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1.
Ann Neurol ; 96(2): 234-246, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38721781

RESUMO

OBJECTIVE: Bradykinesia and rigidity are considered closely related motor signs in Parkinson disease (PD), but recent neurophysiological findings suggest distinct pathophysiological mechanisms. This study aims to examine and compare longitudinal changes in bradykinesia and rigidity in PD patients treated with bilateral subthalamic nucleus deep brain stimulation (STN-DBS). METHODS: In this retrospective cohort study, the clinical progression of appendicular and axial bradykinesia and rigidity was assessed up to 15 years after STN-DBS in the best treatment conditions (ON medication and ON stimulation). The severity of bradykinesia and rigidity was examined using ad hoc composite scores from specific subitems of the Unified Parkinson's Disease Rating Scale motor part (UPDRS-III). Short- and long-term predictors of bradykinesia and rigidity were analyzed through linear regression analysis, considering various preoperative demographic and clinical data, including disease duration and severity, phenotype, motor and cognitive scores (eg, frontal score), and medication. RESULTS: A total of 301 patients were examined before and 1 year after surgery. Among them, 101 and 56 individuals were also evaluated at 10-year and 15-year follow-ups, respectively. Bradykinesia significantly worsened after surgery, especially in appendicular segments (p < 0.001). Conversely, rigidity showed sustained benefit, with unchanged clinical scores compared to preoperative assessment (p > 0.05). Preoperative motor disability (eg, composite scores from the UPDRS-III) predicted short- and long-term outcomes for both bradykinesia and rigidity (p < 0.01). Executive dysfunction was specifically linked to bradykinesia but not to rigidity (p < 0.05). INTERPRETATION: Bradykinesia and rigidity show long-term divergent progression in PD following STN-DBS and are associated with independent clinical factors, supporting the hypothesis of partially distinct pathophysiology. ANN NEUROL 2024;96:234-246.


Assuntos
Estimulação Encefálica Profunda , Hipocinesia , Rigidez Muscular , Doença de Parkinson , Núcleo Subtalâmico , Humanos , Doença de Parkinson/terapia , Doença de Parkinson/fisiopatologia , Doença de Parkinson/complicações , Estimulação Encefálica Profunda/efeitos adversos , Estimulação Encefálica Profunda/métodos , Masculino , Feminino , Hipocinesia/etiologia , Hipocinesia/fisiopatologia , Pessoa de Meia-Idade , Núcleo Subtalâmico/fisiopatologia , Rigidez Muscular/etiologia , Rigidez Muscular/fisiopatologia , Idoso , Estudos Retrospectivos , Progressão da Doença , Estudos de Coortes
2.
Brain ; 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38884572

RESUMO

Alpha-tubulin 4A encoding gene (TUBA4A) has been associated with familial amyotrophic lateral sclerosis (fALS) and fronto-temporal dementia (FTD), based on identification of likely pathogenic variants in patients from distinct ALS and FTD cohorts. By screening a multicentric French cohort of 448 unrelated probands presenting with cerebellar ataxia, we identified ultra-rare TUBA4A missense variants, all being absent from public databases and predicted pathogenic by multiple in-silico tools. In addition, gene burden analyses in the 100,000 genomes project (100KGP) showed enrichment of TUBA4A rare variants in the inherited ataxia group compared to controls (OR: 57.0847 [10.2- 576.7]; p = 4.02 x10-07). Altogether, we report 12 patients presenting with spasticity and/or cerebellar ataxia and harboring a predicted pathogenic TUBA4A missense mutation, including 5 confirmed de novo cases and a mutation previously reported in a large family presenting with spastic ataxia. Cultured fibroblasts from 3 patients harboring distinct TUBA4A missense showed significant alterations in microtubule organisation and dynamics, providing insight of TUBA4A variants pathogenicity. Our data confirm the identification of a hereditary spastic ataxia disease gene with variable age of onset, expanding the clinical spectrum of TUBA4A associated phenotypes.

