Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities.

OBJECTIVES: The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses. METHODS: We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient-derived cells. RESULTS: Analysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 109 ). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome-lysosome fusion. A total of 18 individuals harboring heterozygous loss-of-function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function. INTERPRETATION: Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867-877.

Cortical [18 F]PI-2620 Binding Differentiates Corticobasal Syndrome Subtypes.

BACKGROUND: Corticobasal syndrome is associated with cerebral protein aggregates composed of 4-repeat (~50% of cases) or mixed 3-repeat/4-repeat tau isoforms (~25% of cases) or nontauopathies (~25% of cases). OBJECTIVES: The aim of this single-center study was to investigate the diagnostic value of the tau PET-ligand [18 F]PI-2620 in patients with corticobasal syndrome. METHODS: Forty-five patients (71.5 ± 7.6 years) with corticobasal syndrome and 14 age-matched healthy controls underwent [18 F]PI-2620-PET. Beta-amyloid status was determined by cerebral ß-amyloid PET and/or CSF analysis. Subcortical and cortical [18 F]PI-2620 binding was quantitatively and visually compared between ß-amyloid-positive and -negative patients and controls. Regional [18 F]PI-2620 binding was correlated with clinical and demographic data. RESULTS: Twenty-four percent (11 of 45) were ß-amyloid-positive. Significantly elevated [18 F]PI-2620 distribution volume ratios were observed in both ß-amyloid-positive and ß-amyloid-negative patients versus controls in the dorsolateral prefrontal cortex and basal ganglia. Cortical [18 F]PI-2620 PET positivity was distinctly higher in ß-amyloid-positive compared with ß-amyloid-negative patients with pronounced involvement of the dorsolateral prefrontal cortex. Semiquantitative analysis of [18 F]PI-2620 PET revealed a sensitivity of 91% for ß-amyloid-positive and of 65% for ß-amyloid-negative cases, which is in excellent agreement with prior clinicopathological data. Regardless of ß-amyloid status, hemispheric lateralization of [18 F]PI-2620 signal reflected contralateral predominance of clinical disease severity. CONCLUSIONS: Our data indicate a value of [18 F]PI-2620 for evaluating corticobasal syndrome, providing quantitatively and regionally distinct signals in ß-amyloid-positive as well as ß-amyloid-negative corticobasal syndrome. In corticobasal syndrome, [18 F]PI-2620 may potentially serve for a differential diagnosis and for monitoring disease progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

In Vivo Assessment of Neuroinflammation in 4-Repeat Tauopathies.

BACKGROUND: Neuroinflammation has received growing interest as a therapeutic target in neurodegenerative disorders, including 4-repeat tauopathies. OBJECTIVES: The aim of this cross-sectional study was to investigate 18 kDa translocator protein positron emission tomography (PET) as a biomarker for microglial activation in the 4-repeat tauopathies corticobasal degeneration and progressive supranuclear palsy. METHODS: Specific binding of the 18 kDa translocator protein tracer 18 F-GE-180 was determined by serial PET during pharmacological depletion of microglia in a 4-repeat tau mouse model. The 18 kDa translocator protein PET was performed in 30 patients with corticobasal syndrome (68 ± 9 years, 16 women) and 14 patients with progressive supranuclear palsy (69 ± 9 years, 8 women), and 13 control subjects (70 ± 7 years, 7 women). Group comparisons and associations with parameters of disease progression were assessed by region-based and voxel-wise analyses. RESULTS: Tracer binding was significantly reduced after pharmacological depletion of microglia in 4-repeat tau mice. Elevated 18 kDa translocator protein labeling was observed in the subcortical brain areas of patients with corticobasal syndrome and progressive supranuclear palsy when compared with controls and was most pronounced in the globus pallidus internus, whereas only patients with corticobasal syndrome showed additionally elevated tracer binding in motor and supplemental motor areas. The 18 kDa translocator protein labeling was not correlated with parameters of disease progression in corticobasal syndrome and progressive supranuclear palsy but allowed sensitive detection in patients with 4-repeat tauopathies by a multiregion classifier. CONCLUSIONS: Our data indicate that 18 F-GE-180 PET detects microglial activation in the brain of patients with 4-repeat tauopathy, fitting to predilection sites of the phenotype. The 18 kDa translocator protein PET has a potential for monitoring neuroinflammation in 4-repeat tauopathies. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Bilateral double beta peaks in a PD patient with STN electrodes.

