One-Year Follow-Up of Subthalamic Nucleus Deep Brain Stimulation in SNCA Mutation Parkinsonism: A Case Report.

Background: Deep brain stimulation (DBS) has shown some efficacy in monogenic Parkinson's disease; however, data about its long-term benefit in SNCA mutations remain scarce. Case report: Subthalamic nucleus DBS was implanted in a 60-year-old female patient with Parkinson's disease due to SNCA duplication. One year later, the patient walked unassisted and was independent for most activities of daily living, without requiring any anti-Parkinson's medication. Discussion: To our knowledge, four cases of bilateral subthalamic DBS have been reported previously. This case report adds an additional body of evidence of improved one-year outcome after DBS surgery in a patient with SNCA mutation. Highlights: This is a case report of a patient with genetic parkinsonism due to SNCA duplication undergoing bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) surgery. The outcome was favorable one year after implantation, with the patient coming off all anti-Parkinson's medications. This further clarifies DBS outcome in monogenic Parkinson's disease.

Cerebellar Volume and Disease Staging in Parkinson's Disease: An ENIGMA-PD Study.

BACKGROUND: Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non-motor functioning remain to be elucidated. OBJECTIVE: To quantify cross-sectional regional cerebellar lobule volumes using three dimensional T1-weighted anatomical brain magnetic resonance imaging from the global ENIGMA-PD working group. METHODS: Cerebellar parcellation was performed using a deep learning-based approach from 2487 people with PD and 1212 age and sex-matched controls across 22 sites. Linear mixed effects models compared total and regional cerebellar volume in people with PD at each Hoehn and Yahr (HY) disease stage, to an age- and sex- matched control group. Associations with motor symptom severity and Montreal Cognitive Assessment scores were investigated. RESULTS: Overall, people with PD had a regionally smaller posterior lobe (dmax = -0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (dmax = 0.28) in people with PD in HY stage 1 compared to controls. In contrast, smaller bilateral lobule VII volume in the posterior lobe was observed in HY stages 3, 4, and 5 (dmax = -0.76), which was incrementally lower with higher disease stage. Within PD, cognitively impaired individuals had lower total cerebellar volume compared to cognitively normal individuals (d = -0.17). CONCLUSIONS: We provide evidence of a dissociation between anterior "motor" lobe and posterior "non-motor" lobe cerebellar regions in PD. Whereas less severe stages of the disease are associated with larger motor lobe regions, more severe stages of the disease are marked by smaller non-motor regions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Effectiveness and safety of safinamide in routine clinical practice in a Belgian Parkinson's disease population: an open-label, levodopa add-on study.

BACKGROUND: Safinamide is a recent multimodal antiparkinsonian drug that inhibits monoamine oxidase B and modulates the glutamatergic system with positive effects on motor and nonmotor symptoms of Parkinson's disease (PD). This post-hoc analysis of the European SYNAPSES study provides first-time data on the use of safinamide in routine clinical practice in Belgium. OBJECTIVE: To describe the efficacy and safety of safinamide in Belgian PD patients in real-life conditions. METHODS: Post-hoc analysis of the Belgian cohort from the European SYNAPSES trial, which was an observational, multicenter, retrospective-prospective cohort study. Patients were followed up to 12 months. Analyses were performed in the overall population and according to different criteria such as the age limit (> 75 years), presence or absence of relevant comorbidities, presence or absence of psychiatric conditions such as depression and anxiety, patients on levodopa monotherapy or levodopa in combination with other treatments, patients on rasagiline before inclusion or not. RESULTS: Of the 172 patients included, 29.2% were > 75 years, 58.9% had relevant comorbidities and 32.7% had psychiatric conditions. Almost all the patients reported motor (98.8%) or non-motor (86.3%) symptoms. During the study, 36.3% of patients reported drug-related reactions. The adverse drug reactions were those already described in the patients' information leaflet. The majority were mild or moderate and completely resolved and no differences were detected between the subgroups of patients. Almost 35% of the patients demonstrated a clinically significant improvement in the UPDRS and 50% of the patients with wearing-off at baseline, did not report wearing-off anymore after one year of treatment. Patients under levodopa monotherapy compared to patients receiving levodopa combined with other antiparkinsonian treatments benefit more from safinamide treatment. Patients switched from rasagiline to safinamide seemed also to benefit more from safinamide treatment. CONCLUSION: The study confirms the excellent safety and efficacy profile of safinamide, particularly in more vulnerable groups of patients such as the elderly and patients with significant comorbidities or psychiatric conditions such as depression or anxiety.