3.
J Med Genet ; 60(7): 717-721, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36599645

RESUMO

Usually, molecular diagnosis of spinocerebellar ataxia is based on a step-by-step approach with targeted sizing of four repeat expansions accounting for most dominant cases, then targeted sequencing of other genes. Nowadays, genome sequencing allows detection of most pathogenic variants in a single step. The ExpansionHunter tool can detect expansions in short-read genome sequencing data. Recent studies have shown that ExpansionHunter can also be used to identify repeat expansions in exome sequencing data. We tested ExpansionHunter on spinocerebellar ataxia exomes in a research context as a second-line analysis, after exclusion of main CAG repeat expansions in half of the probands. First, we confirmed the detection of expansions in seven known expansion carriers and then, after targeted analysis of ATXN1, 2, 3 and 7, CACNA1A, TBP, ATN1, NOP56, AR and HTT in 498 exomes, we found 22 additional pathogenic expansions. Comparison with capillary migration sizing in 247 individuals and confirmation of all expanded alleles detected by ExpansionHunter demonstrated that for these loci, sensitivity and specificity reached 100%. ExpansionHunter detected but underestimated the repeat size for larger expansions, and the normal alleles distribution at each locus should be taken into account to detect expansions. Exome combined with ExpansionHunter is reliable to detect repeat expansions in selected loci as first-line analysis in spinocerebellar ataxia.


Assuntos
Exoma , Ataxias Espinocerebelares , Humanos , Exoma/genética , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/genética , Alelos , Heterozigoto
4.
Genet Med ; 25(2): 100327, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36422518

RESUMO

PURPOSE: CAG/CAA repeat expansions in TBP>49 are responsible for spinocerebellar ataxia (SCA) type 17 (SCA17). We previously detected cosegregation of STUB1 variants causing SCA48 with intermediate alleles of TBP in 2 families. This cosegregation questions the existence of SCA48 as a monogenic disease. METHODS: We systematically sequenced TBP repeats in 34 probands of dominant ataxia families with STUB1 variants. In addition, we searched for pathogenic STUB1 variants in probands with expanded alleles of TBP>49 (n = 2) or intermediate alleles of TBP≥40 (n = 47). RESULTS: STUB1 variants were found in half of the TBP40-49 cohort. Mirroring this finding, TBP40-49 alleles were detected in 40% of STUB1 probands. The longer the TBP repeat length, the more likely the occurrence of cognitive impairment (P = .0129) and the faster the disease progression until death (P = .0003). Importantly, 13 STUB1 probands presenting with the full SCA48 clinical phenotype had normal TBP37-39 alleles, excluding digenic inheritance as the sole mode. CONCLUSION: We show that intermediate TBP40-49 alleles act as disease modifiers of SCA48 rather than a STUB1/TBP digenic model. This distinction from what has been proposed before has crucial consequences for genetic counseling in SCA48.


Assuntos
Ataxia Cerebelar , Ataxias Espinocerebelares , Humanos , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia , Ataxia Cerebelar/genética , Fenótipo , Alelos , Expansão das Repetições de Trinucleotídeos/genética , Ubiquitina-Proteína Ligases/genética
5.
Ann Neurol ; 89(3): 587-597, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33349939

RESUMO

OBJECTIVE: This study was undertaken to identify preoperative predictive factors of long-term motor outcome in a large cohort of consecutive Parkinson disease (PD) patients with bilateral subthalamic nucleus deep brain stimulation (STN-DBS). METHODS: All consecutive PD patients who underwent bilateral STN-DBS at the Grenoble University Hospital (France) from 1993 to 2015 were evaluated before surgery, at 1 year (short-term), and in the long term after surgery. All available demographic variables, neuroimaging data, and clinical characteristics were collected. Preoperative predictors of long-term motor outcome were investigated by performing survival and univariate/multivariate Cox regression analyses. Loss of motor benefit from stimulation in the long term was defined as a reduction of less than 25% in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III scores compared to the baseline off-medication scores. As a secondary objective, potential predictors of short-term motor outcome after STN-DBS were assessed by performing univariate and multivariate linear regression analyses. RESULTS: In the long-term analyses (mean follow-up = 8.4 ± 6.26 years, median = 10 years, range = 1-17 years), 138 patients were included. Preoperative higher frontal score and off-medication MDS-UPDRS part III scores predicted a better long-term motor response to stimulation, whereas the presence of vascular changes on neuroimaging predicted a worse motor outcome. In 357 patients with available 1-year follow-up, preoperative levodopa response, tremor dominant phenotype, baseline frontal score, and off-medication MDS-UPDRS part III scores predicted the short-term motor outcome. INTERPRETATION: Frontal lobe dysfunction, disease severity in the off-medication condition, and the presence of vascular changes on neuroimaging represent the main preoperative clinical predictors of long-term motor STN-DBS effects. ANN NEUROL 2021;89:587-597.


