Improvement by Medication Less than Expected in Parkinson's Disease: Blinded Evaluation of Levodopa Response.

Background: The latest Movement Disorder Society (MDS) diagnostic criteria require a good and sustained response to medication to get a diagnosis of Parkinson's disease, PD. Objective: The aim of this study was to evaluate levodopa response in a group of patients with probable PD, diagnosed by movement disorder specialists. Methods: An acute levodopa challenge test (LDCT) was performed after pausing the dopaminergic medication for 6 half-times. The motor part of the Unified Parkinson's Disease Rating Scale was performed in the OFF-state and after LDCT (ON). A good effect was defined as >30% improvement. A video-protocol was used to secure standardized motor examination with blinded assessments of the UPDRS-III OFF and ON. An age-matched group of control subjects (CS) was included but did not go through LDCT. All participants were evaluated with Montreal Cognitive Assessment (MoCA) and Beck's Depression Inventory (BDI). Results: In the statistical analysis, 37 patients were included. Twenty-one patients showed an improvement ≤30%, while 16 patients showed an improvement >30%. LDCT showed an overall mean improvement of 27.3% of motor UPDRS. In 43.2%, there was a discrepancy between the effect seen with the LDCT and the patients' self-perceived medicine evaluation. Patients with PD had a significantly lower MoCA score and more depressive symptoms compared to CS. Conclusions: We showed an acute effect of levodopa using LDCT that was around 30% improvement. While it lends support to the use of this limit in the MDS diagnostic criteria, an acute effect of less than 30% should be considered acceptable in some patients. Our study highlights a discrepancy in the objective measure of medicine effect on motor symptoms and the patient's subjective evaluation.

Linking Impulsivity to Activity Levels in Pre-Supplementary Motor Area during Sequential Gambling.

Impulsivity refers to the tendency to act prematurely or without forethought, and excessive impulsivity is a key problem in many neuropsychiatric disorders. Since the pre-supplementary motor area (pre-SMA) has been implicated in inhibitory control, this region may also contribute to impulsivity. Here, we examined whether functional recruitment of pre-SMA may contribute to risky choice behavior (state impulsivity) during sequential gambling and its relation to self-reported trait impulsivity. To this end, we performed task-based functional MRI (fMRI) after low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) of the pre-SMA. We expected low-frequency rTMS to modulate task-related engagement of the pre-SMA and, hereby, tune the tendency to make risky choices. Twenty-four healthy volunteers (12 females; age range, 19-52 years) received real or sham-rTMS on separate days in counterbalanced order. Thereafter, participants performed a sequential gambling task with concurrently increasing stakes and risk during whole-brain fMRI. In the sham-rTMS session, self-reported trait impulsivity scaled positively with state impulsivity (riskier choice behavior) during gambling. The higher the trait impulsivity, the lower was the task-related increase in pre-SMA activity with increasingly risky choices. Following real-rTMS, low-impulsivity participants increased their preference for risky choices, while the opposite was true for high-impulsivity participants, resulting in an overall decoupling of trait impulsivity and state impulsivity during gambling. This rTMS-induced behavioral shift was mirrored in the rTMS-induced change in pre-SMA activation. These results provide converging evidence for a causal link between the level of task-related pre-SMA activity and the propensity for impulsive risk-taking behavior in the context of sequential gambling.SIGNIFICANCE STATEMENT Impulsivity is a personal trait characterized by a tendency to act prematurely or without forethought, and excessive impulsivity is a key problem in many neuropsychiatric disorders. Here we provide evidence that the pre-supplementary motor area (pre-SMA) is causally involved in implementing general impulsive tendencies (trait impulsivity) into actual behavior (state impulsivity). Participants' self-reported impulsivity levels (trait impulsivity) were reflected in their choice behavior (state impulsivity) when involved in a sequential gambling task. This relationship was uncoupled after perturbing the pre-SMA with repetitive transcranial stimulation (rTMS). This effect was contingent on trait impulsivity and was echoed in rTMS-induced changes in pre-SMA activity. Pre-SMA is key in translating trait impulsivity into behavior, possibly by integrating prefrontal goals with corticostriatal motor control.

