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.

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.

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.

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.

Neocortical Neuronal Loss in Patients with Multiple System Atrophy: A Stereological Study.

To determine the extent of neocortical involvement in multiple system atrophy (MSA), we used design-based stereological methods to estimate the total numbers of neurons, oligodendrocytes, astrocytes, and microglia in the frontal, parietal, temporal, and occipital cortex of brains from 11 patients with MSA and 11 age- and gender-matched control subjects. The stereological data were supported by cell marker expression analyses in tissue samples from the prefrontal cortex. We found significantly fewer neurons in the frontal and parietal cortex of MSA brains compared with control brains. Significantly more astrocytes and microglia were observed in the frontal, parietal, and temporal cortex of MSA brains, whereas no change in the total number of oligodendrocytes was seen in any of the neocortical regions. There were significantly fewer neurons in the frontal cortex of MSA patients with impaired executive function than in patients with normal executive function. Our results indicate that the involvement of the neocortex in MSA is far more widespread and substantial than previously thought. In addition, our results suggest that the increasingly recognized cognitive impairment in MSA may be related to neuronal loss in the frontal cortex.

Altered sensorimotor activation patterns in idiopathic dystonia-an activation likelihood estimation meta-analysis of functional brain imaging studies.

Dystonia is characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements or postures. Functional neuroimaging studies have yielded abnormal task-related sensorimotor activation in dystonia, but the results appear to be rather variable across studies. Further, study size was usually small including different types of dystonia. Here we performed an activation likelihood estimation (ALE) meta-analysis of functional neuroimaging studies in patients with primary dystonia to test for convergence of dystonia-related alterations in task-related activity across studies. Activation likelihood estimates were based on previously reported regional maxima of task-related increases or decreases in dystonia patients compared to healthy controls. The meta-analyses encompassed data from 179 patients with dystonia reported in 18 functional neuroimaging studies using a range of sensorimotor tasks. Patients with dystonia showed bilateral increases in task-related activation in the parietal operculum and ventral postcentral gyrus as well as right middle temporal gyrus. Decreases in task-related activation converged in left supplementary motor area and left postcentral gyrus, right superior temporal gyrus and dorsal midbrain. Apart from the midbrain cluster, all between-group differences in task-related activity were retrieved in a sub-analysis including only the 14 studies on patients with focal dystonia. For focal dystonia, an additional cluster of increased sensorimotor activation emerged in the caudal cingulate motor zone. The results show that dystonia is consistently associated with abnormal somatosensory processing in the primary and secondary somatosensory cortex along with abnormal sensorimotor activation of mesial premotor and right lateral temporal cortex. Hum Brain Mapp 37:547-557, 2016. © 2015 Wiley Periodicals, Inc.

Resting-state connectivity predicts levodopa-induced dyskinesias in Parkinson's disease.

BACKGROUND: Levodopa-induced dyskinesias are a common side effect of dopaminergic therapy in PD, but their neural correlates remain poorly understood. OBJECTIVES: This study examines whether dyskinesias are associated with abnormal dopaminergic modulation of resting-state cortico-striatal connectivity. METHODS: Twelve PD patients with peak-of-dose dyskinesias and 12 patients without dyskinesias were withdrawn from dopaminergic medication. All patients received a single dose of fast-acting soluble levodopa and then underwent resting-state functional magnetic resonance imaging before any dyskinesias emerged. Levodopa-induced modulation of cortico-striatal resting-state connectivity was assessed between the putamen and the following 3 cortical regions of interest: supplementary motor area, primary sensorimotor cortex, and right inferior frontal gyrus. These functional connectivity measures were entered into a linear support vector classifier to predict whether an individual patient would develop dyskinesias after levodopa intake. Linear regression analysis was applied to test which connectivity measures would predict dyskinesia severity. RESULTS: Dopaminergic modulation of resting-state connectivity between the putamen and primary sensorimotor cortex in the most affected hemisphere predicted whether patients would develop dyskinesias with a specificity of 100% and a sensitivity of 91% (P < .0001). Modulation of resting-state connectivity between the supplementary motor area and putamen predicted interindividual differences in dyskinesia severity (R(2) = 0.627, P = .004). Resting-state connectivity between the right inferior frontal gyrus and putamen neither predicted dyskinesia status nor dyskinesia severity. CONCLUSIONS: The results corroborate the notion that altered dopaminergic modulation of cortico-striatal connectivity plays a key role in the pathophysiology of dyskinesias in PD.

Abnormal dopaminergic modulation of striato-cortical networks underlies levodopa-induced dyskinesias in humans.

