RESUMO
INTRODUCTION: Gait disorders and falls occur early in progressive supranuclear palsy (PSP-RS) and Caribbean atypical parkinsonism (Caribbean AP). However, the link between these signs and brain lesions has never been explored in these patient populations. Here, we investigate and compare the imaging factors that relate to gait and balance disorders in Caribbean AP and PSP-RS patients. METHODS: We assessed gait and balance using clinical scales and gait recordings in 16 Caribbean AP and 15 PSP-RS patients and 17 age-matched controls. We measured the grey and white matter brain volumes on 3 T brain MRI images. We performed a principal component analysis (PCA) including all the data to determine differences and similarities between groups, and explore the relationship between gait disorders and brain volumes. RESULTS: Both Caribbean AP patients and PSP-RS have marked gait and balance disorders with similar severity. In both groups, gait and balance disorders were found to be most strongly related to structural changes in the lateral cerebellum, caudate nucleus, and fronto-parietal areas. In Caribbean AP patients, gait disorders were also related to additional changes in the cortex, including frontal, insular, temporal and cuneus lobes, whereas in PSP-RS patients, additional white matter changes involved the mesencephalon and parahippocampal gyrus. CONCLUSION: Gait and balance disorders in Caribbean AP patients are mainly related to dysfunction of cortical brain areas involved in visuo-sensorimotor processing and self-awareness, whereas these signs mainly result from premotor-brainstem-cerebellar network dysfunction in PSP-RS patients, brain areas involved in initiation and maintenance of locomotor pattern and postural adaptation.
Assuntos
Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Humanos , Paralisia Supranuclear Progressiva/patologia , Transtornos Parkinsonianos/diagnóstico por imagem , Encéfalo , Região do Caribe , MarchaRESUMO
Freezing of gait is a challenging sign of Parkinson's disease associated with disease severity and progression and involving the mesencephalic locomotor region. No predictive factor of freezing has been reported so far. The primary objective of this study was to identify predictors of freezing occurrence at 5 years. In addition, we tested whether functional connectivity of the mesencephalic locomotor region could explain the oculomotor factors at baseline that were predictive of freezing onset. We performed a prospective study investigating markers (parkinsonian signs, cognitive status and oculomotor recordings, with a particular focus on the antisaccade latencies) of disease progression at baseline and at 5 years. We identified two groups of patients defined by the onset of freezing at 5 years of follow-up; the 'Freezer' group was defined by the onset of freezing in the ON medication condition during follow-up (n = 17), while the 'non-Freezer' group did not (n = 8). Whole brain resting-state functional MRI was recorded at baseline to determine how antisaccade latencies were associated with connectivity of the mesencephalic locomotor region networks in patients compared to 25 age-matched healthy volunteers. Results showed that, at baseline and compared to the non-Freezer group, the Freezer group had equivalent motor or cognitive signs, but increased antisaccade latencies (P = 0.008). The 5-year course of freezing of gait was correlated with worsening antisaccade latencies (P = 0.0007). Baseline antisaccade latencies was also predictive of the freezing onset (χ2 = 0.008). Resting state connectivity of mesencephalic locomotor region networks correlated with (i) antisaccade latency differently in patients and healthy volunteers at baseline; and (ii) the further increase of antisaccade latency at 5 years. We concluded that antisaccade latency is a predictive marker of the 5-year onset of freezing of gait. Our study suggests that functional networks associated with gait and gaze control are concurrently altered during the course of the disease.
