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.

Speech and Nonspeech Parameters in the Clinical Assessment of Dysarthria: A Dimensional Analysis.

Nonspeech (or paraspeech) parameters are widely used in clinical assessment of speech impairment in persons with dysarthria (PWD). Virtually every standard clinical instrument used in dysarthria diagnostics includes nonspeech parameters, often in considerable numbers. While theoretical considerations have challenged the validity of these measures as markers of speech impairment, only a few studies have directly examined their relationship to speech parameters on a broader scale. This study was designed to investigate how nonspeech parameters commonly used in clinical dysarthria assessment relate to speech characteristics of dysarthria in individuals with movement disorders. Maximum syllable repetition rates, accuracies, and rates of isolated and repetitive nonspeech oral-facial movements and maximum phonation times were compared with auditory-perceptual and acoustic speech parameters. Overall, 23 diagnostic parameters were assessed in a sample of 130 patients with movement disorders of six etiologies. Each variable was standardized for its distribution and for age and sex effects in 130 neurotypical speakers. Exploratory Graph Analysis (EGA) and Confirmatory Factor Analysis (CFA) were used to examine the factor structure underlying the diagnostic parameters. In the first analysis, we tested the hypothesis that nonspeech parameters combine with speech parameters within diagnostic dimensions representing domain-general motor control principles. In a second analysis, we tested the more specific hypotheses that diagnostic parameters split along effector (lip vs. tongue) or functional (speed vs. accuracy) rather than task boundaries. Our findings contradict the view that nonspeech parameters currently used in dysarthria diagnostics are congruent with diagnostic measures of speech characteristics in PWD.

Resistance Training Combined with Balance or Gait Training for Patients with Parkinson's Disease: A Randomized Controlled Pilot Study.

Background: Gait and balance disorders in patients with idiopathic Parkinson's disease (PD) lead to major mobility limitations. To counteract this, physical therapy such as gait, balance, or resistance training is applied. Integrative training methods, which combine these elements, could be particularly effective. Objective: The objective of this study is to evaluate and compare the effects of two integrative interventions on gait and balance of patients with PD. Methods: Twenty-six patients with PD received either resistance training in combination with gait training (gait resistance training, GRT) or resistance training in combination with balance training (stability resistance training, SRT) for six weeks. Gait and balance outcome parameters were assessed before, immediately after, and six weeks after the interventions. The primary outcome parameters were the functional reach test to evaluate balance and stride length to evaluate gait. Secondary outcomes included further gait analysis parameters, knee extension strength, the timed up and go test, and the six-minute walk test. Results: The functional reach test results were significantly better after the intervention in both groups. Stride length increased significantly only in the GRT group. Several further gait parameters and the six-minute walk test improved in the GRT group, and the increase in gait speed was significantly higher than in the SRT group. The SRT group performed better after the intervention regarding the timed up and go test and knee extension strength, the latter being significantly more improved than in the SRT group. At six-week follow-up, the improvement in functional reach was maintained in the SRT group. Conclusions: Integrative therapies, combining gait or balance training with resistance training, have specific positive effects in PD rehabilitation. More pronounced effects on gait parameters are achieved by GRT, while SRT has more impact on balance. Thus, the combination of both training methods might be particularly efficient in improving the mobility of PD patients.

