Cognitive outcomes in patients with essential tremor treated with deep brain stimulation: a systematic review.

Introduction: Essential tremor (ET) is a common neurological disease. Deep brain stimulation (DBS) to the thalamic ventral intermediate nucleus (VIM) or the adjacent structures, such as caudal zona incerta/ posterior subthalamic area (cZi/PSA), can be effective in treating medication refractory tremor. However, it is not clear whether DBS can cause cognitive changes, in which domain, and to what extent if so. Methods: We systematically searched PubMed and the Web of Science for available publications reporting on cognitive outcomes in patients with ET who underwent DBS following the PICO (population, intervention, comparators, and outcomes) concept. The PRISMA guideline for systematic reviews was applied. Results: Twenty relevant articles were finally identified and included for review, thirteen of which were prospective (one also randomized) studies and seven were retrospective. Cognitive outcomes included attention, memory, executive function, language, visuospatial function, and mood-related variables. VIM and cZi/PSA DBS were generally well tolerated, although verbal fluency and language production were affected in some patients. Additionally, left-sided VIM DBS was associated with negative effects on verbal abstraction, word recall, and verbal memory performance in some patients. Conclusion: Significant cognitive decline after VIM or cZi/PSA DBS in ET patients appears to be rare. Future prospective randomized controlled trials are needed to meticulously study the effect of the location, laterality, and stimulation parameters of the active contacts on cognitive outcomes while considering possible medication change post-DBS, timing, standard neuropsychological battery, practice effects, the timing of assessment, and effect size as potential confounders.

Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study.

BACKGROUND: An understanding of the genetic mechanisms underlying diseases in ancestrally diverse populations is an important step towards development of targeted treatments. Research in African and African admixed populations can enable mapping of complex traits, because of their genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. We aimed to do a comprehensive genome-wide assessment in African and African admixed individuals to better understand the genetic architecture of Parkinson's disease in these underserved populations. METHODS: We performed a genome-wide association study (GWAS) in people of African and African admixed ancestry with and without Parkinson's disease. Individuals were included from several cohorts that were available as a part of the Global Parkinson's Genetics Program, the International Parkinson's Disease Genomics Consortium Africa, and 23andMe. A diagnosis of Parkinson's disease was confirmed clinically by a movement disorder specialist for every individual in each cohort, except for 23andMe, in which it was self-reported based on clinical diagnosis. We characterised ancestry-specific risk, differential haplotype structure and admixture, coding and structural genetic variation, and enzymatic activity. FINDINGS: We included 197 918 individuals (1488 cases and 196 430 controls) in our genome-wide analysis. We identified a novel common risk factor for Parkinson's disease (overall meta-analysis odds ratio for risk of Parkinson's disease 1·58 [95% CI 1·37-1·80], p=2·397 × 10-14) and age at onset at the GBA1 locus, rs3115534-G (age at onset ß=-2·00 [SE=0·57], p=0·0005, for African ancestry; and ß=-4·15 [0·58], p=0·015, for African admixed ancestry), which was rare in non-African or non-African admixed populations. Downstream short-read and long-read whole-genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. The identified signal seems to be associated with decreased glucocerebrosidase activity. INTERPRETATION: Our study identified a novel genetic risk factor in GBA1 in people of African ancestry, which has not been seen in European populations, and it could be a major mechanistic basis of Parkinson's disease in African populations. This population-specific variant exerts substantial risk on Parkinson's disease as compared with common variation identified through GWAS and it was found to be present in 39% of the cases assessed in this study. This finding highlights the importance of understanding ancestry-specific genetic risk in complex diseases, a particularly crucial point as the Parkinson's disease field moves towards targeted treatments in clinical trials. The distinctive genetics of African populations highlights the need for equitable inclusion of ancestrally diverse groups in future trials, which will be a valuable step towards gaining insights into novel genetic determinants underlying the causes of Parkinson's disease. This finding opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk of Parkinson's disease. FUNDING: The Global Parkinson's Genetics Program, which is funded by the Aligning Science Across Parkinson's initiative, and The Michael J Fox Foundation for Parkinson's Research.

Genome-wide Association Identifies Novel Etiological Insights Associated with Parkinson's Disease in African and African Admixed Populations.

