Toxina botulínica: un nou tractament per a les distonies focals i l'espasme hemifacial.

La teràpia amb toxina botulínica (TB), fàrmac a hores d'ara encara experimental, ha suposat per a milers de persones afectes de síndrome distònica una finestra oberta a l'esperança. Des que el Dr. Alan Scott la va usar per primer cop per tractar l'estrabisme s'ha aplicat, la majoria de les vegades amb èxit, en les distonies focals i multifocals. La TB actua bloquejant a nivell pre-sinàptic l'alliberament de l'acetilcolina a la placa motora, causant una parèsia transitòria de la musculatura on s'injecta. Actualment es coneixen cinc tipus diferents de toxina, essent la de tipus A la que s'empra per al tractament de l'estrabisme i les distonies focals..

A loud auditory stimulus overcomes voluntary movement limitation in cervical dystonia

Background Patients with cervical dystonia (CD) present with an impaired performance of voluntary neck movements, which are usually slow and limited. We hypothesized that such abnormality could involve defective preparation for task execution. Therefore, we examined motor preparation in CD patients using the StartReact method. In this test, a startling auditory stimulus (SAS) is delivered unexpectedly at the time of the imperative signal (IS) in a reaction time task to cause a faster execution of the prepared motor programme. We expected that CD patients would show an abnormal StartReact phenomenon. Methods Fifteen CD patients and 15 age matched control subjects (CS) were asked to perform a rotational movement (RM) to either side as quick as possible immediately after IS perception (a low intensity electrical stimulus to the II finger). In randomly interspersed test trials (25%) a 130 dB SAS was delivered simultaneously with the IS. We recorded RMs in the horizontal plane with a high speed video camera (2.38 ms per frame) in synchronization with the IS. The RM kinematic-parameters (latency, velocity, duration and amplitude) were analyzed using video-editing software and screen protractor. Patients were asked to rate the difficulty of their RMs in a numerical rating scale. Results In control trials, CD patients executed slower RMs (repeated measures ANOVA, p<0.10−5), and reached a smaller final head position angle relative to the midline (p<0.05), than CS. In test trials, SAS improved all RMs in both groups (p<0.10−14). In addition, patients were more likely to reach beyond their baseline RM than CS (χ2, p<0.001) and rated their performance better than in control trials (t-test, p<0.01). Conclusion We found improvement of kinematic parameters and subjective perception of motor performance in CD patients with StartReact testing. Our results suggest that CD patients reach an adequate level of motor preparation before task execution

Functional brain networks and cognitive deficits in Parkinson's disease

Abstract: Graph-theoretical analyses of functional networks obtained with resting-state functional mag-netic resonance imaging (fMRI) have recently proven to be a useful approach for the study of the sub-strates underlying cognitive deficits in different diseases. We used this technique to investigate whethercognitive deficits in Parkinson's disease (PD) are associated with changes in global and local networkmeasures. Thirty-six healthy controls (HC) and 66 PD patients matched for age, sex, and education wereclassified as having mild cognitive impairment (MCI) or not based on performance in the three mainlyaffected cognitive domains in PD: attention/executive, visuospatial/visuoperceptual (VS/VP), anddeclarative memory. Resting-state fMRI and graph theory analyses were used to evaluate network meas-ures. We have found that patients with MCI had connectivity reductions predominantly affecting long-range connections as well as increased local interconnectedness manifested as higher measures of cluster-ing, small-worldness, and modularity. The latter measures also tended to correlate negatively with cogni-tive performance in VS/VP and memory functions. Hub structure was also reorganized: normal hubsdisplayed reduced centrality and degree in MCI PD patients. Our study indicates that the topologicalproperties of brain networks are changed in PD patients with cognitive deficits. Our findings providenovel data regarding the functional substrate of cognitive impairment in PD, which may prove to havevalue as a prognostic marker

Discriminating cognitive status in Parkinson's disease through functional connectomics and machine learning

There is growing interest in the potential of neuroimaging to help develop non-invasive biomarkers in neurodegenerative diseases. In this study, connection-wise patterns of functional connectivity were used to distinguish Parkinson's disease patients according to cognitive status using machine learning. Two independent subject samples were assessed with resting-state fMRI. The first (training) sample comprised 38 healthy controls and 70 Parkinson's disease patients (27 with mild cognitive impairment). The second (validation) sample included 25 patients (8 with mild cognitive impairment). The Brainnetome atlas was used to reconstruct the functional connectomes. Using a support vector machine trained on features selected through randomized logistic regression with leave-one-out cross-validation, a mean accuracy of 82.6% (p < 0.002) was achieved in separating patients with mild cognitive impairment from those without it in the training sample. The model trained on the whole training sample achieved an accuracy of 80.0% when used to classify the validation sample (p = 0.006). Correlation analyses showed that the connectivity level in the edges most consistently selected as features was associated with memory and executive function performance in the patient group. Our results demonstrate that connection-wise patterns of functional connectivity may be useful for discriminating Parkinson's disease patients according to the presence of cognitive deficits

