Nationwide Retrospective Analysis of Combinations of Advanced Therapies in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVES: Advanced therapies (ATs; deep brain stimulation [DBS] or pump therapies: continuous subcutaneous apomorphine infusion [CSAI], levodopa/carbidopa intestinal gel [LCIG]) are used in later stages of Parkinson disease (PD). However, decreasing efficacy over time and/or side effects may require an AT change or combination in individual patients. Current knowledge about changing or combining ATs is limited to mostly retrospective and small-scale studies. The nationwide case collection Combinations of Advanced Therapies in PD assessed simultaneous or sequential AT combinations in Germany since 2005 to analyze their clinical outcome, their side effects, and the reasons for AT modifications. METHODS: Data were acquired retrospectively by modular questionnaires in 22 PD centers throughout Germany based on clinical records and comprised general information about the centers/patients, clinical (Mini-Mental Status Test/Montréal Cognitive Assessment, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS], side effects, reasons for AT modification), and therapeutical (ATs with specifications, oral medication) data. Data assessment started with initiation of the second AT. RESULTS: A total of 148 AT modifications in 116 patients were associated with significantly improved objective (median decrease of MDS-UPDRS Part III 4.0 points [p < 0.001], of MDS-UPDRS Part IV 6.0 points [p < 0.001], of MDS-UPDRS Part IV-off-time item 1.0 points [p < 0.001]) and subjective clinical outcome and decreasing side effect rates. Main reasons for an AT modification were insufficient symptom control and side effects of the previous therapy. Subgroup analyses suggest addition of DBS in AT patients with leading dyskinesia, addition of LCIG for leading other cardinal motor symptoms, and addition of LCIG or CSAI for dominant off-time. The most long-lasting therapy-until requiring a modification-was DBS. DISCUSSION: Changing or combining ATs may be beneficial when 1 AT is insufficient in efficacy or side effects. The outcome of an AT combination is comparable with the clinical benefit by introducing the first AT. The added AT should be chosen dependent on dominant clinical symptoms and adverse effects. Furthermore, prospective trials are needed to confirm the results of this exploratory case collection. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with PD, changing or combining ATs is associated with an improvement in the MDS-UPDRS or subjective symptom reporting.

Prospective controlled study on the effects of deep brain stimulation on driving in Parkinson's disease.

To explore the influence of bilateral subthalamic deep brain stimulation (STN-DBS) on car driving ability in patients with Parkinson's disease (PD), we prospectively examined two age-matched, actively driving PD patient groups: one group undergone DBS-surgery (PD-DBS, n = 23) and one group that was eligible for DBS but did not undergo surgery (PD-nDBS, n = 29). In PD-DBS patients, investigation at Baseline was done just prior and at Follow-up 6-12 month after DBS-surgery. In PD-nDBS patients, time interval between Baseline and Follow-up was aimed to be comparable. To assess the general PD driving level, driving was assessed once in 33 age-matched healthy controls at Baseline. As results, clinical and driving characteristics of PD-DBS, PD-nDBS and controls did not differ at Baseline. At Follow-up, PD-DBS patients drove unsafer than PD-nDBS patients. This effect was strongly driven by two single PD-DBS participants (9%) with poor Baseline and disastrous Follow-up driving performance. Retrospectively, we could not identify any of the assessed motor and non-motor clinical Baseline characteristics as predictive for this driving-deterioration at Follow-up. Excluding these two outliers, comparable driving performance between PD-DBS and PD-nDBS patients not only at Baseline but also at Follow-up was demonstrated. Age, disease duration and severity as well as Baseline driving insecurity were associated with poorer driving performance at Follow-up. This first prospective study on driving safety in PD after DBS surgery indicates that DBS usually does not alter driving safety but might increase the risk for driving deterioration, especially in single subjects with already unsafe driving prior to DBS surgery.

Device-Aided Therapies in Parkinson's Disease-Results from the German Care4PD Study.

