Genetic analysis and natural history of Parkinson's disease due to the LRRK2 G2019S variant.

The LRRK2 G2019S variant is the most common cause of monogenic Parkinson's disease (PD); however, questions remain regarding the penetrance, clinical phenotype and natural history of carriers. We performed a 3.5-year prospective longitudinal online study in a large number of 1286 genotyped LRRK2 G2019S carriers and 109 154 controls, with and without PD, recruited from the 23andMe Research Cohort. We collected self-reported motor and non-motor symptoms every 6 months, as well as demographics, family histories and environmental risk factors. Incident cases of PD (phenoconverters) were identified at follow-up. We determined lifetime risk of PD using accelerated failure time modelling and explored the impact of polygenic risk on penetrance. We also computed the genetic ancestry of all LRRK2 G2019S carriers in the 23andMe database and identified regions of the world where carrier frequencies are highest. We observed that despite a 1 year longer disease duration (P = 0.016), LRRK2 G2019S carriers with PD had similar burden of motor symptoms, yet significantly fewer non-motor symptoms including cognitive difficulties, REM sleep behaviour disorder (RBD) and hyposmia (all P-values ≤ 0.0002). The cumulative incidence of PD in G2019S carriers by age 80 was 49%. G2019S carriers had a 10-fold risk of developing PD versus non-carriers. This rose to a 27-fold risk in G2019S carriers with a PD polygenic risk score in the top 25% versus non-carriers in the bottom 25%. In addition to identifying ancient founding events in people of North African and Ashkenazi descent, our genetic ancestry analyses infer that the G2019S variant was later introduced to Spanish colonial territories in the Americas. Our results suggest LRRK2 G2019S PD appears to be a slowly progressive predominantly motor subtype of PD with a lower prevalence of hyposmia, RBD and cognitive impairment. This suggests that the current prodromal criteria, which are based on idiopathic PD, may lack sensitivity to detect the early phases of LRRK2 PD in G2019S carriers. We show that polygenic burden may contribute to the development of PD in the LRRK2 G2019S carrier population. Collectively, the results should help support screening programmes and candidate enrichment strategies for upcoming trials of LRRK2 inhibitors in early-stage disease.

Characterizing the Genetic Architecture of Parkinson's Disease in Latinos.

OBJECTIVE: This work was undertaken in order to identify Parkinson's disease (PD) risk variants in a Latino cohort, to describe the overlap in the genetic architecture of PD in Latinos compared to European-ancestry subjects, and to increase the diversity in PD genome-wide association (GWAS) data. METHODS: We genotyped and imputed 1,497 PD cases and controls recruited from nine clinical sites across South America. We performed a GWAS using logistic mixed models; variants with a p-value <1 × 10-5 were tested in a replication cohort of 1,234 self-reported Latino PD cases and 439,522 Latino controls from 23andMe, Inc. We also performed an admixture mapping analysis where local ancestry blocks were tested for association with PD status. RESULTS: One locus, SNCA, achieved genome-wide significance (p-value <5 × 10-8 ); rs356182 achieved genome-wide significance in both the discovery and the replication cohorts (discovery, G allele: 1.58 OR, 95% CI 1.35-1.86, p-value 2.48 × 10-8 ; 23andMe, G allele: 1.26 OR, 95% CI 1.16-1.37, p-value 4.55 × 10-8 ). In our admixture mapping analysis, a locus on chromosome 14, containing the gene STXBP6, achieved significance in a joint test of ancestries and in the Native American single-ancestry test (p-value <5 × 10-5 ). A second locus on chromosome 6, containing the gene RPS6KA2, achieved significance in the African single-ancestry test (p-value <5 × 10-5 ). INTERPRETATION: This study demonstrated the importance of the SNCA locus for the etiology of PD in Latinos. By leveraging the demographic history of our cohort via admixture mapping, we identified two potential PD risk loci that merit further study. ANN NEUROL 2021;90:353-365.

Current practice trends for lacrimal gland neurotoxin in the management of epiphora-a BOPSS survey.