Background: Understanding the genetic mechanisms underlying diseases in ancestrally diverse populations is a critical step towards the realization of the global application of precision medicine. The African and African admixed populations enable mapping of complex traits given their greater levels of genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. Methods: Here we perform a comprehensive genome-wide assessment of Parkinson's disease (PD) in 197,918 individuals (1,488 cases; 196,430 controls) of African and African admixed ancestry, characterizing population-specific risk, differential haplotype structure and admixture, coding and structural genetic variation and polygenic risk profiling. Findings: We identified a novel common risk factor for PD and age at onset at the GBA1 locus (risk, rs3115534-G; OR=1.58, 95% CI = 1.37 - 1.80, P=2.397E-14; age at onset, BETA =-2.004, SE =0.57, P = 0.0005), that was found to be rare in non-African/African admixed populations. Downstream short- and long-read whole genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. However, we identified that this signal mediates PD risk via expression quantitative trait locus (eQTL) mechanisms. While previously identified GBA1 associated disease risk variants are coding mutations, here we suggest a novel functional mechanism consistent with a trend in decreasing glucocerebrosidase activity levels. Given the high population frequency of the underlying signal and the phenotypic characteristics of the homozygous carriers, we hypothesize that this variant may not cause Gaucher disease. Additionally, the prevalence of Gaucher's disease in Africa is low. Interpretation: The present study identifies a novel African-ancestry genetic risk factor in GBA1 as a major mechanistic basis of PD in the African and African admixed populations. This striking result contrasts to previous work in Northern European populations, both in terms of mechanism and attributable risk. This finding highlights the importance of understanding population-specific genetic risk in complex diseases, a particularly crucial point as the field moves toward precision medicine in PD clinical trials and while recognizing the need for equitable inclusion of ancestrally diverse groups in such trials. Given the distinctive genetics of these underrepresented populations, their inclusion represents a valuable step towards insights into novel genetic determinants underlying PD etiology. This opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk. Evidence Before this Study: Our current understanding of Parkinson's disease (PD) is disproportionately based on studying populations of European ancestry, leading to a significant gap in our knowledge about the genetics, clinical characteristics, and pathophysiology in underrepresented populations. This is particularly notable in individuals of African and African admixed ancestries. Over the last two decades, we have witnessed a revolution in the research area of complex genetic diseases. In the PD field, large-scale genome-wide association studies in the European, Asian, and Latin American populations have identified multiple risk loci associated with disease. These include 78 loci and 90 independent signals associated with PD risk in the European population, nine replicated loci and two novel population-specific signals in the Asian population, and a total of 11 novel loci recently nominated through multi-ancestry GWAS efforts.Nevertheless, the African and African admixed populations remain completely unexplored in the context of PD genetics. Added Value of this Study: To address the lack of diversity in our research field, this study aimed to conduct the first genome-wide assessment of PD genetics in the African and African admixed populations. Here, we identified a genetic risk factor linked to PD etiology, dissected African-specific differences in risk and age at onset, characterized known genetic risk factors, and highlighted the utility of the African and African admixed risk haplotype substructure for future fine-mapping efforts. We identified a novel disease mechanism via expression changes consistent with decreased GBA1 activity levels. Future large scale single cell expression studies should investigate the neuronal populations in which expression differences are most prominent. This novel mechanism may hold promise for future efficient RNA-based therapeutic strategies such as antisense oligonucleotides or short interfering RNAs aimed at preventing and decreasing disease risk. We envisage that these data generated under the umbrella of the Global Parkinson's Genetics Program (GP2) will shed light on the molecular mechanisms involved in the disease process and might pave the way for future clinical trials and therapeutic interventions. This work represents a valuable resource in an underserved population, supporting pioneering research within GP2 and beyond. Deciphering causal and genetic risk factors in all these ancestries will help determine whether interventions, potential targets for disease modifying treatment, and prevention strategies that are being studied in the European populations are relevant to the African and African admixed populations. Implications of all the Available Evidence: We nominate a novel signal impacting GBA1 as the major genetic risk factor for PD in the African and African admixed populations. The present study could inform future GBA1 clinical trials, improving patient stratification. In this regard, genetic testing can help to design trials likely to provide meaningful and actionable answers. It is our hope that these findings may ultimately have clinical utility for this underrepresented population.