Data on the use of device-aided therapies (DATs) in people with Parkinson's disease (PwP) are scarce. Analyzing data from the Care4PD patient survey, we (1) evaluated application frequency and type of DAT in a larger, nationwide, cross-sectoral PwP sample in Germany; (2) analyzed the frequency of symptoms indicative for advanced PD (aPD) and need for DAT amongst the remaining patients and (3) compared the most bothersome symptoms and need for professional long-term care (LTC) of patients with and without suspected aPD. Data from 1269 PwP were analyzed. In total, 153 PwP (12%) received DAT, mainly deep brain stimulation (DBS). Of the remaining 1116 PwP without DAT, >50% fulfilled at least one aPD criterion. Akinesia/rigidity and autonomic problems were most bothersome for PwP with and without suspected aPD, with more tremor in the non-aPD and more motor fluctuations and falls in the aPD group. To recapitulate, the German DAT application rate is rather low, although a large proportion of PwP fulfills aPD criteria indicating a need for intensified treatment strategies. Many reported bothersome symptoms could be overcome with DAT with benefits even for LTC patients. Thus, precise and early identification of aPD symptoms (and therapy-resistant tremor) should be implemented in future DAT preselection tools and educational trainings.

Predictors of post-stroke depression: Validation of established risk factors and introduction of a dynamic perspective in two longitudinal studies.

Introduction: Cerebral insults lead in many cases not only to cognitive impairment but also to disturbed emotionality. After stroke, one in three survivors develops a depression which impacts quality of life and rehabilitation. Meta-analyses have identified five main predictors of post-stroke depression (PSD): history of mental disorder, stroke severity, physical disability, cognitive impairment, and social support. However, these five established variables have never been conjointly investigated in a sample of stroke survivors. Therefore, their independent predictive values remain unclear. Moreover, predictors are most often used as time-invariant factors (status scores), neglecting the intraindividual dynamics after stroke. Methods: Our study analyses the data of two prospective longitudinal studies, investigating stroke survivors from two rehabilitation hospitals (N 1 = 273) and one acute care hospital (N 2 = 226). Baseline assessments included the five established predictors and depressive symptoms. After 6 months, depressive symptoms were reassessed in both studies (n 1 = 176, n 2 = 183), and physical disability and social support were reassessed in study 2. The predictivity of the five predictors and the additional predictivity of intraindividual dynamics for PSD were examined in multiple linear regression analyses. Results: History of mental disorder was a risk factor for depressive symptoms after stroke at all measurement times (B = 3.32 to 3.97; p < 0.01). Physical disability was a risk factor at all measurement times (B = -0.09 to -0.03; p < 0.05) except 6 months after rehabilitation. Social support was a protective factor (B = -2.69 to -1.91; p < 0.01) outside the acute phase (R 2 = 0.15-0.39). Intraindividual changes in physical disability and perceived social support were independent predictors of PSD 6 months after the acute phase (B = -0.08/-0.14; p < 0.01), in addition to status scores on established variables (ΔR 2 = 0.08, p < 0.001). Discussion: History of mental disorder, physical disability, and social support are independent predictors of depressive symptoms in the first year post-stroke, also when considered conjointly. Future studies should control for these variables when investigating new predictors of PSD. In addition, intraindividual changes in known predictors after stroke play a relevant role in the pathogenesis of PSD and should be considered in clinical practice and future research.

Comparative analysis of machine learning algorithms for multi-syndrome classification of neurodegenerative syndromes.

IMPORTANCE: The entry of artificial intelligence into medicine is pending. Several methods have been used for the predictions of structured neuroimaging data, yet nobody compared them in this context. OBJECTIVE: Multi-class prediction is key for building computational aid systems for differential diagnosis. We compared support vector machine, random forest, gradient boosting, and deep feed-forward neural networks for the classification of different neurodegenerative syndromes based on structural magnetic resonance imaging. DESIGN, SETTING, AND PARTICIPANTS: Atlas-based volumetry was performed on multi-centric T1-weighted MRI data from 940 subjects, i.e., 124 healthy controls and 816 patients with ten different neurodegenerative diseases, leading to a multi-diagnostic multi-class classification task with eleven different classes. INTERVENTIONS: N.A. MAIN OUTCOMES AND MEASURES: Cohen's kappa, accuracy, and F1-score to assess model performance. RESULTS: Overall, the neural network produced both the best performance measures and the most robust results. The smaller classes however were better classified by either the ensemble learning methods or the support vector machine, while performance measures for small classes were comparatively low, as expected. Diseases with regionally specific and pronounced atrophy patterns were generally better classified than diseases with widespread and rather weak atrophy. CONCLUSIONS AND RELEVANCE: Our study furthermore underlines the necessity of larger data sets but also calls for a careful consideration of different machine learning methods that can handle the type of data and the classification task best.