PURPOSE: Injection of botulinum neurotoxin A (BoNTA) to the lacrimal gland (LG) offers a simple and effective treatment in the management of epiphora. However, there is little data on current practice trends or uptake as an alternative to surgery. This study assesses current practice trends of such treatment amongst BOPSS (British Oculoplastic Surgery Society) members. METHODS: All consultant BOPSS members were invited to participate in a web-based survey which consisted of 5 questions, with a reminder invitation to participate. The role, dose, potential side effects, use as an alternative to surgical intervention, and impact on service delivery were assessed. RESULTS: Fifty-one BOPSS consultants (43% uptake) completed the survey. Ninety percent of respondents were regularly using LG BoNTA in their management of epiphora. The main indicators for considering BoNTA use were medical comorbidities and elderly patients. The mean first treatment dose of Botox® was 3.6 units (SD 1.5). Diplopia and ptosis complications were always discussed in the consent for treatment in addition to dry eye. Twenty-five percent of surgeons reported doing less conjunctivo-dacryocystorhinostomies (cDCR) due to the availability of LG BoNTA. No respondents felt that the requirement for repeated BoNTA treatments was impacting on their service delivery. CONCLUSION: Uptake of LG BoNTA in the management of epiphora is at a similar rate to all other available treatments. As a result, respondents are performing less surgical procedures, particularly cDCR in patients at higher surgical morbidity.

Cutaneous pleomorphic adenoma of the periocular region - a case series.

Mixed tumour of the skin is a rare entity also known as chondroid syringoma and pleomorphic adenoma. These usually present as slow-growing skin nodules with a smooth surface, clear boundaries, and no ulceration. Case series exist describing pleomorphic adenomas in the periocular region including the lids and orbit, separate to the more familiar lacrimal gland pleomorphic adenoma. These may arise from accessory or ectopic lacrimal gland tissue but in the eyelids are more likely to arise from sweat glands in the skin. Histopathological analysis of these lesions is important to identify complete excision, minimising recurrences and in identifying rare but potential malignant transformation. We describe the clinical features and outcomes in three cases of pleomorphic adenoma with two at the medial canthus (including one recurrence) and one in the brow region.

Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies.

OBJECTIVE: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. METHODS: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis. RESULTS: A 5'-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5' risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3' of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3' variant rs356182) had an opposite direction of effect in iRBD compared to PD. INTERPRETATION: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3' of SNCA. Several 5' SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584-598.

Functional Measures of Grip Strength and Gait Remain Altered Long-term in a Rat Model of Post-traumatic Elbow Contracture.

Post-traumatic joint contracture (PTJC) is a debilitating condition, particularly in the elbow. Previously, we established an animal model of elbow PTJC quantifying passive post-mortem joint mechanics and histological changes temporally. These results showed persistent motion loss similar to what is experienced in humans. Functional assessment of PTJC in our model was not previously considered; however, these measures would provide a clinically relevant measure and would further validate our model by demonstrating persistently altered joint function. To this end, a custom bilateral grip strength device was developed, and a recently established open-source gait analysis system was used to quantify forelimb function in our unilateral injury model. In vivo joint function was shown to be altered long-term and never fully recover. Specifically, forelimb strength in the injured limbs showed persistent deficits at all time points; additionally, gait patterns remained imbalanced and asymmetric throughout the study (although a few gait parameters did return to near normal levels). A quantitative understanding of these longitudinal, functional disabilities further strengthens the clinical relevance of our rat PTJC model enabling assessment of the effectiveness of future interventions aimed at reducing or preventing PTJC.

Real-time superchannel transmission over 10,500 km submarine link at 4.66 b/s/Hz spectral efficiency.

We show real-time measurement of error-free superchannel transmission over more than 10,500 km of large-area fiber at a spectral efficiency of 4.66 b/s/Hz, utilizing subcarrier based signal processing optimized at 5.4 GBd.

Multigene phylogenetic analysis detects cryptic species of Tryblidiopsis in China.

Tryblidiopsis pinastri (Rhytismatales) has been recognized as being distributed throughout northern temperate regions. In the present study, comparative studies showed that species of Tryblidiopsis from China were distinct from the European type species. They are shown to belong to two new Tryblidiopsis species, T sichuanensis and T. sinensis, with a third known to be present in China but not described because the reference material is immature. Combined LSU rDNA, ITS rDNA and mtSSU rDNA sequences analyses revealed that Chinese species and European species formed a monophyletic clade. Collections of Tryblidiopsis from North America need to be re-examined and sequenced; they are probably not conspecific with T. pinastri. Tryblidiopsis species appear to be highly host specific and are probably restricted to the host genus Picea.