Subthalamic local field potentials in the beta band are considered as potential biomarkers for closed-loop deep brain stimulation. To investigate the subthalamic beta band peak amplitudes in a Parkinson's disease patient over an extended period of time by using a novel and commercially available neurostimulator with permanent sensing capability. We recorded local field potentials of the subthalamic nucleus using the Medtronic Percept™ implantable neurostimulator at rest and during physical activity (gait) with and in response to deep brain stimulation. We found a double-peaked beta activity on both sides. Increasing stimulation and physical activity resulted in a decreased beta band amplitude, but was accompanied by the appearance of a second, and previously unrecognized peak at 13 Hz in the right hemisphere. Our results will support the investigation of distinct different peaks in the beta band and their relevance and usefulness as closed-loop biomarkers.

Loss of fragile X mental retardation protein precedes Lewy pathology in Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and the gradual appearance of α-synuclein (α-syn)-containing neuronal protein aggregates. Although the exact mechanism of α-syn-mediated cell death remains elusive, recent research suggests that α-syn-induced alterations in neuronal excitability contribute to cell death in PD. Because the fragile X mental retardation protein (FMRP) controls the expression and function of numerous neuronal genes related to neuronal excitability and synaptic function, we here investigated the role of FMRP in α-syn-associated pathological changes in cell culture and mouse models of PD as well as in post-mortem human brain tissue from PD patients. We found FMRP to be decreased in cultured DA neurons and in the mouse brain in response to α-syn overexpression. FMRP was, furthermore, lost in the SNc of PD patients and in patients with early stages of incidental Lewy body disease (iLBD). Unlike fragile X syndrome (FXS), FMR1 expression in response to α-syn was regulated by a mechanism involving Protein Kinase C (PKC) and cAMP response element-binding protein (CREB). Reminiscent of FXS neurons, α-syn-overexpressing cells exhibited an increase in membrane N-type calcium channels, increased phosphorylation of ERK1/2, eIF4E and S6, increased overall protein synthesis, and increased expression of Matrix Metalloproteinase 9 (MMP9). FMRP affected neuronal function in a PD animal model, because FMRP-KO mice were resistant to the effect of α-syn on striatal dopamine release. In summary, our results thus reveal a new role of FMRP in PD and support the examination of FMRP-regulated genes in PD disease progression.

Early-phase [18F]PI-2620 tau-PET imaging as a surrogate marker of neuronal injury.