Case report: Thirty-year progression of an EMPF1 encephalopathy due to defective mitochondrial and peroxisomal fission caused by a novel de novo heterozygous DNM1L variant.

Mutations in DNM1L (DRP1), which encode a key player of mitochondrial and peroxisomal fission, have been reported in patients with the variable phenotypic spectrum, ranging from non-syndromic optic atrophy to lethal infantile encephalopathy. Here, we report a case of an adult female patient presenting with a complex neurological phenotype that associates axonal sensory neuropathy, spasticity, optic atrophy, dysarthria, dysphasia, dystonia, and ataxia, worsening with aging. Whole-exome sequencing revealed a heterozygous de novo variant in the GTPase domain of DNM1L [NM_001278464.1: c.176C>A p.(Thr59Asn)] making her the oldest patient suffering from encephalopathy due to defective mitochondrial and peroxisomal fission-1. In silico analysis suggested a protein destabilization effect of the variant Thr59Asn. Unexpectedly, Western blotting disclosed profound decrease of DNM1L expression, probably related to the degradation of DNM1L complexes. A detailed description of mitochondrial and peroxisomal anomalies in transmission electron and 3D fluorescence microscopy studies confirmed the exceptional phenotype of this patient.

Monitoring of a progressive functional dopaminergic deficit in the A53T-AAV synuclein rats by combining 6-[18F]fluoro-L-m-tyrosine imaging and motor performances analysis.

With the emergence of disease-modifying therapies for Parkinson's disease, reliable longitudinal markers are needed to quantify pathology and demonstrate disease progression. We developed the A53T-AAV rat model of synucleinopathy by combining longitudinal measures over 12 weeks. We first characterized the progression of the motor and dopaminergic deficits. Then, we monitored the disease progression using the [18F]FMT Positron Emission Tomography (PET) radiotracer. The nigral injection of A53T-AAV led to an increase in phosphorylated α-synuclein on S129, a progressive accumulation of α-synuclein aggregates, and a decrease of dopaminergic function associated with a deterioration of motor activity. The longitudinal monitoring of A53T-AAV rats with [18F]FMT PET showed a progressive reduction of the Kc outcome parameter in the caudate putamen from the lesioned side. Interestingly, the progressive reduction in the [18F]FMT PET signal correlated with defects in the stepping test. In conclusion, we established a progressive rat model of α-synuclein pathology which monitors the deficit longitudinally using both the [18F]FMT PET tracer and behavioral parameters, 2 features that have strong relevance for translational approaches.

Parkinson's disease multimodal imaging: F-DOPA PET, neuromelanin-sensitive and quantitative iron-sensitive MRI.

Parkinson's disease (PD) is a neurodegenerative synucleinopathy characterized by the degeneration of neuromelanin (NM)-containing dopaminergic neurons and deposition of iron in the substantia nigra (SN). How regional NM loss and iron accumulation within specific areas of SN relate to nigro-striatal dysfunction needs to be clarified. We measured dopaminergic function in pre- and postcommissural putamen by [18F]DOPA PET in 23 Parkinson's disease patients and 23 healthy control (HC) participants in whom NM content and iron load were assessed in medial and lateral SN, respectively, by NM-sensitive and quantitative R2* MRI. Data analysis consisted of voxelwise regressions testing the group effect and its interaction with NM or iron signals. In PD patients, R2* was selectively increased in left lateral SN as compared to healthy participants, suggesting a local accumulation of iron in Parkinson's disease. By contrast, NM signal differed between PD and HC, without specific regional specificity within SN. Dopaminergic function in posterior putamen decreased as R2* increased in lateral SN, indicating that dopaminergic function impairment progresses with iron accumulation in the SN. Dopaminergic function was also positively correlated with NM signal in lateral SN, indicating that dopaminergic function impairment progresses with depigmentation in the SN. A complex relationship was detected between R2* in the lateral SN and NM signal in the medial SN. In conclusion, multimodal imaging reveals regionally specific relationships between iron accumulation and depigmentation within the SN of Parkinson's disease and provides in vivo insights in its neuropathology.