Assuntos
Encéfalo/fisiopatologia , Transtornos Neurológicos da Marcha/diagnóstico , Transtornos Neurológicos da Marcha/fisiopatologia , Doença de Parkinson/complicações , Movimentos Sacádicos , Idoso , Biomarcadores , Mapeamento Encefálico , Tecnologia de Rastreamento Ocular , Feminino , Transtornos Neurológicos da Marcha/complicações , Humanos , Imageamento por Ressonância Magnética , Masculino , Mesencéfalo/fisiopatologia , Pessoa de Meia-Idade , Vias Neurais/fisiopatologia , Doença de Parkinson/fisiopatologia , Sensibilidade e EspecificidadeAssuntos
Estimulação Encefálica Profunda , Distúrbios Distônicos , Torcicolo , Marcha , Globo Pálido , HumanosRESUMO
BACKGROUND: Good short-term results of pallidal deep brain stimulation have been reported in myoclonus-dystonia. Efficacy and safety in the long term remain to be established. In addition, the actual impact of DBS treatment on social inclusion is unknown. The objective of this study was to assess the long-term clinical outcome, quality of life, and social adjustment of GPi-DBS in patients with ε-sarcoglycan (DYT11)-positive myoclonus-dystonia. METHODS: Consecutive myoclonus-dystonia patients with ε-sarcoglycan mutations who underwent GPi-DBS were evaluated at least 5 years postoperatively. Motor symptoms were assessed using the Burke-Fahn-Marsden Dystonia Rating Scale including the Disability Scale, a composite score combining the rest and action parts of the Unified Myoclonus Rating Scale and modified Abnormal Involuntary Movement Scale. Standardized video-protocols were assessed by a blinded and external movement disorder specialist. Social adjustment, cognition, and mood were evaluated. RESULTS: Nine patients (5 women) with long-term GPi-DBS (8.7 ± 3.1 years) were included. There was significant improvement in the composite myoclonus score (94.1% ± 4% improvement; P = 0.008). Dystonia severity was also markedly improved (71.4% ± 28.33% improvement; P = 0.008) as well as motor disability (88.3% ± 20% improvement; P = 0.008) and abnormal involuntary movement score (71.1% ± 15.0% improvement; P = 0.008). No patients experienced postoperative speech or gait problems or any permanent adverse effects. Eight of the 9 patients had fully enhanced social adjustment and personal achievement, with little or no mood or behavioral disorders. CONCLUSIONS: GPi-DBS seems to be a safe and efficacious treatment for medically refractory É-sarcoglycan myoclonus-dystonia, with sustained motor benefit, good quality of life, and social adjustment in long-term follow-up. © 2018 International Parkinson and Movement Disorder Society.
Assuntos
Estimulação Encefálica Profunda , Distúrbios Distônicos/terapia , Transtornos Motores/terapia , Ajustamento Social , Adolescente , Adulto , Idoso , Estimulação Encefálica Profunda/métodos , Pessoas com Deficiência/psicologia , Distúrbios Distônicos/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Motores/psicologia , Tempo , Resultado do Tratamento , Adulto JovemRESUMO
In a rapidly changing environment, we often know when to do something before we have to do it. This preparation in the temporal domain is based on a 'perception' of elapsed time and short-term memory of previous stimulation in a similar context. These functions could be perturbed in Parkinson's disease. Therefore, we investigated their role in eye movement preparation in sporadic Parkinson's disease and in a very infrequent variant affecting the Parkin gene. We used a simple oculomotor task where subjects had to orient to a visual target and movement latency was measured. We found that in spite of an increased average reaction time, the influence of elapsed time on movement preparation was similar in controls and the two groups of PD patients. However, short-term temporal memory of previous stimulation was severely affected in sporadic PD patients either ON or OFF dopaminergic therapy. We conclude that the two different contributions to temporal preparation could be dissociated. Moreover, a short-term temporal memory deficit might underlie temporal cognition deficits previously observed in PD.
Assuntos
Disfunção Cognitiva/etiologia , Movimentos Oculares/fisiologia , Transtornos da Memória/etiologia , Memória de Curto Prazo , Mutação , Doença de Parkinson/complicações , Ubiquitina-Proteína Ligases/genética , Adulto , Estudos de Casos e Controles , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Feminino , Humanos , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/genética , Doença de Parkinson/fisiopatologia , Tempo de ReaçãoRESUMO
BACKGROUND: Based on the hypothesis of a brain energy deficit, we investigated the safety and efficacy of triheptanoin on paroxysmal episodes in patients with alternating hemiplegia of childhood due to ATP1A3 mutations. METHODS: We conducted a randomized, double-blind, placebo-controlled crossover study of triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Each treatment period consisted of a 12-week fixed-dose phase, separated by a 4-week washout period. The primary outcome was the total number of paroxysmal events. Secondary outcomes included the number of paroxysmal motor-epileptic events; a composite score taking into account the number, severity and duration of paroxysmal events; interictal neurological manifestations; the clinical global impression-improvement scale (CGI-I); and safety parameters. The paired non-parametric Wilcoxon test was used to analyze treatment effects. RESULTS: In an intention-to-treat analysis, triheptanoin failed to reduce the total number of paroxysmal events (p = 0.646), including motor-epileptic events (p = 0.585), or the composite score (p = 0.059). CGI-I score did not differ between triheptanoin and placebo periods. Triheptanoin was well tolerated. CONCLUSIONS: Triheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting. TRIAL REGISTRATION: The study has been registered with clinicaltrials.gov ( NCT002408354 ) the 03/24/2015.
