Mild cognitive impairment among LRRK2 and GBA1 patients with Parkinson's disease.

BACKGROUND: Mild cognitive impairment (MCI) is common in Parkinson's disease (PD). We aimed to assess the incidence of MCI among patients with PD, carriers of mutations in LRRK2 and GBA1 genes, based on the movement disorder society (MDS) criteria for the diagnosis of MCI in early-stage PD. METHODS: Patients with PD were included if they scored ≤2 on the Hoehn and Yahr and ≤6 years since motor symptom onset. A group of age and gender matched healthy adults served as controls. A neuropsychological cognitive battery was used covering five cognitive domains (executive functions, working memory, memory, visuospatial and language). MCI was explored while applying two methods (level I and II). Frequency of MCI was assessed in comparison between groups. RESULTS: 70 patients with idiopathic PD (iPD) (68 % males), 42 patients with LRRK2-PD (61 % males), 83 patients with GBA1-PD (63 % males) and 132 age and gender matched controls (61 % males), participated in this study. PD groups were similar in clinical characteristics. Level I criteria were positive in 57.5 % of iPD, 43 % of LRRK2-PD and 63.4 % of the GBA1-PD (p = 0.071). Level II criteria was met by 39 % of iPD, 14 % LRRK2-PD and 41 % of GBA1-PD (p < 0.001), when using a 2 standard-deviation (SD) threshold. GBA1-PD and iPD showed impairments on multiple domains even in the more conservative 2 SD, reflecting MCI. CONCLUSIONS: The majority of our PD cohort was classified as MCI when assessed with strict criteria. GBA1-PD and iPD showed a more widespread pattern of MCI compared with LRRK2-PD.

Validity of the Short Weekly Calendar Planning Activity in patients with Parkinson disease and nonmanifesting LRRK2 and GBA carriers.

BACKGROUND AND PURPOSE: Subtle executive dysfunction is common in people newly diagnosed with Parkinson disease (PD), even when general cognitive abilities are intact. This study examined the Short Weekly Calendar Planning Activity (WCPA-10)'s known-group construct validity, comparing persons with PD to healthy controls (HCs) and nonmanifesting carriers of LRRK2 and GBA gene mutations to HCs. Additionally, convergent and ecological validity was examined. METHODS: The study included 73 participants: 22 with idiopathic PD (iPD) who do not carry any of the founder GBA mutations or LRRK2-G2019S, 29 nonmanifesting carriers of the G2019S-LRRK2 (n = 14) and GBA (n = 15) mutations, and 22 HCs. Known-group validity was determined using the WCPA-10, convergent validity by also using the Montreal Cognitive Assessment (MoCA) and Color Trails Test (CTT), and ecological validity by using the WCPA-10, Schwab and England Activities of Daily Living Scale (SE ADL), and Physical Activity Scale for the Elderly (PASE). RESULTS: Known-group validity of the WCPA-10 was established for the iPD group only; they followed fewer rules (p = 0.020), were slower (p = 0.003) and less efficient (p = 0.001), used more strategies (p = 0.017) on the WCPA-10, and achieved significantly lower CTT scores (p < 0.001) than the HCs. The nonmanifesting carriers and HCs were similar on all cognitive tests. Convergent and ecological validity of the WCPA-10 were partially established, with few correlations between WCPA-10 outcome measures and the MoCA (r = 0.50, r = 0.41), CTT-2 (r = 0.43), SE ADL (r = 0.41), and PASE (r = 0.54, r = 0.46, r = 0.31). CONCLUSIONS: This study affirms the known-group validity for most (four) WCPA-10 scores and partially confirms its convergent and ecological validity for PD.

Digital Mobility Measures: A Window into Real-World Severity and Progression of Parkinson's Disease.