Regional changes of brain structure during progression of idiopathic Parkinson's disease - A longitudinal study using deformation based morphometry.

Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder with a broad spectrum of motor and non-motor symptoms. The neuropathological characteristics of idiopathic PD are the degeneration of dopaminergic neurons in the striatum, and the propagation of aggregates of misfolded α-synuclein in the brain following a specific pattern (Braak et al., 2006). The relationship of this pattern with motor and cognitive symptoms is still equivocal. Therefore, we investigated longitudinally the spatio-temporal patterns of atrophy propagation in PD, their inter-individual variability and associations with clinical symptoms. Magnetic resonance (MR) images of 37 PD patients and 27 controls were acquired at up to 15 time-points per subject, and over observation periods of up to 8.8 years (mean: 3.7 years). MR images were analyzed by Deformation-based Morphometry to measure region volumes and their longitudinal changes. Differences of these regional volume data between patients and controls and their associations with clinical symptoms were calculated. At baseline, group differences in the regional volumes were found mainly in areas of the sensory, motor and orbitofrontal cortices, areas in the frontal operculum, inferior frontal sulcus, hippocampus and entorhinal cortex, and in the substantia nigra, among others. The longitudinal analysis yielded more widespread and more pronounced group differences, with significantly accelerated volume decreases in PD patients in the occipital and temporal lobes, the inferior parietal lobule, as well as in the insula, putamen and nucleus basalis Meynert. The white matter was less affected than the gray matter. Worse clinical scores (MMSE, PDQ-39, UPDRS-III) were in particular associated with volume decreases of cortical areas, amygdala and basal forebrain nuclei, but not of the basal ganglia. The observed longitudinal patterns of accelerated volume decrease in PD patients largely coincide with the pattern of α-synuclein pathology in PD stages 3-5 as proposed by Braak and colleagues. Thus, longitudinal DBM appears to depict already in-vivo the progression of neuropathological changes.

Brain volume patterns in corticobasal syndrome versus idiopathic Parkinson's disease.

BACKGROUND AND PURPOSE: Patients with a corticobasal syndrome (CBS) present a rare form of atypical parkinsonism characterized by asymmetric clinical symptoms and progressive motor and nonmotor impairment, such as apraxia, alien limb phenomenon, aphasia, myoclonus, dystonia, and cognitive impairment. At early stages, clinical differentiation between CBS and idiopathic Parkinson's disease (IPD) can be challenging. METHODS: Using high-resolution T1-weighted images and voxel-based morphometry (VBM), we sought to identify disease-specific patterns of brain atrophy in a small sample of CBS and IPD patients at early stages of disease. We acquired MR images of 17 patients diagnosed with CBS and compared them with MR images of 17 subjects affected by IPD. Images were preprocessed and analyzed using VBM. RESULTS: When compared to each other, the CBS and IPD patients of our cohort showed differences in regional gray and white matter volume depending on the diagnosis, specifically in the superior longitudinal fascicle. CONCLUSIONS: In our small patients' group, VBM was able to detect changes in regional gray and white matter volume between patients affected by CBS and patients with IPD as early as 1.5-2 years after the onset of the first motor symptoms.

The Post-Stroke Depression Risk Scale (PoStDeRiS): Development of an Acute-Phase Prediction Model for Depression 6 Months After Stroke.