Assuntos
Hemiplegia/tratamento farmacológico , Triglicerídeos/uso terapêutico , Adolescente , Estudos Cross-Over , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Humanos , Masculino , Adulto JovemRESUMO
OBJECTIVE: To describe the relation between gaze and posture/gait control in Parkinson disease (PD) and to determine the role of the mesencephalic locomotor region (MLR) and cortex-MLR connection in saccadic behavior because this structure is a major area involved in both gait/postural control and gaze control networks. METHODS: We recruited 30 patients with PD with or without altered postural control and 25 age-matched healthy controls (HCs). We assessed gait, balance, and neuropsychological status and separately recorded gait initiation and eye movements (visually guided saccades and volitional antisaccades). We identified correlations between the clinical and physiologic parameters that best characterized patients with postural instability. We measured resting-state functional connectivity in 2 pathways involving the frontal oculomotor cortices and the MLR and sought correlations with saccadic behavior. RESULTS: Patients with PD with postural instability showed altered antisaccade latencies that correlated with the stand-walk-sit time (r = 0.78, p < 0.001) and the duration of anticipatory postural adjustments before gait initiation (r = 0.61, p = 0.001). Functional connectivity between the pedunculopontine nucleus (PPN) and the frontal eye field correlated with antisaccade latency in the HCs (r = -0.54, p = 0.02) but not in patients with PD. CONCLUSIONS: In PD, impairment of antisaccade latencies, a simple and robust parameter, may be an indirect marker correlated with impaired release of anticipatory postural program. PPN alterations may account for both antisaccade and postural impairments.
Assuntos
Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/fisiopatologia , Núcleo Tegmental Pedunculopontino/diagnóstico por imagem , Núcleo Tegmental Pedunculopontino/fisiopatologia , Equilíbrio Postural/fisiologia , Movimentos Sacádicos/fisiologia , Fenômenos Biomecânicos , Cognição/fisiologia , Medições dos Movimentos Oculares , Feminino , Marcha/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Testes Neuropsicológicos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/psicologiaRESUMO
The time to initiate a movement can, even implicitly, be influenced by the environment. All primates, including humans, respond faster and with greater accuracy to stimuli that are brighter, louder or associated with larger reward, than to neutral stimuli. Whether this environment also modulates the executive functions which allow ongoing actions to be suppressed remains an issue of debate. In this study, we investigated the implicit learning of spatial selectivity of movement inhibition in humans and macaque monkeys performing a saccade-countermanding task. The occurrence of stop trials, in which subjects were visually instructed to cancel a prepared movement, was manipulated according to the target location. One visual target was associated with higher probability of stop signal appearance (e.g., 80 %), while the second target was associated with low fraction of stop (e.g., 20 %). The absolute occurrence of stop trials across the two targets (50 %) remains constant. The results show that human and macaque monkeys can selectively adapt their behaviors according to the implicit probability of stopping. Behavioral adjustments were larger when targets were in different hemifields and for larger distances between targets. Reduced selective inhibitory behaviors were observed when 15° of visual angle separated the targets, and this effect vanished when targets were separated by only 2°. Overall, our study shows that both response and inhibition times can be modulated by the relative spatial occurrence of stop signals. We speculate that beyond the particular effect we observed in the context of the saccade paradigm, selective motor execution may imply a disinhibitory mechanism that modulates the motor pathways associated with the fronto-median cortex and basal ganglia circuits.