International Multicenter Analysis of Brain Structure Across Clinical Stages of Parkinson's Disease.

BACKGROUND: Brain structure abnormalities throughout the course of Parkinson's disease have yet to be fully elucidated. OBJECTIVE: Using a multicenter approach and harmonized analysis methods, we aimed to shed light on Parkinson's disease stage-specific profiles of pathology, as suggested by in vivo neuroimaging. METHODS: Individual brain MRI and clinical data from 2357 Parkinson's disease patients and 1182 healthy controls were collected from 19 sources. We analyzed regional cortical thickness, cortical surface area, and subcortical volume using mixed-effects models. Patients grouped according to Hoehn and Yahr stage were compared with age- and sex-matched controls. Within the patient sample, we investigated associations with Montreal Cognitive Assessment score. RESULTS: Overall, patients showed a thinner cortex in 38 of 68 regions compared with controls (dmax  = -0.20, dmin  = -0.09). The bilateral putamen (dleft  = -0.14, dright  = -0.14) and left amygdala (d = -0.13) were smaller in patients, whereas the left thalamus was larger (d = 0.13). Analysis of staging demonstrated an initial presentation of thinner occipital, parietal, and temporal cortices, extending toward rostrally located cortical regions with increased disease severity. From stage 2 and onward, the bilateral putamen and amygdala were consistently smaller with larger differences denoting each increment. Poorer cognition was associated with widespread cortical thinning and lower volumes of core limbic structures. CONCLUSIONS: Our findings offer robust and novel imaging signatures that are generally incremental across but in certain regions specific to disease stages. Our findings highlight the importance of adequately powered multicenter collaborations. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Using supervised learning machine algorithm to identify future fallers based on gait patterns: A two-year longitudinal study.

INTRODUCTION: Given their major health consequences in the elderly, identifying people at risk of fall is a major challenge faced by clinicians. A lot of studies have confirmed the relationships between gait parameters and falls incidence. However, accurate tools to predict individual risk among independent older adults without a history of falls are lacking. OBJECTIVE: This study aimed to apply a supervised learning algorithm to a data set recorded in a two-year longitudinal study, in order to build a classification tree that could discern subsequent fallers based on their gait patterns. METHODS: A total of 105 adults aged >65 years, living independently at home and without a recent fall history were included in a two-year longitudinal study. All underwent physical and functional assessment. Gait speed, stride length, frequency, symmetry and regularity, and minimum toe clearance were recorded in comfortable, fast and dual task walking conditions in a standardized laboratory environment. Fall events were recorded using personal falls diaries. A supervised machine learning algorithm (J48) has been applied to the data recorded at inclusion in order to obtain a classification tree able to identify future fallers. RESULTS: Based on fall information from 96 volunteers, a classification tree correctly identifying 80% of future fallers based on gait patterns, gender, and stiffness, was obtained, with accuracy of 84%, sensitivity of 80%, specificity of 87%, a positive predictive value of 78%, and a negative predictive value of 88%. DISCUSSION: While the performances of the classification tree warrant further confirmation, it is the first predictive tool based on gait parameters that are identified (not clustered) allowing its use by other research teams. CONCLUSION: This original longitudinal pilot study using a supervised machine learning algorithm, shows that gait parameters and clinical data can be used to identify future fallers among independent older adults.

Gait symmetry in the dual task condition as a predictor of future falls among independent older adults: a 2-year longitudinal study.