Brain proteome profiling implicates the complement and coagulation cascade in multiple system atrophy brain pathology.

BACKGROUND: Multiple system atrophy (MSA) is a rare, progressive, neurodegenerative disorder presenting glia pathology. Still, disease etiology and pathophysiology are unknown, but neuro-inflammation and vascular disruption may be contributing factors to the disease progression. Here, we performed an ex vivo deep proteome profiling of the prefrontal cortex of MSA patients to reveal disease-relevant molecular neuropathological processes. Observations were validated in plasma and cerebrospinal fluid (CSF) of novel cross-sectional patient cohorts. METHODS: Brains from 45 MSA patients and 30 normal controls (CTRLs) were included. Brain samples were homogenized and trypsinized for peptide formation and analyzed by high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS). Results were supplemented by western blotting, immuno-capture, tissue clearing and 3D imaging, immunohistochemistry and immunofluorescence. Subsequent measurements of glial fibrillary acid protein (GFAP) and neuro-filament light chain (NFL) levels were performed by immunoblotting in plasma of 20 MSA patients and 20 CTRLs. Finally, we performed a proteome profiling of 144 CSF samples from MSA and CTRLs, as well as other parkinsonian disorders. Data were analyzed using relevant parametric and non-parametric two-sample tests or linear regression tests followed by post hoc tests corrected for multiple testing. Additionally, high-throughput bioinformatic analyses were applied. RESULTS: We quantified more than 4,000 proteins across samples and identified 49 differentially expressed proteins with significantly different abundances in MSA patients compared with CTRLs. Pathway analyses showed enrichment of processes related to fibrinolysis and complement cascade activation. Increased fibrinogen subunit ß (FGB) protein levels were further verified, and we identified an enriched recognition of FGB by IgGs as well as intra-parenchymal accumulation around blood vessels. We corroborated blood-brain barrier leakage by a significant increase in GFAP and NFL plasma levels in MSA patients that correlated to disease severity and/or duration. Proteome profiling of CSF samples acquired during the disease course, confirmed increased total fibrinogen levels and immune-related components in the soluble fraction of MSA patients. This was also true for the other atypical parkinsonian disorders, dementia with Lewy bodies and progressive supra-nuclear palsy, but not for Parkinson's disease patients. CONCLUSION: Our results implicate activation of the fibrinolytic cascade and immune system in the brain as contributing factors in MSA associated with a more severe disease course.

Gastric Emptying Is Not Delayed and Does Not Correlate With Attenuated Postprandial Blood Flow Increase in Medicated Patients With Early Parkinson's Disease.

Background: We have recently used phase-contrast magnetic resonance imaging (PC-MRI) to demonstrate an attenuated postprandial blood flow response in the superior mesenteric artery (SMA) in 23 medicated patients with Parkinson's disease (PD) compared to 23 age- and sex-matched healthy controls. Objective: To investigate in a sub-sample of the original cohort whether the observed blood flow response in SMA after oral food intake is related to a delay in gastric emptying. Methods: We studied 15 patients with PD in an "ON-medication" state with a mean disease duration of 3.9 ± 2.2 years and 15 healthy age- and sex-matched individuals. Participants underwent dynamic gastric scintigraphy 0, 30, 60, 120, 180 and 240 minutes after the intake of a standardized radiolabeled test meal. Gastric emptying was compared between groups. 14 of the 15 PD patients and 12 of the 15 healthy control subjects had previously undergone serial postprandial PC-MRI measurements. In these individuals, we tested for a relationship between gastric emptying and postprandial blood flow response in the SMA. Results: The dynamics of gastric emptying did not differ between groups (p = 0.68). There was substantial inter-subject variability of gastric emptying in PD patients and healthy participants. Only a single PD patient had delayed gastric emptying. In those participants who had undergone PC-MRI, postprandial increase in SMA blood flow was attenuated in PD compared to healthy controls as reported previously (p = 0.006). Gastric emptying did not correlate with the timing and amplitude of postprandial blood flow increase in SMA. Conclusion: Our preliminary results, obtained in a small group of early-stage PD patients who continued their usual dopamine replacement therapy, suggest that variations in gastric emptying after solid meal intake is within the normal range in the majority of cases. There is also no evidence for a tight relationship between the attenuated postprandial blood flow response in the SMA and normal variations in gastric emptying.