Assuntos
Comportamento Animal/fisiologia , Função Executiva/fisiologia , Inibição Psicológica , Atividade Motora/fisiologia , Desempenho Psicomotor/fisiologia , Percepção Espacial/fisiologia , Adulto , Animais , Feminino , Humanos , Macaca mulatta , Masculino , Movimentos SacádicosRESUMO
The preclinical stage of frontotemporal lobar degeneration (FTLD) is not well characterized. We conducted a brain metabolism (FDG-PET) and structural (cortical thickness) study to detect early changes in asymptomatic GRN mutation carriers (aGRN+) that were evaluated longitudinally over a 20-month period. At baseline, a left lateral temporal lobe hypometabolism was present in aGRN+ without any structural changes. Importantly, this is the first longitudinal study and, across time, the metabolism more rapidly decreased in aGRN+ in lateral temporal and frontal regions. The main structural change observed in the longitudinal study was a reduction of cortical thickness in the left lateral temporal lobe in carriers. A limit of this study is the relatively small sample (nâ=â16); nevertheless, it provides important results. First, it evidences that the pathological processes develop a long time before clinical onset, and that early neuroimaging changes might be detected approximately 20 years before the clinical onset of disease. Second, it suggests that metabolic changes are detectable before structural modifications and cognitive deficits. Third, both the baseline and longitudinal studies provide converging results implicating lateral temporal lobe as early involved in GRN disease. Finally, our study demonstrates that structural and metabolic changes could represent possible biomarkers to monitor the progression of disease in the presymptomatic stage toward clinical onset.
Assuntos
Degeneração Lobar Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação , Lobo Temporal/metabolismo , Lobo Temporal/patologia , Adulto , Doenças Assintomáticas , Progressão da Doença , Feminino , Fluordesoxiglucose F18 , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Degeneração Lobar Frontotemporal/diagnóstico , Degeneração Lobar Frontotemporal/genética , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Tamanho do Órgão , Tomografia por Emissão de Pósitrons , Progranulinas , Compostos Radiofarmacêuticos , Lobo Temporal/diagnóstico por imagemRESUMO
BACKGROUND: Blurred near vision is a common non-motor symptom in patients with Parkinson's disease (PD), however detailed characterization of vergence eye movements (VEM) is lacking. METHODS: Convergence and divergence were examined in 18 patients with PD and 18 control subjects using infrared video-oculography. VEM metrics analyzed included latency, velocity and accuracy, in vertical and horizontal planes. RESULTS: The latency of convergence and divergence was significantly increased in PD subjects. Additionally, divergence was slow and hypometric, while other convergence metrics were similar to controls. CONCLUSION: We provide evidence in favor of disrupted VEM in PD.
Assuntos
Transtornos da Motilidade Ocular/diagnóstico , Transtornos da Motilidade Ocular/fisiopatologia , Doença de Parkinson/diagnóstico , Doença de Parkinson/fisiopatologia , Gravação em Vídeo/métodos , Adulto , Idoso , Movimentos Oculares , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos da Motilidade Ocular/epidemiologia , Doença de Parkinson/epidemiologia , Estimulação Luminosa/métodosRESUMO
OBJECTIVE: To assess the clinical spectrum of ataxia-telangiectasia (A-T) in adults, with a focus on movement disorders. METHODS: A total of 14 consecutive adults with A-T were included at 2 tertiary adult movement disorders centers and compared to 53 typical patients with A-T. Clinical evaluation, neurophysiologic and video-oculographic recording, imaging, laboratory investigations, and ATM analysis were performed. RESULTS: In comparison with typical A-T cases, our patients demonstrated later mean age at onset (6.1 vs 2.5 years, p < 0.0001), later loss of walking ability (p = 0.003), and longer survival (p = 0.0039). The presenting feature was ataxia in 71% and dysarthria and dystonia in 14% each. All patients displayed movement disorders, among which dystonia and subcortical myoclonus were the most common (86%), followed by tremor (43%). Video-oculographic recordings revealed mostly dysmetric saccades and 46% of patients had normal latencies (i.e., no oculomotor apraxia) and velocities. The α-fetoprotein (AFP) level was normal in 7%, chromosomal instability was found in 29% (vs 100% of typical patients, p = 0.0006), and immunoglobulin deficiency was found in 29% (vs 69%, p = 0.057). All patients exhibited 2 ATM mutations, including at least 1 missense mutation in 79% of them (vs 36%, p = 0.0067). CONCLUSION: There is great variability of phenotype and severity in A-T, including a wide spectrum of movement disorders. Karyotype and repeated AFP level assessments should be performed in adults with unexplained movement disorders as valuable clues towards the diagnosis. In case of a compatible phenotype, A-T should be considered even if age at onset is late and progression is slow.