Assuntos
Estimulação Encefálica Profunda , Doença de Parkinson/terapia , Núcleo Subtalâmico , Adulto , Idoso , Transtornos Cerebrovasculares/diagnóstico por imagem , Transtornos Cerebrovasculares/epidemiologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/psicologia , Função Executiva , Feminino , Seguimentos , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Testes Neuropsicológicos , Doença de Parkinson/epidemiologia , Doença de Parkinson/fisiopatologia , Doença de Parkinson/psicologia , Prognóstico , Modelos de Riscos Proporcionais , Índice de Gravidade de Doença , Resultado do Tratamento
6.
Mov Disord ; 37(6): 1211-1221, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35238430

RESUMO

BACKGROUND: De novo Parkinson's disease (PD) patients with apathy exhibit prominent limbic serotonergic dysfunction and microstructural disarray. Whether this distinctive lesion profile at diagnosis entails different prognosis remains unknown. OBJECTIVES: To investigate the progression of dopaminergic and serotonergic dysfunction and their relation to motor and nonmotor impairment in PD patients with or without apathy at diagnosis. METHODS: Thirteen de novo apathetic and 13 nonapathetic PD patients were recruited in a longitudinal double-tracer positron emission tomography cohort study. We quantified the progression of presynaptic dopaminergic and serotonergic pathology using [11 C]PE2I for dopamine transporter and [11 C]DASB for serotonin transporter at baseline and 3 to 5 years later, using linear mixed-effect models and mediation analysis to compare the longitudinal evolution between groups for clinical impairment and region-of-interest-based analysis. RESULTS: After the initiation of dopamine replacement therapy, apathy, depression, and anxiety improved at follow-up in patients with apathy at diagnosis (n = 10) to the level of patients without apathy (n = 11). Patients had similar progression of motor impairment, whereas mild impulsive behaviors developed in both groups. Striato-pallidal and mesocorticolimbic presynaptic dopaminergic loss progressed similarly in both groups, as did serotonergic pathology in the putamen, caudate nucleus, and pallidum. Contrastingly, serotonergic innervation selectively increased in the ventral striatum and anterior cingulate cortex in apathetic patients, contributing to the reversal of apathy besides dopamine replacement therapy. CONCLUSION: Patients suffering from apathy at diagnosis exhibit compensatory changes in limbic serotonergic innervation within 5 years of diagnosis, with promising evidence that serotonergic plasticity contributes to the reversal of apathy. The relationship between serotonergic plasticity and dopaminergic treatments warrants further longitudinal investigations. © 2022 International Parkinson and Movement Disorder Society.


Assuntos
Apatia , Doença de Parkinson , Estudos de Coortes , Dopamina , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos
7.
Eur J Neurol ; 29(9): 2645-2653, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35666167