A randomised double-blind controlled study of Deep Brain Stimulation for dystonia in STN or GPi - A long term follow-up after up to 15 years.

AIM: This is a long-term open follow-up of a prospective double-blind crossover study, where electrodes were bilaterally implanted in both the Subthalamic nucleus (STN) and internal pallidum (GPi) in patients with isolated dystonia. METHODS: Patients with isolated dystonia were included to undergo surgery with Deep Brain stimulation (DBS) and after randomization, in a double-blind cross-over study, receiving bilateral stimulation of either STN or GPi for 6 months in each target. Preoperative and postoperative assessments with the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the 36-item Short Form Health Survey (SF-36) were performed. In this long-term follow-up (LFU), these ratings were repeated, and patients were evaluated with cognitive tests. RESULTS: 21 patients were included in the protocol, 9 patients with generalized dystonia, 12 with a diagnosis of cervical dystonia. The mean duration of disease was 19.3 years, age at time of surgery 50.1 years. Fourteen patients participated in the LFU. At a mean follow-up of 10.2 years (range 4.8-15.4), BFMDRS movement score was improved with a mean of 36% (p < 0.05) compared with baseline. At LFU both a statistically significant improvement of stimulation in STN on BFMDRS movement score (p = 0.029) and Gpi (p = 0.008) was demonstrated, no significant difference was found between the two targets (p = 0.076). SF-36 improved for both targets. CONCLUSION: In this study we performed a long-term follow-up in 14 patients with cervical or generalized dystonia, who received stimulation in GPi, STN or both. The mean follow-up time was more than 10 years. Our data support a long-term effect of both STN-DBS and GPi-DBS in dystonia with equal effect and safety for up to 15 years. STN has been proven a viable safe and effective target and may be used as an alternative to GPi in both adult-onset cervical dystonia and generalized dystonia.

Locus Coeruleus Shows a Spatial Pattern of Structural Disintegration in Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) causes a loss of neuromelanin-positive, noradrenergic neurons in the locus coeruleus (LC), which has been implicated in nonmotor dysfunction. OBJECTIVES: We used "neuromelanin sensitive" magnetic resonance imaging (MRI) to localize structural disintegration in the LC and its association with nonmotor dysfunction in PD. METHODS: A total of 42 patients with PD and 24 age-matched healthy volunteers underwent magnetization transfer weighted (MTw) MRI of the LC. The contrast-to-noise ratio of the MTw signal (CNRMTw ) was used as an index of structural LC integrity. We performed slicewise and voxelwise analyses to map spatial patterns of structural disintegration, complemented by principal component analysis (PCA). We also tested for correlations between regional CNRMTw and severity of nonmotor symptoms. RESULTS: Mean CNRMTw of the right LC was reduced in patients relative to controls. Voxelwise and slicewise analyses showed that the attenuation of CNRMTw was confined to the right mid-caudal LC and linked regional CNRMTw to nonmotor symptoms. CNRMTw attenuation in the left mid-caudal LC was associated with the orthostatic drop in systolic blood pressure, whereas CNRMTw attenuation in the caudal most portion of right LC correlated with apathy ratings. PCA identified a bilateral component that was more weakly expressed in patients. This component was characterized by a gradient in CNRMTw along the rostro-caudal and dorso-ventral axes of the nucleus. The individual expression score of this component reflected the overall severity of nonmotor symptoms. CONCLUSION: A spatially heterogeneous disintegration of LC in PD may determine the individual expression of specific nonmotor symptoms such as orthostatic dysregulation or apathy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease.