Assuntos
Ataxia Telangiectasia/fisiopatologia , Disartria/fisiopatologia , Distonia/fisiopatologia , Adulto , Idade de Início , Ataxia Telangiectasia/epidemiologia , Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Instabilidade Cromossômica/genética , Estudos de Coortes , Progressão da Doença , Disartria/genética , Distonia/genética , Medições dos Movimentos Oculares , Feminino , Pleiotropia Genética , Humanos , Imunoglobulinas/deficiência , Masculino , Limitação da Mobilidade , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/fisiopatologia , Mutação de Sentido Incorreto , Mioclonia/genética , Mioclonia/fisiopatologia , Transtornos da Motilidade Ocular/genética , Transtornos da Motilidade Ocular/fisiopatologia , Fenótipo , Índice de Gravidade de Doença , Adulto Jovem , alfa-FetoproteínasRESUMO
Patients with ephedrone parkinsonism (EP) show a complex, rapidly progressive, irreversible, and levodopa non-responsive parkinsonian and dystonic syndrome due to manganese intoxication. Eye movements may help to differentiate parkinsonian syndromes providing insights into which brain networks are affected in the underlying disease, but they have never been systematically studied in EP. Horizontal and vertical eye movements were recorded in 28 EP and compared to 21 Parkinson's disease (PD) patients, and 27 age- and gender-matched healthy subjects using standardized oculomotor tasks with infrared videooculography. EP patients showed slow and hypometric horizontal saccades, an increased occurrence of square wave jerks, long latencies of vertical antisaccades, a high error rate in the horizontal antisaccade task, and made more errors than controls when pro- and antisaccades were mixed. Based on oculomotor performance, a direct differentiation between EP and PD was possible only by the velocity of horizontal saccades. All remaining metrics were similar between both patient groups. EP patients present extensive oculomotor disturbances probably due to manganese-induced damage to the basal ganglia, reflecting their role in oculomotor system.
Assuntos
Movimentos Oculares/fisiologia , Transtornos Parkinsonianos/induzido quimicamente , Propiofenonas/efeitos adversos , Movimentos Sacádicos/fisiologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Adulto , Gânglios da Base/fisiopatologia , Encéfalo/fisiopatologia , Feminino , Humanos , Masculino , Manganês/toxicidade , Pessoa de Meia-Idade , Transtornos Parkinsonianos/fisiopatologiaRESUMO
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.
Assuntos
Esclerose Lateral Amiotrófica/genética , Expansão das Repetições de DNA , Demência Frontotemporal/genética , Proteínas do Tecido Nervoso/genética , Proteínas/genética , Paralisia Supranuclear Progressiva/genética , Ataxinas , Proteína C9orf72 , Estudos de Coortes , Análise Mutacional de DNA , França , Predisposição Genética para Doença , Heterozigoto , Humanos , Peptídeos/genética , Fatores de RiscoRESUMO
TMEM106B was identified as a risk factor for frontotemporal lobar degeneration (FTD) with TAR DNA-binding protein 43 kDa inclusions. It has been reported that variants in this gene are genetic modifiers of the disease and that this association is stronger in patients carrying a GRN mutation or a pathogenic expansion in chromosome 9 open reading frame 72 (C9orf72) gene. Here, we investigated the contribution of TMEM106B polymorphisms in cohorts of FTD and FTD with amyotrophic lateral sclerosis patients from France and Italy. Patients carrying the C9orf72 expansion (n = 145) and patients with GRN mutations (n = 76) were compared with a group of FTD patients (n = 384) negative for mutations and to a group of healthy controls (n = 552). In our cohorts, the presence of the C9orf72 expansion did not correlate with TMEM106B genotypes but the association was very strong in individuals with pathogenic GRN mutations (p = 9.54 × 10(-6)). Our data suggest that TMEM106B genotypes differ in FTD patient cohorts and strengthen the protective role of TMEM106B in GRN carriers. Further studies are needed to determine whether TMEM106B polymorphisms are associated with other genetic causes for FTD, including C9orf72 repeat expansions.
