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Abstract Genetic testing for Parkinson’s disease (PD) is infrequently performed due to perceptions of low utility. We investigated the personal utility in PD GENEration and how results lead to enrollment in additional research studies. Participants (n = 972) underwent genetic testing, results disclosure, genetic counseling, and completed a survey examining the perceived personal utility of their results and interest in participating in additional studies. Most participants found their genetic test results useful, including satisfying curiosity (81%), feeling good about helping the medical community (80%), and having information to share with family (77%). There were no significant differences in responses based on result type. Forty-five percent of participants expressed interest in participating in research studies; whereas 16% of participants confirmed enrollment. Our results suggest that participants find personal utility in genetic testing regardless of results. Although participants may be interested in enrolling in additional research, they may need support and resources.

This paper aims to present and discuss the issues, challenges, and strategies related to recruitment and retention in clinical trials involving participants with chronic pain. The randomized controlled clinical trial (RCT) is widely regarded as the gold standard for evaluating clinical interventions. However, it is crucial to acknowledge and address the challenges associated with recruiting and retaining participants. To prioritize the experience of the study population, targeted outreach strategies and a patient-centric approach are necessary. Researchers should consider incorporating recruitment and retention strategies during the study design phase. Implementing multi-pronged recruitment methods, leveraging relationships with community providers, and involving representatives of the patient population are helpful approaches. Effective communication and maintaining a professional environment are vital for optimizing engagement and supporting the successful execution of clinical trials involving participants with chronic pain.

Abstract Clinical Research Coordinators (CRCs) are vital collaborators in a clinical research project. They often are the primary liaisons between investigators and human participants in studies and are involved in every aspect of many protocols, including participant recruitment, care (both usual medical care and specific study‐related monitoring and procedures), data collection, specimen processing, and follow‐up. The Clinical Translational Science Award program, which was created by the National Institutes of Health in 2006, has significantly expanded the venues in which Clinical Research Resource (CRR) – based CRCs are embedded. CRCs functioning in these areas, outside of the research‐focused in‐patient environment of the CRR, are designated as “off‐site” CRCs. Many of these locations, such as intensive care units and emergency departments, require that CRCs interact regularly with healthcare providers whose primary functions are focused on providing optimal patient care rather than research and often involving very complex patients. These off‐site CRCs require additional training and support outside of the usual research‐oriented environment of the CRR. They are required to function within the context of the patient‐care team while fostering implementation of collaborative research. This is a description of such a program specifically geared to off‐site CRCs with the goal of enhancing the quality of research and experiences of CRCs.

Abstract Introduction: Clinical research is critical for healthcare advancement, but participant recruitment remains challenging. Clinical research professionals (CRPs; e.g., clinical research coordinator, research assistant) perform eligibility prescreening, ensuring adherence to study criteria while upholding scientific and ethical standards. This study investigates the key information CRP prioritizes during eligibility prescreening, providing insights to optimize data standardization, and recruitment approaches. Methods: We conducted a freelisting survey targeting 150 CRPs from diverse domains (i.e., neurological disorders, rare diseases, and other diseases) where they listed essential information they look for from medical records, participant/caregiver inquiries, and discussions with principal investigators to determine a potential participant’s research eligibility. We calculated the salience scores of listed items using Anthropac, followed by a two-level analytic procedure to classify and thematically categorize the data. Results: The majority of participants were female (81%), identified as White (44%) and as non-Hispanic (64.5%). The first-level analysis universally emphasized age, medication list, and medical history across all domains. The second-level analysis illuminated domain-specific approaches in information retrieval: for instance, history of present illness was notably significant in neurological disorders during participant and principal investigator inquiries, while research participation was distinctly salient in potential participant inquiries within the rare disease domain. Conclusion: This study unveils the intricacies of eligibility prescreening, with both universal and domain-specific methods observed. Variations in data use across domains suggest the need for tailored prescreening in clinical research. Incorporating these insights into CRP training and refining prescreening tools, combined with an ethical, participant-focused approach, can advance eligibility prescreening practices.