BACKGROUND: Given the potential consequences of falls among older adults, a major challenge is to identify people at risk before the first event. In this context, gait parameters have been suggested as markers of fall risk. AIM: To examine, among older people, the prospective relationship between gait patterns assessed in comfortable and challenging walking conditions, and future fall(s). METHOD: A total of 105 adults older than 65 years, living independently at home and without a recent fall history were included in a 2-year, longitudinal, observational study. All underwent physical and functional assessment. Gait speed, stride length, frequency, symmetry and regularity and Minimum Toe Clearance (MTC) were recorded in comfortable (CW), fast (FW) and dual task walking (DTW) conditions. Gait parameter changes occurring between CW and FW and between CW and DTW were calculated and expressed in percent. DTW cost was calculated as the change of DTW relative to CW. Fall events were recorded using fall diaries. Comparisons according to fall occurrence were performed by means of univariate analysis and multivariate binary logistic regression analysis. RESULTS: Two-year follow-up was available for 96 participants, of whom 35 (36.5%) fell at least once. Comparative analysis showed that future fallers had shorter FW stride length and higher symmetry DTW cost than non-fallers (p < 0.05). Binary logistic regression analysis showed that each additional percent of stride symmetry cost was associated with an increase in future fall risk (odds ratio 1.018, 95% Confidence Interval (CI) 1.002-1.033; p = 0.027). DISCUSSION: Our results confirm the association between a symmetry decrease in DTW and future fall(s). Indeed in this study, the mean symmetry DTW cost in fallers is almost 20% higher than in non-fallers, meaning a fall risk that is around 36% higher than among non-fallers. CONCLUSION: This exploratory study shows the usefulness of considering gait parameters, particularly symmetry in challenging walking conditions, for early identification of future fallers.

Separation and determination of alpha-synuclein monomeric and oligomeric species using two electrophoretic approaches.

Parkinson's disease (PD) is a frequent degenerative disorder that is diagnosed based on clinical symptoms. When the first symptoms appear, more than 70% of the dopaminergic cells are already lost. Therefore, it is of utmost importance to have reliable biomarkers to diagnose much earlier PD. In this context, alpha-synuclein (aSyn) is a protein of high interest because of its tendency to form oligomers and amyloid fibrils. The oligomeric forms seem to play a critical pathological role in PD. To date, most of studies aiming at detecting and quantifying aSyn oligomers were performed by immunoassays, mainly by ELISA using specific antibodies. In this study a capillary gel electrophoresis (CGE) coupled with fluorescence detection method was developed to detect and quantify the oligomeric forms of aSyn formed in vitro. All the results obtained were supported by SDS-PAGE analysis, a widely used and well-known technique but exhibiting a main drawback since it is not an automated technique. The repeatability and the intermediate precision of the method were evaluated, as well as the stability of the labeled and non-labeled aSyn samples. After careful screening and optimization of various labeling reagents, 4-fluoro-7-nitrobenzofurazan (NBD-F) was selected and used to establish a calibration curve with monomeric fluorescently-labeled aSyn. Finally, the method was used to study the effect of doxycycline on the oligomerization process. Altogether, our results show that CGE is a very promising automated technique to analyze aSyn monomers, as well as small oligomers.

Correlation between deep brain stimulation effects on freezing of gait and audio-spinal reflex.

OBJECTIVE: A network of cortical, subcortical and brainstem structures might be involved in freezing of gait (FOG). Subthalamic nucleus (STN) deep brain stimulation (DBS) could modulate this network. The audio-spinal reflex (ASR), reduced in PD, but increased by treatment, can be used to further investigate that locomotor network. The aim of this study is to find whether a correlation exists between ASR and FOG in PD patients under DBS. METHODS: In 14 PD patients with STN DBS and previous FOG, ASR was recorded, with DBS switched on and off. We also assessed FOG Questionnaire (FOGQ) and Unified Parkinson's Disease Rating Scale (UPDRS) Part III. RESULTS: Switching "on" DBS increased ASR amplitude (+ 33.2% with DBS ON, p = 0.048). We also found a significant inverse correlation between FOGQ and modulation of ASR by DBS (r = -0.59, r2 = 0.35, p < 0.05). CONCLUSIONS: This study shows that the incremental effect of DBS on ASR is greater in PD patients with less severe FOG. SIGNIFICANCE: This study shows a link between electrophysiological and clinical data about gait control. It might contribute to better understand why some DBS patients report heavy FOG and others do not. ASR might be used to evaluate or maybe predict the effect of stimulation parameters changes on FOG.