Assuntos
Degeneração Lobar Frontotemporal/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Polimorfismo Genético , Proteínas/genética , Expansão das Repetições de Trinucleotídeos/genética , Idoso , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/genética , Proteína C9orf72 , Estudos de Coortes , Feminino , França , Degeneração Lobar Frontotemporal/complicações , Estudos de Associação Genética , Genótipo , Humanos , Itália , Masculino , Pessoa de Meia-Idade , ProgranulinasRESUMO
IMPORTANCE: Progressive supranuclear palsy (PSP) is usually sporadic, but few pedigrees with familial clustering of PSP-like phenotypes have been described. Occasionally, MAPT, C9ORF72, and TARDBP mutations have been identified. OBJECTIVE: To analyze the DCTN1 gene in 19 families with a clinical phenotype of PSP (PSP-like phenotype). DESIGN, SETTING, AND PARTICIPANTS: Sequencing of the DCTN1 gene in familial forms of PSP at a referral center among 21 patients with familial PSP-like phenotypes. In addition, 8 patients and relatives from a family carrying a DCTN1 mutation were evaluated. MAIN OUTCOMES AND MEASURES: Identification of the DCTN1 mutation and clinical description of DCTN1 mutation carriers. RESULTS: We identified a DCTN1 mutation in a large family characterized by high intrafamilial clinical phenotype variability. Two patients had PSP-like phenotypes with dystonia, vertical gaze slowness, dysexecutive syndrome, predominant axial rigidity, and midbrain atrophy on brain magnetic resonance imaging. The other patients manifested Perry syndrome, isolated parkinsonism, or a predominant behavioral variant of frontotemporal dementia. CONCLUSIONS AND RELEVANCE: Mutations of the DCTN1 gene have been previously associated with amyotrophic lateral sclerosis and with Perry syndrome, a rare autosomal dominant disorder characterized by weight loss, parkinsonism, central hypoventilation, and psychiatric disturbances. Our study demonstrates that DCTN1 mutations should be searched for in patients with clinical PSP-like phenotypes and a behavioral variant of frontotemporal dementia, especially when a familial history of dementia, psychiatric disturbances, associated parkinsonism, or an autosomal dominant disorder is present.
Assuntos
Análise Mutacional de DNA/métodos , Proteínas Associadas aos Microtúbulos/genética , Fenótipo , Mutação Puntual/genética , Paralisia Supranuclear Progressiva/diagnóstico , Paralisia Supranuclear Progressiva/genética , Adulto , Complexo Dinactina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Paralisia Supranuclear Progressiva/sangueRESUMO
OBJECTIVE: To assist other eye movement investigators in the design and analysis of their studies. METHODS: We examined basic saccadic eye movements and smooth pursuit in the horizontal and vertical directions with video-oculography in a group of 145 healthy subjects between 19 and 82 years of age. RESULTS: Gender and education level did not influence eye movement metrics. With age, the latency of leftward and vertical pro- and antisaccades increased (p<0.001), velocity of upward prosaccades decreased (p<0.001), gain of rightward and upward prosaccades diminished (p<0.001), and the error rate of antisaccades increased (p<0.001). Prosaccades and antisaccades were influenced by the direction of the target, resulting in a right/left and up/down asymmetry. The skewness of the saccade velocity profile was stable throughout the lifespan, and within the range of saccades analyzed in the present study, correlated with amplitude and duration only for antisaccades (p<0.001). CONCLUSIONS: Some eye movement metrics must be separated by the direction of movement, others according to subject age, while others may be pooled. SIGNIFICANCE: This study provides important information for new oculomotor laboratories concerning the constitution of subject groups and the analysis of eye movement metrics.
Assuntos
Eletroculografia/métodos , Movimentos Oculares/fisiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Feminino , Lateralidade Funcional/fisiologia , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Acompanhamento Ocular Uniforme/fisiologia , Tempo de Reação , Movimentos Sacádicos/fisiologia , Adulto JovemRESUMO
Frontotemporal dementia (FTD) refers to a disease spectrum including the behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy/corticobasal degeneration syndrome (PSP/CBDS), and FTD with amyotrophic lateral sclerosis (FTD-ALS). A GGGGCC expansion in C9ORF72 is a major cause of FTD and ALS. C9ORF72 was analyzed in 833 bvFTD, FTD-ALS, PPA, and PSP/CBDS probands; 202 patients from 151 families carried an expansion. C9ORF72 expansions were much more frequent in the large subgroup of patients with familial FTD-ALS (65.9%) than in those with pure FTD (12.8%); they were even more frequent than in familial pure ALS, according to estimated frequencies in the literature (23-50%). The frequency of carriers in non-familial FTD-ALS (12.7%) indicates that C9ORF72 should be analyzed even when family history is negative. Mutations were detected in 6.8% of PPA patients, and in 3.2% of patients with a clinical phenotype of PSP, thus enlarging the phenotype spectrum of C9ORF72. Onset was later in C9ORF72 (57.4 years, 95%CI: 55.9-56.1) than in MAPT patients (46.8, 95%CI: 43.0-50.6; p = 0.00001) and the same as in PGRN patients (59.6 years; 95%CI: 57.6-61.7; p = 0.4). ALS was more frequent in C9ORF72 than in MAPT and PGRN patients; onset before age 50 and parkinsonism were indicative of MAPT mutations, whereas hallucinations were indicative of PGRN mutations; prioritization of genetic testing is thus possible. Penetrance was age- and gender-dependent: by age 50, 78% of male carriers were symptomatic, but only 52% of females. This can also guide genetic testing and counseling. A flowchart for genetic testing is thus proposed.