Incidence of canalicular closure with endonasal dacryocystorhinostomy without intubation in primary nasolacrimal duct obstruction.

PURPOSE: To describe the incidence of canalicular closure with powered endonasal dacryocystorhinostomy (DCR) without canalicular intubation in primary acquired nasolacrimal duct obstruction (PANDO). DESIGN: A single-surgeon, prospective, nonrandomized, noncomparative, interventional case series. PARTICIPANTS: Consecutive patients attending a specialist clinic of an oculoplastic surgeon (DS) with radiologically confirmed diagnosis of PANDO. Cases of canalicular disease were excluded. METHODS: Patients with radiologically confirmed PANDO without canalicular involvement underwent endonasal DCR without intubation. The operation was performed by 1 surgeon (DS) and follow-up was at 4 weeks and 12 months. MAIN OUTCOME MEASURES: Outcomes were recorded as subjective symptomatic relief at 12 months and endoscopic evidence of ostium patency and canalicular patency. RESULTS: There were 132 cases that fulfilled the inclusion criteria. Three cases were lost to follow-up. Preoperatively, 96.3% of cases had Munk scores of >2. Of the 129 cases, 127 (98.5%) had endoscopic evidence of a patent ostium with a positive endoscopic dye test at the 12-month follow-up. All cases had a patent canalicular system as demonstrated by syringing and probing. Of the 129 cases, 117 (90.7%) had subjective improvement of epiphora at 12 months with 88.4% of cases reporting Munk scores of ≤1. CONCLUSIONS: In this prospective series of nonintubation for PANDO, there were no cases of canalicular closure or stenosis at 12 months. Anatomic and functional success was similar to reported outcomes for DCR with intubation for PANDO. We advocate that routine intubation for the purpose of maintaining canalicular patency is not necessary when performing endonasal DCR in PANDO. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Endoscopic transcaruncular repair of large medial orbital wall fractures near the orbital apex.

PURPOSE: To study the suitability of an endoscopic transcaruncular approach (ETA) for repair of large medial orbital wall fractures (MOWFs) near the orbital apex. DESIGN: A retrospective, noncomparative case series with description of the surgical technique. PARTICIPANTS: Ninety-three consecutive patients (93 orbits) with large isolated MOWFs near the orbital apex. METHODS: The isolated MOWFs were determined by computed tomography (CT) scans of the orbit in all patients. All patients underwent fracture repair by an ETA, and the vertical and horizontal dimensions of the defects were measured during surgery. Porous polyethylene sheets (1.0 mm thick) were used to repair the bony defects. Patients were followed for 6 to 15 months. MAIN OUTCOME MEASURES: Size of vertical and horizontal fracture defects, rate of complete repair of the fracture defects, correction of enophthalmos, resolution of diplopia, and complications 6 months after surgery. RESULTS: All surgeries were completed uneventfully. The mean postoperative follow-up time was 9.7 ± 3.0 months. Under direct endoscopic visualization, all entrapped and herniated orbital contents were released and reposited, the entire boundary of the fractures were exposed adequately, and the implants were placed to overlie all edges of the fracture stably in all cases. The vertical and horizontal fracture defects measured during surgeries ranged from 16 to 30 mm and from 25 to 34 mm, respectively. Six months after surgery, complete reconstruction of the bony defects was demonstrated by orbital CT scans, and symmetry of the both eyes was acquired in 92 of 93 patients (98.9%). Of 30 patients with significant preoperative enophthalmos of more than 2 mm, 29 (96.7%) were corrected, with a mean improvement of 3.37 ± 0.77 mm. Diplopia within the 30° visual field of the gaze was resolved in 40 of 43 patients (93.0%). Three patients (7.0%) had residual diplopia on medial gaze because of presumed paralysis of the medial rectus muscle. Intraorbital hemorrhage occurred in 1 patient the day after surgery and resolved with conservative treatment. CONCLUSIONS: The ETA seems to be a useful method for recovery of the normal anatomic features of the orbits for patients with large MOWFs near the orbital apex.

Factors associated with recruitment to randomised controlled trials in general practice: a systematic mixed studies review.

