PD participants (n = 161) completed the PDAQ-15.

An Alzheimer's Disease-Derived Biomarker Signature Identifies Parkinson's Disease Patients with Dementia.

Biomarkers from multiple modalities have been shown to correlate with cognition in Parkinson's disease (PD) and in Alzheimer's disease (AD). However, the relationships of these markers with each other, and the use of multiple markers in concert to predict an outcome of interest, are areas that are much less explored. Our objectives in this study were (1) to evaluate relationships among 17 biomarkers previously reported to associate with cognition in PD or AD and (2) to test performance of a five-biomarker classifier trained to recognize AD in identifying PD with dementia (PDD).

Pathological α-synuclein distribution in subjects with coincident Alzheimer's and Lewy body pathology.

We investigated the distribution patterns of Lewy body-related pathology (LRP) and the effect of coincident Alzheimer disease (AD) pathology using a data-driven clustering approach that identified groups with different LRP pathology distributions without any diagnostic or researcher's input in two cohorts including: Parkinson disease patients without (PD, n = 141) and with AD (PD-AD, n = 80), dementia with Lewy bodies subjects without AD (DLB, n = 13) and demented subjects with AD and LRP pathology (Dem-AD-LB, n = 308). The Dem-AD-LB group presented two LRP patterns, olfactory-amygdala and limbic LRP with negligible brainstem pathology, that were absent in the PD groups, which are not currently included in the DLB staging system and lacked extracranial LRP as opposed to the PD group. The Dem-AD-LB individuals showed relative preservation of substantia nigra cells and dopamine active transporter in putamen.

Longitudinal study of normal cognition in Parkinson disease.

Objective: To report the rates and predictors of progression from normal cognition to either mild cognitive impairment (MCI) or dementia using standardized neuropsychological methods.

Methods: A prospective cohort of patients diagnosed with Parkinson disease (PD) and baseline normal cognition was assessed for cognitive decline, performance, and function for a minimum of 2 years, and up to 6. A panel of movement disorders experts classified patients as having normal cognition, MCI, or dementia, with 55/68 (80.

Development and initial testing of the Penn Parkinson's Daily Activities Questionnaire.

Objective: The aim of this work was to describe the development and psychometric analysis of the Penn Parkinson's Daily Activities Questionnaire. The questionnaire is an item response theory-based tool for rating cognitive instrumental activities of daily living in PD.

Methods: Candidate items for the Penn Parkinson's Daily Activities Questionnaire were developed through literature review and focus groups of patients and knowledgeable informants.