18F-PI-2620 Tau PET Improves the Imaging Diagnosis of Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy movement disorder that can be imaged by the 18F-labeled tau PET tracer 2-(2-([18F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine (18F-PI-2620). The in vivo diagnosis is currently established on clinical grounds and supported by midbrain atrophy estimation in structural MRI. Here, we investigate whether 18F-PI-2620 tau PET has the potential to improve the imaging diagnosis of PSP. Methods: In this multicenter observational study, dynamic (0-60 min after injection) 18F-PI-2620 PET and structural MRI data for 36 patients with PSP, 22 with PSP-Richardson syndrome, and 14 with a clinical phenotype other than Richardson syndrome (i.e., variant PSP) were analyzed along with data for 10 age-matched healthy controls (HCs). The PET data underwent kinetic modeling, which resulted in distribution volume ratio (DVR) images. These and the MR images were visually assessed by 3 masked experts for typical PSP signs. Furthermore, established midbrain atrophy parameters were measured in structural MR images, and regional DVRs were measured in typical tau-in-PSP target regions in the PET data. Results: Visual assessments discriminated PSP patients and HCs with an accuracy of 63% for MRI and 80% for the combination of MRI and 18F-PI-2620 PET. As compared with patients of the PSP-Richardson syndrome subgroup, those of the variant PSP subgroup profited more in terms of sensitivity from the addition of the visual 18F-PI-2620 PET to the visual MRI information (35% vs. 22%). In quantitative image evaluation, midbrain-to-pons area ratio and globus pallidus DVRs discriminated best between the PSP patients and HCs, with sensitivities and specificities of 83% and 90%, respectively, for MRI and 94% and 100%, respectively, for the combination of MRI and 18F-PI-2620 PET. The gain of sensitivity by adding 18F-PI-2620 PET to MRI data was more marked in clinically less affected patients than in more affected patients (37% vs. 19% for visual, and 16% vs. 12% for quantitative image evaluation). Conclusion: These results provide evidence for an improved imaging-based PSP diagnosis by adding 18F-PI-2620 tau PET to structural MRI. This approach seems to be particularly promising at earlier disease stages and could be of value both for improving early clinical PSP diagnosis and for enriching PSP cohorts for trials of disease-modifying drugs.

Cognitive task-related oscillations in human internal globus pallidus and subthalamic nucleus.

Recently it has been acknowledged that the basal ganglia nuclei play a major role in cognitive control; however, the contribution by their network remains unclear. Previous studies have demonstrated the role of the subthalamic nucleus (STN) in cognitive processing and suggested that its connections to cortical and other associated regions regulate response inhibition during conflict conditions. By contrast, the role of the internal globus pallidus (GPi) as the output nucleus before the thalamic relay has not yet been investigated during cognitive processing. We recorded local field potentials (LFPs) from externalized deep brain stimulation (DBS) electrodes implanted bilaterally in the GPi (n = 9 participants with dystonia) and STN (n = 8 participants with Parkinson's disease (PD)) during a primed flanker task. Both dystonia (GPi group) and PD participants (STN group) responded faster to the congruent trials than the incongruent trials. Overall, the dystonic GPi group was significantly faster than the PD STN group. LFPs showed elevated cue-triggered theta (3-7 Hz) power in GPi and STN groups in a similar way. Response-triggered LFP beta power (13-25 Hz) was significantly increased in the GPi group compared to the STN group. Results demonstrate that GPi activity appears to be critical in the cognitive processing of action selection and response during the presence of conflict tasks similar to the STN group.

Impact of Partial Volume Correction on [18F]GE-180 PET Quantification in Subcortical Brain Regions of Patients with Corticobasal Syndrome.

Corticobasal syndrome (CBS) is a rare neurodegenerative condition characterized by four-repeat tau aggregation in the cortical and subcortical brain regions and accompanied by severe atrophy. The aim of this study was to evaluate partial volume effect correction (PVEC) in patients with CBS compared to a control cohort imaged with the 18-kDa translocator protein (TSPO) positron emission tomography (PET) tracer [18F]GE-180. Eighteen patients with CBS and 12 age- and sex-matched healthy controls underwent [18F]GE-180 PET. The cortical and subcortical regions were delineated by deep nuclei parcellation (DNP) of a 3D-T1 MRI. Region-specific subcortical volumes and standardized uptake values and ratios (SUV and SUVr) were extracted before and after region-based voxel-wise PVEC. Regional volumes were compared between patients with CBS and controls. The % group differences and effect sizes (CBS vs. controls) of uncorrected and PVE-corrected SUVr data were compared. Single-region positivity in patients with CBS was assessed by a >2 SD threshold vs. controls and compared between uncorrected and PVE-corrected data. Smaller regional volumes were detected in patients with CBS compared to controls in the right ventral striatum (p = 0.041), the left putamen (p = 0.005), the right putamen (p = 0.038) and the left pallidum (p = 0.015). After applying PVEC, the % group differences were distinctly higher, but the effect sizes of TSPO uptake were only slightly stronger due to the higher variance after PVEC. The single-region positivity of TSPO PET increased in patients with CBS after PVEC (100 vs. 83 regions). PVEC in the cortical and subcortical regions is valuable for TSPO imaging of patients with CBS, leading to the improved detection of elevated [18F]GE-180 uptake, although the effect sizes in the comparison against the controls did not improve strongly.