BACKGROUND: Depression after stroke is common but often undertreated as increasing depression prevalence and decreasing health care contacts diverge after the event. OBJECTIVE: To develop an acute-phase prediction scale for prognosis of depression 6 months after stroke. METHODS: Participants (N = 226) were consecutively recruited and assessed within the first week after ischemic stroke for history of depression, stroke severity (National Institutes of Health Stroke Scale), and functional independence (Barthel Index). Early depressive symptoms were self-reported via the Patient Health Questionnaire-2 and external-rated by nurses via the Signs of Depression Scale. Six months later, 183 participants were assessed for Diagnostic and Statistical Manual of Mental Disorders, 5th edition diagnosis of depression. Significant predictors of depression were identified in multivariate logistic regression analysis and their coefficients transformed into a risk scale. Measurement precision was identified using receiver operating characteristic curve analysis. RESULTS: Depression was diagnosed in 32 (17.5%) participants 6 months after stroke. History of depression, the Barthel Index, and the Patient Health Questionnaire-2 were significant predictors of depression. Transformation of the coefficients yielded the Post-Stroke Depression Risk Scale that demonstrated good discrimination (area under the receiver operating characteristic curve = 0.84; 95% confidence interval = 0.78/0.90). The optimum cutoff showed a sensitivity of 0.81, a specificity of 0.72, a positive predictive value of 0.38, and a negative predictive value of 0.95. CONCLUSIONS: The Post-Stroke Depression Risk Scale accurately identifies people in the acute phase with low risk of depression 6 months later. While the sensitivity indicates that recognition of people with later depression is adequate, positive results in the acute phase show low predictivity. Clinical and methodological reasons for these results as well as implications for future research to increase case-finding ability are discussed.

A case of longitudinally extensive transverse myelitis following vaccination against Covid-19.

BACKGROUND: Longitudinally extensive transverse myelitis (LETM) is a rare subtype of transverse myelitis (TM) that potentially results in relevant disability. Apart from association to neuromyelitis optica and other chronic demyelinating diseases of the central nervous system, many other aetiologies are known. Particularly systemic infections and vaccination are considered potential triggers for immune mediated inflammation of the spinal cord. In the course of the current Covid-19 pandemic several cases of TM following Covid-19 infection have been described. Here we present a case of LETM following vaccination against Covid-19 with AZD1222, AstraZeneca. An extensive diagnostic work up was performed to rule out alternative causes, including prior and current Covid-19 infection. CONCLUSION: To our knowledge this is first case of LETM possibly related to Covid-19 vaccination that is published after marketing authorisation of various vaccine candidates.

Within- and across-network alterations of the sensorimotor network in Parkinson's disease.

PURPOSE: Parkinson's disease (PD) is primarily defined by motor symptoms and is associated with alterations of sensorimotor areas. Evidence for network changes of the sensorimotor network (SMN) in PD is inconsistent and a systematic evaluation of SMN in PD yet missing. We investigate functional connectivity changes of the SMN in PD, both, within the network, and to other large-scale connectivity networks. METHODS: Resting-state fMRI was assessed in 38 PD patients under long-term dopaminergic treatment and 43 matched healthy controls (HC). Independent component analysis (ICA) into 20 components was conducted and the SMN was identified within the resulting networks. Functional connectivity within the SMN was analyzed using a dual regression approach. Connectivity between the SMN and the other networks from group ICA was investigated with FSLNets. We investigated for functional connectivity changes between patients and controls as well as between medication states (OFF vs. ON) in PD and for correlations with clinical parameters. RESULTS: There was decreased functional connectivity within the SMN in left inferior parietal and primary somatosensory cortex in PD OFF. Across networks, connectivity between SMN and two motor networks as well as two visual networks was diminished in PD OFF. All connectivity decreases partially normalized in PD ON. CONCLUSION: PD is accompanied by functional connectivity losses of the SMN, both, within the network and in interaction to other networks. The connectivity changes in short- and long-range connections are probably related to impaired sensory integration for motor function in PD. SMN decoupling can be partially compensated by dopaminergic therapy.

Impact of COVID-19 Pandemic on (Health) Care Situation of People with Parkinson's Disease in Germany (Care4PD).