Structural correlates of facial emotion recognition deficits in Parkinson's disease patients

The ability to recognize facial emotion expressions, especially negative ones, is described to be impaired in Parkinson's disease (PD) patients. Previous neuroimaging work evaluating the neural substrate of facial emotion recognition (FER) in healthy and pathological subjects has mostly focused on functional changes. This study was designed to evaluate gray matter (GM) and white matter (WM) correlates of FER in a large sample of PD. Thirty-nine PD patients and 23 healthy controls (HC) were tested with the Ekman 60 test for FER and with magnetic resonance imaging. Effects of associated depressive symptoms were taken into account. In accordance with previous studies, PD patients performed significantly worse in recognizing sadness, anger and disgust. In PD patients, voxel-based morphometry analysis revealed areas of positive correlation between individual emotion recognition and GM volume: in the right orbitofrontal cortex, amygdala and postcentral gyrus and sadness identification; in the right occipital fusiform gyrus, ventral striatum and subgenual cortex and anger identification, and in the anterior cingulate cortex (ACC) and disgust identification. WM analysis through diffusion tensor imaging revealed significant positive correlations between fractional anisotropy levels in the frontal portion of the right inferior fronto-occipital fasciculus and the performance in the identification of sadness. These findings shed light on the structural neural bases of the deficits presented by PD patients in this skill

Resting-state frontostriatal functional connectivity in Parkinson's disease-related apathy

Background: One of the most common neuropsychiatric symptoms in PD is apathy, affecting between 23 and 70% of patients and thought to be related to frontostriatal dopamine deficits. In the present study, we assessed functional resting-state frontostriatal connectivity and structural changes associated with the presence of apathy in a large sample of PD subjects and healthy controls, while controlling for the presence of comorbid depression and cognitive decline. Methods: Thirty-one healthy controls (HC) and 62 age, sex and education-matched PD patients underwent resting-state functional MRI. Apathy symptoms were evaluated with the Apathy Scale (AS). The 11 Beck Depression Inventory-II items that measure dysphoric mood symptoms as well as relevant neuropsychological scores were used as nuisance factors in connectivity analyses. Voxel-wise analyses of functional connectivity between frontal lobes (limbic, executive, rostral motor and caudal motor regions), striata (limbic, executive, sensorimotor regions) and thalami were performed. Subcortical volumetry/shape analysis and fronto-subcortical voxel-based morphometry were performed to assess structural changes. Results: Twenty-five PD patients were classified as apathetic (PD-A) (AS>13). PD-A patients showed functional connectivity reductions compared with HC and with non-apathetic patients (PD-NA), mainly in left-sided circuits, and predominantly involving limbic striatal and frontal territories. Similarly, severity of apathy negatively correlated with connectivity in these circuits. No significant effects were found in structural analyses. Conclusions: Our results indicate that the presence of apathy in PD is associated with functional connectivity reductions in frontostriatal circuits, predominating in the left hemisphere and mainly involving its limbic components

α-synuclein RT-QuIC in cerebrospinal fluid of LRRK2 linked Parkinson’s disease

Background: leucine-rich kinase 2 (LRRK2)-linked Parkinson's disease (PD) is clinically indistinguishable from idiopathic PD (IPD). A pleiotropic neuropathology has been recognized but the majority of studies in LRRK2 p.G2019S patients reveal Lewy-type synucleinopathy as its principal histological substrate. To date no in vivo biomarkers of synucleinopathy have been found in LRRK2 mutation carriers. Objectives: we used real-time quaking-induced conversion (RT-QuIC) technique to assess the presence of alpha-synuclein (a-syn) aggregates in cerebrospinal fluid (CSF) of LRRK2 p.G2019S carriers. Methods: CSF samples of 51 subjects were analyzed: 15 LRRK2 p.G2019S PD, 10 IPD, 16 LRRK2 p.G2019S nonmanifesting carriers (NMC) and 10 healthy controls. The presence of parkinsonism and prodromal symptoms was assessed in all study subjects. Results: forty percent (n = 6) LRRK2-PD, and 18.8% (n = 3) LRRK2-NMC had a positive a-syn RT-QuIC response. RT-QuIC detected IPD with 90% sensitivity and 80% specificity. No clinical differences were detected between LRRK2-PD patients with positive and negative RT-QuIC. A positive RT-QuIC result in LRRK2-NMC occurred in a higher proportion of subjects meeting the Movement Disorder Society research criteria for prodromal PD. Interpretation: RT-QuIC detects a-syn aggregation in CSF in a significant number of patients with LRRK2-PD, but less frequently than in IPD. A small percentage of LRRK2-NMC tested also positive. If appropriately validated in long-term studies with large number of mutation carriers, and hopefully, postmortem or in vivo confirmation of histopathology, RT-QuIC could contribute to the selection of candidates to receive disease modifying drugs, in particular treatments targeting a-syn deposition