BACKGROUND: Real-world monitoring using wearable sensors has enormous potential for assessing disease severity and symptoms among persons with Parkinson's disease (PD). Many distinct features can be extracted, reflecting multiple mobility domains. However, it is unclear which digital measures are related to PD severity and are sensitive to disease progression. OBJECTIVES: The aim was to identify real-world mobility measures that reflect PD severity and show discriminant ability and sensitivity to disease progression, compared to the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scale. METHODS: Multicenter real-world continuous (24/7) digital mobility data from 587 persons with PD and 68 matched healthy controls were collected using an accelerometer adhered to the lower back. Machine learning feature selection and regression algorithms evaluated associations of the digital measures using the MDS-UPDRS (I-III). Binary logistic regression assessed discriminatory value using controls, and longitudinal observational data from a subgroup (n = 33) evaluated sensitivity to change over time. RESULTS: Digital measures were only moderately correlated with the MDS-UPDRS (part II-r = 0.60 and parts I and III-r = 0.50). Most associated measures reflected activity quantity and distribution patterns. A model with 14 digital measures accurately distinguished recently diagnosed persons with PD from healthy controls (81.1%, area under the curve: 0.87); digital measures showed larger effect sizes (Cohen's d: [0.19-0.66]), for change over time than any of the MDS-UPDRS parts (Cohen's d: [0.04-0.12]). CONCLUSIONS: Real-world mobility measures are moderately associated with clinical assessments, suggesting that they capture different aspects of motor capacity and function. Digital mobility measures are sensitive to early-stage disease and to disease progression, to a larger degree than conventional clinical assessments, demonstrating their utility, primarily for clinical trials but ultimately also for clinical care. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Overnight Distribution of REM Sleep Features in People with Parkinson's Disease (PD) and Non-PD Controls.

BACKGROUND: Rapid eye movement (REM) sleep behavior disorder (RBD) is a leading predictor of Parkinson's disease (PD). Diagnosis is performed in the sleep laboratory by detecting pathological REM sleep without atonia (RSWA). The evidence on the overnight distribution of RSWA% is conflicting. OBJECTIVE: To investigate the temporal distribution of the number of ocular movements per REM sleep minute (REM density), and RSWA% in people with PD and non-PD controls. METHODS: All participants underwent a single overnight evaluation in a sleep laboratory. Clinical evaluation was performed on a separate day. REM density and RSWA% were compared between PD and controls both across four sleep periods and individual REM cycles. RESULTS: A total of 51 participants with recorded RSWA in polysomnography laboratory were included, 28 with PD aged 64±9 years with a disease duration of 3.3±2.9 years, and 23 controls aged 55±8 years. People with PD had lower REM density and higher RSWA% compared to controls. As expected, REM density was higher towards the morning. In contrast, RSWA% was equally distributed across the night, for both PD and controls. CONCLUSIONS: PD pathology affects REM sleep features, but not the overnight distribution of those features. While REM density increased towards the end of the night, RSWA% was equally distributed across the night for both PD and controls. Our findings have clinical implications for diagnosing RBD, as quantification of RSWA% in any sleep cycle is sufficient for reliably evaluating total RSWA% and reduced REM density may be a marker of PD.

Imaging Markers in Genetic Forms of Parkinson's Disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by motor symptoms such as bradykinesia, rigidity, and resting tremor. While the majority of PD cases are sporadic, approximately 15-20% of cases have a genetic component. Advances in neuroimaging techniques have provided valuable insights into the pathophysiology of PD, including the different genetic forms of the disease. This literature review aims to summarize the current state of knowledge regarding neuroimaging findings in genetic PD, focusing on the most prevalent known genetic forms: mutations in the GBA1, LRRK2, and Parkin genes. In this review, we will highlight the contributions of various neuroimaging modalities, including positron emission tomography (PET), single-photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI), in elucidating the underlying pathophysiological mechanisms and potentially identifying candidate biomarkers for genetic forms of PD.

Perspective on the current state of the LRRK2 field.

Almost 2 decades after linking LRRK2 to Parkinson's disease, a vibrant research field has developed around the study of this gene and its protein product. Recent studies have begun to elucidate molecular structures of LRRK2 and its complexes, and our understanding of LRRK2 has continued to grow, affirming decisions made years ago to therapeutically target this enzyme for PD. Markers of LRRK2 activity, with potential to monitor disease progression or treatment efficacy, are also under development. Interestingly, there is a growing understanding of the role of LRRK2 outside of the central nervous system in peripheral tissues such as gut and immune cells that may also contribute to LRRK2 mediated pathology. In this perspective, our goal is to take stock of LRRK2 research by discussing the current state of knowledge and critical open questions in the field.