Using Downgaze Palsy Progression Rate to Model Survival in Progressive Supranuclear Palsy-Richardson Syndrome.

BACKGROUND: Rapid development of downgaze palsy, the most specific symptom of progressive supranuclear palsy (PSP), has been associated with shorter survival in small studies. OBJECTIVE: We hypothesized that the progression rate of downgaze palsy and other disease features could predict survival if assessed soon after the onset of downgaze palsy in a large data set. METHODS: We used a longitudinal database of 414 patients with probable PSP-Richardson syndrome from 1994 to 2020. The data set comprised demographics and, for each visit, 28 PSP Rating Scale (PSPRS) items and PSP stage scores. We calculated the rate of progression of each PSPRS item as its item score when the downgaze item first reached 1 or more (on a 0-4 scale) divided by disease duration at that point. Multivariate Cox regression was applied to identify variables independently associated with survival. We also explored the progression pattern of total PSPRS and downgaze palsy scores with disease course. RESULTS: Independently associated with shorter survival were older onset age and faster progression of downgaze palsy, dysphagia for liquids, difficulty in returning to seat, and PSP stage. Patients with survival duration within 1 year of the median survival (6.58 years) showed approximately linear progression of the PSPRS score and downgaze palsy score during years 2 through 6 of the disease course. CONCLUSIONS: Older onset age and faster progression of downgaze palsy and several axial features are associated with shorter survival. The disease typically progresses in approximately linear fashion during years 2 through 6. These results may aid study design and patient counseling. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Severity of Downgaze Palsy in the Context of Disease Duration Could Estimate Survival Duration in Patients With Progressive Supranuclear Palsy.

It is an unmet need to estimate survival duration for patients with progressive supranuclear palsy (PSP). The objective of this study was to identify factors associated with the survival duration in patients with PSP. We followed up 23 patients with probable PSP-RS (Richardson syndrome) or PSP-P (parkinsonism) in our PSP center until death from 2011 to 2019. We prospectively and quantitatively rated their downgaze palsy whenever first noticed in our clinic. This was utilized along with the disease duration, motor function, medication use for parkinsonism, sex, age at onset of PSP, comorbid pulmonary and cardiovascular diseases, and the total survival duration from the onset of PSP to death for prediction analysis. A well-fitted linear regression model and a multivariant Cox model were applied to identify predicting factors for total survival duration. All patients had the specific hummingbird sign on brain MRI for PSP when downgaze palsy was documented. We found that the severity of downgaze palsy and the disease duration at the assessment were consistently correlated with the total survival duration in both models. The total survival duration could be further estimated by a formed regression equation. We conclude that severity and time to develop downgaze palsy could help to estimate the total survival duration in patients with probable PSP-RS and PSP-P, the major forms of PSP, which has significant clinical applications in clinical counseling and trial enrollment.

Disparities in diagnosis, treatment and survival between Black and White Parkinson patients.

INTRODUCTION: Racial disparities in diagnosis, treatment and survival in Black patients with Parkinson's disease (PD) compared to White patients have not been well studied, largely due to limited number of studies and information on Black patients in healthcare systems. Studying racial disparities and identifying underlying factors in large populations are important to understand PD and improve care. METHODS: We retrospectively identified PD patients on both races from 1/1/2006 to 10/31/2017 and compared demographics, socioeconomic status (educations, incomes and insurances), comorbidities (all categories, including mood, cognition and psychosis), treatment (medications for parkinsonism and major non-motor symptoms, and frequency and locations of healthcare) and survival, and identified factors associated with medication usage and survival. RESULTS: We retrospectively studied 2033 PD patients, of whom 725 were Black. Black patients lacked male predominance, were 4 years older at first diagnosis here, more likely to smoke and live in a low education and income community, and possessed limited insurances compared to White patients. Black patients also had more comorbidities and were more likely to receive care through emergency or inpatient service, but less likely to be on medications for parkinsonism and mood disorders. Race, age, smoking status, insurance type, frequency and locations of healthcare and comorbidities were associated with medication usage. Black race, older age, inpatient admission and malignancy were associated with increased risk of death. CONCLUSION: We revealed racial disparities in diagnosis, treatment and survival, and factors associated with medication usage and survival in the largest reported Black PD cohort from a single center.