Dysfunctional dopaminergic neurotransmission is central to movement disorders and mental diseases. The dopamine transporter (DAT) regulates extracellular dopamine levels, but the genetic and mechanistic link between DAT function and dopamine-related pathologies is not clear. Particularly, the pathophysiological significance of monoallelic missense mutations in DAT is unknown. Here, we use clinical information, neuroimaging, and large-scale exome-sequencing data to uncover the occurrence and phenotypic spectrum of a DAT coding variant, DAT-K619N, which localizes to the critical C-terminal PSD-95/Discs-large/ZO-1 homology-binding motif of human DAT (hDAT). We identified the rare but recurrent hDAT-K619N variant in exome-sequenced samples of patients with neuropsychiatric diseases and a patient with early-onset neurodegenerative parkinsonism and comorbid neuropsychiatric disease. In cell cultures, hDAT-K619N displayed reduced uptake capacity, decreased surface expression, and accelerated turnover. Unilateral expression in mouse nigrostriatal neurons revealed differential effects of hDAT-K619N and hDAT-WT on dopamine-directed behaviors, and hDAT-K619N expression in Drosophila led to impairments in dopamine transmission with accompanying hyperlocomotion and age-dependent disturbances of the negative geotactic response. Moreover, cellular studies and viral expression of hDAT-K619N in mice demonstrated a dominant-negative effect of the hDAT-K619N mutant. Summarized, our results suggest that hDAT-K619N can effectuate dopamine dysfunction of pathological relevance in a dominant-negative manner.

Cerebrospinal fluid and plasma distribution of anti-α-synuclein IgMs and IgGs in multiple system atrophy and Parkinson's disease.

INTRODUCTION: Ubiquitous naturally occurring autoantibodies (nAbs) against alpha-synuclein (α-syn) may play important roles in the pathogenesis of Multiple System Atrophy (MSA) and Parkinson's disease (PD). Recently, we reported reduced high-affinity/avidity anti-α-syn nAbs levels in plasma from MSA and PD patients, along with distinct inter-group immunoglobulin (Ig)G subclass distributions. The extent to which these observations in plasma may reflect corresponding levels in the cerebrospinal fluid (CSF) is unknown. METHODS: Using competitive and indirect ELISAs, we investigated the affinity/avidity of CSF anti-α-syn nAbs as well as the CSF and plasma distribution of IgG subclasses and IgM nAbs in a cross-sectional cohort of MSA and PD patients. RESULTS: Repertoires of high-affinity/avidity anti-α-syn IgG nAbs were reduced in CSF samples from MSA and PD patients compared to controls. Furthermore, anti-α-syn IgM nAb levels were relatively lower in CSF and plasma from MSA patients but were reduced only in plasma from PD patients. Interestingly, anti-α-syn IgG subclasses presented disease-specific profiles both in CSF and plasma. Anti-α-syn IgG1, IgG2 and IgG3 levels were relatively increased in CSF of MSA patients, whereas PD patients showed increased anti-α-syn IgG2 and reduced anti-α-syn IgG4 levels. CONCLUSIONS: Differences in the plasma/CSF distribution of anti-α-syn nAbs seem to be a common feature of synucleinopathies. Our data add further support to the notion that MSA and PD patients may have compromised immune reactivity towards α-syn. The differing α-syn-specific systemic immunological responses may reflect their specific disease pathophysiologies. These results are encouraging for further investigation of these immunological mechanisms in neurodegenerative diseases.

Postprandial Increase in Mesenteric Blood Flow is Attenuated in Parkinson's Disease: A Dynamic PC-MRI Study.