RESUMO

BACKGROUND AND PURPOSE: Studies on long-term nonmotor outcomes of subthalamic nucleus stimulation in Parkinson disease (PD) are scarce. This study reports on very long-term non-motor and motor outcomes in one of the largest cohorts of people with advanced PD, treated for >10 years with subthalamic nucleus stimulation. The main outcome was to document the evolution of independence in activities of daily living. The secondary outcomes were to measure the change in quality of life, as well as non-motor and motor outcomes. METHODS: Patients were studied preoperatively, at 1 year, and beyond 10 years after subthalamic stimulation with an established protocol including motor, non-motor, and neuropsychological assessments. RESULTS: Eighty-five people with PD were included. Independence scores in the off-medication condition (measured with the Schwab & England Activities of Daily Living Scale) as well as quality of life (measured with the Parkinson's Disease Questionnaire [PDQ]-37) remained improved at longest follow-up compared to preoperatively (respectively, p < 0.001, p = 0.015). Cognitive scores, measured with the Mattis Dementia Rating Scale, significantly worsened compared to before and 1 year after surgery (p < 0.001), without significant change in depression, measured with the Beck Depression Inventory. Motor fluctuations, dyskinesias, and off dystonia remained improved at longest follow-up (p < 0.001), with a significant reduction in dopaminergic treatment (45%, p < 0.001). CONCLUSIONS: This study highlights the long-term improvement of subthalamic stimulation on independence and quality of life, despite the progression of disease and the occurrence of levodopa-resistant symptoms.


Assuntos
Estimulação Encefálica Profunda , Doença de Parkinson , Atividades Cotidianas , Estimulação Encefálica Profunda/métodos , Seguimentos , Humanos , Doença de Parkinson/complicações , Qualidade de Vida , Resultado do Tratamento
8.
Neurol Sci ; 43(6): 3641-3647, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35043355

RESUMO

INTRODUCTION: In Parkinson's disease (PD), non-motor fluctuations (NMFs), especially neuropsychiatric fluctuations, often coexist with motor fluctuations (MFs) but are often under-recognized by physicians and patients. OBJECTIVE: To investigate the relationship between MFs and neuropsychiatric fluctuations in PD. METHODS: PD patients with MFs and NMFs were enrolled. The Parkinson's Kinetigraph (PKG), a wearable device to detect MFs and dyskinesia, was used to confirm and measure MFs. The Neuropsychiatric Fluctuation Scale (NFS), a scale composed by subscores for both the ON and OFF neuropsychiatric states, was used to identify and quantify neuropsychiatric fluctuations. Patients were asked to wear the PKG for six consecutive days to identify the ON and OFF motor periods, and then to fill the NFS during the ON and OFF motor periods for three consecutive days wearing the PKG. The PKG system provided a bradykinesia score (BKS) and a dyskinesia score (DKS). Relations between BKS, DKS, and ON and OFF NFS subscores were analyzed. RESULTS: In 18 PD patients, anxiety, apathy, and depression characterized the OFF condition, whereas self-confidence, competency, and interest in doing things were typically in the ON condition. There was a positive correlation between the BKS and the OFF NFS subscores (p = 0.036, r = 0.51), whereas no correlation was found between the DKS and the ON NFS subscores (p = 0.38, r = 0.22). CONCLUSION: Neuropsychiatric fluctuations temporarily matched the OFF MFs only in the OFF condition. These findings are useful to better manage OFF NMSs and support the need to further investigate associations between non-motor and motor symptoms in PD patients.


Assuntos
Discinesias , Doença de Parkinson , Transtornos de Ansiedade/complicações , Discinesias/etiologia , Humanos , Hipocinesia , Doença de Parkinson/diagnóstico
9.
Genet Med ; 23(11): 2160-2170, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34234304

RESUMO

PURPOSE: Diagnosis of inherited ataxia and related diseases represents a real challenge given the tremendous heterogeneity and clinical overlap of the various causes. We evaluated the efficacy of molecular diagnosis of these diseases by sequencing a large cohort of undiagnosed families. METHODS: We analyzed 366 unrelated consecutive patients with undiagnosed ataxia or related disorders by clinical exome-capture sequencing. In silico analysis was performed with an in-house pipeline that combines variant ranking and copy-number variant (CNV) searches. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. RESULTS: We established the molecular diagnosis in 46% of the cases. We identified 35 mildly affected patients with causative variants in genes that are classically associated with severe presentations. These cases were explained by the occurrence of hypomorphic variants, but also rarely suspected mechanisms such as C-terminal truncations and translation reinitiation. CONCLUSION: A significant fraction of the clinical heterogeneity and phenotypic overlap is explained by hypomorphic variants that are difficult to identify and not readily predicted. The hypomorphic C-terminal truncation and translation reinitiation mechanisms that we identified may only apply to few genes, as it relies on specific domain organization and alterations. We identified PEX10 and FASTKD2 as candidates for translation reinitiation accounting for mild disease presentation.