International Genetic Testing and Counseling Practices for Parkinson's Disease.

BACKGROUND: There is growing clinical and research utilization of genetic testing in Parkinson's disease (PD), including direct-to-consumer testing. OBJECTIVES: The aim is to determine the international landscape of genetic testing in PD to inform future worldwide recommendations. METHODS: A web-based survey assessing current practices, concerns, and barriers to genetic testing and counseling was administered to the International Parkinson and Movement Disorders Society membership. RESULTS: Common hurdles across sites included cost and access to genetic testing, and counseling, as well as education on genetic counseling. Region-dependent differences in access to and availability of testing and counseling were most notable in Africa. High-income countries also demonstrated heterogeneity, with European nations more likely to have genetic testing covered through insurance than Pan-American and Asian countries. CONCLUSIONS: This survey highlights not only diversity of barriers in different regions but also the shared and highly actionable needs for improved education and access to genetic counseling and testing for PD worldwide. © 2023 International Parkinson and Movement Disorder Society.

Genome-wide case-only analysis of gene-gene interactions with known Parkinson's disease risk variants reveals link between LRRK2 and SYT10.

The effects of one genetic factor upon Parkinson's disease (PD) risk may be modified by other genetic factors. Such gene-gene interaction (G×G) could explain some of the 'missing heritability' of PD and the reduced penetrance of known PD risk variants. Using the largest single nucleotide polymorphism (SNP) genotype data set currently available for PD (18,688 patients), provided by the International Parkinson's Disease Genomics Consortium, we studied G×G with a case-only (CO) design. To this end, we paired each of 90 SNPs previously reported to be associated with PD with one of 7.8 million quality-controlled SNPs from a genome-wide panel. Support of any putative G×G interactions found was sought by the analysis of independent genotype-phenotype and experimental data. A total of 116 significant pairwise SNP genotype associations were identified in PD cases, pointing towards G×G. The most prominent associations involved a region on chromosome 12q containing SNP rs76904798, which is a non-coding variant of the LRRK2 gene. It yielded the lowest interaction p-value overall with SNP rs1007709 in the promoter region of the SYT10 gene (interaction OR = 1.80, 95% CI: 1.65-1.95, p = 2.7 × 10-43). SNPs around SYT10 were also associated with the age-at-onset of PD in an independent cohort of carriers of LRRK2 mutation p.G2019S. Moreover, SYT10 gene expression during neuronal development was found to differ between cells from affected and non-affected p.G2019S carriers. G×G interaction on PD risk, involving the LRRK2 and SYT10 gene regions, is biologically plausible owing to the known link between PD and LRRK2, its involvement in neural plasticity, and the contribution of SYT10 to the exocytosis of secretory vesicles in neurons.

Genetic Testing in Parkinson's Disease.

Genetic testing for persons with Parkinson's disease is becoming increasingly common. Significant gains have been made regarding genetic testing methods, and testing is becoming more readily available in clinical, research, and direct-to-consumer settings. Although the potential utility of clinical testing is expanding, there are currently no proven gene-targeted therapies, but clinical trials are underway. Furthermore, genetic testing practices vary widely, as do knowledge and attitudes of relevant stakeholders. The specter of testing mandates financial, ethical, and physician engagement, and there is a need for guidelines to help navigate the myriad of challenges. However, to develop guidelines, gaps and controversies need to be clearly identified and analyzed. To this end, we first reviewed recent literature and subsequently identified gaps and controversies, some of which were partially addressed in the literature, but many of which are not well delineated or researched. Key gaps and controversies include: (1) Is genetic testing appropriate in symptomatic and asymptomatic individuals without medical actionability? (2) How, if at all, should testing vary based on ethnicity? (3) What are the long-term outcomes of consumer- and research-based genetic testing in presymptomatic PD? (4) What resources are needed for clinical genetic testing, and how is this impacted by models of care and cost-benefit considerations? Addressing these issues will help facilitate the development of consensus and guidelines regarding the approach and access to genetic testing and counseling. This is also needed to guide a multidisciplinary approach that accounts for cultural, geographic, and socioeconomic factors in developing testing guidelines. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Novel variants in genes related to vesicle-mediated-transport modify Parkinson's disease risk.

OBJECTIVES: VPS35 and VPS13 have been associated with Parkinson's disease (PD), and their shared phenotype in yeast when reduced in function is abnormal vacuolar transport. We aim to test if additional potentially deleterious variants in other genes that share this phenotype can modify the risk for PD. METHODS: 77 VPS and VPS-related genes were analyzed using whole-genome-sequencing data from 202 PD patients of Ashkenazi Jewish (AJ) ancestry. Filtering was done based on quality and functionality scores. Ten variants in nine genes were further genotyped in 1200 consecutively recruited unrelated AJ-PD patients, and allele frequencies and odds ratio calculated compared to gnomAD-AJ-non-neuro database, in un-stratified (n = 1200) and stratified manner (LRRK2-G2019S-PD patients (n = 145), GBA-PD patients (n = 235), and non-carriers of these mutations (NC, n = 787)). RESULTS: Five variants in PIK3C3, VPS11, AP1G2, HGS and VPS13D were significantly associated with PD-risk. PIK3C3-R768W showed a significant association in an un-stratified (all PDs) analysis, as well as in stratified (LRRK2, GBA, and NC) analyses (Odds ratios = 2.71, 5.32, 3.26. and 2.19 with p = 0.0015, 0.002, 0.0287, and 0.0447, respectively). AP1G2-R563W was significantly associated in LRRK2-carriers (OR = 3.69, p = 0.006) while VPS13D-D2932N was significantly associated in GBA-carriers (OR = 5.45, p = 0.0027). VPS11-C846G and HGS-S243Y were significantly associated in NC (OR = 2.48 and 2.06, with p = 0.022 and 0.0163, respectively). CONCLUSIONS: Variants in genes involved in vesicle-mediated protein transport and recycling pathways, including autophagy and mitophagy, may differentially modify PD-risk in LRRK2-carriers, GBA carriers, or NC. Specifically, PIK3C3-R768W is a PD-risk allele, with the highest effect size in LRRK2-G2019S carriers. These results suggest oligogenic effect that may depends on the genetic background of the patient. An unbiased burden of mutations approach in these genes should be evaluated in additional PD and control groups. The mechanisms by which these novel variants interact and increase PD-risk should be researched in depth for better tailoring therapeutic intervention for PD prevention or slowing disease progression.

The natural history study of preclinical genetic Creutzfeldt-Jakob Disease (CJD): a prospective longitudinal study protocol.

BACKGROUND: Creutzfeldt-Jakob Disease (CJD) is the most common prion disease in humans causing a rapidly progressive neurological decline and dementia and is invariably fatal. The familial forms (genetic CJD, gCJD) are caused by mutations in the PRNP gene encoding for the prion protein (PrP). In Israel, there is a large cluster of gCJD cases, carriers of an E200K mutation in the PRNP gene, and therefore the largest population of at-risk individuals in the world. The mutation is not necessarily sufficient for the formation and accumulation of the pathological prion protein (PrPsc), suggesting that other, genetic and non-genetic factors affect the age at symptoms onset. Here we present the protocol of a cross-sectional and longitudinal natural history study of gCJD patients and first-degree relatives of gCJD patients, aiming to identify biological markers of preclinical CJD and risk factors for phenoconversion. METHODS: The study has two groups: Patients diagnosed with gCJD, and first-degree healthy relatives (HR) (both carriers and non-carriers of the E200K mutation in the PRNP gene) of patients diagnosed with gCJD. At baseline, and at the end of every year, healthy participants are invited for an "in-depth" visit, which includes a clinical evaluation, blood and urine collection, gait assessment, brain MRI, lumbar puncture (LP), and Polysomnography (PSG). At 6 months from baseline, and then halfway through each year, participants are invited for a "brief" visit, which includes a clinical evaluation, short cognitive assessment, and blood and urine collection. gCJD patients will be invited for one "in-depth" visit, similar to the baseline visit of healthy relatives. DISCUSSION: This continuous follow-up of the participants and the frequent assessments will allow early identification and diagnosis in case of conversion into disease. The knowledge generated from this study is likely to advance the understanding of the underlying clinicopathological processes that occur at the very beginning of CJD, as well as potential genetic and environmental risk factors for the development of the disease, therefore advancing the development of safe and efficient interventions. TRIAL REGISTRATION: The study is an observational study. It has registered retrospectively in https://clinicaltrials.gov/ and has been assigned an identification number NCT05746715.

The Influence of GBA and LRRK2 on Mood Disorders in Parkinson's Disease.

Background: Mood disorders have emerged as major non-motor comorbidities in Parkinson's disease (PD) even at the prodromal stage of the disease. Mutations in the LRRK2 and GBA genes are common among Ashkenazi Jews, with more severe phenotype reported for GBA-PD. Objective: To explore the association between genetic status and mood related disorders before and after diagnosis of PD and the association between mood-related medications, phenotype, and genetic status. Methods: Participants were genotyped for mutations in the LRRK2 and GBA genes. State of depression, anxiety and non-motor features were evaluated using validated questionnaires. History of mood disorders prior to diagnosis of PD and use of mood-related medications were assessed. Results: The study included 105 idiopathic PD (iPD), 55 LRRK2-PD and 94 GBA-PD. Scores on mood related questionnaires and frequency of depression and anxiety before diagnosis were similar between the groups (p>0.05). However, more GBA-PD patients used mood related medications before PD diagnosis than LRRK2-PD and iPD (16.5% vs 7.1% and 8.2%, p=0.044). LRRK2-PD and GBA-PD receiving mood-related medications at time of assessment had worse motor and non-motor phenotype compared to those that did not (p<0.05). LRRK2-PD receiving mood related-medications at time of assessment, scored higher on mood-related questionnaires compared to LRRK2-PD not receiving such medications (p<0.04). Conclusions: Prodromal GBA-PD are more frequently treated with mood related-medications despite equal rates of reported mood-related disorders, while LRRK2-PD with mood-related disorders experience high rates of anxiety and depression despite treatment, attesting to the need of more precise assessment and treatment of these genetic subgroups.

Variants in PSMB9 and FGR differentially affect Parkinson's disease risk in GBA and LRRK2 mutation carriers.

INTRODUCTION: Recent studies found an association between Parkinson's disease (PD) and alterations in the innate immune system. However, whether the involvement of this system in two of the known genetic forms of PD, GBA-PD and LRRK2-PD, and in patients who do not carry these mutations is different, is yet to be determined. We aimed to test if genetic variations in the innate immune genes are differentially associated with PD in these subgroups. METHODS: Innate immune genes were identified and classified into sub-lists according to Reactome pathways. Whole-genome-sequencing (WGS) was performed on 201 unrelated Ashkenazi-Jewish (AJ) PD patients including 104 GBA-PD, 32 LRRK2-PD, and 65 non-carriers-PD (NC-PD). To identify genes with different burden between these subgroups of PD, gene-based Sequence kernel association optimal unified test (SKAT-O) analysis was performed on innate immune pathways. Candidate variants within the significant genes were further genotyped in a cohort of 1200 unrelated, consecutively recruited, AJ-PD patients, and to evaluate their association with PD-risk their allele frequencies were compared to AJ-non-neuro cases in gnomAD database, in a stratified and un-stratified manner. RESULTS: SKAT-O analysis showed significantly different burden for PSMB9 (GBA-PD versus NC-PD) and FGR (GBA-PD versus LRRK2-PD). Two candidate variants in PSMB9 showed an association with GBA-PD-risk and NC-PD-risk while one FGR variant showed an association with LRRK2-PD-risk. CONCLUSION: Our data supports differential involvement of innate immunity risk alleles in PD and emphasizes the differences between the GBA- and LRRK2-PD subgroups.

MAPT Locus in Parkinson's Disease Patients of Ashkenazi Origin: A Stratified Analysis.

Introduction: MAPT locus is associated with Parkinson's disease (PD), which is located within a large inversion region of high linkage disequilibrium (LD). We aimed to determine whether the H2-haplotype protective effect and its effect size depends on the GBA1 or LRRK2 risk allele carrier status, and to further characterize genetic alterations that might contribute to its effect. Methods: LD analysis was performed using whole-genome sequencing data of 202 unrelated Ashkenazi Jewish (AJ) PDs. A haplotype-divergent variant was genotyped in a cohort of 1200 consecutively recruited AJ-PDs. The odd ratios were calculated using AJ-non-neuro cases from the gnomAD database as the controls in an un-stratified and a stratified manner according to the mutation carrier status, and the effect on the Age at Motor Symptom Onset (AMSO) was examined. Expression and splicing quantitative trait locus (eQTL and sQTL) analyses were carried out using brain tissues from a database. Results: The H2 haplotype exhibited significant association with PD protection, with a similar effect size in GBA1 carriers, LRRK2-G2019S carriers, and non-carriers (OR = 0.77, 0.69, and 0.82, respectively), and there was no effect on AMSO. The LD interval was narrowed to approximately 1.2 Mb. The H2 haplotype carried potential variants in candidate genes (MAPT and SPPL2C); structural deletions and segmental duplication (KANSL1); and variants affecting gene expression and intron excision ratio in brain tissues (LRRC37A/2). Conclusions: Our results demonstrate that H2 is associated with PD and its protective effect is not influenced by the GBA1/LRRK2 risk allele carrier status. This effect may be genetically complex, resulting from different levels of variations such as missense mutations in relevant genes, structural variations, epigenetic modifications, and RNA expression changes, which may operate independently or in synergy.

Neural activation in the prefrontal cortex during the digital clock drawing test measured with functional near-infrared spectroscopy in early stage Parkinson's disease.

INTRODUCTION: The clock drawing test (CDT) is a neuropsychological test for the screening of global cognitive functioning. The test requires use of multiple cognitive domains including executive functions, visuospatial abilities and semantic memory and can be a suitable tool for screening cognitive decline in participants in the early stages of Parkinson's Disease (PD). Behavioral performance on the CDT has been studied in depth, however, neural activation during real-time performance has not been extensively investigated. In this study we explored changes in prefrontal cortex (PFC) activation during the performance of CDT in participants with PD compared to healthy controls (HC) and assessed the correlations between PFC activation and CDT performance. METHODS: The study included 60 participants, 29 PD and 31 HC participants whom performed a digital CDT (DCTclock) in conjunction with a Functional Near-Infrared Spectroscopy (fNIRS) system measuring neural activation in the PFC. RESULTS: HbO2 signals derived from the fNIRS during the CDT revealed that PD participants showed more moderate slopes than the HC in the right hemisphere in the command (p = 0.042) and copy task (p = 0.009). Better score on the measurement of information processing correlated with steeper right hemisphere HbO2 slope in the copy task in the PD group (p = 0.003). CONCLUSION: Our results reflect slower PFC activation in participants with PD which correlates with behavioral measures. In addition, the findings of the study indicate the importance of performing the CDT copy task condition that detect early cognitive decline in participants with PD.

Diagnosis and Medical Management of Parkinson Disease.

PURPOSE OF REVIEW: Parkinson disease (PD) is a common neurodegenerative movement disorder, the prevalence of which is rising as the world population ages. It may present with motor and nonmotor symptoms, and symptomatic treatment significantly improves quality of life. This article provides an overview of the workup and differential diagnosis for PD and reviews genetic and environmental risk factors and current treatments. RECENT FINDINGS: Novel treatments for the motor (eg, fluctuations and off times) and nonmotor (eg, hallucinations and orthostatic hypotension) complications of PD have been approved in recent years. In addition, with recent advances in our understanding of the genetics of PD, significant research is focusing on identifying at-risk populations and introducing genetically targeted interventions (precision medicine). SUMMARY: PD is a heterogeneous neurodegenerative movement disorder. Affected individuals may receive substantial symptomatic relief from nonpharmacologic, pharmacologic, and surgical interventions. Although no intervention to modify the progression of PD is currently available, precision medicine and modulation of the immune system are a major focus of ongoing research.