Research Priorities of Individuals and Caregivers With Lewy Body Dementia: A Web-based Survey.

INTRODUCTION: Lewy body dementia (LBD) is common, yet under-recognized and under-researched. To plan studies with the highest impact, engagement of the community personally affected by these conditions is essential. METHODS: A web-based survey of people living with LBD and current and former caregivers of people with LBD queried research priorities through forced ranking and exploration of burden of LBD symptoms. Specific caregiving needs in LBD and perceptions of research participation were also investigated. RESULTS: Between April 7, 2021 and July 1, 2021, 984 responses were recorded. Top research priorities included disease-modifying therapies and improved disease detection and staging. People with LBD were interested in pathophysiology and more bothered by motor symptoms; caregivers were interested in risk factors and symptomatic therapies and more bothered by neuropsychiatric symptoms. Few available LBD treatments and resources were rated as helpful, and many valuable services were never received. Previous participation in LBD research was infrequent, but interest was high. DISCUSSION: People with LBD and caregivers highlighted the need for research across all aspects of LBD, from pathophysiology and disease modification to prognosis, education, symptomatic treatments, and caregiver support. Funders should increase support for all aspects of LBD research to target the many needs identified by individuals and families living with LBD.

Effect of best practice advisory on the administration of contraindicated medications to hospitalized patients with Parkinson's disease and related disorders.

Objective: To determine the effect of a Best Practice Advisory (BPA) on the ordering and administration of contraindicated dopamine blocking agents (DBA) to hospitalized patients with Parkinson's disease (PD) and related disorders. Background: Patients with PD are more likely to require hospitalization and are at increased risk of complications. Administration of contraindicated DBA contributes to worsened outcomes in this patient population. Electronic medical record (EMR) warnings (also referred to as BPA) have been proposed as a way to prevent the administration of contraindicated medications. Methods: A BPA was launched in January 2020 within the University of Rochester EMR system, which alerts the provider when a contraindicated DBA is ordered in hospitalized patients with PD and related disorders. Patients with PD and related disorders hospitalized at two hospitals affiliated to the University of Rochester during a time period before (t1: 1/1/2019-1/1/2020) and after (t2: 1/8/2020-1/8/2021) the implementation of the BPA were included in this study. Epic SliderDicer was used to collect the data from the University of Rochester EMR. The number of patients who had contraindicated DBA orders and administrations in both time periods, and the number of patients who had the BPA triggered during t2 were obtained. We compared the results before and after the implementation of the BPA. Results: 306 patients with PD and related disorders were hospitalized during t1 and 273 during t2. There was significantly less percentage of patients who had contraindicated DBA orders (41.5% in t1 vs. 17.6% in t2) and patients who had contraindicated DBA administrations (16% in t1 vs. 8.8% in t2) during t2 (p < 0.05 for both comparisons). There was no significant difference between the percentage of patients who had contraindicated DBA orders in t1 and patients with attempted orders (BPA triggered) in t2 (p = 0.27). Conclusion: The results of this study increase the evidence of the potential benefit of EMR warnings for the optimization of inpatient medication management in patients with PD and related disorders. In particular, our results suggest that EMR warnings help reduce the administration of contraindicated medications, which is a known contributing factor for hospital complications in this patient population.

Standardizing default electronic health record tools to improve safety for hospitalized patients with Parkinson's disease.

Electronic Health Record (EHR) systems are often configured to address challenges and improve patient safety for persons with Parkinson's disease (PWP). For example, EHR systems can help identify Parkinson's disease (PD) patients across the hospital by flagging a patient's diagnosis in their chart, preventing errors in medication and dosing through the use of clinical decision support, and supplementing staff education through care plans that provide step-by-step road maps for disease-based care of a specific patient population. However, most EHR-based solutions are locally developed and, thus, difficult to scale widely or apply uniformly across hospital systems. In 2020, the Parkinson's Foundation, a national and international leader in PD research, education, and advocacy, and Epic, a leading EHR vendor with more than 35% market share in the United States, launched a partnership to reduce risks to hospitalized PWP using standardized EHR-based solutions. This article discusses that project which included leadership from physician informaticists, movement disorders specialists, hospital quality officers, the Parkinson's Foundation and members of the Parkinson's community. We describe the best practice solutions developed through this project. We highlight those that are currently available as standard defaults or options within the Epic EHR, discuss the successes and limitations of these solutions, and consider opportunities for scalability in environments beyond a single EHR vendor. The Parkinson's Foundation and Epic launched a partnership to develop best practice solutions in the Epic EHR system to improve safety for PWP in the hospital. The goal of the partnership was to create the EHR tools that will have the greatest impact on outcomes for hospitalized PWP.

A Remote Longitudinal Observational Study of Individuals at Genetic Risk for Parkinson Disease: Baseline Results.