BACKGROUND: A common challenge for randomised controlled trials (RCTs) is recruiting enough participants to be adequately powered to answer the research question. Recruitment has been set as a priority research area in trials to improve recruitment and thereby reduce wasted resources in conducted trials that fail to recruit sufficiently. METHODS: We conducted a systematic mixed studies review to identify the factors associated with recruitment to RCTs in general practice. On September 8, 2020, English language studies were identified from MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and CENTRAL databases for published studies. NTIS and OpenGrey were searched for grey literature, and BMC Trials was hand searched. A narrative synthesis was conducted for qualitative studies and a thematic synthesis for qualitative studies. RESULTS: Thirty-seven studies met the inclusion criteria. These were of different study types (10 cross-sectional, 5 non-randomised studies of interventions, 2 RCTs, 10 qualitative and 10 mixed methods). The highest proportion was conducted in the UK (48%). The study quality was generally poor with 24 (65%) studies having major concerns. A complex combination of patient, practitioner or practice factors, and patient, practitioner or practice recruitment were assessed to determine the possible associations. There were more studies of patients than of practices or practitioners. CONCLUSIONS: For practitioners and patients alike, a trial that is clinically relevant is critical in influencing participation. Competing demands are given as an important reason for declining participation. There are concerns about randomisation relating to its impact on shared decision-making and not knowing which treatment will be assigned. Patients make decisions about whether they are a candidate for the trial even when they objectively fulfil the eligibility criteria. General practice processes, such as difficulties arranging appointments, can hinder recruitment, and a strong pre-existing doctor-patient relationship can improve recruitment. For clinicians, the wish to contribute to the research enterprise itself is seldom an important reason for participating, though clinicians reported being motivated to participate when the research could improve their clinical practice. One of the few experimental findings was that opportunistic recruitment resulted in significantly faster recruitment compared to systematic recruitment. These factors have clear implications for trial design. Methodologically, recruitment research of practices and practitioners should have increased priority. Higher quality studies of recruitment are required to find out what actually works rather than what might work. TRIAL REGISTRATION: PROSPERO CRD42018100695. Registered on 03 July 2018.

Fascicular elastin within tendon contributes to the magnitude and modulus gradient of the elastic stress response across tendon type and species.

Elastin, the main component of elastic fibers, has been demonstrated to significantly influence tendon mechanics using both elastin degradation studies and elastinopathic mouse models. However, it remains unclear how prior results differ between species and functionally distinct tendons and, in particular, how results translate to human tendon. Differences in function between fascicular and interfascicular elastin are also yet to be fully elucidated. Therefore, this study evaluated the quantity, structure, and mechanical contribution of elastin in functionally distinct tendons across species. Tendons with an energy-storing function had slightly more elastin content than tendons with a positional function, and human tendon had at least twice the elastin content of other species. While distinctions in the organization of elastic fibers between fascicles and the interfascicular matrix were observed, differences in structural arrangement of the elastin network between species and tendon type were limited. Mechanical testing paired with enzyme-induced elastin degradation was used to evaluate the contribution of elastin to tendon mechanics. Across all tendons, elastin degradation affected the elastic stress response by decreasing stress values while increasing the modulus gradient of the stress-strain curve. Only the contributions of elastin to viscoelastic properties varied between tendon type and species, with human tendon and energy-storing tendon being more affected. These data suggest that fascicular elastic fibers contribute to the tensile mechanical response of tendon, likely by regulating collagen engagement under load. Results add to prior findings and provide evidence for a more mechanistic understanding of the role of elastic fibers in tendon. STATEMENT OF SIGNIFICANCE: Elastin has previously been shown to influence the mechanical properties of tendon, and degraded or abnormal elastin networks caused by aging or disease may contribute to pain and an increased risk of injury. However, prior work has not fully determined how elastin contributes differently to tendons with varying functional demands, as well as within distinct regions of tendon. This study determined the effects of elastin degradation on the tensile elastic and viscoelastic responses of tendons with varying functional demands, hierarchical structures, and elastin content. Moreover, volumetric imaging and protein quantification were used to thoroughly characterize the elastin network in each distinct tendon. The results presented herein can inform tendon-specific strategies to maintain or restore native properties in elastin-degraded tissue.

Early Joint Use Following Elbow Dislocation Limits Range-of-Motion Loss and Tissue Pathology in Posttraumatic Joint Contracture.