PURPOSE: Second-generation tau radiotracers for use with positron emission tomography (PET) have been developed for visualization of tau deposits in vivo. For several ß-amyloid and first-generation tau-PET radiotracers, it has been shown that early-phase images can be used as a surrogate of neuronal injury. Therefore, we investigated the performance of early acquisitions of the novel tau-PET radiotracer [18F]PI-2620 as a potential substitute for [18F]fluorodeoxyglucose ([18F]FDG). METHODS: Twenty-six subjects were referred with suspected tauopathies or overlapping parkinsonian syndromes (Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, multi-system atrophy, Parkinson's disease, multi-system atrophy, Parkinson's disease, frontotemporal dementia) and received a dynamic [18F]PI-2620 tau-PET (0-60 min p.i.) and static [18F]FDG-PET (30-50 min p.i.). Regional standardized uptake value ratios of early-phase images (single frame SUVr) and the blood flow estimate (R1) of [18F]PI-2620-PET were correlated with corresponding quantification of [18F]FDG-PET (global mean/cerebellar normalization). Reduced tracer uptake in cortical target regions was also interpreted visually using 3-dimensional stereotactic surface projections by three more and three less experienced readers. Spearman rank correlation coefficients were calculated between early-phase [18F]PI-2620 tau-PET and [18F]FDG-PET images for all cortical regions and frequencies of disagreement between images were compared for both more and less experienced readers. RESULTS: Highest agreement with [18F]FDG-PET quantification was reached for [18F]PI-2620-PET acquisition from 0.5 to 2.5 min p.i. for global mean (lowest R = 0.69) and cerebellar scaling (lowest R = 0.63). Correlation coefficients (summed 0.5-2.5 min SUVr & R1) displayed strong agreement in all cortical target regions for global mean (RSUVr 0.76, RR1 = 0.77) and cerebellar normalization (RSUVr 0.68, RR1 = 0.68). Visual interpretation revealed high regional correlations between early-phase tau-PET and [18F]FDG-PET. There were no relevant differences between more and less experienced readers. CONCLUSION: Early-phase imaging of [18F]PI-2620 can serve as a surrogate biomarker for neuronal injury. Dynamic imaging or a dual time-point protocol for tau-PET imaging could supersede additional [18F]FDG-PET imaging by indexing both the distribution of tau and the extent of neuronal injury.

Interrelation between Sarcopenia and the Number of Motor Neurons in Patients with Parkinsonian Syndromes.

INTRODUCTION: Pathogenesis in a subgroup of sarcopenic patients seems to be based on a reduced number of motor neurons. This study aimed at investigating the overlap between sarcopenia and neurodegeneration, as reflected by a low number of motor neurons in patients with Parkinsonian syndromes (PS). METHODS: The motor unit number index (MUNIX) of the hypothenar muscle was used to assess the number and size (MUSIX) of motor units (MUs) in patients with idiopathic Parkinson disease (iPD, n = 53), patients with atypical Parkinsonian syndrome (aPS, n = 21), and a control group (n = 30). Mean age of participants was 70.3 years and 54.1% were female. Skeletal muscle mass by bioelectrical impedance analysis, hand-grip strength and gait speed were measured. Based on these assessments, sarcopenia was diagnosed according to the criteria of the European Working Group on Sarcopenia in Older People. RESULTS: Sarcopenia criteria were met by 10 patients with PS (13.5%). The study group had significantly lower MUNIX values than the control group (109 [SD ±39.1] vs. 129 [SD ±45.1]; p = 0.020) even after adjustment for age and sex. Three of the 5 sarcopenic iPD patients (75%) had pathological low MUNIX values (<80). DISCUSSION/CONCLUSION: Sarcopenia is a frequent comorbidity in PS. The pathologically low MUNIX values found in 75% of our sarcopenic iPD patients provides further support for the existence of a neurodegenerative overlap syndrome with a reduced number of MUs potentially leading to sarcopenia. This finding warrants further evaluation.

Subthalamic stimulation, oscillatory activity and connectivity reveal functional role of STN and network mechanisms during decision making under conflict.

Inhibitory control is an important executive function that is necessary to suppress premature actions and to block interference from irrelevant stimuli. Current experimental studies and models highlight proactive and reactive mechanisms and claim several cortical and subcortical structures to be involved in response inhibition. However, the involved structures, network mechanisms and the behavioral relevance of the underlying neural activity remain debated. We report cortical EEG and invasive subthalamic local field potential recordings from a fully implanted sensing neurostimulator in Parkinson's patients during a stimulus- and response conflict task with and without deep brain stimulation (DBS). DBS made reaction times faster overall while leaving the effects of conflict intact: this lack of any effect on conflict may have been inherent to our task encouraging a high level of proactive inhibition. Drift diffusion modelling hints that DBS influences decision thresholds and drift rates are modulated by stimulus conflict. Both cortical EEG and subthalamic (STN) LFP oscillations reflected reaction times (RT). With these results, we provide a different interpretation of previously conflict-related oscillations in the STN and suggest that the STN implements a general task-specific decision threshold. The timecourse and topography of subthalamic-cortical oscillatory connectivity suggest the involvement of motor, frontal midline and posterior regions in a larger network with complementary functionality, oscillatory mechanisms and structures. While beta oscillations are functionally associated with motor cortical-subthalamic connectivity, low frequency oscillations reveal a subthalamic-frontal-posterior network. With our results, we suggest that proactive as well as reactive mechanisms and structures are involved in implementing a task-related dynamic inhibitory signal. We propose that motor and executive control networks with complementary oscillatory mechanisms are tonically active, react to stimuli and release inhibition at the response when uncertainty is resolved and return to their default state afterwards.