We have greater knowledge about the genetic contributions to Parkinson’s disease (PD) with major gene discoveries occurring in the last few decades and the identification of risk alleles revealed by genome-wide association studies (GWAS). This has led to increased genetic testing fueled by both patient and consumer interest and emerging clinical trials targeting genetic forms of the disease. Attention has turned to prodromal forms of neurodegenerative diseases, including PD, resulting in assessments of individuals at risk, with genetic testing often included in the evaluation. These trends suggest that neurologists, clinical geneticists, genetic counselors, and other clinicians across primary care and various specialties should be prepared to answer questions about PD genetic risks and test results. The aim of this article is to provide genetic information for professionals to use in their communication to patients and families who have experienced PD. This includes up-to-date information on PD genes, variants, inheritance patterns, and chances of disease to be used for risk counseling, as well as insurance considerations and ethical issues.

Abstract Huntington disease is characterized by progressive neurodegeneration, especially of the striatum, and the presence of polyglutamine huntingtin (HTT) inclusions. Although HTT inclusions are most abundant in the neocortex, their neocortical distribution and density in relation to the extent of CAG repeat expansion in the HTT gene and striatal pathologic grade have yet to be formally established. We immunohistochemically studied 65 brains with a pathologic diagnosis of Huntington disease to investigate the cortical distributions and densities of HTT inclusions within the calcarine (BA17), precuneus (BA7), motor (BA4) and prefrontal (BA9) cortices; in 39 of these brains, a p62 immunostain was used for comparison. HTT inclusions predominate in the infragranular cortical layers (layers V-VI) and layer III, however, the densities of HTT inclusions across the human cerebral cortex are not uniform but are instead regionally contingent. The density of HTT and p62 inclusions (intranuclear and extranuclear) in layers V-VI increases caudally to rostrally (BA17

Abstract Background: Randomized clinical trials (RCT) are the foundation for medical advances, but participant recruitment remains a persistent barrier to their success. This retrospective data analysis aims to (1) identify clinical trial features associated with successful participant recruitment measured by accrual percentage and (2) compare the characteristics of the RCTs by assessing the most and least successful recruitment, which are indicated by varying thresholds of accrual percentage such as ≥ 90% vs ≤ 10%, ≥ 80% vs ≤ 20%, and ≥ 70% vs ≤ 30%. Methods: Data from the internal research registry at Columbia University Irving Medical Center and Aggregated Analysis of ClinicalTrials.gov were collected for 393 randomized interventional treatment studies closed to further enrollment. We compared two regularized linear regression and six tree-based machine learning models for accrual percentage (i.e., reported accrual to date divided by the target accrual) prediction. The outperforming model and Tree SHapley Additive exPlanations were used for feature importance analysis for participant recruitment. The identified features were compared between the two subgroups. Results: CatBoost regressor outperformed the others. Key features positively associated with recruitment success, as measured by accrual percentage, include government funding and compensation. Meanwhile, cancer research and non-conventional recruitment methods (e.g., websites) are negatively associated with recruitment success. Statistically significant subgroup differences (corrected p-value < .05) were found in 15 of the top 30 most important features. Conclusion: This multi-source retrospective study highlighted key features influencing RCT participant recruitment, offering actionable steps for improvement, including flexible recruitment infrastructure and appropriate participant compensation.

Abstract In 2019, the Lewy Body Dementia Association formed an Industry Advisory Council to bring together a collaborative group of stakeholders with the goal of accelerating clinical research into Lewy body dementia treatments. At the second annual meeting of the Industry Advisory Council, held virtually on June 18, 2020, the key members presented ongoing and planned efforts toward the council’s goals. The meeting also featured a discussion about the effects of the COVID-19 pandemic on Lewy body dementia clinical research, lessons learned from that experience, and how those lessons can be applied to the design and conduct of future clinical trials. This report provides a brief summary of the meeting proceedings with a focus on efforts to improve and adapt future Lewy body dementia clinical research.