Peaks in the beta band of the human subthalamic nucleus: a case for low beta and high beta activity.

OBJECTIVE: Peaks in the beta band of local field potentials (LFPs) may serve as a biological feedback signal for closed-loop deep brain stimulation (DBS) in Parkinson's disease (PD). However, the specific frequency of such peaks and their response to DBS and to different types of movement remains uncertain. In the present study, the authors examined the abundance of discernible peaks in the beta band and the effect of different types of movement and DBS on these peaks. METHODS: Subthalamic nucleus LFPs were analyzed from 38 patients with PD in a frequency range between 10 and 35 Hz, as well as the impact of movement (gait, hand movements) and electrical stimulation on these peaks. The position of the electrode segments from which LFPs were recorded was computed. RESULTS: The authors found a bimodal distribution of peaks in the beta band with discernible high- (27 Hz) and low-frequency (15 Hz) peaks. Movement of either hand had no significant effect on these peaks, whereas walking significantly reduced high-frequency beta peaks but not the peaks in the low beta band. Stimulation caused an amplitude-dependent suppression of both peaks. CONCLUSIONS: DBS suppresses LFP beta peaks of different frequencies, whereas beta suppression caused by movement is dependent on the type of movement and frequency of the peak. These results will support the investigation of distinct LFP spectra for the application of closed-loop DBS.

Differential expression of gut miRNAs in idiopathic Parkinson's disease.

OBJECTIVE: In the present work, we aimed to investigate the expression of microRNAs (miRNAs) in routine colonic biopsies obtained from patients with idiopathic Parkinson's disease (PD) and to address their value as a diagnostic biomarker for PD and their mechanistic contribution to PD onset and progression. METHODS: Patients with PD (n = 13) and healthy controls (n = 17) were prospectively recruited to undergo routine colonic biopsies for cancer screening. Total RNA was extracted from the biopsy material and the expression of miRNAs was quantified by Illumina High-Throughput Sequencing. RESULTS: Statistical analysis revealed a significant submucosal enrichment of the miRNA hsa-miR-486-5p in colonic biopsies from PD patients compared to the control subjects. The expression of miR-486-5p correlated with age and disease severity as measured by the UPDRS and Hoehn & Yahr scale. miRNA gene target analysis identified 301 gene targets that are affected by miR-486-5p. A follow-up associated target identification and pathway enrichment analysis further determined their role in distinct biological processes in the enteric nervous system (ENS). INTERPRETATION: Our work demonstrates an enrichment of submucosal miR-486-5p in routine colonic biopsies from PD patients. Our results will support the examination of miR-486-5p as a PD biomarker and help to understand the significance of the miR-486-5p gene targets for PD onset and progression. In addition, our data will support the investigation of the molecular and cellular mechanisms of GI dysfunction in PD.

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.

Binding characteristics of [18F]PI-2620 distinguish the clinically predicted tau isoform in different tauopathies by PET.