Assuntos
Expansão das Repetições de DNA/genética , Demência Frontotemporal/genética , Marcadores Genéticos/genética , Testes Genéticos/métodos , Proteínas/genética , Design de Software , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Proteína C9orf72 , Estudos de Coortes , Feminino , Demência Frontotemporal/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fatores SexuaisRESUMO
Hereditary spastic paraplegias (HSPs) are rare neurological conditions caused by degeneration of the long axons of the cerebrospinal tracts, leading to locomotor impairment and additional neurological symptoms. There are more than 40 different causative genes, 24 of which have been identified, including SPG11 and SPG15 mutated in complex clinical forms. Since the vast majority of the causative mutations lead to loss of function of the corresponding proteins, we made use of morpholino-oligonucleotide (MO)-mediated gene knock-down to generate zebrafish models of both SPG11 and SPG15 and determine how invalidation of the causative genes (zspg11 and zspg15) during development might contribute to the disease. Micro-injection of MOs targeting each gene caused locomotor impairment and abnormal branching of spinal cord motor neurons at the neuromuscular junction. More severe phenotypes with abnormal tail developments were also seen. Moreover, partial depletion of both proteins at sub-phenotypic levels resulted in the same phenotypes, suggesting for the first time, in vivo, a genetic interaction between these genes. In conclusion, the zebrafish orthologues of the SPG11 and SPG15 genes are important for proper development of the axons of spinal motor neurons and likely act in a common pathway to promote their proper path finding towards the neuromuscular junction.
Assuntos
Axônios/metabolismo , Neurônios Motores/metabolismo , Neurogênese/fisiologia , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Animais , Proteínas de Transporte/metabolismo , Embrião não Mamífero , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Proteínas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência de Aminoácidos , Peixe-Zebra/metabolismoRESUMO
BACKGROUND: Vitamin D could play a protective role in multiple sclerosis. METHODS: In an observational, uncontrolled study, vitamin D3 supplementation (3010 IU/day on average) was given to 156 consecutive patients with relapsing-remitting multiple sclerosis, under first-line immunomodulatory therapy and with initial 25-OH-D serum level lower than 100 nmol/l (40 ng/ml). Relapses were determined for 29.1 ± 8.4 months during vitamin D and 29.8 ± 10.1 months before supplementation. The 25-OH-D level was measured before supplementation and several times during supplementation. The incidence rate of relapses before and during supplementation was estimated using negative binomial regression models with follow-up durations as offset terms. The incidence rate and incidence rate ratio of relapses at various 25-OH-D levels were also calculated using negative binomial regression models. RESULTS: In 76 patients, immunomodulatory therapy preceded vitamin D supplementation (by 4.2 ± 2.7 years) and in 80 patients both treatments were started simultaneously. Under supplementation, the 25-OH-D level increased from 49 ± 22 nmol/l to 110 ± 26 nmol/l on average. Pooling data collected before and during supplementation, we found a significant strong inverse relationship between the relapse incidence rate and the 25-OH-D level (p < 0.0001), suggesting that vitamin D did indeed influence the relapse rate. Results of univariate, bivariate and multivariate analyses were analogous: in the multivariate model adjusted for age, disease duration and previous use of immunomodulatory therapy, every 10 nmol increase in 25-OH-D level was associated with a reduction in the relapse incidence rate of 13.7%. Dividing iteratively the population made up of pooled periods into two subgroups according to the 25-OH-D levels, the relapse incidence rate ratio decreased as the 25-OH-D level increased up to 110 nmol/l, but a plateau effect was observed beyond this limit. CONCLUSION: Further studies are warranted for accurate quantification of the vitamin D effect.