Cognitive impairment and resting-state network connectivity in Parkinson's disease

Previous functional MRI studies have revealed changes in the default-mode network (DMN) in Parkinson's disease (PD). The purpose of this work was to evaluate changes in the connectivity patterns of a set of cognitively relevant, dynamically interrelated brain networks in association with cognitive deficits in PD using resting-state functional MRI. Sixty-five non-demented PD patients and 36 matched healthy controls (HC) were included. Thirty-four percent of PD patients were classified as having mild cognitive impairment (MCI) based on performance in the three mainly-affected cognitive domains in Parkinson's disease (attention/executive, visuospatial/visuoperceptual and declarative memory). Data-driven analyses through independent-component analysis (ICA) was used to identify the DMN, the dorsal attention network (DAN) and the bilateral frontoparietal networks (FPN), which were compared between groups using a dual-regression approach. Additional seed-based analyses using a-priori defined regions of interest were used to characterize local changes in intra and inter-network connectivity. ICA results revealed reduced connectivity between the DAN and right frontoinsular cortical regions in MCI patients, which correlated with worse performance in attention/executive functions. The DMN, on the other hand, displayed increased connectivity with medial and lateral occipito-parietal regions in MCI patients; these increases correlated with worse visuospatial/visuoperceptual performance. In line with data-driven results, seed-based analyses mainly revealed reduced within-DAN, within-DMN and DAN-FPN connectivity, as well as increased DAN-DMN coupling in MCI patients. Our findings demonstrate differential connectivity changes affecting the networks evaluated, which we hypothesize to be related to the pathophysiological bases of different types of cognitive impairment in PD

Progression of cortical thinning in early Parkinson's disease

The aim of this study was to investigate the progression of cortical thinning and gray-matter (GM) volume loss in early Parkinson's disease (PD). MRI and neuropsychological assessment were obtained at baseline and follow-up (mean ± standard deviation = 35.50 ± 1.88 months) in a group of 16 early-PD patients (H & Y stage ≤II and disease duration ≤5 years) and 15 healthy controls matched for age, gender, and years of education. FreeSurfer software was used for the analysis of cortical thickness as well as for cortical and subcortical volumetric analyses. Voxel-based morphometry analysis was performed using SPM8. Compared to controls, PD patients showed greater regional cortical thinning in bilateral frontotemporal regions as well as greater over-time total GM loss and amygdalar volume reduction. PD patients and controls presented similar over-time changes in cognitive functioning. In early-PD patients, global GM loss, amygdalar atrophy, and cortical thinning in frontotemporal regions are specifically associated with the PD-degenerative process

Patterns of cortical thinning in nondemented Parkinson's disease patients

Background: Clinical variability in the Parkinson's disease phenotype suggests the existence of disease subtypes. We investigated whether distinct anatomical patterns of atrophy can be identified in Parkinson's disease using a hypothesis-free, datadriven approach based on cortical thickness data. Methods: T1-weighted 3-tesla MRI and a comprehensive neuropsychological assessment were performed in a sample of 88 nondemented Parkinson's disease patients and 31 healthy controls. We performed a hierarchical cluster analysis of imaging data using Ward's linkage method. A general linear model with cortical thickness data was used to compare clustering groups. Results: We observed 3 patterns of cortical thinning in patients when compared with healthy controls. Pattern 1 (n530, 34.09%) consisted of cortical atrophy in bilateral precentral gyrus, inferior and superior parietal lobules, cuneus, posterior cingulate, and parahippocampal gyrus. These patients showed worse cognitive performance when compared with controls and the other 2 patterns. Pattern 2 (n529, 32.95%) consisted of cortical atrophy involving occipital and frontal as well as superior parietal areas and included patients with younger age at onset. Finally, in pattern 3 (n529, 32.95%), there was no detectable cortical thinning. Patients in the 3 patterns did not differ in disease duration, motor severity, dopaminergic medication doses, or presence of mild cognitive impairment. Conclusions: Three cortical atrophy subtypes were identified in nondemented Parkinson's disease patients: (1) parieto-temporal pattern of atrophy with worse cognitive performance, (2) occipital and frontal cortical atrophy and younger disease onset, and (3) patients without detectable cortical atrophy. These findings may help identify prognosis markers in Parkinson's disease. VC 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Societ