Effect of Deep Brain Stimulation on Cerebellar Tremor Compared to Non-Cerebellar Tremor Using a Wearable Device in a Patient With Multiple Sclerosis: Case Report.

Tremor of the upper extremity is a significant cause of disability in some patients with multiple sclerosis (MS). The MS tremor is complex because it contains an ataxic intentional tremor component due to the involvement of the cerebellum and cerebellar outflow pathways by MS plaques, which makes the MS tremor, in general, less responsive to medications or deep brain stimulation (DBS) than those associated with essential tremor or Parkinson's disease. The cerebellar component has been thought to be the main reason for making DBS less effective, although it is not clear whether it is due to the lack of suppression of the ataxic tremor by DBS or else. The goal of this study was to clarify the effect of DBS on cerebellar tremor compared to non-cerebellar tremor in a patient with MS. By wearing an accelerometer on the index finger of each hand, we were able to quantitatively characterize kinetic tremor by frequency and amplitude, with cerebellar ataxia component on one hand and that without cerebellar component on the other hand, at the beginning and end of the hand movement approaching a target at DBS Off and On status. We found that cerebellar tremor surprisingly had as good a response to DBS as the tremor without a cerebellar component, but the function control on cerebellar tremor was not as good due to its distal oscillation, which made the amplitude of tremor increasingly greater as it approached the target. This explains why cerebellar tremor or MS tremor with cerebellar component has a poor functional transformation even with a good percentage of tremor control. This case study provides a better understanding of the effect of DBS on cerebellar tremor and MS tremor by using a wearable device, which could help future studies improve patient selection and outcome prediction for DBS treatment of this disabling tremor.

Deep Brain Stimulation Impedance Decreases Over Time Even When Stimulation Settings Are Held Constant.

Objectives: To study whether and to what extent the therapeutic impedance and current change under long-term deep brain stimulation (DBS) with constant stimulation settings, which could inform the role of constant current stimulation. Methods: Therapy impedance and current measurements were retrospectively collected from patients with Parkinson's disease (PD) undergoing DBS of the subthalamic nucleus (STN) or essential tremor (ET) undergoing ventral intermediate nucleus (VIM). Baseline and follow-up measurements were obtained for intervals of at least 6 months without changes in stimulation settings. The single longest interval of constant stimulation for each electrode was included. Temporal trends in impedance and current were analyzed as absolute and relative differences and as the rate of change. Results: Impedance and current data from 79 electrodes (60 in STN, 19 in VIM) in 44 patients (32 with PD, 12 with ET) met inclusion criteria. The duration between baseline and follow-up measurements with constant stimulation settings was 17 months (median, with an interquartile range of 12-26 months) in the mixed group. Therapy impedance decreased by 27 ± 12 Ω/year (mean ± 2 standard errors; p < 0.0001), and therapy current increased at a rate of 0.142 ± 0.063 mA/year (p < 0.0001). Similar results were observed in the STN and VIM subgroups. Conclusions: Impedance decreases gradually over time, even when stimulation settings are kept constant. The rate of decrease is smaller than previously reported, suggesting that changes in stimulation settings contribute to impedance drift. Stimulation-independent impedance drift is gradual but relevant to constant-current programming.

Long-term effect of low frequency stimulation of STN on dysphagia, freezing of gait and other motor symptoms in PD.