BACKGROUND: Simple elbow dislocation occurs at an incidence of 2.9 to 5.21 dislocations per 100,000 person-years, with as many as 62% of these patients experiencing long-term elbow joint contracture, stiffness, and/or pain. Poor outcomes and the need for secondary surgical intervention can often be prevented nonoperatively with early or immediate active mobilization and physical therapy. However, immobilization or limited mobilization may be necessary following trauma, and it is unknown how different periods of immobilization affect pathological changes in elbow joint tissue and how these changes relate to range of motion (ROM). The purpose of this study was to investigate the effects of varying the initiation of free mobilization on elbow ROM and histological features in an animal model of elbow posttraumatic joint contracture. METHODS: Traumatic elbow dislocation was surgically induced unilaterally in rats. Injured forelimbs were immobilized in bandages for 3, 7, 14, or 21 days; free mobilization was then allowed until 42 days after injury. Post-mortem joint ROM testing and histological analysis were performed. One-way analysis of variance was used to compare ROM data between control and injured groups, and Pearson correlations were performed between ROM parameters and histological outcomes. RESULTS: Longer immobilization periods resulted in greater ROM reductions. The anterior and posterior capsule showed increases in cellularity, fibroblasts, adhesions, fibrosis, and thickness, whereas the measured outcomes in cartilage were mostly unaffected. All measured histological characteristics of the capsule were negatively correlated with ROM, indicating that higher degrees of pathology corresponded with less ROM. CONCLUSIONS: Longer immobilization periods resulted in greater ROM reductions, which correlated with worse histological outcomes in the capsule in an animal model of posttraumatic elbow contracture. The subtle differences in the timing of ROM and capsule tissue changes revealed in the present study provide new insight into the distinct timelines of biomechanical changes as well as regional tissue pathology. CLINICAL RELEVANCE: This study showed that beginning active mobilization 3 days after injury minimized posttraumatic joint contracture, thereby supporting an immediate-motion clinical treatment strategy (when possible). Furthermore, uninjured but pathologically altered periarticular tissues near the injury location may contribute to more severe contracture during longer immobilization periods as the disease state progresses.

A new species of Melanospora on truffles from China.

The new species Melanospora subterranea is described from China, based on morphological and phylogenetic analyses. This is the first record of Melanospora species parasitizing Chinese black and white truffles (Tuber indicum and T. huidongense), and its host range indicates that the new species might be a disease threat to commercially exploited European truffles including Tuber melanosporum and Tuber magnatum. Apparent polyphyly within the Ceratostomataceae can be explained at least in part by inadvertent sequencing of the host fungus instead of the parasite.

Upstream interventions to promote oral health and reduce socioeconomic oral health inequalities: a scoping review protocol.

INTRODUCTION: Improving oral health and reducing oral health inequalities is an important global health priority. 'Upstream interventions' are a vital part of the collective effort to reduce oral disease burdens, however it is a rather nebulous term. Furthermore, there is little evidence on the effectiveness, impact and sustainability of upstream interventions that have focused on oral health and wider public health measures that impact on oral health. The aim of this scoping review is to systematically map and synthesise evidence on the effectiveness, impact and sustainability of upstream interventions on population oral health and reducing socioeconomic oral health inequalities. METHODS AND ANALYSIS: This scoping review will be conducted in accordance with the Joanna Briggs Institute methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews checklist. A detailed search strategy will be used to conduct a comprehensive search of electronic databases: Scopus, Embase and MEDLINE, PsycINFO and CINAHL, ASSIA and Cochrane Database of Systematic Reviews. A search of grey literature will also be completed to identify relevant dissertations, governmental reports and evaluations of implemented policies. Identification and extraction of data will be performed by two pairs of reviewers. Oversight and feedback will be provided by an independent expert advisory group. ETHICS AND DISSEMINATION: This study will review published and available grey literature and does not require an ethics review. The scoping review protocol has been registered with the Open Science Framework. The final report will be circulated and disseminated through publication and feed into the work of the ongoing Lancet Commission on Oral Health. Due to the policy relevance of this work, discussions will take place with key stakeholders regarding the implications of the findings for future policy development.

Donor age and sex have limited effects on the mechanical and microstructural properties of human connective tissues.

