Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders.

OBJECTIVE: The aim of this study was to establish the frequency of ATXN2 polyglutamine (polyQ) expansion in large cohorts of patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), and to evaluate whether ATXN2 could act as a modifier gene in patients carrying the C9orf72 expansion. METHODS: We screened a large cohort of French patients (1,144 ALS, 203 FTD, 168 FTD-ALS, and 109 PSP) for ATXN2 CAG repeat length. We included in our cohort 322 carriers of the C9orf72 expansion (202 ALS, 63 FTD, and 57 FTD-ALS). RESULTS: We found a significant association with intermediate repeat size (≥29 CAG) in patients with ALS (both familial and sporadic) and, for the first time, in patients with familial FTD-ALS. Of interest, we found the co-occurrence of pathogenic C9orf72 expansion in 23.2% of ATXN2 intermediate-repeat carriers, all in the FTD-ALS and familial ALS subgroups. In the cohort of C9orf72 carriers, 3.1% of patients also carried an intermediate ATXN2 repeat length. ATXN2 repeat lengths in patients with PSP and FTD were found to be similar to the controls. CONCLUSIONS: ATXN2 intermediary repeat length is a strong risk factor for ALS and FTD-ALS. Furthermore, we propose that ATXN2 polyQ expansions could act as a strong modifier of the FTD phenotype in the presence of a C9orf72 repeat expansion, leading to the development of clinical signs featuring both FTD and ALS.

Optimal target localization for subthalamic stimulation in patients with Parkinson disease.

OBJECTIVE: To further determine the causes of variable outcome from deep brain stimulation of the subthalamic nucleus (DBS-STN) in patients with Parkinson disease (PD). METHODS: Data were obtained from our cohort of 309 patients with PD who underwent DBS-STN between 1996 and 2009. We examined the relationship between the 1-year motor, cognitive, and psychiatric outcomes and (1) preoperative PD clinical features, (2) MRI measures, (3) surgical procedure, and (4) locations of therapeutic contacts. RESULTS: Pre- and postoperative results were obtained in 262 patients with PD. The best motor outcome was obtained when stimulating contacts were located within the STN as compared with the zona incerta (64% vs 49% improvement). Eighteen percent of the patients presented a postoperative cognitive decline, which was found to be principally related to the surgical procedure. Other factors predictive of poor cognitive outcome were perioperative confusion and psychosis. Nineteen patients showed a stimulation-induced hypomania, which was related to both the form of the disease (younger age, shorter disease duration, higher levodopa responsiveness) and the ventral contact location. Postoperative depression was more frequent in patients already showing preoperative depressive and/or residual axial motor symptoms. CONCLUSION: In this homogeneous cohort of patients with PD, we showed that (1) the STN is the best target to improve motor symptoms, (2) postoperative cognitive deficit is mainly related to the surgery itself, and (3) stimulation-induced hypomania is related to a combination of both the disease characteristics and a more ventral STN location.

Working memory in Parkinson's disease patients: clinical features and response to levodopa / Memória de trabalho em pacientes com doença de Parkinson: características clínicas e resposta a levodopa

OBJECTIVE: To evaluate the clinical features of the working memory (WM) in Parkinson's disease (PD) patients and to test the effect of levodopa on WM. METHOD: The paradigm was based on the 'n-back' tasks, which enables to study the level of executive demand (three levels of difficulty) and the domain of the information being processed (spatial items, faces and letters). The effect of levodopa was studied by testing PD patients in "on" and "off" states. RESULTS: PD patients performed less well in WM tasks than controls. There was no interaction between groups and complexity. Levodopa therapy had a positive effect only on spatial WM tasks but no effect on complexity. CONCLUSION: Our results suggest that impairment observed may result from a maintenance deficit within WM regardless the level of processing and levodopa therapy presents a positive effect on spatial WM.

OBJETIVO: Avaliar as características clínicas da memória de trabalho (MT) em pacientes com doença de Parkinson (DP) e testar o efeito da levodopa na MT. MÉTODO: O paradigma baseou-se nas tarefas 'n-back', que permitem avaliar o nível de demanda executiva (três níveis de dificuldade) e o domínio da informação sendo processado (posições espaciais, faces e letras). O efeito da levodopa foi estudado pela testagem dos pacientes no estado "on" e "off". RESULTADOS: Pacientes com DP apresentam desempenho inferior ao dos controles em tarefas de MT. Não foi observada interação entre grupos e complexidade. A terapia com levodopa mostrou efeito positivo sobre a modalidade espacial, e nenhum efeito sobre a complexidade. CONCLUSÃO: Nossos resultados sugerem que o comprometimento observado pode resultar de défict de manutenção da MT, independente do nível de processamento. A terapia com levodopa apresenta efeito positivo sobre a MT espacial.

Mortality in patients with Parkinson's disease treated by stimulation of the subthalamic nucleus.