Abstract Lewy body dementia (LBD), including dementia with Lewy bodies and Parkinson’s disease dementia, affects over a million people in the USA and has a substantial impact on patients, caregivers, and society. Symptomatic treatments for LBD, which can include cognitive, neuropsychiatric, autonomic, sleep, and motor features, are limited with only two drugs (cholinesterase inhibitors) currently approved by regulatory agencies for dementia in LBD. Clinical trials represent a top research priority, but there are many challenges in the development and implementation of trials in LBD. To address these issues and advance the field of clinical trials in the LBDs, the Lewy Body Dementia Association formed an Industry Advisory Council (LBDA IAC), in addition to its Research Center of Excellence program. The LBDA IAC comprises a diverse and collaborative group of experts from academic medical centers, pharmaceutical industries, and the patient advocacy foundation. The inaugural LBDA IAC meeting, held in June 2019, aimed to bring together this group, along with representatives from regulatory agencies, to address the topic of optimizing the landscape of LBD clinical trials. This review highlights the formation of the LBDA IAC, current state of LBD clinical trials, and challenges and opportunities in the field regarding trial design, study populations, diagnostic criteria, and biomarker utilization. Current gaps include a lack of standardized clinical assessment tools and evidence-based management strategies for LBD as well as difficulty and controversy in diagnosing LBD. Challenges in LBD clinical trials include the heterogeneity of LBD pathology and symptomatology, limited understanding of the trajectory of LBD cognitive and core features, absence of LBD-specific outcome measures, and lack of established standardized biologic, imaging, or genetic biomarkers that may inform study design. Demands of study participation (e.g., travel, duration, and frequency of study visits) may also pose challenges and impact trial enrollment, retention, and outcomes. There are opportunities to improve the landscape of LBD clinical trials by harmonizing clinical assessments and biomarkers across cohorts and research studies, developing and validating outcome measures in LBD, engaging the patient community to assess research needs and priorities, and incorporating biomarker and genotype profiling in study design.

Abstract Background Mapping of allele-specific DNA methylation (ASM) can be a post-GWAS strategy for localizing regulatory sequence polymorphisms (rSNPs). The advantages of this approach, and the mechanisms underlying ASM in normal and neoplastic cells, remain to be clarified. Results We perform whole genome methyl-seq on diverse normal cells and tissues and three cancer types. After excluding imprinting, the data pinpoint 15,112 high-confidence ASM differentially methylated regions, of which 1838 contain SNPs in strong linkage disequilibrium or coinciding with GWAS peaks. ASM frequencies are increased in cancers versus matched normal tissues, due to widespread allele-specific hypomethylation and focal allele-specific hypermethylation in poised chromatin. Cancer cells show increased allele switching at ASM loci, but disruptive SNPs in specific classes of CTCF and transcription factor binding motifs are similarly correlated with ASM in cancer and non-cancer. Rare somatic mutations affecting these same motif classes track with de novo ASM. Allele-specific transcription factor binding from ChIP-seq is enriched among ASM loci, but most ASM differentially methylated regions lack such annotations, and some are found in otherwise uninformative “chromatin deserts.” Conclusions ASM is increased in cancers but occurs by a shared mechanism involving disruptive SNPs in CTCF and transcription factor binding sites in both normal and neoplastic cells. Dense ASM mapping in normal plus cancer samples reveals candidate rSNPs that are difficult to find by other approaches. Together with GWAS data, these rSNPs can nominate specific transcriptional pathways in susceptibility to autoimmune, cardiometabolic, neuropsychiatric, and neoplastic diseases.

Abstract Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.

Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.

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.