A diffusion-based connectivity map of the GPi for optimised stereotactic targeting in DBS.

BACKGROUND: The GPi (globus pallidus internus) is an important target nucleus for Deep Brain Stimulation (DBS) in medically refractory movement disorders, in particular dystonia and Parkinson's disease. Beneficial clinical outcome critically depends on precise electrode localization. Recent evidence indicates that not only neurons, but also axonal fibre tracts contribute to promoting the clinical effect. Thus, stereotactic planning should, in the future, also take the individual course of fibre tracts into account. OBJECTIVE: The aim of this project is to explore the GPi connectivity profile and provide a connectivity-based parcellation of the GPi. METHODS: Diffusion MRI sequences were performed in sixteen healthy, right-handed subjects. Connectivity-based parcellation of the GPi was performed applying two independent methods: 1) a hypothesis-driven, seed-to-target approach based on anatomic priors set as connectivity targets and 2) a purely data-driven approach based on k-means clustering of the GPi. RESULTS: Applying the hypothesis-driven approach, we obtained five major parcellation clusters, displaying connectivity to the prefrontal cortex, the brainstem, the GPe (globus pallidus externus), the putamen and the thalamus. Parcellation clusters obtained by both methods were similar in their connectivity profile. With the data-driven approach, we obtained three major parcellation clusters. Inter-individual variability was comparable with results obtained in thalamic parcellation. CONCLUSION: The three parcellation clusters obtained by the purely data-driven method might reflect GPi subdivision into a sensorimotor, associative and limbic portion. Clinical and physiological studies indicate greatest clinical DBS benefit for electrodes placed in the postero-ventro-lateral GPi, the region displaying connectivity to the thalamus in our study and generally attributed to the sensorimotor system. Clinical studies relating DBS electrode positions to our GPi connectivity map would be needed to complement our findings.

The role of the pallidothalamic fibre tracts in deep brain stimulation for dystonia: A diffusion MRI tractography study.

BACKGROUND: Deep Brain Stimulation (DBS) of the Globus pallidus internus (GPi) is gold standard treatment in medically refractory dystonia. Recent evidence indicates that stimulation effects are also due to axonal modulation and affection of a fibre network. For the GPi, the pallidothalamic tracts are known to be the major motor efferent pathways. The aim of this study is to explore the anatomic vicinity of these tracts and DBS electrodes in dystonia applying diffusion tractography. METHODS: Diffusion MRI was acquired in ten patients presenting for DBS for dystonia. We applied both a conventionally used probabilistic tractography algorithm (FSL) as well as a probabilistic streamline tracking approach, based on constrained spherical deconvolution and particle filtering with anatomic priors, to the datasets. DBS electrodes were coregistered to the diffusion datasets. RESULTS: We were able to delineate the pallidothalamic tracts in all patients. Using the streamline approach, we were able to distinguish between the two sub-components of the tracts, the ansa lenticularis and the fasciculus lenticularis. Clinically efficient DBS electrodes displayed a close anatomic vicinity pathway of the pallidothalamic tracts, and their course was consistent with previous tracer labelling studies. Although we present only anatomic data, we interpret these findings as evidence of the possible involvement of fibre tracts to the clinical effect in DBS. Electrophysiological intraoperative recordings would be needed to complement our findings. In the future, a clear and individual delineation of the pallidothalamic tracts could optimize the stereotactic process of optimal electrode localization. Hum Brain Mapp 38:1224-1232, 2017. © 2016 Wiley Periodicals, Inc.