Subthalamic nucleus (STN) stimulation improves motor disability and quality of life in patients with advanced Parkinson's disease (PD). Short-term mortality is low, but little is known about long-term mortality. We assessed mortality and causes of death in 171 consecutive PD patients treated by STN stimulation. Surgery was performed after a median lagtime of 13 years from PD onset at a median age of 57 years. The median follow-up after surgery was 41 months. Sixteen patients died 8 to 83 months after neurosurgery. Poorer cognitive function was the only predictive factor for mortality (standardized mortality ratio = 2.9; 95% confidence interval [CI], 1.6-4.7; P < 0.0001). Based on a historical comparison of 118 operated patients with 39 nonoperated patients from a different population, survival among operated patients was not better (hazard ratio = 1.2; 95% CI, 0.7-2.1).

Subthalamic stimulation in Parkinson disease: with or without anesthesia?

OBJECTIVE: To study the effects of general anesthesia on the postoperative outcome of patients with Parkinson disease (PD) who underwent surgery using bilateral placement of stimulating electrodes within the subthalamic nucleus (STN). DESIGN: Retrospective analysis. SETTING: Hôpital de la Salpêtrière, Paris, France. PATIENTS: Fifteen PD patients who underwent bilateral implantation of electrodes within the STN received general anesthesia because of severe anxiety, poorly tolerated off-period dystonia, or respiratory difficulties. These patients were compared with 15 patients matched for age, disease duration, and parkinsonian motor disability who underwent the same neurosurgical procedure under local anesthesia. MAIN OUTCOME MEASURE: Motor disability scores. RESULTS: After surgery, the severity of parkinsonian motor disability was markedly improved in both groups of patients. Compared with patients who were under local anesthesia during the operation, the residual parkinsonian motor score under stimulation (with ["on"] or without ["off"] levodopa) and the intensity of stimulation were higher in patients who were under general anesthesia during the operation. CONCLUSIONS: Although the improvement of parkinsonian motor disability is greater in PD patients who receive local anesthesia during surgery, general anesthesia can be performed in patients unable to tolerate prolonged states without levodopa.

Parkinson's disease, subthalamic stimulation, and selection of candidates: a pathological study.

We report on a patient with Parkinson's disease (PD) who was moderately improved by stimulation of the subthalamic nucleus (STN) and died 2 years after electrode implantation. After neurosurgery, symptoms that had responded to levodopa treatment preoperatively continued to improve. Postural instability, dysarthria, and cognitive impairment continued to worsen, despite STN stimulation and levodopa treatment. Postmortem examination of the brain confirmed the diagnosis of PD and showed that the electrodes had been correctly positioned within the STN. The failure of STN stimulation in this patient confirms the importance of screening and excluding patients from surgery with evolving parkinsonian axial symptoms or cognitive impairment.

Subthalamic stimulation in Parkinson disease: intraoperative predictive factors.

BACKGROUND: High-frequency stimulation of the subthalamic nucleus (STN) is an effective treatment for advanced forms of Parkinson disease. Postoperative improvement of motor parkinsonian disability is known to depend on patient selection and surgical targeting. OBJECTIVE: To determine which clinical and electrophysiological variables evaluated during the operation predict the postoperative clinical outcome of patients with Parkinson disease treated by bilateral high-frequency stimulation of the STN. METHODS: Intraoperative clinical and electrophysiological data obtained in 41 patients with Parkinson disease who underwent bilateral implantation of electrodes for STN stimulation were correlated with the improvement in parkinsonian disability assessed 6 months after the operation. RESULTS: The extent of STN neuronal activity recorded along the trajectory of the therapeutic electrode had no effect on the postoperative clinical outcome. The intraoperative improvement in segmental akinesia, but not rigidity, was predictive of the postoperative improvement in parkinsonian motor disability and reduction in daily levodopa-equivalent dosage. Parkinsonian motor disability scores assessed after surgery were lower in patients with intraoperative stimulation-induced dyskinesias than in those without stimulation-induced dyskinesias. CONCLUSION: The improvement of segmental akinesia and the observation of dyskinesias provoked by stimulation during the operation predict the best postoperative effects of bilateral STN stimulation on parkinsonian motor disability.

Association study between iron-related genes polymorphisms and Parkinson's disease.

We have conducted a case-control study in order to test for an association between 8 intragenic polymorphisms of 5 iron-related genes (transferrin, transferrin receptor1, HFE, frataxin and lactoferrin) and Parkinson disease. Comparison of genotypes and allele frequencies did not differ significantly between cases and controls for all studied polymorphisms except the G258S transferrin polymorphism, for which a higher frequency of the G allele was found among cases (p=0.033), particularly among cases with onset older than 60 (p=0.0017) and with negative family history (p=0.022). This finding suggests that genetic variations in the control of iron metabolism may contribute to the pathogenesis of the disease.