Introduction: The Montreal Cognitive Assessment (MoCA), an instrument widely used for cognitive screening in Parkinson's disease (PD), is validated in Hebrew and English. However, it remains unknown whether the scores are comparable. Methods: The MoCA was analyzed in 483 Ashkenazi Jewish PD patients in Tel-Aviv and New York who had MoCA ≥21. Each section of the MoCA was compared between English and Hebrew. Linear regression models were used to test the association between MoCA performance and language. Results: Total MoCA scores were lower in Hebrew than in English (25.4 versus 26.1; P = 0.007), even after adjustment for age, sex, PD duration, genotype, levodopa equivalent dose, the Unified Parkinson's Disease Rating Scale (UPDRS-III), and Geriatric Depression Scale score in a linear model (P

Mutations in the LRRK2 and GBA genes are the most common inherited causes of Parkinson's disease (PD). Studies exploring phenotypic differences based on genetic status used hypothesis-driven data-gathering and statistical-analyses focusing on specific symptoms, which may influence the validity of the results. We aimed to explore phenotypic expression in idiopathic PD (iPD) patients, G2019S-LRRK2-PD, and GBA-PD using a data-driven approach, allowing screening of large numbers of features while controlling selection bias. Data was collected from 1525 Ashkenazi Jews diagnosed with PD from the Tel-Aviv Medical center; 161 G2019S-LRRK2-PD, 222 GBA-PD, and 1142 iPD (no G2019S-LRRK2 or any of the 7 AJ GBA mutations tested). Data included 771 measures: demographics, cognitive, physical and neurological functions, performance-based measures, and non-motor symptoms. The association of the genotypes with each of the measures was tested while accounting for age at motor symptoms onset, gender, and disease duration; p-values were reported and corrected in a hierarchical approach for an average over the selected measures false discovery rate control, resulting in 32 measures. GBA-PD presented with more severe symptoms expression while LRRK2-PD had more benign symptoms compared to iPD. GBA-PD presented greater cognitive and autonomic involvement, more frequent hyposmia and REM sleep behavior symptoms while these were less frequent among LRRK2-PD compared to iPD. Using a data-driven analytical approach strengthens earlier studies and extends them to portray a possible unique disease phenotype based on genotype among AJ PD. Such findings could help direct a more personalized therapeutic approach.

Objectives. As genetic testing is becoming more widely commercially available for Parkinson’s disease (PD) and may have implications regarding clinical outcomes for deep brain stimulation (DBS) and other therapies, we aimed to determine patient knowledge and attitudes towards genetic testing. Methods. A sample of 88 PD subjects with bilateral STN-DBS completed a Genetic Attitudes Questionnaire (GAQ). Knowledge and attitudes towards genetic testing were assessed. Results. The mean percent of correct responses regarding genetic testing knowledge was 58.5%. Nearly 90% of subjects were unfamiliar with Genetic Information Nondiscrimination Act (GINA). The most important reasons subjects cited in deciding whether to undergo genetic testing included (1) to be a candidate for clinical trials if positive, (2) to learn that they do not carry a mutation, and (3) because a healthcare provider had recommended it. Individuals who influence decision-making include spouses and children. About 88% of subjects would share results with spouses, children, and siblings. Discussion. These results reveal that there is a major knowledge gap regarding genetic testing in PD and the implications of testing results on treatment, work, insurance, and privacy. Also, subjects would mainly seek genetic testing to participate in clinical trials, with spouses and children being the key stakeholders in decision-making.

Identification of early changes in Dopamine-Transporter (DaT) SPECT imaging expected in the prodromal phase of Parkinson's disease (PD), are usually overlooked. Carriers of the G2019S LRRK2 mutation are known to be at high risk for developing PD, compared to non-carriers. In this work we aimed to study early changes in Dopamine uptake in non-manifesting PD carriers (NMC) of the G2019S LRRK2 mutation using quantitative DaT-SPECT analysis and to examine the potential for early prediction of PD. Eighty Ashkenazi-Jewish subjects were included in this study: eighteen patients with PD; thirty-one NMC and thirty-one non-manifesting non-carriers (NMNC). All subjects underwent a through clinical assessment including evaluation of motor, olfactory, affective and non-motor symptoms and DaT-SPECT imaging. A population based DaT-SPECT template was created based on the NMNC cohort, and data driven volumes-of-interest (VOIs) were defined. Comparisons between groups were performed based on VOIs and voxel-wise analysis. The striatum area of all three cohorts was segmented into four VOIs, corresponding to the right/left dorsal and ventral striatum. Significant differences in clinical measures were found between patients with PD and non-manifesting subjects with no differences between NMC and NMNC. Significantly lower uptake (p