Multivariate Analysis of 18F-DMFP PET Data to Assist the Diagnosis of Parkinsonism.

An early and differential diagnosis of parkinsonian syndromes still remains a challenge mainly due to the similarity of their symptoms during the onset of the disease. Recently, 18F-Desmethoxyfallypride (DMFP) has been suggested to increase the diagnostic precision as it is an effective radioligand that allows us to analyze post-synaptic dopamine D2/3 receptors. Nevertheless, the analysis of these data is still poorly covered and its use limited. In order to address this challenge, this paper shows a novel model to automatically distinguish idiopathic parkinsonism from non-idiopathic variants using DMFP data. The proposed method is based on a multiple kernel support vector machine and uses the linear version of this classifier to identify some regions of interest: the olfactory bulb, thalamus, and supplementary motor area. We evaluated the proposed model for both, the binary separation of idiopathic and non-idiopathic parkinsonism and the multigroup separation of parkinsonian variants. These systems achieved accuracy rates higher than 70%, outperforming DaTSCAN neuroimages for this purpose. In addition, a system that combined DaTSCAN and DMFP data was assessed.

Comparative assessment of 6-[18 F]fluoro-L-m-tyrosine and 6-[18 F]fluoro-L-dopa to evaluate dopaminergic presynaptic integrity in a Parkinson's disease rat model.

Because of the progressive loss of nigro-striatal dopaminergic terminals in Parkinson's disease (PD), in vivo quantitative imaging of dopamine (DA) containing neurons in animal models of PD is of critical importance in the preclinical evaluation of highly awaited disease-modifying therapies. Among existing methods, the high sensitivity of positron emission tomography (PET) is attractive to achieve that goal. The aim of this study was to perform a quantitative comparison of brain images obtained in 6-hydroxydopamine (6-OHDA) lesioned rats using two dopaminergic PET radiotracers, namely [18 F]fluoro-3,4-dihydroxyphenyl-L-alanine ([18 F]FDOPA) and 6-[18 F]fluoro-L-m-tyrosine ([18 F]FMT). Because the imaging signal is theoretically less contaminated by metabolites, we hypothesized that the latter would show stronger relationship with behavioural and post-mortem measures of striatal dopaminergic deficiency. We used a within-subject design to measure striatal [18 F]FMT and [18 F]FDOPA uptake in eight partially lesioned, eight fully lesioned and ten sham-treated rats. Animals were pretreated with an L-aromatic amino acid decarboxylase inhibitor. A catechol-O-methyl transferase inhibitor was also given before [18 F]FDOPA PET. Quantitative estimates of striatal uptake were computed using conventional graphical Patlak method. Striatal dopaminergic deficiencies were measured with apomorphine-induced rotations and post-mortem striatal DA content. We observed a strong relationship between [18 F]FMT and [18 F]FDOPA estimates of decreased uptake in the denervated striatum using the tissue-derived uptake rate constant Kc . However, only [18 F]FMT Kc succeeded to discriminate between the partial and the full 6-OHDA lesion and correlated well with the post-mortem striatal DA content. This study indicates that the [18 F]FMT could be more sensitive, with respect of [18 F]FDOPA, to investigate DA terminals loss in 6-OHDA rats, and open the way to in vivo L-aromatic amino acid decarboxylase activity targeting in future investigations on progressive PD models.

Effects of twelve weeks of aerobic or strength training in addition to standard care in Parkinson's disease: a controlled study.