Background and Objectives: To recruit and characterize a national cohort of individuals who have a genetic variant (LRRK2 G2019S) that increases risk of Parkinson disease (PD), assess participant satisfaction with a decentralized, remote research model, and evaluate interest in future clinical trials. Methods: In partnership with 23andMe, Inc., a personal genetics company, LRRK2 G2019S carriers with and without PD were recruited to participate in an ongoing 36-month decentralized, remote natural history study. We examined concordance between self-reported and clinician-determined PD diagnosis. We applied the Movement Disorder Society Prodromal Parkinson's Disease Criteria and asked investigators to identify concern for parkinsonism to distinguish participants with probable prodromal PD. We compared baseline characteristics of LRRK2 G2019S carriers with PD, with prodromal PD, and without PD. Results: Over 15 months, we enrolled 277 LRRK2 G2019S carriers from 34 states. At baseline, 60 had self-reported PD (mean [SD] age 67.8 years [8.4], 98% White, 52% female, 80% Ashkenazi Jewish, and 67% with a family history of PD), and 217 did not (mean [SD] age 53.7 years [15.1], 95% White, 59% female, 73% Ashkenazi Jewish, and 57% with a family history of PD). Agreement between self-reported and clinician-determined PD status was excellent (κ = 0.94, 95% confidence interval 0.89-0.99). Twenty-four participants had prodromal PD; 9 met criteria for probable prodromal PD and investigators identified concern for parkinsonism in 20 cases. Compared with those without prodromal PD, participants with prodromal PD were older (63.9 years [9.0] vs 51.9 years [15.1], p < 0.001), had higher modified Movement Disorders Society-Unified Parkinson's Disease Rating Scale motor scores (5.7 [4.3] vs 0.8 [2.1], p < 0.001), and had higher Scale for Outcomes in PD for Autonomic Symptoms scores (11.5 [6.2] vs 6.9 [5.7], p = 0.002). Two-thirds of participants enrolled were new to research, 97% were satisfied with the overall study, and 94% of those without PD would participate in future preventive clinical trials. Discussion: An entirely remote national cohort of LRRK2 G2019S carriers was recruited from a single site. This study will prospectively characterize a large LRRK2 G2019S cohort, refine a new model of clinical research, and engage new research participants willing to participate in future therapeutic trials.

Design of a virtual longitudinal observational study in Parkinson's disease (AT-HOME PD).

OBJECTIVE: The expanding power and accessibility of personal technology provide an opportunity to reduce burdens and costs of traditional clinical site-centric therapeutic trials in Parkinson's disease and generate novel insights. The value of this approach has never been more evident than during the current COVID-19 pandemic. We sought to (1) establish and implement the infrastructure for longitudinal, virtual follow-up of clinical trial participants, (2) compare changes in smartphone-based assessments, online patient-reported outcomes, and remote expert assessments, and (3) explore novel digital markers of Parkinson's disease disability and progression. METHODS: Participants from two recently completed phase III clinical trials of inosine and isradipine enrolled in Assessing Tele-Health Outcomes in Multiyear Extensions of Parkinson's Disease trials (AT-HOME PD), a two-year virtual cohort study. After providing electronic informed consent, individuals complete annual video visits with a movement disorder specialist, smartphone-based assessments of motor function and socialization, and patient-reported outcomes online. RESULTS: From the two clinical trials, 226 individuals from 42 states in the United States and Canada enrolled. Of these, 181 (80%) have successfully downloaded the study's smartphone application and 161 (71%) have completed patient-reported outcomes on the online platform. INTERPRETATION: It is feasible to conduct a large-scale, international virtual observational study following the completion of participation in brick-and-mortar clinical trials in Parkinson's disease. This study, which brings research to participants, will compare established clinical endpoints with novel digital biomarkers and thereby inform the longitudinal follow-up of clinical trial participants and design of future clinical trials.

A Virtual Cohort Study of Individuals at Genetic Risk for Parkinson's Disease: Study Protocol and Design.

BACKGROUND: The rise of direct-to-consumer genetic testing has enabled many to learn of their possible increased risk for rare diseases, some of which may be suitable for gene-targeted therapies. However, recruiting a large and representative population for rare diseases or genetically defined sub-populations of common diseases is slow, difficult, and expensive. OBJECTIVE: To assess the feasibility of recruiting and retaining a cohort of individuals who carry a genetic mutation linked to Parkinson's disease (G2019S variant of LRRK2); to characterize this cohort relative to the characteristics of traditional, in-person studies; and to evaluate this model's ability to create an engaged study cohort interested in future clinical trials of gene-directed therapies. METHODS: This single-site,3-year national longitudinal observational study will recruit between 250 to 350 LRRK2 carriers without Parkinson's disease and approximately 50 with the condition. Participants must have undergone genetic testing by the personal genetics company, 23andMe, Inc., have knowledge of their carrier status, and consent to be contacted for research studies. All participants undergo standardized assessments, including video-based cognitive and motor examination, and complete patient-reported outcomes on an annual basis. RESULTS: 263 individuals living in 33 states have enrolled. The cohort has a mean (SD) age of 56.0 (15.9) years, 59% are female, and 76% are of Ashkenazi Jewish descent. 233 have completed the baseline visit: 47 with self-reported Parkinson's disease and 186 without. CONCLUSIONS: This study establishes a promising model for developing a geographically dispersed and well-characterized cohort ready for participation in future clinical trials of gene-directed therapies.