The novel tau-PET tracer [18F]PI-2620 detects the 3/4-repeat-(R)-tauopathy Alzheimer's disease (AD) and the 4R-tauopathies corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). We determined whether [18F]PI-2620 binding characteristics deriving from non-invasive reference tissue modelling differentiate 3/4R- and 4R-tauopathies. Ten patients with a 3/4R tauopathy (AD continuum) and 29 patients with a 4R tauopathy (CBS, PSP) were evaluated. [18F]PI-2620 PET scans were acquired 0-60 min p.i. and the distribution volume ratio (DVR) was calculated. [18F]PI-2620-positive clusters (DVR ≥ 2.5 SD vs. 11 healthy controls) were evaluated by non-invasive kinetic modelling. R1 (delivery), k2 & k2a (efflux), DVR, 30-60 min standardized-uptake-value-ratios (SUVR30-60) and the linear slope of post-perfusion phase SUVR (9-60 min p.i.) were compared between 3/4R- and 4R-tauopathies. Cortical clusters of 4R-tau cases indicated higher delivery (R1SRTM: 0.92 ± 0.21 vs. 0.83 ± 0.10, p = 0.0007), higher efflux (k2SRTM: 0.17/min ±0.21/min vs. 0.06/min ± 0.07/min, p < 0.0001), lower DVR (1.1 ± 0.1 vs. 1.4 ± 0.2, p < 0.0001), lower SUVR30-60 (1.3 ± 0.2 vs. 1.8 ± 0.3, p < 0.0001) and flatter slopes of the post-perfusion phase (slope9-60: 0.006/min ± 0.007/min vs. 0.016/min ± 0.008/min, p < 0.0001) when compared to 3/4R-tau cases. [18F]PI-2620 binding characteristics in cortical regions differentiate 3/4R- and 4R-tauopathies. Higher tracer clearance indicates less stable binding in 4R tauopathies when compared to 3/4R-tauopathies.

Pathophysiological Changes in the Enteric Nervous System of Rotenone-Exposed Mice as Early Radiological Markers for Parkinson's Disease.

Parkinson's disease (PD) is known to involve the peripheral nervous system (PNS) and the enteric nervous system (ENS). Functional changes in PNS and ENS appear early in the course of the disease and are responsible for some of the non-motor symptoms observed in PD patients like constipation, that can precede the appearance of motor symptoms by years. Here we analyzed the effect of the pesticide rotenone, a mitochondrial Complex I inhibitor, on the function and neuronal composition of the ENS by measuring intestinal contractility in a tissue bath and by analyzing related protein expression. Our results show that rotenone changes the normal physiological response of the intestine to carbachol, dopamine and electric field stimulation (EFS). Changes in the reaction to EFS seem to be related to the reduction in the cholinergic input but also related to the noradrenergic input, as suggested by the non-adrenergic non-cholinergic (NANC) reaction to the EFS in rotenone-exposed mice. The magnitude and direction of these alterations varies between intestinal regions and exposure times and is associated with an early up-regulation of dopaminergic, cholinergic and adrenergic receptors and an irregular reduction in the amount of enteric neurons in rotenone-exposed mice. The early appearance of these alterations, that start occurring before the substantia nigra is affected in this mouse model, suggests that these alterations could be also observed in patients before the onset of motor symptoms and makes them ideal potential candidates to be used as radiological markers for the detection of Parkinson's disease in its early stages.

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.

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.

Establishment of a Visual Analog Scale for DBS Programming (VISUAL-STIM Trial).

Background: Deep brain stimulation (DBS) has become a standard treatment for advanced stages of Parkinson's disease, essential tremor, and dystonia. In addition to the correct surgical device implantation, effective programming is regarded to be the most important factor for clinical outcome. Despite established strategies for adjusting neurostimulation, DBS programming remains time- and resource-consuming. Although kinematic and neuronal biosignals have recently been examined as potential feedback for closed-loop DBS (CL-DBS), there is an ongoing need for programming strategies to adapt the stimulation parameters and electrode configurations accurately and effectively. Methods: Here, we tested the usefulness of a patient-rated visual analog scale (VAS) for real-time adjustment of DBS parameters. The stimulation parameters (contact and amplitude) in Parkinson's patients with STN-DBS (n = 17) were optimized based on the patient's subjective VAS rating. A Minkowski distance (Md) was calculated to compare the individual combination of contact selection and amplitude to the stimulation parameters that resulted from classical programming based on clinical signs and symptoms. Results: We found no statistically significant difference between VAS-based and classical programming in regard to the specific contact or amplitude used or in regard to the clinical disease severity (UPDRS). Conclusions: Our data suggest that VAS-based and classical programming strategies both lead to similar short-term results. Although further research will be required to assess the validity of VAS-based DBS programming, our results support the investigation of the patient's subjective rating as an additional and valid feedback signal for individualized DBS adjustment.