BACKGROUND: Gastrointestinal dysfunction and related clinical symptoms are common in Parkinson's disease (PD), but the underlying mechanisms are still poorly understood. OBJECTIVE: In this study, we investigated how PD affects the postprandial vascular response in the splanchnic circulation. METHODS: 23 patients with PD in the "ON-medication" state and 23 age- and sex-matched healthy control participants underwent serial phase-contrast magnetic resonance imaging (PC-MRI) to measure the postprandial blood flow response in the superior mesenteric artery (SMA). Participants ingested a standardized liquid test meal (∼400 kcal) and underwent four PC-MRI runs within the following hour. Each PC-MRI run consisted of six consecutive measurements of SMA blood flow. RESULTS: In both groups, standardized food intake triggered an increase of blood flow in the SMA, but absolute and relative increases in blood flow were attenuated in patients compared to the control group (p < 0.001). While baseline blood flow in the SMA was comparable in both groups, the postprandial maximum blood flow was attenuated in patients (p = 0.03). The temporal dynamics of the postprandial blood flow did not differ between groups. Postprandial SMA blood flow increase in patients correlated neither with subjective reports of non-motor symptoms or upper gastrointestinal complaints, nor with levodopa equivalent daily dose or disease duration. Blood glucose measurements in between the PC-MRI runs showed a smaller postprandial increase in blood glucose in the patient group (p = 0.006). CONCLUSION: This study provides first-time evidence that patients with PD have an attenuated postprandial blood flow response in the SMA, indicating an impaired functional regulation of gastrointestinal perfusion in response to food intake in PD.

Effects of Computer-Based Cognitive Rehabilitation on Attention, Executive Functions, and Quality of Life in Patients with Parkinson's Disease: A Randomized, Controlled, Single-Blinded Pilot Study.

BACKGROUND: Cognitive decline in Parkinson's disease (PD) has become increasingly recognized in recent years, and there is a need to identify methods for cognitive rehabilitation in PD patients. OBJECTIVE: The aim of this study was to explore the feasibility and effects of 2 different computer-based cognitive rehabilitation (CBCR) interventions on attention, executive functions, and quality of life (QoL) in PD patients. METHODS: Thirty nondemented PD patients were randomly assigned to one of 3 groups: one passive control group and 2 intervention groups with 2 different CBCR programmes. The intervention period was 8 weeks with follow-up visits in clinic every second week. Before and after the intervention period, patients were tested with a neuropsychological battery of attention, executive functions, and QoL. RESULTS: Twenty-four patients completed the study. Patients in one of the CBCR groups experienced a significant within-group increase on the primary measures of attention, executive functions, and QoL. However, this effect was not significant between groups. No significant differences were observed for the other CBCR group or the control group. CONCLUSIONS: CBCR is a feasible intervention for cognitive rehabilitation in nondemented PD patients. The effects of training were modest and should be further explored in larger clinical trials. Some CBCR programmes might be more effective than others for PD patients. The protocol for this study was published prospectively at ClinicalTrials.gov on September 18, 2017 with ID: NCT03285347.

Low-frequency transcranial stimulation of pre-supplementary motor area alleviates levodopa-induced dyskinesia in Parkinson's disease: a randomized cross-over trial.

Levodopa-induced dyskinesia gradually emerges during long-term dopamine therapy, causing major disability in patients with Parkinson disease. Using pharmacodynamic functional MRI, we have previously shown that the intake of levodopa triggers an excessive activation of the pre-supplementary motor area in Parkinson disease patients with peak-of-dose dyskinesia. In this pre-registered, interventional study, we tested whether the abnormal responsiveness of the pre-supplementary motor area to levodopa may constitute a 'stimulation target' for treating dyskinesia. A gender-balanced group of 17 Parkinson disease patients with peak-of-dose dyskinesia received 30 min of robot-assisted repetitive transcranial magnetic stimulation, after they had paused their anti-Parkinson medication. Real-repetitive transcranial magnetic stimulation at 100% or sham-repetitive transcranial magnetic stimulation at 30% of individual resting corticomotor threshold of left first dorsal interosseous muscle was applied on separate days in counterbalanced order. Following repetitive transcranial magnetic stimulation, patients took 200 mg of oral levodopa and underwent functional MRI to map brain activity, while they performed the same go/no-go task as in our previous study. Blinded video assessment revealed that real-repetitive transcranial magnetic stimulation delayed the onset of dyskinesia and reduced its severity relative to sham-repetitive transcranial magnetic stimulation. Individual improvement in dyskinesia severity scaled linearly with the modulatory effect of real-repetitive transcranial magnetic stimulation on task-related activation in the pre-supplementary motor area. Stimulation-induced delay in dyskinesia onset correlated positively with the induced electrical field strength in the pre-supplementary motor area. Our results provide converging evidence that the levodopa-triggered increase in pre-supplementary motor area activity plays a causal role in the pathophysiology of peak-of-dose dyskinesia and constitutes a promising cortical target for brain stimulation therapy.