Dopaminergic signalling in the striatum contributes to reinforcement of actions and motivational enhancement of motor vigour. Parkinson's disease leads to progressive dopaminergic denervation of the striatum, impairing the function of cortico-basal ganglia networks. While levodopa therapy alleviates basal ganglia dysfunction in Parkinson's disease, it often elicits involuntary movements, referred to as levodopa-induced peak-of-dose dyskinesias. Here, we used a novel pharmacodynamic neuroimaging approach to identify the changes in cortico-basal ganglia connectivity that herald the emergence of levodopa-induced dyskinesias. Twenty-six patients with Parkinson's disease (age range: 51-84 years; 11 females) received a single dose of levodopa and then performed a task in which they had to produce or suppress a movement in response to visual cues. Task-related activity was continuously mapped with functional magnetic resonance imaging. Dynamic causal modelling was applied to assess levodopa-induced modulation of effective connectivity between the pre-supplementary motor area, primary motor cortex and putamen when patients suppressed a motor response. Bayesian model selection revealed that patients who later developed levodopa-induced dyskinesias, but not patients without dyskinesias, showed a linear increase in connectivity between the putamen and primary motor cortex after levodopa intake during movement suppression. Individual dyskinesia severity was predicted by levodopa-induced modulation of striato-cortical feedback connections from putamen to the pre-supplementary motor area (Pcorrected = 0.020) and primary motor cortex (Pcorrected = 0.044), but not feed-forward connections from the cortex to the putamen. Our results identify for the first time, aberrant dopaminergic modulation of striatal-cortical connectivity as a neural signature of levodopa-induced dyskinesias in humans. We argue that excessive striato-cortical connectivity in response to levodopa produces an aberrant reinforcement signal producing an abnormal motor drive that ultimately triggers involuntary movements.

Changes in total cell numbers of the basal ganglia in patients with multiple system atrophy - A stereological study.

Total numbers of neurons, oligodendrocytes, astrocytes, and microglia in the basal ganglia and red nucleus were estimated in brains from 11 patients with multiple system atrophy (MSA) and 11 age- and gender-matched control subjects with unbiased stereological methods. Compared to the control subjects, the MSA patients had a substantially lower number of neurons in the substantia nigra (p=0.001), putamen (p=0.001), and globus pallidus (p<0.001), and, to a lesser extent in the caudate nucleus (p=0.03). A significantly lower number of oligodendrocytes were only observed in the putamen (p=0.04) and globus pallidus (p=0.01). In the MSA brains the total number of astrocytes was significantly higher in the putamen (p=0.04) and caudate nucleus (p=0.01). In all examined regions a higher number of microglia were found in the MSA brains with the greatest difference observed in the otherwise unaffected red nucleus (p=0.001). The results from the stereological study were supported by cell marker expression analyses showing increased markers for activated microglia. Our results suggest that microgliosis is a consistent and severe neuropathological feature of MSA, whereas no widespread and substantial loss of oligodendrocytes was observed. We have demonstrated significant neuronal loss in the substantia nigra, striatum, and globus pallidus of patients with MSA, while neurons in other basal ganglia nuclei were spared, supporting the region-specific patterns of neuropathological changes in MSA.

The acute brain response to levodopa heralds dyskinesias in Parkinson disease.

OBJECTIVE: In Parkinson disease (PD), long-term treatment with the dopamine precursor levodopa gradually induces involuntary "dyskinesia" movements. The neural mechanisms underlying the emergence of levodopa-induced dyskinesias in vivo are still poorly understood. Here, we applied functional magnetic resonance imaging (fMRI) to map the emergence of peak-of-dose dyskinesias in patients with PD. METHODS: Thirteen PD patients with dyskinesias and 13 PD patients without dyskinesias received 200mg fast-acting oral levodopa following prolonged withdrawal from their normal dopaminergic medication. Immediately before and after levodopa intake, we performed fMRI, while patients produced a mouse click with the right or left hand or no action (No-Go) contingent on 3 arbitrary cues. The scan was continued for 45 minutes after levodopa intake or until dyskinesias emerged. RESULTS: During No-Go trials, PD patients who would later develop dyskinesias showed an abnormal gradual increase of activity in the presupplementary motor area (preSMA) and the bilateral putamen. This hyperactivity emerged during the first 20 minutes after levodopa intake. At the individual level, the excessive No-Go activity in the predyskinesia period predicted whether an individual patient would subsequently develop dyskinesias (p < 0.001) as well as severity of their day-to-day symptomatic dyskinesias (p < 0.001). INTERPRETATION: PD patients with dyskinesias display an immediate hypersensitivity of preSMA and putamen to levodopa, which heralds the failure of neural networks to suppress involuntary dyskinetic movements.