Assuntos
Ataxia Cerebelar , Genômica , Estudos de Coortes , Variações do Número de Cópias de DNA/genética , Humanos , Peroxinas , Receptores Citoplasmáticos e Nucleares , Estados Unidos , Sequenciamento do Exoma
10.
Mov Disord ; 36(12): 2888-2900, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34494685

RESUMO

BACKGROUND: Parkinson's disease (PD) is characterized by heterogeneous motor and nonmotor manifestations related to alterations in monoaminergic neurotransmission systems. Nevertheless, the characterization of concomitant dopaminergic and serotonergic dysfunction after different durations of Parkinson's disease, as well as their respective involvement in the expression and severity of neuropsychiatric signs, has gained little attention so far. METHODS: To fill this gap, we conducted a cross-sectional study combining clinical and dual-tracer positron emission tomography (PET) neuroimaging approaches, using radioligands of dopamine ([11 C]-N-(3-iodoprop-2E-enyl)-2-beta-carbomethoxy-3-beta-(4-methylphenyl)-nortropane) ([11 C]PE2I) and serotonin ([11 C]-N,N-dimethyl-2-(-2-amino-4-cyanophenylthio)-benzylamine) ([11 C]DASB) reuptake, after different durations of Parkinson's disease (ie, in short-disease duration drug-naive de novo (n = 27, 0-2 years-duration), suffering from apathy (n = 14) or not (n = 13); intermediate-disease duration (n = 15, 4-7 years-duration) and long-disease duration, non-demented (n = 15, 8-10 years-duration) patients). Fifteen age-matched healthy subjects were also enrolled. RESULTS: The main findings are threefold: (1) both dopaminergic and serotonergic lesions worsen with the duration of Parkinson's disease, spreading from midbrain/subcortical to cortical regions; (2) the presence of apathy at PD onset is associated with more severe cortical and subcortical serotonergic and dopaminergic disruption, similar to the denervation pattern observed in intermediate-disease duration patients; and (3) the severity of parkinsonian apathy, depression, and trait-anxiety appears primarily related to serotonergic alteration within corticostriatal limbic areas. CONCLUSIONS: Altogether, these findings highlight the prominent role of serotonergic degeneration in the expression of several neuropsychiatric symptoms occurring after different durations of Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society.


Assuntos
Apatia , Doença de Parkinson , Ansiedade , Estudos Transversais , Dopamina , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Tomografia por Emissão de Pósitrons/métodos
11.
Stereotact Funct Neurosurg ; 98(2): 80-84, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32050205

RESUMO

Giant perivascular spaces (PVS) are rare, CSF-filled, dilated cavities lined by the pia mater that are most often asymptomatic radiological findings but can sometimes cause neurological symptoms. We present two exceptional cases of secondary focal dystonia induced by the mass effect on the basal ganglia caused by giant diencephalic PVSs. In both cases, we chose a surgical stereotactic drainage approach as a treatment strategy that allowed controlling the movement disorders. The beneficial therapeutic effect was sustained at long-term follow-up. We believe that similar cases could be addressed successfully with this method.


Assuntos
Gânglios da Base/diagnóstico por imagem , Gânglios da Base/cirurgia , Distúrbios Distônicos/diagnóstico por imagem , Distúrbios Distônicos/cirurgia , Sistema Glinfático/diagnóstico por imagem , Sistema Glinfático/cirurgia , Adulto , Dilatação Patológica/complicações , Dilatação Patológica/diagnóstico por imagem , Dilatação Patológica/cirurgia , Drenagem/métodos , Distúrbios Distônicos/etiologia , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Técnicas Estereotáxicas
12.
Hum Mutat ; 40(10): 1713-1730, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31050087

RESUMO

Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Processamento Alternativo , Ciclo Celular , Linhagem Celular , Análise Mutacional de DNA , Estudos de Associação Genética/métodos , Genótipo , Humanos , Mutação , Fenótipo
13.
Mov Disord ; 34(11): 1644-1654, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31309609