Assessment of 18F-PI-2620 as a Biomarker in Progressive Supranuclear Palsy.

Importance: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis. Objective: To investigate the potential of the novel tau radiotracer 18F-PI-2620 as a biomarker in patients with clinically diagnosed PSP. Design, Setting, and Participants: In this cross-sectional study, participants underwent dynamic 18F-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP-non-RS were excluded from final data analysis owing to incomplete dynamic PET scans. Data were collected from December 2016 to October 2019 and were analyzed from December 2018 to December 2019. Main Outcomes and Measures: Postmortem autoradiography was performed in independent PSP-RS and healthy control samples. By in vivo PET imaging, 18F-PI-2620 distribution volume ratios were obtained in globus pallidus internus and externus, putamen, subthalamic nucleus, substantia nigra, dorsal midbrain, dentate nucleus, dorsolateral, and medial prefrontal cortex. PET data were compared between patients with PSP and control groups and were corrected for center, age, and sex. Results: Of 60 patients with PSP, 40 (66.7%) had RS (22 men [55.0%]; mean [SD] age, 71 [6] years; mean [SD] PSP rating scale score, 38 [15]; score range, 13-71) and 20 (33.3%) had PSP-non-RS (11 men [55.0%]; mean [SD] age, 71 [9] years; mean [SD] PSP rating scale score, 24 [11]; score range, 11-41). Ten healthy controls (2 men; mean [SD] age, 67 [7] years) and 20 controls with disease (of 10 [50.0%] with Parkinson disease and multiple system atrophy, 7 were men; mean [SD] age, 61 [8] years; of 10 [50.0%] with Alzheimer disease, 5 were men; mean [SD] age, 69 [10] years). Postmortem autoradiography showed blockable 18F-PI-2620 binding in patients with PSP and no binding in healthy controls. The in vivo findings from the first large-scale observational study in PSP with 18F-PI-2620 indicated significant elevation of tracer binding in PSP target regions with strongest differences in PSP vs control groups in the globus pallidus internus (mean [SD] distribution volume ratios: PSP-RS, 1.21 [0.10]; PSP-non-RS, 1.12 [0.11]; healthy controls, 1.00 [0.08]; Parkinson disease/multiple system atrophy, 1.03 [0.05]; Alzheimer disease, 1.08 [0.06]). Sensitivity and specificity for detection of PSP-RS vs any control group were 85% and 77%, respectively, when using classification by at least 1 positive target region. Conclusions and Relevance: This multicenter evaluation indicates a value of 18F-PI-2620 to differentiate suspected patients with PSP, potentially facilitating more reliable diagnosis of PSP.

FGF2 Affects Parkinson's Disease-Associated Molecular Networks Through Exosomal Rab8b/Rab31.