Functional neuroimaging of motor control in Parkinson's disease: a meta-analysis.

Functional neuroimaging has been widely used to study the activation patterns of the motor network in patients with Parkinson's disease (PD), but these studies have yielded conflicting results. This meta-analysis of previous neuroimaging studies was performed to identify patterns of abnormal movement-related activation in PD that were consistent across studies. We applied activation likelihood estimation (ALE) of functional neuroimaging studies probing motor function in patients with PD. The meta-analysis encompassed data from 283 patients with PD reported in 24 functional neuroimaging studies and yielded consistent alterations in neural activity in patients with PD. Differences in cortical activation between PD patients and healthy controls converged in a left-lateralized fronto-parietal network comprising the presupplementary motor area, primary motor cortex, inferior parietal cortex, and superior parietal lobule. Both, increases as well as decreases in motor cortical activity, which were related to differences in movement timing and selection in the applied motor tasks, were reported in these cortical areas. In the basal ganglia, PD patients expressed a decrease of motor activation in the posterior motor putamen, which improved with dopaminergic medication. The likelihood of detecting a decrease in putaminal activity increased with motor impairment. This reduced motor activation of the posterior putamen across previous neuroimaging studies indicates that nigrostriatal dopaminergic denervation affects neural processing in the denervated striatal motor territory. In contrast, fronto-parietal motor areas display both increases as well as decreases in movement related activation. This points to a more complex relationship between altered cortical physiology and nigrostriatal dopaminergic denervation in PD.

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.

Improved clinical status, quality of life, and walking capacity in Parkinson's disease after body weight-supported high-intensity locomotor training.

OBJECTIVE: To evaluate the effect of body weight-supported progressive high-intensity locomotor training in Parkinson's disease (PD) on (1) clinical status; (2) quality of life; and (3) gait capacity. DESIGN: Open-label, fixed sequence crossover study. SETTING: University motor control laboratory. PARTICIPANTS: Patients (N=13) with idiopathic PD (Hoehn and Yahr stage 2 or 3) and stable medication use. INTERVENTIONS: Patients completed an 8-week (3 × 1h/wk) training program on a lower-body positive-pressure treadmill. Body weight support was used to facilitate increased intensity and motor challenges during treadmill training. The training program contained combinations of (1) running and walking intervals, (2) the use of sudden changes (eg, in body weight support and speed), (3) different types of locomotion (eg, chassé, skipping, and jumps), and (4) sprints at 50 percent body weight. MAIN OUTCOME MEASURES: The Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Parkinson's Disease Questionnaire-39 items (PDQ-39), and the six-minute walk test were conducted 8 weeks before and pre- and posttraining. RESULTS: At the end of training, statistically significant improvements were found in all outcome measures compared with the control period. Total MDS-UPDRS score changed from (mean ± 1SD) 58±18 to 47±18, MDS-UPDRS motor part score changed from 35±10 to 29±12, PDQ-39 summary index score changed from 22±13 to 13±12, and the six-minute walking distance changed from 576±93 to 637±90m. CONCLUSIONS: Body weight-supported progressive high-intensity locomotor training is feasible and well tolerated by patients with PD. The training improved clinical status, quality of life, and gait capacity significantly.

Severe and rapidly progressing cognitive phenotype in a SCA17-family with only marginally expanded CAG/CAA repeats in the TATA-box binding protein gene: a case report.

BACKGROUND: The autosomal dominant spinocerebellar ataxias (SCAs) confine a group of rare and heterogeneous disorders, which present with progressive ataxia and numerous other features e.g. peripheral neuropathy, macular degeneration and cognitive impairment, and a subset of these disorders is caused by CAG-repeat expansions in their respective genes. The diagnosing of the SCAs is often difficult due to the phenotypic overlap among several of the subtypes and with other neurodegenerative disorders e.g. Huntington's disease. CASE PRESENTATION: We report a family in which the proband had rapidly progressing cognitive decline and only subtle cerebellar symptoms from age 42. Sequencing of the TATA-box binding protein gene revealed a modest elongation of the CAG/CAA-repeat of only two repeats above the non-pathogenic threshold of 41, confirming a diagnosis of SCA17. Normally, repeats within this range show reduced penetrance and result in a milder disease course with slower progression and later age of onset. Thus, this case presented with an unusual phenotype. CONCLUSIONS: The current case highlights the diagnostic challenge of neurodegenerative disorders and the need for a thorough clinical and paraclinical examination of patients presenting with rapid cognitive decline to make a precise diagnosis on which further genetic counseling and initiation of treatment modalities can be based.

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.

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.

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.

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.

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.