Connective tissues, such as tendons, ligaments, and capsules, play a large role in locomotion and joint stability and are often subjected to traumatic injuries and degeneration. The purpose of this study was to evaluate if the mechanical and microstructural properties of connective tissues correlate with the age and sex of the human donor. Dissected samples were prepared for mechanical testing, consisting of 10 cycles of preconditioning, a stress-relaxation ramp and hold, and a quasi-static ramp to failure. During the testing protocol, the microstructural organization of tissues was analyzed using quantitative polarized light imaging. A linear mixed model was used to assess whether tissue type, donor age, or donor sex were significantly associated with mechanical and microstructural tissue properties. Tissue type had a significant effect on all parameters, while donor age and sex did not. Groupings by tissue type (i.e., tendon vs. ligament vs. capsule) were evident for microstructural data, with tendons having a tighter grouping and ligaments having a larger spread of values. The interaction of tissue type and age yielded a significant effect for linear modulus only (p = 0.007), with the palmaris tendon appearing to have the largest contribution to this effect. There were no significant interaction effects between sex and tissue type or donor age. Donor age appears to affect linear modulus in some, but not all, tissue types. Otherwise, age and sex do not have significant effects on the mechanical and microstructural properties of the range of connective tissues that were analyzed in this study.

Genetic prediction of impulse control disorders in Parkinson's disease.

OBJECTIVE: To develop a clinico-genetic predictor of impulse control disorder (ICD) risk in Parkinson's disease (PD). METHODS: In 5770 individuals from three PD cohorts (the 23andMe, Inc.; the University of Pennsylvania [UPenn]; and the Parkinson's Progression Markers Initiative [PPMI]), we used a discovery-replication strategy to develop a clinico-genetic predictor for ICD risk. We first performed a Genomewide Association Study (GWAS) for ICDs anytime during PD in 5262 PD individuals from the 23andMe cohort. We then combined newly discovered ICD risk loci with 13 ICD risk loci previously reported in the literature to develop a model predicting ICD in a Training dataset (n = 339, from UPenn and PPMI cohorts). The model was tested in a non-overlapping Test dataset (n = 169, from UPenn and PPMI cohorts) and used to derive a continuous measure, the ICD-risk score (ICD-RS), enriching for PD individuals with ICD (ICD+ PD). RESULTS: By GWAS, we discovered four new loci associated with ICD at p-values of 4.9e-07 to 1.3e-06. Our best logistic regression model included seven clinical and two genetic variables, achieving an area under the receiver operating curve for ICD prediction of 0.75 in the Training and 0.72 in the Test dataset. The ICD-RS separated groups of PD individuals with ICD prevalence of nearly 40% (highest risk quartile) versus 7% (lowest risk quartile). INTERPRETATION: In this multi-cohort, international study, we developed an easily computed clinico-genetic tool, the ICD-RS, that substantially enriches for subgroups of PD at very high versus very low risk for ICD, enabling pharmacogenetic approaches to PD medication selection.

Recruitment for Remote Decentralized Studies in Parkinson's Disease.

BACKGROUND: Traditional in-person Parkinson's disease (PD) research studies are often slow to recruit and place unnecessary burden on participants. The ongoing COVID-19 pandemic has added new impetus to the development of new research models. OBJECTIVE: To compare recruitment processes and outcomes of three remote decentralized observational PD studies with video visits. METHODS: We examined the number of participants recruited, speed of recruitment, geographic distribution of participants, and strategies used to enhance recruitment in FIVE, a cross-sectional study of Fox Insight participants with and without PD (n = 203); VALOR-PD, a longitudinal study of 23andMe, Inc. research participants carrying the LRRK2 G2019S variant with and without PD (n = 277); and AT-HOME PD, a longitudinal study of former phase III clinical trial participants with PD (n = 226). RESULTS: Across the three studies, 706 participants from 45 U.S. states and Canada enrolled at a mean per study rate of 4.9 participants per week over an average of 51 weeks. The cohorts were demographically homogenous with regard to race (over 95%white) and level of education (over 90%with more than a high school education). The number of participants living in primary care Health Professional Shortage Areas in each study ranged from 30.3-42.9%. Participants reported interest in future observational (98.5-99.6%) and interventional (76.1-87.6%) research studies with remote video visits. CONCLUSION: Recruitment of large, geographically dispersed remote cohorts from a single location is feasible. Interest in participation in future remote decentralized PD studies is high. More work is needed to identify best practices for recruitment, particularly of diverse participants.

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.