Although the huntingtin gene is expressed in brain throughout life, phenotypically Huntington's disease (HD) begins only in midlife and affects specific brain regions. Here, to investigate regional vulnerability in the disease, we used functional magnetic resonance imaging (fMRI) to translationally link studies in patients with a mouse model of disease. Using fMRI, we mapped cerebral blood volume (CBV) in three groups: HD patients, symptom-free carriers of the huntingtin genetic mutation, and age-matched controls. In contrast to a region in the anterior caudate, in which dysfunction was linked to genotype independent of phenotype, a region in the posterior body of the caudate was differentially associated with disease phenotype. Guided by these observations, we harvested regions from the anterior and posterior body of the caudate in postmortem control and HD human brain tissue. Gene-expression profiling identified two molecules whose expression levels were most strongly correlated with regional vulnerability — protein phosphatase 1 regulatory subunit 7 (PPP1R7) and Wnt inhibitory factor-1 (WIF-1). To verify and potentially extend these findings, we turned to the YAC128 (C57BL/6J) HD transgenic mice. By fMRI we longitudinally mapped CBV in transgenic and wildtype (WT) mice, and over time, abnormally low fMRI signal emerged selectively in the dorsal striatum. A relatively unaffected brain region, primary somatosensory cortex (S1), was used as a control. Both dorsal striatum and S1 were harvested from transgenic and WT mice and molecular analysis confirmed that PPP1R7 deficiency was strongly correlated with the phenotype. Together, converging findings in human HD patients and this HD mouse model suggest a functional pattern of caudate vulnerability and that variation in expression levels of herein identified molecules correlate with this pattern of vulnerability.

Variants in GBA are associated with Lewy Body (LB) pathology. We investigated whether variants in other lysosomal storage disorder (LSD) genes also contribute to disease pathogenesis.We performed a genetic analysis of four LSD genes including GBA, HEXA, SMPD1, and MCOLN1 in 231 brain autopsies. Brain autopsies included neuropathologically defined LBD without Alzheimer Disease (AD) changes (n = 59), AD without significant LB pathology (n = 71), Alzheimer disease and lewy body variant (ADLBV) (n = 68), and control brains without LB or AD neuropathology (n = 33). Sequencing of HEXA, SMPD1, MCOLN1 and GBA followed by 'gene wise' genetic association analysis was performed. To determine the functional effect, a biochemical analysis of GBA in a subset of brains was also performed. GCase activity was measured in a subset of brain samples (n = 64) that included LBD brains, with or without GBA mutations, and control brains. A lipidomic analysis was also performed in brain autopsies (n = 67) which included LBD (n = 34), ADLBV (n = 3), AD (n = 4), PD (n = 9) and control brains (n = 17), comparing GBA mutation carriers to non-carriers.In a 'gene-wise' analysis, variants in GBA, SMPD1 and MCOLN1 were significantly associated with LB pathology (p range: 0.03-4.14 x10(-5)). Overall, the mean levels of GCase activity were significantly lower in GBA mutation carriers compared to non-carriers (p

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expansion of CAG repeats in the IT15 gene. The age-at-onset (AAO) of HD is inversely related to the CAG repeat length and the minimum length thought to cause HD is 36. Accurate estimation of the AAO distribution based on CAG repeat length is important for genetic counseling and the design of clinical trials. In the Cooperative Huntington's Observational Research Trial (COHORT) study, the CAG repeat length is known for the proband participants. However, whether a family member shares the huntingtin gene status (CAG expanded or not) with the proband is unknown. In this work, we use the expectation-maximization (EM) algorithm to handle the missing huntingtin gene information in first-degree family members in COHORT, assuming that a family member has the same CAG length as the proband if the family member carries a huntingtin gene mutation. We perform simulation studies to examine performance of the proposed method and apply the methods to analyze COHORT proband and family combined data. Our analyses reveal that the estimated cumulative risk of HD symptom onset obtained from the combined data is slightly lower than the risk estimated from the proband data alone.

Crohn's disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD-susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2-4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p