The Care4PD study examined the impact of the COVID-19 pandemic on the care situation of people (PwP) with Parkinson's disease in Germany. A comprehensive, nationwide, anonymous questionnaire for PwP was distributed by the members' journal of the German Parkinson's Disease Association and in several PD specialized in- and outpatient institutions. PwP subjectively evaluated their general care situation and individual impairments during the pandemic. We analyzed 1269 eligible out of 1437 returned questionnaires (88.3%) and compared PwP with (p-LTC) and without (np-LTC) professional long-term care. Both groups rated the general pandemic-related consequences as being rather mild to moderate (e.g., worsening of symptom or concerns). However, familial/social contact restrictions were indicated as most compromising, whereas access to outpatient professional health care providers was less affected. PwP with professional LTC reported more impairment than those without. COVID-19 vaccination rates and acceptance were generally high (p-LTC: 64.3%, np-LTC: 52.3%) at the time of the study, but realization of sanitary measures-especially wearing masks as a patient during care sessions-still needs to be improved. Technical options for telemedicine were principally available but only rarely used. Altogether, during the COVID-19 pandemic, PwP in Germany seemed to have a relatively stable health care access, at least in outpatient settings, while mainly social isolation compromised them. The p-LTC group was more impaired in everyday live compared with the np-LTC group.

Investigating the 1-year decline in midbrain-to-pons ratio in the differential diagnosis of PSP and IPD.

BACKGROUND: A reliable measure of PSP-specific midbrain atrophy, the midbrain-to-pons ratio (MTPR) has been reported to support the differential diagnosis of progressive supranuclear palsy (PSP) from idiopathic Parkinson's disease (IPD). Since longitudinal analyses are lacking so far, the present study aimed to evaluate the diagnostic value of the relative change of MTPR (relΔt_MTPR) over a 1-year period in patients with PSP, IPD, and healthy controls (HC). METHODS: Midsagittal individual MRIs of patients with PSP (n = 15), IPD (n = 15), and healthy controls (HC; n = 15) were assessed and the MTPR at baseline and after 1 year were defined. The diagnostic accuracy of the MTPR and its relative change were evaluated using ROC curve analyses. RESULTS: PSP-patients had a significantly lower MTPR at baseline (M = 0.45 ± 0.06), compared to both non-PSP groups (F (2, 41) = 62.82, p < 0.001), with an overall predictive accuracy of 95.6% for an MTPR ≤ 0.54. PSP-patients also presented a significantly stronger 1-year decline in MTPR compared to IPD (p < 0.001). Though predictive accuracy of relΔt_MTPR for PSP (M = - 4.74% ± 4.48) from IPD (M = + 1.29 ± 3.77) was good (76.6%), ROC analysis did not reveal a significant improvement of diagnostic accuracy by combining the MTPR and relΔt_MTPR (p = 0.670). Still, specificity for PSP increased, though not significantly (p = 0.500). CONCLUSION: The present results indicate that the relΔt_MTPR is a potentially useful tool to support the differential diagnosis of PSP from IPD. For its relative 1-year change, still, more evaluation is needed.

Somatosensory area 3b is selectively unaffected in corticobasal syndrome: combining MRI and histology.

An increasing number of neuroimaging studies addressing patients with corticobasal syndrome use macroscopic definitions of brain regions. As a closer link to functionally relevant units, we aimed at identifying magnetic resonance-based atrophy patterns in regions defined by probability maps of cortical microstructure. For this purpose, three analyses were conducted: (1) Whole-brain cortical thickness was compared between 36 patients with corticobasal syndrome and 24 controls. A pattern of pericentral atrophy was found, covering primary motor area 4, premotor area 6, and primary somatosensory areas 1, 2, and 3a. Within the central region, only area 3b was without atrophy. (2) In 18 patients, longitudinal measures with follow-ups of up to 59 months (mean 21.3 ± 15.4) were analyzed. Areas 1, 2, and 6 showed significantly faster atrophy rates than primary somatosensory area 3b. (3) In an individual autopsy case, longitudinal in vivo morphometry and postmortem pathohistology were conducted. The rate of magnetic resonance-based atrophy was significantly correlated with tufted-astrocyte load in those cytoarchitectonically defined regions also seen in the group study, with area 3b being selectively unaffected.