MR imaging differentiation of Fe2+ and Fe3+ based on relaxation and magnetic susceptibility properties.

PURPOSE: The aim of this study is to evaluate the MR imaging behavior of ferrous (Fe2+) and ferric (Fe3+) iron ions in order to develop a noninvasive technique to quantitatively differentiate between both forms of iron. METHODS: MRI was performed at 3 T in a phantom consisting of 21 samples with different concentrations of ferrous and ferric chloride solutions (between 0 and 10 mmol/L). A multi-echo spoiled gradient-echo pulse sequence with eight echoes was used for both T 2* and quantitative susceptibility measurements. The transverse relaxation rate, R 2* = 1/T 2*, was determined by nonlinear exponential fitting based on the mean signals in each sample. The susceptibilities, χ, of the samples were calculated after phase unwrapping and background field removal by fitting the spatial convolution of a unit dipole response to the measured internal field map. Relaxation rate changes, ΔR 2*(c Fe), and susceptibility changes, Δχ(c Fe), their linear slopes, as well as the ratios ΔR 2*(c Fe) / Δχ(c Fe) were determined for all concentrations. RESULTS: The linear slopes of the relaxation rate were (12.5 ± 0.4) s-1/(mmol/L) for Fe3+ and (0.77 ± 0.09) s-1/(mmol/L) for Fe2+ (significantly different, z test P < 0.0001). The linear slopes of the susceptibility were (0.088 ± 0.003) ppm/(mmol/L) for Fe3+ and (0.079 ± 0.006) ppm/(mmol/L) for Fe2+. The individual ratios ΔR 2*/Δχ were greater than 40 s-1/ppm for all samples with ferric solution and lower than 20 s-1/ppm for all but one of the samples with ferrous solution. CONCLUSION: Ferrous and ferric iron ions show significantly different relaxation behaviors in MRI but similar susceptibility patterns. These properties can be used to differentiate ferrous and ferric samples.

The PROMESA-protocol: progression rate of multiple system atrophy under EGCG supplementation as anti-aggregation-approach.

Formation of toxic α-synuclein oligomers appears to be a key underlying pathological mechanism of synucleinopathies such as Parkinson's disease or multiple system atrophy (MSA). Given that Epigallocatechin-gallate has been shown to inhibit α-synuclein aggregation, it might represent a causal treatment option. Therefore, we set out to evaluate the safety, tolerability and a potential disease-modifying effect of Epigallocatechin-gallate in patients with MSA after 48 weeks of treatment. Power calculation was performed on existing natural history data on the progression of the Unified MSA Rating Scale as primary readout parameter. To assess the efficacy of Epigallocatechin-gallate versus placebo regarding the reduction of disease progression measured during the study period (80 % power, 5 % p level, 50 % effect size) 36 patients per group are needed. Considering a drop-out rate of 20 % a total of 86 patients will be recruited in this multicentre study. These data provide a solid rationale to investigate whether supplementation of Epigallocatechin-gallate can delay the progression of the MSA-related disability.

Visual cues combined with treadmill training to improve gait performance in Parkinson's disease: a pilot randomized controlled trial.