Ras-associated binding (Rab) proteins are small GTPases that regulate the trafficking of membrane components during endocytosis and exocytosis including the release of extracellular vesicles (EVs). Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorder in the elderly population, where pathological proteins such as alpha-synuclein (α-Syn) are transmitted in EVs from one neuron to another neuron and ultimately across brain regions, thereby facilitating the spreading of pathology. We recently demonstrated fibroblast growth factor-2 (FGF2) to enhance the release of EVs and delineated the proteomic signature of FGF2-triggered EVs in cultured primary hippocampal neurons. Out of 235 significantly upregulated proteins, we found that FGF2 specifically enriched EVs for the two Rab family members Rab8b and Rab31. Consequently, we investigated the interactions of Rab8b and Rab31 using a network analysis approach in order to estimate the global influence of their enrichment in EVs. To achieve this, we have demarcated a protein-protein interaction network (PPiN) for these Rabs and identified the proteins associated with PD in various cellular components of the central nervous system (CNS), in different brain regions, and in the enteric nervous system (ENS). A total of 126 direct or indirect interactions were reported for two Rab candidates, out of which 114 are Rab8b interactions and 54 are Rab31 interactions, ultimately resulting in an individual interaction score (IS) of 90.48 and 42.86%, respectively. Conclusively, these results for the first time demonstrate the relevance of FGF2-induced Rab-enrichment in EVs and its potential to regulate PD pathophysiology.

What have we learned from 8 years of deep brain stimulation of the anterior thalamic nucleus? Experiences and insights of a single center.

OBJECTIVE: In the absence of a standard or guideline for the treatment of epilepsy patients with deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT), systematic single-center investigations are essential to establish effective approaches. Here, the authors report on the long-term results of one of the largest single-center ANT DBS cohorts. METHODS: The outcome data of 23 consecutive patients with transventricularly implanted electrodes were retrospectively analyzed with regard to adverse events, lead placement, stimulation-related side effects, and changes in seizure frequency. Depression and quality-of-life scores were collected in a subgroup of 9 patients. RESULTS: All but 2 patients initially underwent bilateral implantation, and 84.4% of all DBS leads were successfully located within the ANT. The mean follow-up time was 46.57 ± 23.20 months. A seizure reduction > 50% was documented in 73.9% of patients, and 34.6% achieved an Engel class I outcome. In 3 patients, clinical response was achieved by switching the electrode contact or changing from the monopolar to bipolar stimulation mode. Unilateral implantation seemed ineffective, whereas bilateral stimulation with successful ANT implantation only on one side led to a clinical response. Double stimulation with additional vagus nerve stimulation was safe. Changes in cycling mode or stimulation amplitude influenced therapy tolerability and, only to a lesser extent, seizure frequency. Side effects were rare and typically vanished by lowering the stimulation amplitude or changing the active electrode contact. Furthermore, depression and aspects of quality of life significantly improved with ANT DBS treatment. CONCLUSIONS: The transventricular approach as well as double stimulation proved safe. The anteroventral ANT appeared to be the most efficacious stimulation site. This systematic investigation with reluctant medication changes allowed for the development of a better idea of the association between parameter changes and outcome in ANT DBS patients, but larger samples are still needed to assess the potential of bipolar stimulation and distinct cycling frequencies. Furthermore, more multifaceted and objective assessments of treatment outcome are needed to fully assess the effects of ANT DBS treatment.

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.

Basic Fibroblast Growth Factor 2-Induced Proteome Changes Endorse Lewy Body Pathology in Hippocampal Neurons.

Hippocampal Lewy body pathology (LBP) is associated with changes in neurotrophic factor signaling and neuronal energy metabolism. LBP progression is attributed to the aggregation of α-synuclein (α-Syn) and its cell-to-cell transmission via extracellular vehicles (EVs). We recently discovered an enhanced EV release in basic fibroblast growth factor (bFGF)-treated hippocampal neurons. Here, we examined the EV and cell lysate proteome changes in bFGF-treated hippocampal neurons. We identified n = 2,310 differentially expressed proteins (DEPs) induced by bFGF. We applied weighted protein co-expression network analysis (WPCNA) to generate protein modules from DEPs and mapped them to published LBP datasets. This approach revealed n = 532 LBP-linked DEPs comprising key α-Syn-interacting proteins, LBP-associated RNA-binding proteins (RBPs), and neuronal ion channels and receptors that can impact LBP onset and progression. In summary, our deep proteomic analysis affirms the potential influence of bFGF signaling on LBP-related proteome changes and associated molecular interactions.