Pallidal Deep Brain Stimulation Reduces Sensorimotor Cortex Activation in Focal/Segmental Dystonia.

BACKGROUND: Although deep brain stimulation of the globus pallidus internus (GPi-DBS) is an established treatment for many forms of dystonia, including generalized as well as focal forms, its effects on brain (dys-)function remain to be elucidated, particularly for focal and segmental dystonia. Clinical response to GPi-DBS typically comes with some delay and lasts up to several days, sometimes even weeks, once stimulation is discontinued. OBJECTIVE: This study investigated how neural activity during rest and motor activation is affected by GPi-DBS while excluding the potential confound of altered feedback as a result of therapy-induced differences in dystonic muscle contractions. METHODS: Two groups of patients with focal or segmental dystonia were included in the study: 6 patients with GPi-DBS and 8 without DBS (control group). All 14 patients had cervical dystonia. Using H215 O PET, regional cerebral blood flow was measured at rest and during a motor task performed with a nondystonic hand. RESULTS: In patients with GPi-DBS (stimulation ON and OFF), activity at rest was reduced in a prefrontal network, and during the motor task, sensorimotor cortex activity was lower than in patients without DBS. Within-group contrasts (tapping > rest) showed less extensive task-induced motor network activation in GPi-DBS patients than in non-DBS controls. Reduced sensorimotor activation amounted to a significant group-by-task interaction only in the stimulation ON state. CONCLUSIONS: These findings support previous observations in generalized dystonia that suggested that GPi-DBS normalizes dystonia-associated sensorimotor and prefrontal hyperactivity, indicating similar mechanisms in generalized and focal or segmental dystonia. Evidence is provided that these effects extend into the OFF state, which was not previously demonstrated by neuroimaging. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Pre-stimulus beta power modulation during motor sequence learning is reduced in 'Parkinson's disease.

Beta oscillations within motor-cortical areas have been linked to sensorimotor function. In line with this, pathologically altered beta activity in cortico-basal ganglia pathways has been suggested to contribute to the pathophysiology of Parkinson's disease (PD), a neurodegenerative disorder primarily characterized by motor impairment. Although its precise function is still discussed, beta activity might subserve an anticipatory role in preparation of future actions. By reanalyzing previously published data, we aimed at investigating the role of pre-stimulus motor-cortical beta power modulation in motor sequence learning and its alteration in PD. 20 PD patients and 20 healthy controls (HC) performed a serial reaction time task (SRTT) in which reaction time gain presumably reflects the ability to anticipate subsequent sequence items. Randomly varying patterns served as control trials. Neuromagnetic activity was recorded using magnetoencephalography (MEG) and data was reanalyzed with respect to task stimuli onset. Assuming that pre-stimulus beta power modulation is functionally related to motor sequence learning, reaction time gain due to training on the SRTT should vary depending on the amount of beta power suppression prior to stimulus onset. We hypothesized to find less pre-stimulus beta power suppression in PD patients as compared to HC associated with reduced motor sequence learning in patients. Behavioral analyses revealed that PD patients exhibited smaller reaction time gain in sequence relative to random control trials than HC indicating reduced learning in PD. This finding was indeed paralleled by reduced pre-stimulus beta power suppression in PD patients. Further strengthening its functional relevance, the amount of pre-stimulus beta power suppression during sequence training significantly predicted subsequent reaction time advantage in sequence relative to random trials in patients. In conclusion, the present data provide first evidence for the contribution of pre-stimulus motor-cortical beta power suppression to motor sequence learning and support the hypothesis that beta oscillations may subserve an anticipatory, predictive function, possibly compromised in PD.