RESUMO

BACKGROUND: Whether structural alterations underpin apathy and depression in de novo parkinsonian patients is unknown. The objectives of this study were to investigate whether apathy and depression in de novo parkinsonian patients are related to structural alterations and how structural abnormalities relate to serotonergic or dopaminergic dysfunction. METHODS: We compared the morphological and microstructural architecture in gray matter using voxel-based morphometry and diffusion tensor imaging coupled with white matter tract-based spatial statistics in a multimodal imaging case-control study enrolling 14 apathetic and 13 nonapathetic patients with de novo Parkinson's disease and 15 age-matched healthy controls, paired with PET imaging of the presynaptic dopaminergic and serotonergic systems. RESULTS: De novo parkinsonian patients with apathy had bilateral microstructural alterations in the medial corticostriatal limbic system, exhibiting decreased fractional anisotropy and increased mean diffusivity in the anterior striatum and pregenual anterior cingulate cortex in conjunction with serotonergic dysfunction. Furthermore, microstructural alterations extended to the medial frontal cortex, the subgenual anterior cingulate cortex and subcallosal gyrus, the medial thalamus, and the caudal midbrain, suggesting disruption of long-range nondopaminergic projections originating in the brainstem, in addition to microstructural alterations in callosal interhemispheric connections and frontostriatal association tracts early in the disease course. In addition, microstructural abnormalities related to depressive symptoms in apathetic and nonapathetic patients revealed a distinct, mainly right-sided limbic subnetwork involving limbic and frontal association tracts. CONCLUSIONS: Early limbic microstructural alterations specifically related to apathy and depression emphasize the role of early disruption of ascending nondopaminergic projections and related corticocortical and corticosubcortical networks which underpin the variable expression of nonmotor and neuropsychiatric symptoms in Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.


Assuntos
Depressão/patologia , Transtorno Depressivo/patologia , Doença de Parkinson/patologia , Substância Branca/patologia , Depressão/fisiopatologia , Transtorno Depressivo/complicações , Imagem de Difusão por Ressonância Magnética/métodos , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Doença de Parkinson/complicações
14.
Am J Hum Genet ; 97(5): 726-37, 2015 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-26456284

RESUMO

Hereditary cerebellar ataxias (CAs) are neurodegenerative disorders clinically characterized by a cerebellar syndrome, often accompanied by other neurological or non-neurological signs. All transmission modes have been described. In autosomal-dominant CA (ADCA), mutations in more than 30 genes are implicated, but the molecular diagnosis remains unknown in about 40% of cases. Implication of ion channels has long been an ongoing topic in the genetics of CA, and mutations in several channel genes have been recently connected to ADCA. In a large family affected by ADCA and mild pyramidal signs, we searched for the causative variant by combining linkage analysis and whole-exome sequencing. In CACNA1G, we identified a c.5144G>A mutation, causing an arginine-to-histidine (p.Arg1715His) change in the voltage sensor S4 segment of the T-type channel protein Cav3.1. Two out of 479 index subjects screened subsequently harbored the same mutation. We performed electrophysiological experiments in HEK293T cells to compare the properties of the p.Arg1715His and wild-type Cav3.1 channels. The current-voltage and the steady-state activation curves of the p.Arg1715His channel were shifted positively, whereas the inactivation curve had a higher slope factor. Computer modeling in deep cerebellar nuclei (DCN) neurons suggested that the mutation results in decreased neuronal excitability. Taken together, these data establish CACNA1G, which is highly expressed in the cerebellum, as a gene whose mutations can cause ADCA. This is consistent with the neuropathological examination, which showed severe Purkinje cell loss. Our study further extends our knowledge of the link between calcium channelopathies and CAs.