OBJECTIVE: To evaluate the effects of visual cues combined with treadmill training on gait performance in patients with Parkinson's disease and to compare the strategy with pure treadmill training. DESIGN: Pilot, exploratory, non-blinded, randomized controlled trial. SETTING: University Hospital of Munich, Germany. SUBJECTS: Twenty-three outpatients with Parkinson's disease (Hoehn and Yahr stage II-IV). INTERVENTIONS: Patients received 12 training sessions within five weeks of either visual cues combined with treadmill training (n = 12) or pure treadmill training (n = 11). MAIN MEASURES: Outcome measures were gait speed, stride length and cadence recorded on the treadmill. Functional tests included the Timed Up and Go Test, the Unified Parkinson's Disease Rating Scale and the Freezing of gait-questionnaire. Assessments were conducted at baseline, after the training period and at two months follow-up. RESULTS: After the training period (n = 20), gait speed and stride length had increased in both groups (p ⩽ 0.05). Patients receiving the combined training scored better in the Timed Up and Go Test compared with the patients receiving pure treadmill training (p ⩽ 0.05). At two months follow-up (n = 13), patients who underwent the combined training sustained better results in gait speed and stride length (p ⩽ 0.05) and sustained the improvement in the Timed Up and Go Test (p ⩽ 0.05). CONCLUSIONS: This pilot study suggests that visual cues combined with treadmill training have more beneficial effects on gait than pure treadmill training in patients with a moderate stage of Parkinson's disease. A large-scale study with longer follow-up is required.

Connectivity patterns of pallidal DBS electrodes in focal dystonia: a diffusion tensor tractography study.

Deep brain stimulation (DBS) of the internal pallidal segment (GPi: globus pallidus internus) is gold standard treatment for medically intractable dystonia, but detailed knowledge of mechanisms of action is still not available. There is evidence that stimulation of ventral and dorsal GPi produces opposite motor effects. The aim of this study was to analyse connectivity profiles of ventral and dorsal GPi. Probabilistic tractography was initiated from DBS electrode contacts in 8 patients with focal dystonia and connectivity patterns compared. We found a considerable difference in anterior-posterior distribution of fibres along the mesial cortical sensorimotor areas between the ventral and dorsal GPi connectivity. This finding of distinct GPi connectivity profiles further confirms the clinical evidence that the ventral and dorsal GPi belong to different functional and anatomic motor subsystems. Their involvement could play an important role in promoting clinical DBS effects in dystonia.

Onset latency of segmental dystonia after deep brain stimulation cessation: a randomized, double-blind crossover trial.

BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus internus is an effective treatment for cervical dystonia (CD). Interestingly, the onset of initial DBS effects is significantly prolonged compared with that in other diseases, such as Parkinson's disease. The return of symptoms after cessation of DBS could be delayed as well, but this has not been studied systematically. METHODS: In patients who were treated for CD using DBS and had a good treatment effect, we compared interruption of DBS with sham-OFF in a randomized, double-blind crossover trial. RESULTS: We observed that dystonic features appeared within a few minutes at almost full intensity in all patients after the cessation of DBS. CONCLUSIONS: The almost immediate onset of dystonic features in our sample seems to exclude mechanisms with long time constants from the pathophysiology of dystonia. Thus, it is likely that, in these patients, an aberrant pattern of neural activity representing an inappropriate set point value for the position of the head is responsible for dystonia.

Globus pallidus internus oscillatory activity is related to movement speed.

Local field potentials (LFPs) recorded from deep brain stimulation electrodes implanted in the globus pallidus internus (GPi) of patients with hyperkinetic movement disorders (dystonia and Tourette's syndrome) have shown desynchronized activity at 8-20 Hz and synchronized activity at 30-90 Hz during voluntary movements. However, the impact of the speed of the motor task on these frequency shifts is still unclear. In the current study, we recorded LFPs bilaterally from the GPi in seven patients with hyperkinetic movement disorders during normal/slow and fast horizontal line drawing movements as well as during rest. In comparison with rest, the low beta band showed a significant decrease in power during the motor tasks. Low beta power was more suppressed with increasing speed of the movement on the contralateral side. In contrast, a significant increase in power was induced by movements in the high beta and gamma bands on the contralateral side. When comparing slow and fast movements, the power of the low gamma frequency band was significantly elevated on the contralateral side with fast movements. In conclusion, an increase in movement speed changes the power of GPi oscillations by means of a reduction of the activity in the low beta band and an elevation of activity in the gamma band. The current study yields new insights into the physiological mechanism of GPi during the execution of the motor task at low and high speed.

Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease.