BACKGROUND: Physical exercise in addition to standard care (SC) in patients with Parkinson's disease (PD) is now a common practice in many care units. However, exercises can cover a wide range of interventions, and the specific effects of different interventions still deserve to be further investigated. AIM: The aim of this study was to compare the effects of 12 weeks of two different types of physical exercises with SC in patients suffering from PD. DESIGN: Pseudo-randomized controlled trial. SETTING: University laboratory for outcomes, University Hospital Centre for interventions. POPULATION: Fifty-two outpatients suffering from mild to moderate PD at baseline. METHODS: Participants were allocated to three groups: the strength training (ST) group performed individualized upper and lower limbs strength training, the aerobic training (AE) group performed tailored gradual aerobic cycling, and the third group received SC. The effects of the interventions on body function were assessed by measuring isokinetic concentric peak torque for knee extension and flexion, peak oxygen consumption (VO2peak) and peak work load (PWL) during an incremental maximal cycling test. Changes in mobility were evaluated from spatial-temporal gait features measured by mean of an accelerometer system and the Six-Minute Walk Distance (6MWD) Test. We used questionnaires to estimate health-related quality of life and habitual physical activity. RESULTS: No significant changes in any outcome measures occurred in the SC group. More than 80% of the participants adequately completed the AE and the ST interventions. The ST group significantly improved all peak torque measures (P≤0.01), except knee extension in the least affected side (P=0.13). This group also improved the PWL (P=0.009) and 6mwd (P=0.03). The AE group improved the VO2peak (P=0.02) and PWL (P<0.001). CONCLUSIONS: Physical fitness in patients with PD rapidly improved in compliance with training specificities, but better fitness hardly translated into better mobility and health-related quality of life. CLINICAL REHABILITATION IMPACT: Physiotherapists can efficiently propose physical conditioning to patients with mild to moderate PD, but these interventions are insufficient to improve gait and participation. Notwithstanding, ST is an efficient intervention for improving walking capacity.

Evaluation of the interaction between LRRK2 and PARK16 loci in determining risk of Parkinson's disease: analysis of a large multicenter study.

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed interaction between LRRK2 and PARK16 variants in modifying PD risk using a large multicenter series of PD patients (7715) and controls (8261) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Our data does not support a strong direct interaction between LRRK2 and PARK16 variants; however, given the role of retromer and lysosomal pathways in PD, further studies are warranted.

Contribution of four lifelong factors of cognitive reserve on late cognition in normal aging and Parkinson's disease.

INTRODUCTION: Cognitive reserve (CR) was proposed to explain how individual differences in brain function help to cope with the effects of normal aging and neurodegenerative diseases. Education, professional solicitations, and engagement in leisure and physical activities across the lifetime are considered as major determinants of this reserve. METHOD: Using multiple linear regression analyses, we tested separately in healthy elderly and Parkinson's disease (PD) populations to what extent cognitive performance in several domains was explained by (a) any of these four environmental lifespan variables; (b) demographic and clinical variables (age, gender, depression score, and, for the PD group, duration of disease and dopaminergic drugs). We also tested for an interaction, if any, between these lifespan variables and brain pathology indexed by global atrophy measured from high-resolution anatomical magnetic resonance imaging. RESULTS: Age was negatively associated with cognitive performance in the PD group. In healthy elderly participants, we observed significant positive associations between cognitive performance and (a) education, (b) leisure activities, and (c) professional solicitation (decisional latitude). Furthermore, participants with greater brain atrophy benefited more from CR. In PD patients, education and professional solicitations contributed to cognitive performance but to a lesser extent than in controls. CR factors modulated the relationship between cognition and brain atrophy only in patients with a slight or moderate brain atrophy. CONCLUSIONS: Education is the CR factor that contributed the most to late cognitive functioning in both groups, closely followed by leisure activity in normal aging and professional solicitations in PD. Our results also provide evidence suggesting that the effects of CR does not express similarly in normal aging and PD. From a broader perspective, these results seem to indicate that CR factors the most consistently practiced across lifespan (education and professional solicitation) are those that are the more strongly associated to late cognitive efficiency.

The Network Model of Depression as a Basis for New Therapeutic Strategies for Treating Major Depressive Disorder in Parkinson's Disease.