OBJECTIVE: To evaluate the long-term effect of 60 Hz stimulation of the subthalamic nucleus (STN) on dysphagia, freezing of gait (FOG) and other motor symptoms in patients with Parkinson's disease (PD) who have FOG at the usual 130 Hz stimulation. METHODS: This is a prospective, sequence randomised, crossover, double-blind study. PD patients with medication refractory FOG at 130 Hz stimulation of the STN were randomised to the sequences of 130 Hz, 60 Hz or deep brain stimulation off to assess swallowing function (videofluoroscopic evaluation and swallowing questionnaire), FOG severity (stand-walk-sit test and FOG questionnaire) and motor function (Unified PD Rating Scale, Part III motor examination (UPDRS-III)) at initial visit (V1) and follow-up visit (V2, after being on 60 Hz stimulation for an average of 14.5 months), in their usual medications on state. The frequency of aspiration events, perceived swallowing difficulty and FOG severity at 60 Hz compared with 130 Hz stimulation at V2, and their corresponding changes at V2 compared with V1 at 60 Hz were set as primary outcomes, with similar comparisons in UPDRS-III and its subscores as secondary outcomes. RESULTS: All 11 enrolled participants completed V1 and 10 completed V2. We found the benefits of 60 Hz stimulation compared with 130 Hz in reducing aspiration frequency, perceived swallowing difficulty, FOG severity, bradykinesia and overall axial and motor symptoms at V1 and persistent benefits on all of them except dysphagia at V2, with overall decreasing efficacy when comparing V2 to V1. CONCLUSIONS: The 60 Hz stimulation, when compared with 130 Hz, has long-term benefits on reducing FOG, bradykinesia and overall axial and motor symptoms except dysphagia, although the overall benefits decrease with long-term use. CLINICAL TRIAL REGISTRATION: NCT02549859; Pre-results.

Effect of low versus high frequency stimulation on freezing of gait and other axial symptoms in Parkinson patients with bilateral STN DBS: a mini-review.

Some studies have shown that low frequency stimulation (LFS, most commonly 60 Hz), compared to high frequency stimulation (HFS, most commonly 130 Hz), has beneficial effects, short-term or even long-term, on improving freezing of gait (FOG) and other axial symptoms, including speech and swallowing function, in Parkinson disease (PD) patients with bilateral subthalamic nucleus deep brain stimulation (STN DBS). However, other studies failed to confirm this. It seems not clear what determines the difference in response to LFS. Differences in study design, such as presence or absence of FOG, exact LFS used (60 Hz versus 80 Hz), study size, open label versus randomized double blind assessment, retrospective versus prospective evaluation, medication On or Off state, total electric energy delivered maintained or not with the change in frequency, and the location of active contacts could all potentially affect the results. This mini-review goes over the literature with the aforementioned factors in mind, focusing on the effect of LFS versus HFS on FOG and other axial symptoms in PD with bilateral STN DBS, in an effort to extract the essential data to guide our clinical management of axial symptoms and explore the potential underlying mechanisms as well. Overall, LFS of 60 Hz seems to be consistently effective in patients with FOG at the usual HFS in regards to improving FOG, speech, swallowing function and other axial symptoms, though LFS could reduce tremor control in some patients. Whether LFS simply addresses the axial symptoms in the context of HFS or has other beneficial effects requires further studies, along with the mechanism.

Evaluation of parkinsonism and striatal dopamine transporter loss in patients with spinocerebellar ataxia type 6.

It is unclear whether patients with spinocerebellar ataxia type 6 (SCA6) have parkinsonism and striatal dopamine transporter (DAT) loss, based on previously small size studies without well-matched controls. A study with a larger number of patients and both age- and gender-matched healthy controls (HCs) is needed for a better answer to this question. Twelve genetically confirmed ataxic SCA6 patients (six male six female, age 65.3 ± 11.2 years), and eight age- and gender-matched HCs (five male three female, age 71.3 ± 8.6 years) were enrolled during 2013-2015 from tertiary movement disorders and ataxia clinics. Clinical assessment for parkinsonism, and qualitative and quantitative assessment of DAT level on DaTscan™ imaging were conducted in SCA6 patients compared to HCs. We found no convincing parkinsonism in SCA6 patients, given generalized bradykinesia in the context of significant ataxia in all, with mild symmetric rigidity in five without resting tremor. Furthermore, we found no striatal DAT loss in anterior, posterior, and total putamen and caudate on imaging, assessed independently by qualitative visual inspection in a blinded manner by the nuclear medicine specialist and movement disorder specialist (kappa = 1). Additional quantitative analysis on these areas did not reveal significant DAT loss either in SCA6 patients compared to HCs. We conclude that there is no convincing parkinsonism or DAT loss in SCA6 patients in this unique study with a larger than previously reported number of patients compared to both age- and gender-matched HCs, suggesting that dopaminergic dysfunction is not usually involved in SCA6.