In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and prion diseases, deposits of aggregated disease-specific proteins are found. Oligomeric aggregates are presumed to be the key neurotoxic agent. Here we describe the novel oligomer modulator anle138b [3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole], an aggregation inhibitor we developed based on a systematic high-throughput screening campaign combined with medicinal chemistry optimization. In vitro, anle138b blocked the formation of pathological aggregates of prion protein (PrP(Sc)) and of α-synuclein (α-syn), which is deposited in PD and other synucleinopathies such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Notably, anle138b strongly inhibited all prion strains tested including BSE-derived and human prions. Anle138b showed structure-dependent binding to pathological aggregates and strongly inhibited formation of pathological oligomers in vitro and in vivo both for prion protein and α-synuclein. Both in mouse models of prion disease and in three different PD mouse models, anle138b strongly inhibited oligomer accumulation, neuronal degeneration, and disease progression in vivo. Anle138b had no detectable toxicity at therapeutic doses and an excellent oral bioavailability and blood-brain-barrier penetration. Our findings indicate that oligomer modulators provide a new approach for disease-modifying therapy in these diseases, for which only symptomatic treatment is available so far. Moreover, our findings suggest that pathological oligomers in neurodegenerative diseases share structural features, although the main protein component is disease-specific, indicating that compounds such as anle138b that modulate oligomer formation by targeting structure-dependent epitopes can have a broad spectrum of activity in the treatment of different protein aggregation diseases.

Atypical parkinsonism due to a D202N Gerstmann-Sträussler-Scheinker prion protein mutation: first in vivo diagnosed case.

BACKGROUND: Parkinsonism with dopa-sensitivity and a correlating DaTSCAN turned out to be due to a D202N mutation which is associated with the Gerstmann-Sträussler-Scheinker (GSS) disease. METHODS/RESULTS: We report a 51-year old female who presented with left-dominant parkinsonism and a positive DaTSCAN. She was diagnosed with idiopathic Parkinson's syndrome. Dopaminergic medication reduced her symptoms. In addition, punding-like behavior, deficits in organizing daily life and abnormal sleep behavior were reported. Neuropsychological testing, EEG, polysomnography as well as PET imaging with fluorodexyglucose (FDG), [F-18]-desmethoxyfallypride (DMFP), and [C-11]-6-OH-BTA-1 (PIB) were not diagnostic. Cerebral spinal fluid analysis revealed no 14-3-3 protein, but elevated neuron-specific enolase (NSE) and S100-beta and a very low phospho-tau/total-tau ratio. Analysis of the prion gene disclosed the rare D202N mutation. CONCLUSIONS: The D202N prion mutation has been associated with GSS pathology and up to now was only reported post mortem. Our patient is the very first case diagnosed in vivo.

Subthalamic oscillatory activity during normal and impaired speech.

OBJECTIVE: We studied the relationship between oscillatory activity in the subthalamic nucleus (STN) and speech production in order to better understand the functional role of the STN. METHODS: We simultaneously recorded subthalamic local field potentials and audio recordings from 5 patients with Parkinson's disease while they performed verbal fluency tasks. We then analyzed the oscillatory signals present in the subthalamic nucleus during these tasks. RESULTS: We report that normal speech leads to a suppression of subthalamic alpha and beta power. Contrarily, a patient with motor blocks during speech initiation showed a low beta power increase. We also report an increase in error rates in the phonemic non-alternating verbal fluency task during deep brain stimulation (DBS). CONCLUSIONS: We confirm previous findings that intact speech leads to desynchronization in the beta range in the STN. The speech related narrowband beta power increase in a patient with speech problems suggests that exaggerated synchronization in this frequency band is associated with motor blocks during speech initiation. The increased number of errors in verbal fluency tasks during DBS might be caused by an impairment of the response inhibition network caused by stimulation of the STN. SIGNIFICANCE: We suggest that the inability to attenuate beta activity during motor processes is associated with motor freezing across motor behaviours such as speech and gait, as previously shown for freezing of gait.