Safety and efficacy of epigallocatechin gallate in multiple system atrophy (PROMESA): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Multiple system atrophy is a rare neurodegenerative disease characterised by aggregation of α-synuclein in oligodendrocytes and neurons. The polyphenol epigallocatechin gallate inhibits α-synuclein aggregation and reduces associated toxicity. We aimed to establish if epigallocatechin gallate could safely slow disease progression in patients with multiple system atrophy. METHODS: We did a randomised, double-blind, parallel group, placebo-controlled clinical trial at 12 specialist centres in Germany. Eligible participants were older than 30 years; met consensus criteria for possible or probable multiple system atrophy and could ambulate independently (ie, were at Hoehn and Yahr stages 1-3); and were on stable anti-Parkinson's, anti-dysautonomia, anti-dementia, and anti-depressant regimens (if necessary) for at least 1 month. Participants were randomly assigned (1:1) to epigallocatechin gallate or placebo (mannitol) via a web-generated permuted blockwise randomisation list (block size=2) that was stratified by disease subtype (parkinsonism-predominant disease vs cerebellar-ataxia-predominant disease). All participants and study personnel were masked to treatment assignment. Participants were given one hard gelatin capsule (containing either 400 mg epigallocatechin gallate or mannitol) orally once daily for 4 weeks, then one capsule twice daily for 4 weeks, and then one capsule three times daily for 40 weeks. After 48 weeks, all patients underwent a 4-week wash-out period. The primary endpoint was change in motor examination score of the Unified Multiple System Atrophy Rating Scale (UMSARS) from baseline to 52 weeks. Efficacy analyses were done in all people who received at least one dose of study medication. Safety was analysed in all people who received at least one dose of the study medication to which they had been randomly assigned. This trial is registered with ClinicalTrials.gov (NCT02008721) and EudraCT (2012-000928-18), and is completed. FINDINGS: Between April 23, 2014, and Sept 3, 2015, 127 participants were screened and 92 were randomly assigned-47 to epigallocatechin gallate and 45 to placebo. Of these, 67 completed treatment and 64 completed the study (altough one of these patients had a major protocol violation). There was no evidence of a difference in the mean change from baseline to week 52 in motor examination scores on UMSARS between the epigallocatechin gallate (5·66 [SE 1·01]) and placebo (6·60 [0·99]) groups (mean difference -0·94 [SE 1·41; 95% CI -3·71 to 1·83]; p=0·51). Four patients in the epigallocatechin gallate group and two in the placebo group died. Two patients in the epigallocatechin gallate group had to stop treatment because of hepatotoxicity. INTERPRETATION: 48 weeks of epigallocatechin gallate treatment did not modify disease progression in patients with multiple system atrophy. Epigallocatechin gallate was overall well tolerated but was associated with hepatotoxic effects in some patients, and thus doses of more than 1200 mg should not be used. FUNDING: ParkinsonFonds Deutschland, German Parkinson Society, German Neurology Foundation, Lüneburg Foundation, Bischof Dr Karl Golser Foundation, and Dr Arthur Arnstein Foundation.

Machine-learning identifies Parkinson's disease patients based on resting-state between-network functional connectivity.

OBJECTIVE: Evaluation of a data-driven, model-based classification approach to discriminate idiopathic Parkinson's disease (PD) patients from healthy controls (HC) based on between-network connectivity in whole-brain resting-state functional MRI (rs-fMRI). METHODS: Whole-brain rs-fMRI (EPI, TR = 2.2 s, TE = 30 ms, flip angle = 90°. resolution = 3.1 × 3.1 × 3.1 mm, acquisition time ≈ 11 min) was assessed in 42 PD patients (medical OFF) and 47 HC matched for age and gender. Between-network connectivity based on full and L2-regularized partial correlation measures were computed for each subject based on canonical functional network architectures of two cohorts at different levels of granularity (Human Connectome Project: 15/25/50/100/200 networks; 1000BRAINS: 15/25/50/70 networks). A Boosted Logistic Regression model was trained on the correlation matrices using a nested cross-validation (CV) with 10 outer and 10 inner folds for an unbiased performance estimate, treating the canonical functional network architecture and the type of correlation as hyperparameters. The number of boosting iterations was fixed at 100. The model with the highest mean accuracy over the inner folds was trained using an non-nested 10-fold 20-repeats CV over the whole dataset to determine feature importance. RESULTS: Over the outer folds the mean accuracy was found to be 76.2% (median 77.8%, SD 18.2, IQR 69.4 - 87.1%). Mean sensitivity was 81% (median 80%, SD 21.1, IQR 75 - 100%) and mean specificity was 72.7% (median 75%, SD 20.4, IQR 66.7 - 80%). The 1000BRAINS 50-network-parcellation, using full correlations, performed best over the inner folds. The top features predominantly included sensorimotor as well as sensory networks. CONCLUSION: A rs-fMRI whole-brain-connectivity, data-driven, model-based approach to discriminate PD patients from healthy controls shows a very good accuracy and a high sensitivity. Given the high sensitivity of the approach, it may be of use in a screening setting. ADVANCES IN KNOWLEDGE: Resting-state functional MRI could prove to be a valuable, non-invasive neuroimaging biomarker for neurodegenerative diseases. The current model-based, data-driven approach on whole-brain between-network connectivity to discriminate Parkinson's disease patients from healthy controls shows promising results with a very good accuracy and a very high sensitivity.