Deep Brain Stimulation in Parkinson's Disease: Still Effective After More Than 8 Years.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is well established and the most effective treatment for advanced Parkinson's disease (PD). However, little is known of the long-term effects. OBJECTIVES: The aim of this study was to examine the long-term effects of STN-DBS in PD and evaluate the effect of reprogramming after more than 8 years of treatment. METHODS: A total of 82 patients underwent surgery in Copenhagen between 2001 and 2008. Before surgery and at 8 to 15 years follow-up, the patients were rated with the Unified Parkinson's Disease Rating Scale (UPDRS) with and without stimulation and medicine. Furthermore, at long-term follow-up, the patients were offered a systemic reprogramming of the stimulation settings. Data from patients' medical records were collected. The mean (range) age at surgery was 60 (42-78) years, and the duration of disease was 13 (5-25) years. A total of 30 patients completed the long-term follow-up. RESULTS: The mean reduction of the motor UPDRS by medication before surgery was 52%. The improvement of motor UPDRS with stimulation alone compared with motor UPDRS with neither stimulation nor medication was 61% at 1 year and 39% at 8 to 15 years after surgery (before reprogramming). Compared with before surgery, medication was reduced by 55% after 1 year and 44% after 8 to 15 years. After reprogramming, most patients improved. CONCLUSIONS: STN-DBS remains effective in the long run, with a sustained reduction of medication in the 30 of 82 patients available for long-term follow-up. Reprogramming is effective even in the late stages of PD and after many years of treatment.

Paroxysmal Cranial Dyskinesia and Nail-Patella Syndrome Caused by a Novel Variant in the LMX1B Gene.

BACKGROUND: In a Danish family, multiple individuals in five generations present with early-onset paroxysmal cranial dyskinesia, musculoskeletal abnormalities, and kidney dysfunction. OBJECTIVE: To demonstrate linkage and to identify the underlying genetic cause of disease. METHODS: Genome-wide single-nucleotide polymorphisms analysis, Sequence-Tagged-Site marker analyses, exome sequencing, and Sanger sequencing were performed. RESULTS: Linkage analyses identified a candidate locus on chromosome 9. Exome sequencing revealed a novel variant in LMX1B present in all affected individuals, logarithm of the odds (LOD) score of z = 6.54, predicted to be damaging. Nail-patella syndrome (NPS) is caused by pathogenic variants in LMX1B encoding a transcription factor essential to cytoskeletal and kidney growth and dopaminergic and serotonergic network development. NPS is characterized by abnormal musculoskeletal features and kidney dysfunction. Movement disorders have not previously been associated with NPS. CONCLUSIONS: Paroxysmal dyskinesia is a heretofore unrecognized feature of the NPS spectrum. The pathogenic mechanism might relate to aberrant dopaminergic circuits. © 2020 International Parkinson and Movement Disorder Society.

Linking brain activity during sequential gambling to impulse control in Parkinson's disease.