The high prevalence of major depressive disorder in people with Parkinson's disease (PD), its negative impact on health-related quality of life and the low response rate to conventional pharmacological therapies call to seek innovative treatments. Here, we review the new approaches for treating major depressive disorder in patients with PD within the framework of the network model of depression. According to this model, major depressive disorder reflects maladaptive neuronal plasticity. Non-invasive brain stimulation (NIBS) using high frequency repetitive transcranial magnetic stimulation (rTMS) over the prefrontal cortex has been proposed as a feasible and effective strategy with minimal risk. The neurobiological basis of its therapeutic effect may involve neuroplastic modifications in limbic and cognitive networks. However, the way this networks reorganize might be strongly influenced by the environment. To address this issue, we propose a combined strategy that includes NIBS together with cognitive and behavioral interventions.

Effects of 10 Hz and 20 Hz Transcranial Alternating Current Stimulation on Automatic Motor Control.

BACKGROUND: In a masked prime choice reaction task, presentation of a compatible prime increases the reaction time to the following imperative stimulus if the interval between mask and prime is around 80-250 ms. This is thought to be due to automatic suppression of the motor plan evoked by the prime, which delays reaction to the imperative stimulus. Oscillatory activity in motor networks around the beta frequency range of 20 Hz is important in suppression of movement. Transcranial alternating current at 20 Hz may be able to drive oscillations in the beta range. OBJECTIVE/HYPOTHESIS: To investigate whether transcranial alternating current stimulation (tACS) at 20 Hz would increase automatic inhibition in a masked prime task. As a control we used 10 Hz tACS. METHODS: Stimulation was delivered at alpha (10 Hz) and beta (20 Hz) frequency over the supplementary motor area and the primary motor cortex (simultaneous tACS of SMA-M1), which are part of the BG-cortical motor loop, during the execution of the subliminal masked prime left/right choice reaction task. We measured the effects on reaction times. Corticospinal excitability was assessed by measuring the amplitude of motor evoked potentials (MEPs) evoked in the first dorsal interosseous muscle by transcranial magnetic stimulation (TMS) over M1. RESULTS: The 10 and 20-Hz tACS over SMA-M1 had different effects on automatic inhibition. The 20 Hz tACS increased the duration of automatic inhibition whereas it was decreased by 10 Hz tACS. Neurophysiologically, 20 Hz tACS reduced the amplitude of MEPs evoked from M1, whereas there was no change after 10 Hz tACS. CONCLUSION: Automatic mechanisms of motor inhibition can be modulated by tACS over motor areas of cortex. tACS may be a useful additional tool to investigate the causal links between endogenous brain oscillations and specific cognitive processes.

Large-scale assessment of polyglutamine repeat expansions in Parkinson disease.

OBJECTIVES: We aim to clarify the pathogenic role of intermediate size repeat expansions of SCA2, SCA3, SCA6, and SCA17 as risk factors for idiopathic Parkinson disease (PD). METHODS: We invited researchers from the Genetic Epidemiology of Parkinson's Disease Consortium to participate in the study. There were 12,346 cases and 8,164 controls genotyped, for a total of 4 repeats within the SCA2, SCA3, SCA6, and SCA17 genes. Fixed- and random-effects models were used to estimate the summary risk estimates for the genes. We investigated between-study heterogeneity and heterogeneity between different ethnic populations. RESULTS: We did not observe any definite pathogenic repeat expansions for SCA2, SCA3, SCA6, and SCA17 genes in patients with idiopathic PD from Caucasian and Asian populations. Furthermore, overall analysis did not reveal any significant association between intermediate repeats and PD. The effect estimates (odds ratio) ranged from 0.93 to 1.01 in the overall cohort for the SCA2, SCA3, SCA6, and SCA17 loci. CONCLUSIONS: Our study did not support a major role for definite pathogenic repeat expansions in SCA2, SCA3, SCA6, and SCA17 genes for idiopathic PD. Thus, results of this large study do not support diagnostic screening of SCA2, SCA3, SCA6, and SCA17 gene repeats in the common idiopathic form of PD. Likewise, this largest multicentered study performed to date excludes the role of intermediate repeats of these genes as a risk factor for PD.