Assuntos
Canais de Cálcio Tipo T/genética , Cálcio/metabolismo , Ataxia Cerebelar/genética , Ataxia Cerebelar/patologia , Mutação/genética , Neurônios/patologia , Adolescente , Adulto , Idoso , Sequência de Aminoácidos , Ataxia Cerebelar/metabolismo , Criança , Eletrofisiologia , Feminino , Genes Dominantes , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Neurônios/metabolismo , Linhagem , Fenótipo , Células de Purkinje/metabolismo , Células de Purkinje/patologia , Homologia de Sequência de Aminoácidos , Adulto Jovem
15.
Hum Brain Mapp ; 39(12): 5014-5027, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30259598

RESUMO

Parkinson's disease impairs the decoding of emotional stimuli reflecting alterations of the limbic cortico-subcortical network. The objective of this study was to assess and compare the behavioral and electrophysiological effects of both levodopa and subthalamic stimulation on emotional processing in Parkinson's disease. Operated patients (n =16) and matched healthy subjects performed an emotional Stroop task, in which the emotion expressed by a face must be recognized while ignoring an emotional distractive word and that includes a neutral control sub-task. Patients were tested in the four possible treatment conditions (off stim/off med; on stim/off med; off stim/on med; and on stim/on med). High-resolution electroencephalography was recorded while performing the task. Patients made significantly more mistakes in facial emotion recognition than healthy subjects (p < .005). Untreated patients performed worse in the emotional trials than in the control sub-task (p < .05). Fearful faces induced significantly slower reaction times than happy faces in patients (p = .0002), but not in the healthy subjects. The emotional Stroop effect with levodopa was significantly higher than with subthalamic stimulation when fearful faces were assessed (p = .0243). Conversely, treatments did not modulate the Stroop effect of the control sub-task. EEG demonstrated that, compared with the untreated state, levodopa but not subthalamic stimulation significantly increases the amplitude of the event-related potential N170 (p = .002 vs. p = .1, respectively), an electrophysiological biomarker of early aspects of facial processing. The activity of the N170 cortical sources within the right fusiform gyrus was increased by levodopa (p < .05) but not by stimulation. While levodopa normalizes the recognition of emotional facial expression and early EEG markers of emotional processing, subthalamic stimulation does not. Thus, operated patients require dopaminergic medication in addition to stimulation to treat emotional symptoms of Parkinson's disease.


Assuntos
Antiparkinsonianos/farmacologia , Córtex Cerebral/fisiopatologia , Estimulação Encefálica Profunda/métodos , Eletroencefalografia/métodos , Emoções/fisiologia , Potenciais Evocados/fisiologia , Expressão Facial , Reconhecimento Facial/fisiologia , Levodopa/farmacologia , Doença de Parkinson/fisiopatologia , Doença de Parkinson/terapia , Núcleo Subtalâmico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/tratamento farmacológico , Teste de Stroop , Resultado do Tratamento
16.
J Neurol Neurosurg Psychiatry ; 89(8): 836-843, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29436490

RESUMO

BACKGROUND: Reports on behavioural outcomes after subthalamic nucleus deep brain stimulation in Parkinson's disease are controversial and limited to short-term data. Long-term observation in a large cohort allows a better counselling and management. METHODS: To determine whether a long-term treatment with subthalamic stimulation induces or reduces impulse control behaviours, neuropsychiatric fluctuations and apathy, 69 patients treated with subthalamic stimulation are prospectively and retrospectively assessed using Ardouin Scale of Behavior in Parkinson's Disease before and after 3-10 years of stimulation. RESULTS: At a mean follow-up of 6 years, all impulse control disorders and dopaminergic addiction were significantly decreased, apart from eating behaviour and hypersexuality. Neuropsychiatric fluctuations also significantly improved (ON euphoria: 38% of the patients before surgery and 1% after surgery, P<0.01; OFF dysphoria: 39% of the patients before surgery and 10% after surgery, P<0.01). However, apathy increased (25% of the patients after surgery and 3% before, P<0.01). With the retrospective analysis, several transient episodes of depression, apathy, anxiety and impulse control disorders occurred. CONCLUSIONS: Bilateral subthalamic nucleus stimulation was overall very effective in improving impulse control disorders and neuropsychiatric fluctuations in parkinsonian patients in the long term despite a counteracting frequent apathy. Transient episodes of impulse control disorders still occurred within the follow-up. These findings recommend a close follow-up in parkinsonian patients presenting with neuropsychiatric symptoms before deep brain stimulation surgery. CLINICAL TRIAL REGISTRATION: NCT01705418;Post-results.