Dopaminergic treatment may impair the ability to suppress impulsive behaviours in patients with Parkinson's disease, triggering impulse control disorders. It is unclear how dopaminergic medication affects the neural networks that contribute to withholding inappropriate actions. To address this question, we mapped task-related brain activity with whole-brain functional magnetic resonance imaging at 3 Tesla in 26 patients with Parkinson's disease. Patients performed a sequential gambling task while being ON and OFF their regular dopaminergic treatment. During a gambling round, patients repeatedly decided between the option to continue with gambling and accumulate more monetary reward under increasing risk or the option to bank the current balance and start a new round. 13 patients had an impulse control disorder (ICD + group). These patients did not differ in risk-taking attitude during sequential gambling from 13 patients without impulse control disorder (ICD - group), but they displayed differences in gambling-related activity in cortico-subcortical brain areas supporting inhibitory control. First, the ICD + group showed reduced "continue-to-gamble" activity in right inferior frontal gyrus and subthalamic nucleus. Second, the individual risk-attitude scaled positively with "continue-to-gamble" activity in right subthalamic nucleus and striatum in the ICD - group only. Third, ICD + patients differed in their functional neural responses to dopaminergic treatment from ICD - patients: dopaminergic therapy reduced functional connectivity between inferior frontal gyrus and subthalamic nucleus during "continue-to-gamble" decisions and attenuated striatal responses towards accumulating reward and risk. Together, the medication-independent (trait) and medication-related (state) differences in neural activity may set a permissive stage for the emergence of impulse control disorders during dopamine replacement therapy in Parkinson's disease.

Epigenetic modulation of AREL1 and increased HLA expression in brains of multiple system atrophy patients.

Multiple system atrophy (MSA) is a rare disease with a fatal outcome. To date, little is known about the molecular processes underlying disease development. Its clinical overlap with related neurodegenerative movement disorders underlines the importance for expanding the knowledge of pathological brain processes in MSA patients to improve distinction from similar diseases. In the current study, we investigated DNA methylation changes in brain samples from 41 MSA patients and 37 healthy controls. We focused on the prefrontal cortex, a moderately affected area in MSA. Using Illumina MethylationEPIC arrays, we investigated 5-methylcytosine (5mC) as well as 5-hydroxymethylcytosine (5hmC) changes throughout the genome. We identified five significantly different 5mC probes (adj. P < 0.05), of which one probe mapping to the AREL1 gene involved in antigen presentation was decreased in MSA patients. This decrease correlated with increased 5hmC levels. Further, we identified functional DNA methylation modules involved in inflammatory processes. As expected, the decreased 5mC levels on AREL1 was concordant with increased gene expression levels of both AREL1 as well as MHC Class I HLA genes in MSA brains. We also investigated whether these changes in antigen-related processes in the brain associated with changes in peripheral mononuclear cells. Using flow cytometry on an independent cohort of MSA patients, we identified a decrease in circulating non-classical CD14+CD16++ blood monocytes, whereas T and NK cell populations were unchanged. Taken together, our results support the view of an active neuroimmune response in brains of MSA patients.

The Effects of Computer-Based Cognitive Rehabilitation on Working Memory in Patients with Parkinson's Disease: A Systematic Review.

BACKGROUND: Deterioration of working memory(WM) is a common cognitive deficit in Parkinson's disease (PD), and severely influences the ability to lead an independent life. Interventions which can delay the impact of WM deficits could positively impact the independence and quality of life of patients. OBJECTIVE: To evaluate effects of computer-based cognitive rehabilitation (CBCR) on WM in patients with PD. METHODS: Pubmed, Embase, Psycinfo and Cochrane Library were systematically searched. Authors of included studies were contacted to detect unpublished data or articles not found by database-search. Broad selection criteria were applied because literature was expected to be limited. Studies were eligible for inclusion if they investigated the effects of CBCR on WM in a sample consisting of at least 50% PD patients, or in which the results of PD patients could be isolated. Studies were further eligible for inclusion in a planned meta-analysis if the effects of the CBCR intervention could be isolated, the CBCR intervention was compared to active or passive control groups consisting solely of PD patients, and the WM outcome measure could be isolated. RESULTS: Only six studies were included despite broad inclusion criteria. Study results were heterogeneous, and the risk of bias in study methodology was either unclear or high. Two studies were eligible for meta-analysis. A meta-analysis was not performed, because these studies used different measures of WM which were not rated as equally valid and reliable. CONCLUSION: Existing literature is sparse and provides insufficient evidence to conclude if CBCR benefits WM in PD patients.

