Identification of biomarkers and modifiable risk factors for Parkinson's disease dementia

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide and afflicts approximately 1% of individuals over age 65. The dementia that develops in association with PD is devastating to both the patient and their family and common, with more than 80% of individuals with PD developing dementia by 15 years after symptom onset. Current treatments for both PD and PD-dementia (PDD) have unacceptable side effects and there are no disease modifying therapies. An improved understanding of the pathophysiology of PD and PDD, however, is leading to testing of therapeutics that are targeted to specific pathways that have been implicated in PD pathophysiology. This pathophysiology is reviewed in Chapter 1, with an emphasis in the c-Abl molecule pathways role in PD pathophysiology. A biomarker for both PD and PDD would greatly improve our diagnosis, prognosis, and potentially the efficacy of these new treatment trials. Chapter 2 therefore considers whether poly (ADP-ribose), a molecule downstream in the c-Abl pathway, is a potential biomarker for PDD. Finally, we need to improve the outcomes for our current patients and Chapter 3 explores the role of a modifiable risk factor, namely vascular disease and subsequent vascular pathology, in the development of PDD. Together, these investigations broaden our understanding of PDD and are a step toward improved treatment for individuals with this devastating disease

REM Sleep Behavior and Motor Findings in Parkinson’s Disease: A Cross-sectional Analysis

Background: Parkinson's disease (PD) represents a major public health challenge that will only grow in our aging population. Understanding the connection between PD and associated prodromal conditions, such as rapid eye movement sleep behavioral disorder (RBD), is critical to identifying prevention strategies. However, the relationship between RBD and severity of motor findings in early PD is unknown. This study aims to examine this relationship. Methods: The study population consisted of 418 PD patients who completed the Movement Disorders Society‐United Parkinson's Disease Rating Scale (MDS‐UPDRS) and rapid eye movement sleep (REM) disorder questionnaires at the baseline visit of the Michael J. Fox's Parkinson's Progression Markers Initiative (PPMI). Cross‐sectional analysis was carried out to assess the association between REM Sleep Behavior Screening Questionnaire score and MDS UPDRS‐3 (motor) score categories. Correlation with a higher score category was described as “worse motor findings”. A score of 5 on the REM disorder questionnaire was defined as predictive of RBD. Results: Out of the 418 PD patients, 113 (27.0%) had RBD. With univariate logistic regression analysis, individuals with scores predictive of RBD were 1.66 times more likely to have worse motor findings (p = 0.028). Even with age, gender, and Geriatric Depression Scale scores taken into account, individuals with scores predictive of RBD were 1.69 times more likely to have worse motor findings (p = 0.025). Discussion: PD patients with RBD symptoms had worse motor findings than those unlikely to have RBD. This association provides further evidence for the relationship between RBD and PD

Parkinson's disease biomarkers: perspective from the NINDS Parkinson's Disease Biomarkers Program

Biomarkers for Parkinson's disease (PD) diagnosis, prognostication and clinical trial cohort selection are an urgent need. While many promising markers have been discovered through the National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) and other mechanisms, no single PD marker or set of markers are ready for clinical use. Here we discuss the current state of biomarker discovery for platforms relevant to PDBP. We discuss the role of the PDBP in PD biomarker identification and present guidelines to facilitate their development. These guidelines include: harmonizing procedures for biofluid acquisition and clinical assessments, replication of the most promising biomarkers, support and encouragement of publications that report negative findings, longitudinal follow-up of current cohorts including the PDBP, testing of wearable technologies to capture readouts between study visits and development of recently diagnosed (de novo) cohorts to foster identification of the earliest markers of disease onset

Lewy Body Dementia Association\u27s Research Centers of Excellence Program: Inaugural Meeting Proceedings.

The first Lewy Body Dementia Association (LBDA) Research Centers of Excellence (RCOE) Investigator\u27s meeting was held on December 14, 2017, in New Orleans. The program was established to increase patient access to clinical experts on Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson\u27s disease dementia (PDD), and to create a clinical trials-ready network. Four working groups (WG) were created to pursue the LBDA RCOE aims: (1) increase access to high-quality clinical care, (2) increase access to support for people living with LBD and their caregivers, (3) increase knowledge of LBD among medical and allied (or other) professionals, and (4) create infrastructure for a clinical trials-ready network as well as resources to advance the study of new therapeutics

Lewy Body Dementia Association’s Research Centers of Excellence Program: Inaugural Meeting Proceedings

Abstract The first Lewy Body Dementia Association (LBDA) Research Centers of Excellence (RCOE) Investigator’s meeting was held on December 14, 2017, in New Orleans. The program was established to increase patient access to clinical experts on Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), and to create a clinical trials-ready network. Four working groups (WG) were created to pursue the LBDA RCOE aims: (1) increase access to high-quality clinical care, (2) increase access to support for people living with LBD and their caregivers, (3) increase knowledge of LBD among medical and allied (or other) professionals, and (4) create infrastructure for a clinical trials-ready network as well as resources to advance the study of new therapeutics.https://deepblue.lib.umich.edu/bitstream/2027.42/148286/1/13195_2019_Article_476.pd

A comprehensive screening of copy number variability in dementia with Lewy bodies

The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk. (C) 2019 Elsevier Inc. All rights reserved.Peer reviewe

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition

Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias

We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer’s dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition