Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers.

OBJECTIVE: This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease. METHODS: Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS-), and noncarriers with or without DBS (GBA-DBS+, GBA-DBS-). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status. RESULTS: Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS-, 98 GBA-DBS+, and 128 GBA-DBS- subjects), who were longitudinally followed (range = 36-60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA-DBS- subjects (95% confidence interval [CI] = -2.35 to -1.69), 1.71 points/yr more than GBA+DBS- subjects (95% CI = -2.14 to -1.28), and 1.49 points/yr more than GBA-DBS+ subjects (95% CI = -1.80 to -1.18). INTERPRETATION: Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN-DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision-making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN-DBS so that alternative options may be considered. ANN NEUROL 2022;91:424-435.

Cognitive Effects of Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease with GBA1 Pathogenic Variants.

Genetic subtyping of patients with Parkinson's disease (PD) may assist in predicting the cognitive and motor outcomes of subthalamic deep brain stimulation (STN-DBS). Practical questions were recently raised with the emergence of new data regarding suboptimal cognitive outcomes after STN-DBS in individuals with PD associated with pathogenic variants in glucocerebrosidase gene (GBA1-PD). However, a variety of gaps and controversies remain. (1) Does STN-DBS truly accelerate cognitive deterioration in GBA1-PD? If so, what is the clinical significance of this acceleration? (2) How should the overall risk-to-benefit ratio of STN-DBS in GBA1-PD be established? (3) If STN-DBS has a negative effect on cognition in GBA1-PD, how can this effect be minimized? (4) Should PD patients be genetically tested before STN-DBS? (5) How should GBA1-PD patients considering STN-DBS be counseled? We aim to summarize the currently available relevant data and detail the gaps and controversies that exist pertaining to these questions. In the absence of evidence-based data, all authors strongly agree that clinicians should not categorically deny DBS to PD patients based solely on genotype (GBA1 status). We suggest that PD patients considering DBS may be offered genetic testing for GBA1, where available and feasible, so the potential risks and benefits of STN-DBS can be properly weighed by both the patient and clinician. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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.

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.

Increased Subthalamic Nucleus Deep Brain Stimulation Amplitude Impairs Inhibitory Control of Eye Movements in Parkinson's Disease.

BACKGROUND AND OBJECTIVES: Bilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson's disease (PD) can have detrimental effects on eye movement inhibitory control. To investigate this detrimental effect of bilateral STN DBS, we examined the effects of manipulating STN DBS amplitude on inhibitory control during the antisaccade task. The prosaccade error rate during the antisaccade task, that is, directional errors, was indicative of impaired inhibitory control. We hypothesized that as stimulation amplitude increased, the prosaccade error rate would increase. MATERIALS AND METHODS: Ten participants with bilateral STN DBS completed the antisaccade task on six different stimulation amplitudes (including zero amplitude) after a 12-hour overnight withdrawal from antiparkinsonian medication. RESULTS: We found that the prosaccade error rate increased as stimulation amplitude increased (p < 0.01). Additionally, prosaccade error rate increased as the modeled volume of tissue activated (VTA) and STN overlap decreased, but this relationship depended on stimulation amplitude (p = 0.04). CONCLUSIONS: Our findings suggest that higher stimulation amplitude settings can be modulatory for inhibitory control. Some individual variability in the effect of stimulation amplitude can be explained by active contact location and VTA-STN overlap. Higher stimulation amplitudes are more deleterious if the active contacts fall outside of the STN resulting in a smaller VTA-STN overlap. This is clinically significant as it can inform clinical optimization of STN DBS parameters. Further studies are needed to determine stimulation amplitude effects on other aspects of cognition and whether inhibitory control deficits on the antisaccade task result in a meaningful impact on the quality of life.

The Medial Subthalamic Nucleus Border as a New Anatomical Reference in Stereotactic Neurosurgery for Parkinson's Disease.

INTRODUCTION: The intersection of Bejjani's line with the well-delineated medial subthalamic nucleus (STN) border on MRI has recently been proposed as an individualized reference in subthalamic deep brain stimulation (DBS) surgery for Parkinson's disease (PD). We, therefore, aimed to investigate the applicability across centers of the medial STN border as a patient-specific reference point in STN DBS for PD and explore anatomical variability between left and right mesencephalic area within patients. Furthermore, we aim to evaluate a recently defined theoretic stimulation "hotspot" in a different center. METHODS: Preoperative 3-Tesla T2 and susceptibility-weighted images (SWI) were used to identify the intersection of Bejjani's line with the medial STN border in left and right mesencephalic area. The average stereotactic coordinates of the center of stimulation relative to the medial STN border were compared with the predefined theoretic stimulation "hotspot." RESULTS: Fifty-four patients provided 108 stereotactic coordinates of medial STN borders on both sequences. Significant difference in means was found in the Y-(anteroposterior) and Z-(dorsoventral) directions (T2 vs. SWI; p < 0.001). Mean coordinates in the Y-(anteroposterior) direction differed significantly between left and right mesencephalic area (T2: p < 0.001; SWI: p = 0.021). Sixty-six DBS leads were placed in 36 patients that had finished stimulation programming, and the average stereotactic coordinates of the center of stimulation relative to the medial STN border on T2 sequences were 3.1 mm lateral, 0.7 mm anterior, and 1.8 mm superior, in proximity of the predefined theoretic stimulation "hotspot." CONCLUSION: The medial STN border is applicable across centers as a reference point for STN DBS surgery for PD and seems suitable in order to account for interindividual and intraindividual anatomical variability if one is aware of the discrepancies between T2-weighted imaging and SWI.

Accuracy of Microelectrode Trajectory Adjustments during DBS Assessed by Intraoperative CT.

BACKGROUND/AIMS: Microelectrode recording (MER)-guided deep brain stimulation (DBS) aims to place the DBS lead in the optimal electrophysiological target. When single-track MER or test stimulation yields suboptimal results, trajectory adjustments are made. The accuracy of these trajectory adjustments is unknown. Intraoperative computed tomography can visualize the microelectrode (ME) and verify ME adjustments. We aimed to determine the accuracy of ME movements in patients undergoing MER-guided DBS. METHODS: Coordinates following three methods of adjustment were compared: (1) those within the default "+" configuration of the ME holder; (2) those involving rotation of the default "+" to the "x" configuration; and (3) those involving head stage adjustments. Radial error and absolute differences between coordinates were determined. RESULTS: 87 ME movements in 59 patients were analyzed. Median (IQR) radial error was 0.59 (0.64) mm. Median (IQR) absolute x and y coordinate errors were 0.29 (0.52) and 0.38 (0.44) mm, respectively. Errors were largest after rotating the multielectrode holder to its "x"-shaped setup. CONCLUSION: ME trajectory adjustments can be made accurately. In a considerable number of cases, errors exceeding 1 mm were found. Adjustments from the "+" setup to the "x" setup are most prone to inaccuracies.

Borders of STN determined by MRI versus the electrophysiological STN. A comparison using intraoperative CT.

BACKGROUND: It is unclear which magnetic resonance imaging (MRI) sequence most accurately corresponds with the electrophysiological subthalamic nucleus (STN) obtained during microelectrode recording (MER, MER-STN). CT/MRI fusion allows for comparison between MER-STN and the STN visualized on preoperative MRI (MRI-STN). OBJECTIVE: To compare dorsal and ventral STN borders as seen on 3-Tesla T2-weighted (T2) and susceptibility weighted images (SWI) with electrophysiological STN borders in deep brain stimulation (DBS) for Parkinson's disease (PD). METHODS: Intraoperative CT (iCT) was performed after each MER track. iCT images were merged with preoperative images using planning software. Dorsal and ventral borders of each track were determined and compared to MRI-STN borders. Differences between borders were calculated. RESULTS: A total of 125 tracks were evaluated in 45 patients. MER-STN started and ended more dorsally than respective dorsal and ventral MRI-STN borders. For dorsal borders, differences were 1.9 ± 1.4 mm (T2) and 2.5 ± 1.8 mm (SWI). For ventral borders, differences were 1.9 ± 1.6 mm (T2) and 2.1 ± 1.8 mm (SWI). CONCLUSIONS: Discrepancies were found comparing borders on T2 and SWI to the electrophysiological STN. The largest border differences were found using SWI. Border differences were considerably larger than errors associated with iCT and fusion techniques. A cautious approach should be taken when relying solely on MR imaging for delineation of both clinically relevant STN borders.

Comparison of neuropathology in Parkinson's disease subjects with and without deep brain stimulation.

BACKGROUND: The aim of this postmortem study was to compare, in Parkinson's disease subjects with and without bilateral subthalamic nucleus deep brain stimulation (STN-DBS), the loss of pigmented neurons within the substantia nigra and pathological alpha-synuclein density within the SN and other brain regions. METHODS: PD subjects were identified from the Arizona Study of Aging and Neurodegenerative Disorders database (STN-DBS = 11, non-DBS = 156). Pigmented neuron loss scores within the substantia nigra as well as alpha-synuclein density scores within the substantia nigra and 9 other brain regions were compared, the latter individually and in summary as the Lewy body brain load score. RESULTS: DBS subjects had higher alpha-synuclein density scores within the substantia nigra, olfactory bulb, and locus ceruleus, as well as higher total Lewy body brain load scores when compared with non-DBS subjects. No differences in substantia nigra pigmented neuron loss scores were found. CONCLUSIONS: STN-DBS subjects tend to have higher alpha-synuclein density scores, but do not have a differential loss of substantia nigra pigmented neurons. © 2016 International Parkinson and Movement Disorder Society.

Global cognitive function and processing speed are associated with gait and balance dysfunction in Parkinson's disease.

BACKGROUND: Our primary objective was to determine the relationship between global cognitive function and specific domains of gait and balance in a cohort of Parkinson's disease (PD) subjects. In a secondary analysis, we determined whether specific cognitive domains correlated with gait and balance performance. METHODS: Fourteen PD subjects (mean age 61.1 ± 7.8 years) were recruited from the Rush University Medical Center Movement Disorders clinic. Subjects underwent clinical assessment using the motor subsection of the Unified Parkinson's Disease Rating Scale (UPDRS) followed by quantitative gait and balance assessments using the APDM Mobility Lab™ system (Mobility Lab, APDM Inc., Portland, OR). Subjects completed global cognitive testing using the Mattis Dementia Rating Scale (MDRS) as well as domain specific cognitive measures. Spearman's rho was used to assess correlations between cognitive measures and gait and balance function, with False Discovery Rate (FDR) correction for multiple comparisons. RESULTS: Global cognitive function had the strongest correlation with stride velocity (r = 0.816, p = 0.001), turn duration (r = -0.806, p = 0.001), number of steps to turn (r = -0.830, p = 0.001), and mean velocity of postural sway in the medio-lateral direction (r = -0.726, p = 0.005). A significant correlation was found between processing speed and two turning measures (turn duration, r = -0.884, p = 0.001; number of steps to turn, r = -0.954, p < 0.001), but no other associations were found between specific cognitive domains and gait domains. CONCLUSIONS: This pilot study provides preliminary data regarding the association between global cognitive function and pace-related measures of gait, turning, and postural sway. Furthermore, reduced processing speed was found to be associated with difficulty in performing turns.

Asterixis: a study of 103 patients.

In 1949, asterixis was first described in patients with hepatic encephalopathy. It was quickly recognized that this phenomenon also occurs in other generalized encephalopathies and sometimes results from structural brain lesions. This paper is a study of asterixis in the general neurology clinic and on the inpatient neurology consultation service. The neurologists recorded the findings on inpatients and clinic patients for 12 consecutive months. Of the 1,109 inpatients with adequate examination, asterixis was documented in 97. Eighteen of the 97 cases were unilateral (18.6%) and 79 cases were bilateral (81.4%). Of the 614 outpatient visits with well documented examination, 6 (1%) individuals had asterixis. Since a small number of patients were examined more than once, the study yielded 103 individuals with adequate data for analysis. Asterixis resulted from varied causes: medications, renal disorder, hepatic dysfunction, pulmonary insufficiency, stroke and other brain lesions (including malignancy, subdural hematoma, and epidural abscess). Asterixis occurred in various patterns: in some cases it was easier to elicit in the upper extremities, in some it was easier to elicit in the lower limbs, and some it was solely or predominantly unilateral. The findings are discussed in light of the literature on asterixis with regard to its varied causes, patterns and presentations. Lastly, asterixis is examined from a historical perspective and the terminology is elucidated.

NIH Toolbox performance of persons with Parkinson's disease according to GBA1 and STN-DBS status.

OBJECTIVE: Mutations in the glucocerebrosidase (GBA1) gene and subthalamic nucleus deep brain stimulation (STN-DBS) are independently associated with cognitive dysfunction in persons with Parkinson's disease (PwP). We hypothesized that PwP with both GBA1 mutations and STN-DBS are at greater risk of cognitive dysfunction than PwP with only GBA1 mutations or STN-DBS, or neither. In this study, we determined the pattern of cognitive dysfunction in PwP based on GBA1 mutation status and STN-DBS treatment. METHODS: PwP who are GBA1 mutation carriers with or without DBS (GBA1+DBS+, GBA1+DBS-), and noncarriers with or without DBS (GBA1-DBS+, GBA1-DBS-) were included. Using the NIH Toolbox, cross-sectional differences in response inhibition, processing speed, and episodic memory were compared using analysis of variance with adjustment for relevant covariates. RESULTS: Data were available for 9 GBA1+DBS+, 14 GBA1+DBS-, 17 GBA1-DBS+, and 26 GBA1-DBS- PwP. In this cross-sectional study, after adjusting for covariates, we found that performance on the Flanker test (measure of response inhibition) was lower in GBA1+DBS+ PwP compared with GBA1-DBS+ PwP (P = 0.030). INTERPRETATION: PwP who carry GBA1 mutations and have STN-DBS have greater impaired response inhibition compared with PwP with STN-DBS but without GBA1 mutations. Longitudinal data, including preoperative scores, are required to definitively determine whether GBA1 mutation carriers respond differently to STN-DBS, particularly in the domain of response inhibition.

Neither alpha-synuclein fibril strain nor host murine genotype influences seeding efficacy.

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive motor symptoms and alpha-synuclein (αsyn) aggregation in the nervous system. For unclear reasons, PD patients with certain GBA1 mutations (GBA-PD) have a more aggressive clinical progression. Two testable hypotheses that can potentially account for this phenomenon are that GBA1 mutations promote αsyn spread or drive the generation of highly pathogenic αsyn polymorphs (i.e., strains). We tested these hypotheses by treating homozygous GBA1 D409V knockin (KI) mice with human α-syn-preformed fibrils (PFFs) and treating wild-type mice (WT) with several αsyn-PFF polymorphs amplified from brain autopsy samples collected from patients with idiopathic PD and GBA-PD patients with either homozygous or heterozygous GBA1 mutations. Robust phosphorylated-αsyn (PSER129) positive pathology was observed at the injection site (i.e., the olfactory bulb granule cell layer) and throughout the brain six months following PFF injection. The PFF seeding efficiency and degree of spread were similar regardless of the mouse genotype or PFF polymorphs. We found that PFFs amplified from the human brain, regardless of patient genotype, were generally more effective seeders than wholly synthetic PFFs (i.e., non-amplified); however, PFF concentration differed between these two studies, which might also account for the observed differences. To investigate whether the molecular composition of pathology differed between different seeding conditions, we performed Biotinylation by Antibody Recognition on PSER129 (BAR-PSER129). We found that for BAR-PSER129, the endogenous PSER129 pool dominated identified interactions, and thus, very few potential interactions were explicitly identified for seeded pathology. However, we found Dynactin Subunit 2 (Dctn2) interaction was shared across all PFF conditions, and NCK Associated Protein 1 (Nckap1) and Adaptor Related Protein Complex 3 Subunit Beta 2 (Ap3b2) were unique to PFFs amplified from GBA-PD brains of heterozygous mutation carriers. In conclusion, both the genotype and αsyn strain had little effect on overall seeding efficacy and global PSER129-interactions.

Benefits of subthalamic nucleus deep brain stimulation on visually-guided saccades depend on stimulation side and classic paradigm in Parkinson's disease.

OBJECTIVE: We aimed to gain further insight into previously reported beneficial effects of subthalamic nucleus deep brain stimulation (STN-DBS) on visually-guided saccades by examining the effects of unilateral compared to bilateral stimulation, paradigm, and target eccentricity on saccades in individuals with Parkinson's disease (PD). METHODS: Eleven participants with PD and STN-DBS completed the visually-guided saccade paradigms with OFF, RIGHT, LEFT, and BOTH stimulation. Rightward saccade performance was evaluated for three paradigms and two target eccentricities. RESULTS: First, we found that BOTH and LEFT increased gain, peak velocity, and duration compared to OFF stimulation. Second, we found that BOTH and LEFT stimulation decreased latency during the gap and step paradigms but had no effect on latency during the overlap paradigm. Third, we found that RIGHT was not different compared to OFF at benefiting rightward saccade performance. CONCLUSIONS: Left unilateral and bilateral stimulation both improve the motor outcomes of rightward visually-guided saccades. Additionally, both improve latency, a cognitive-motor outcome, but only in paradigms when attention does not require disengagement from a present stimulus. SIGNIFICANCE: STN-DBS primarily benefits motor and cognitive-motor aspects of visually-guided saccades related to reflexive attentional shifting, with the latter only evident when the fixation-related attentional system is not engaged.

Initiation Patterns of Disease-Modifying Therapies for Multiple Sclerosis Among US Adults and Children, 2001 Through 2020.

Importance: Many disease-modifying therapies (DMTs) have been approved for multiple sclerosis (MS) in the past 2 decades. Research evaluating how these approvals have changed real-world prescribing patterns is scarce. Objective: To evaluate patterns in DMT initiations between 2001 and 2020 among commercially insured US adults and children with MS. Design, Setting, and Participants: This serial cross-sectional study was conducted from 2001 through 2020 (mean patient enrollment duration, 4.8 years) and used US commercial claims data (MarketScan). Analysis took place between January 2022 and March 2023. Of 287 084 patients with MS identified, 113 583 patients (113 095 adults and 488 children) with MS newly initiated at least 1 DMT. Exposure: New initiation episode of a DMT, defined as no claim for the same DMT in the previous year. Main Outcome Measure: The proportion of total DMT initiations per year attributable to each DMT. Trends in initiations were evaluated annually. Results: The study team identified 153 846 DMT initiation episodes among adults (median age, 46 [IQR, 38-53) years]; 86 133 female [76.2%]) and 583 among children (median age, 16 (IQR, 14-17) years; 346 female [70.9%]). Among adults, use of platform injectables showed an absolute decline of 73.8% over the study period, driven by a 61.2% reduction in interferon ß initiations (P < .001 for trend). In contrast, the 2010 introduction of oral DMTs led to a rise in their use from 1.1% (2010) to 62.3% (2020) of all DMT initiations (P = .002 for trend). Infusion therapy initiations remained relatively low, accounting for 3.2% of all initiations since their introduction in 2004 but increased modestly annually after ocrelizumab was introduced (2017), reaching 8.2% of all initiations in 2020 (P < .001 for trend). Children showed similar initiation patterns, except for preferred oral therapy. Between 2019 and 2020, dimethyl fumarate was the most commonly initiated DMT in adults (23.3% to 27.2% of all initiations), while in children fingolimod was the most commonly initiated (34.8% to 68.8%). Conclusions and Relevance: Current MS treatment guidelines emphasize shared decision-making between patients and clinicians to balance treatment efficacy, safety, cost, and convenience. This study found that oral DMTs were the predominant DMT type initiated by 2020. The cause of this shift cannot be determined from this study, but may reflect several factors, including convenience of administration, direct-to-consumer advertising, or insurance restrictions.

Neither alpha-synuclein-preformed fibrils derived from patients with GBA1 mutations nor the host murine genotype significantly influence seeding efficacy in the mouse olfactory bulb.

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive motor symptoms and alpha-synuclein (αsyn) aggregation in the nervous system. For unclear reasons, PD patients with certain GBA mutations (GBA-PD) have a more aggressive clinical progression. Two testable hypotheses that can potentially account for this phenomenon are that GBA1 mutations promote αsyn spread or drive the generation of highly pathogenic αsyn polymorphs (i.e., strains). We tested these hypotheses by treating homozygous GBA1 D409V knockin (KI) mice with human α-syn-preformed fibrils (PFFs) and treating wild-type mice (WT) with several αsyn-PFF polymorphs amplified from brain autopsy samples collected from patients with idiopathic PD and GBA-PD patients with either homozygous or heterozygous GBA1 mutations. Robust phosphorylated-αsyn (PSER129) positive pathology was observed at the injection site (i.e., the olfactory bulb granular layer) and throughout the brain six months following PFF injection. The PFF seeding efficiency and degree of spread were similar regardless of the mouse genotype or PFF polymorphs. We found that PFFs amplified from the human brain, regardless of patient genotype, were generally more effective seeders than wholly synthetic PFFs (i.e., non-amplified); however, PFF concentration differed between these two studies, and this might also account for the observed differences. To investigate whether the molecular composition of pathology differed between different seeding conditions, we permed Biotinylation by Antibody Recognition on PSER129 (BAR-PSER129). We found that for BAR-PSER129, the endogenous PSER129 pool dominated identified interactions, and thus, very few potential interactions were explicitly identified for seeded pathology. However, we found Dctn2 interaction was shared across all PFF conditions, and Nckap1 and Ap3b2 were unique to PFFs amplified from GBA-PD brains of heterozygous mutation carriers. In conclusion, both the genotype and αsyn strain had little effect on overall seeding efficacy and global PSER129-interactions.

Digital gait markers to potentially distinguish fragile X-associated tremor/ataxia syndrome, Parkinson's disease, and essential tremor.

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disease that affects carriers of a 55-200 CGG repeat expansion in the fragile X messenger ribonucleoprotein 1 (FMR1) gene, may be given an incorrect initial diagnosis of Parkinson's disease (PD) or essential tremor (ET) due to overlapping motor symptoms. It is critical to characterize distinct phenotypes in FXTAS compared to PD and ET to improve diagnostic accuracy. Fast as possible (FP) speed and dual-task (DT) paradigms have the potential to distinguish differences in gait performance between the three movement disorders. Therefore, we sought to compare FXTAS, PD, and ET patients using quantitative measures of functional mobility and gait under self-selected (SS) speed, FP, and DT conditions. Methods: Participants with FXTAS (n = 22), PD (n = 23), ET (n = 20), and controls (n = 20) underwent gait testing with an inertial sensor system (APDM™). An instrumented Timed Up and Go test (i-TUG) was used to measure movement transitions, and a 2-min walk test (2MWT) was used to measure gait and turn variables under SS, FP, and DT conditions, and dual-task costs (DTC) were calculated. ANOVA and multinomial logistic regression analyses were performed. Results: PD participants had reduced stride lengths compared to FXTAS and ET participants under SS and DT conditions, longer turn duration than ET participants during the FP task, and less arm symmetry than ET participants in SS gait. They also had greater DTC for stride length and velocity compared to FXTAS participants. On the i-TUG, PD participants had reduced sit-to-stand peak velocity compared to FXTAS and ET participants. Stride length and arm symmetry index during the DT 2MWT was able to distinguish FXTAS and ET from PD, such that participants with shorter stride lengths were more likely to have a diagnosis of PD and those with greater arm asymmetry were more likely to be diagnosed with PD. No gait or i-TUG parameters distinguished FXTAS from ET participants in the regression model. Conclusion: This is the first quantitative study demonstrating distinct gait and functional mobility profiles in FXTAS, PD, and ET which may assist in more accurate and timely diagnosis.