Distinct Autoimmune Anti-α-Synuclein Antibody Patterns in Multiple System Atrophy and Parkinson's Disease.

Aggregation of alpha-synuclein (α-syn) is considered to be the major pathological hallmark and driving force of Multiple System Atrophy (MSA) and Parkinson's disease (PD). Immune dysfunctions have been associated with both MSA and PD and recently we reported that the levels of natural occurring autoantibodies (NAbs) with high-affinity/avidity toward α-synuclein are reduced in MSA and PD patients. Here, we aimed to evaluate the plasma immunoglobulin (Ig) composition binding α-syn and other amyloidogenic neuropathological proteins, and to correlate them with disease severity and duration in MSA and PD patients. All participants were recruited from a single neurological unit and the plasma samples were stored for later research at the Bispebjerg Movement Disorder Biobank. All patients were diagnosed according to current consensus criteria. Using multiple variable linear regression analyses, we observed higher levels of anti-α-syn IgG1 and IgG3 NAbs in MSA vs. PD, higher levels of anti-α-syn IgG2 NAbs in PD compared to controls, whereas anti-α-syn IgG4 NAbs were reduced in PD compared to MSA and controls. Anti-α-syn IgM levels were decreased in both MSA and PD. Further our data supported that MSA patients' immune system was affected with reduced IgG1 and IgM global levels compared to PD and controls, with further reduced global IgG2 levels compared to PD. These results suggest distinct autoimmune patterns in MSA and PD. These findings suggest a specific autoimmune physiological mechanism involving responses toward α-syn, differing in neurodegenerative disease with overlapping α-syn pathology.

[Dystonia].

This review presents the newest classification of dystonia, new evidence regarding aetiology, the diagnosis of dystonia, and the most common forms of treatment. Dystonia is a rare and heterogeneous movement disorder defined as a syn-drome of sustained muscle contractions with twisting and abnormal postures, and tremor. Dystonia is a collective term for different syndromes, primary idiopathic forms as well as genetic and secondary forms.

[Neurosurgical treatment of dystonia].

In this review, we present evidence of treatment effect with deep brain stimulation (DBS) in patients with isolated forms of dystonia with generalised-, segmental- and focal phenotypes as well as tardive dystonia and dyskinetic cerebral palsy. Dystonia is a heterogeneous movement disorder, which can be disabling and difficult to treat. Patients with dystonia, who do not experience relief with medication and botulinum toxin, may be candidates for DBS.

Clinical Practice: Evidence-Based Recommendations for the Treatment of Cervical Dystonia with Botulinum Toxin.

Cervical dystonia (CD) is the most frequent form of focal dystonia. Symptoms often result in pain and functional disability. Local injections of botulinum neurotoxin are currently the treatment of choice for CD. Although this treatment has proven effective and is widely applied worldwide, many issues still remain open in the clinical practice. We performed a systematic review of the literature on botulinum toxin treatment for CD based on a question-oriented approach, with the aim to provide practical recommendations for the treating clinicians. Key questions from the clinical practice were explored. Results suggest that while the beneficial effect of botulinum toxin treatment on different aspects of CD is well established, robust evidence is still missing concerning some practical aspects, such as dose equivalence between different formulations, optimal treatment intervals, treatment approaches, and the use of supportive techniques including electromyography or ultrasounds. Established strategies to prevent or manage common side effects (including excessive muscle weakness, pain at injection site, dysphagia) and potential contraindications to this treatment (pregnancy and lactation, use of anticoagulants, neurological comorbidities) should also be further explored.