Functional Connectivity Changes of Key Regions for Motor Initiation in Parkinson's Disease.

Akinesia, a cardinal symptom of Parkinson's disease, has been linked to abnormal activation in putamen and posterior medial frontal cortex (pMFC). However, little is known whether clinical severity of akinesia is linked to dysfunctional connectivity of these regions. Using a seed-based approach, we here investigated resting-state functional connectivity (RSFC) of putamen, pMFC and primary motor cortex (M1) in 60 patients with Parkinson's disease on regular medication and 72 healthy controls. We found that in patients putamen featured decreases of connectivity for a number of cortical and subcortical areas engaged in sensorimotor and cognitive processing. In contrast, the pMFC showed reduced connectivity with a more focal cortical network involved in higher-level motor-cognition. Finally, M1 featured a selective disruption of connectivity in a network specifically connected with M1. Correlating clinical impairment with connectivity changes revealed a relationship between akinesia and reduced RSFC between pMFC and left intraparietal lobule (IPL). Together, the present study demonstrated RSFC decreases in networks for motor initiation and execution in Parkinson's disease. Moreover, results suggest a relationship between pMFC-IPL decoupling and the manifestation of akinetic symptoms.

Neurostimulation in tardive dystonia/dyskinesia: A delayed start, sham stimulation-controlled randomized trial.

INTRODUCTION: Growing evidence suggests that pallidal deep brain stimulation represents a potential new therapeutic avenue in tardive dystonia/dyskinesia, but controlled and blinded randomized studies (RCT) are missing. The present RCT compares dystonia/dyskinesia severity of pallidal neurostimulation in patients with tardive dystonia using a delayed-start design paradigm. METHODS: Dystonia/dyskinesia severity was assessed via blinded videos following pallidal neurostimulation at 3 (blinded phase) and 6 months (open extension phase). Primary endpoint was the percentage change of dystonia severity (Burke-Fahn-Marsden-Dystonia-Rating-Scale, BFMDRS) at 3 months between active vs. sham neurostimulation using blinded-video assessment. Secondary endpoints comprised clinical rating scores for movement disorders. Clinicaltrials.gov NCT00331669. RESULTS: Twenty-five patients were randomized (1:1) to active (n = 12) or sham neurostimulation (n = 13). In the intention-to-treat analyses the between group difference of dystonia severity (BFMDRS) between active vs. sham stimulation was not significant at 3 months. Three months post-randomisation dystonia severity improved significantly within the neurostimulation by 22.8% and non-significantly within the sham group (12.0%) compared to their respective baseline severity. During the open-label extension with both groups being actively treated, significant and pronounced improvements of 41.5% were observed via blinded evaluation. Adverse events (n = 10) occurred in 10/25 of patients during the 6 months, mostly related to surgical implantation of the device; all resolved without sequelae. CONCLUSION: The primary endpoint of this randomized trial was not significant, most likely due to incomplete recruitment. However, pronounced improvements of most secondary endpoints at 3 and 6 months provide evidence for efficacy and safety of pallidal neurostimulation in tardive dystonia.