Deep Phenotyping of Parkinson's Disease.

Phenotype is the set of observable traits of an organism or condition. While advances in genetics, imaging, and molecular biology have improved our understanding of the underlying biology of Parkinson's disease (PD), clinical phenotyping of PD still relies primarily on history and physical examination. These subjective, episodic, categorical assessments are valuable for diagnosis and care but have left gaps in our understanding of the PD phenotype. Sensors can provide objective, continuous, real-world data about the PD clinical phenotype, increase our knowledge of its pathology, enhance evaluation of therapies, and ultimately, improve patient care. In this paper, we explore the concept of deep phenotyping-the comprehensive assessment of a condition using multiple clinical, biological, genetic, imaging, and sensor-based tools-for PD. We discuss the rationale for, outline current approaches to, identify benefits and limitations of, and consider future directions for deep clinical phenotyping.

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

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.

Call to Caution with the Use of Atypical Antipsychotics for Treatment of Depression in Older Adults.

Atypical antipsychotics are increasingly being used to manage depression in older adults where these symptoms can often be refractory to first-line treatment with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). Unfortunately, atypical antipsychotics can be associated with the development of extrapyramidal symptoms (EPS), with drug-induced parkinsonism (DIP) being the most common movement disorder induced by this class of medication. The management of treatment-resistant depression in older adults is of particular concern as depression is a common feature of idiopathic Parkinson's disease (IPD) and can manifest prior to the development of motor symptoms. Herein, we discuss the use of atypical antipsychotics for the management of depression in older adults including the risk of DIP and propose that antipsychotics may potentially unmask IPD.

The mitochondrial disease associated protein Ndufaf2 is dispensable for Complex-1 assembly but critical for the regulation of oxidative stress.

Deficiency in human mitochondrial Complex-1 has been linked to a wide variety of neurological disorders. Homozygous deletion of the Complex-1 associated protein, Ndufaf2, leads to a severe juvenile onset encephalopathy involving degeneration of the substantia nigra and other sub-cortical regions resulting in adolescent lethality. To understand the precise role of Ndufaf2 in Complex-1 function and its links to neurologic disease, we studied the effects on Complex-1 assembly and function, as well as pathological consequences at the cellular level, in multiple in vitro models of Ndufaf2 deficiency. Using both Ndufaf2-deficient human neuroblastoma cells and primary fibroblasts cultured from Ndufaf2 knock-out mice we found that Ndufaf2-deficiency selectively reduces Complex-1 activity. While Ndufaf2 is traditionally referred to as an assembly factor of Complex-1, surprisingly, however, Ndufaf2-deficient cells were able to assemble a fully mature Complex-1 enzyme, albeit with reduced kinetics. Importantly, no evidence of intermediate or incomplete assembly was observed. Ndufaf2 deficiency resulted in significant increases in oxidative stress and mitochondrial DNA deletion, consistent with contemporary hypotheses regarding the pathophysiology of inherited mutations in Complex-1 disorders. These data suggest that Ndufaf2, unlike other Complex-1 assembly factors, may be more accurately described as a chaperone involved in proper folding during Complex-1 assembly, since it is dispensable for Complex-1 maturation but not its proper function.

Parkin selectively alters the intrinsic threshold for mitochondrial cytochrome c release.

Autosomal-recessive mutations in the Parkin gene are the second most common cause of familial Parkinson's disease (PD). Parkin deficiency leads to the premature demise of the catecholaminergic neurons of the ventral midbrain in familial PD. Thus, a better understanding of parkin function may elucidate molecular aspects of their selective vulnerability in idiopathic PD. Numerous lines of evidence suggest a mitochondrial function for parkin and a protective effect of ectopic parkin expression. Since mitochondria play a critical role in cell survival/cell death through regulated cytochrome c release and control of apoptosis, we sought direct evidence of parkin function in this pathway. Mitochondria were isolated from cells expressing either excess levels of human parkin or shRNA directed against endogenous parkin and then treated with peptides corresponding to the active Bcl-2 homology 3 (BH3) domains of pro-apoptotic proteins and the threshold for cytochrome c release was analyzed. Data obtained from both rodent and human neuroblastoma cell lines showed that the expression levels of parkin were inversely correlated with cytochrome c release. Parkin was found associated with isolated mitochondria, but its binding per se was not sufficient to inhibit cytochrome c release. In addition, pathogenic parkin mutants failed to influence cytochrome c release. Furthermore, PINK1 expression had no effect on cytochrome c release, suggesting a divergent function for this autosomal recessive PD-linked gene. In summary, these data demonstrate a specific autonomous effect of parkin on mitochondrial mechanisms governing cytochrome c release and apoptosis, which may be relevant to the selective vulnerability of certain neuronal populations in PD.