Assuntos
Cognição/fisiologia , Estimulação Encefálica Profunda , Doença de Parkinson/terapia , Núcleo Subtalâmico/fisiopatologia , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/fisiopatologia , Doença de Parkinson/psicologia , Estudos Retrospectivos , Resultado do Tratamento
17.
Mov Disord ; 33(12): 1878-1886, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30444952

RESUMO

BACKGROUND: Impulse control disorders are frequently associated with dopaminergic therapy in Parkinson's disease. Genetic studies have suggested a high heritability of impulse control disorders in the general population and in PD. The aim of this study was to identify candidate gene variants associated with impulse control disorders and related behaviors in PD. METHODS: We performed a multicenter case-control study in PD patients with (cases) or without impulse control disorders and related behaviors despite significant dopamine agonist exposure of >300 mg levodopa-equivalent daily dose during 12 months (controls). Behavioral disorders were assessed using the Ardouin scale. We investigated 50 variants in 24 candidate genes by a multivariate logistic regression analysis adjusted for sex and age at PD onset. RESULTS: The analysis was performed on 172 cases and 132 controls. Cases were younger (60 ± 8 vs 63 ± 8 years; P < 0.001) and had a higher family history of pathological gambling (12% vs 5%, P = 0.03). No variant was significantly associated with impulse control disorders or related behaviors after correction for multiple testing, although the 2 top variants were close to significant (OPRM1 rs179991, OR, 0.49; 95%CI, 0.32-0.76; P = 0.0013; Bonferroni adjusted P = 0.065; DAT1 40-base pair variable number tandem repeat, OR, 1.82; 95%CI, 1.24-2.68; P = 0.0021; Bonferroni adjusted P = 0.105). CONCLUSIONS: Our results are suggestive of a novel association of the opioid receptor gene OPRM1 with impulse control disorders and related behaviors in PD and confirm a previous association with DAT1. Although replication in independent studies is needed, our results bring potential new insights to the understanding of molecular mechanisms of impulse control disorders. © 2018 International Parkinson and Movement Disorder Society.


Assuntos
Transtornos Disruptivos, de Controle do Impulso e da Conduta/tratamento farmacológico , Transtornos Disruptivos, de Controle do Impulso e da Conduta/metabolismo , Agonistas de Dopamina/uso terapêutico , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Receptores Opioides mu/metabolismo , Adulto , Idoso , Transtornos Disruptivos, de Controle do Impulso e da Conduta/complicações , Feminino , Jogo de Azar/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Fatores de Risco
19.
Rev Neurol (Paris) ; 174(9): 653-663, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30224159

RESUMO

Impulse control disorders (ICDs) and other related behaviors, such as punding and dopamine dysregulation syndrome, are frequent yet underrecognized non-motor complications of dopamine replacement therapy (DRT) in Parkinson's disease (PD); they can also have a major negative impact on quality of life. They result from complex interactions between a given individual's predispositions, non-physiological dopaminergic stimulation and PD pathology. Also, sensitization of the mesocorticolimbic pathway, reflected by the psychotropic effects of dopaminergic treatment, plays a crucial role in the emergence of these addictive behaviors. While early detection of changes in behavior, less use of dopamine agonists (DA) that have a relative selectivity for mesocorticolimbic dopamine receptors, and fractionation of levodopa dosages to avoid non-physiological pulsatile stimulation of dopamine receptors are key strategies in the management of this hyperdopaminergic behavioral spectrum, other complementary approaches are also addressed in this review.


Assuntos
Dopaminérgicos/efeitos adversos , Dopaminérgicos/uso terapêutico , Dopamina , Transtornos Mentais/etiologia , Transtornos Mentais/psicologia , Doença de Parkinson/complicações , Doença de Parkinson/psicologia , Transtornos Disruptivos, de Controle do Impulso e da Conduta/etiologia , Transtornos Disruptivos, de Controle do Impulso e da Conduta/psicologia , Humanos , Doença de Parkinson/tratamento farmacológico
20.
J Neurol Neurosurg Psychiatry ; 88(11): 960-967, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28972096

RESUMO

BACKGROUND: Pallidal deep brain stimulation (globus pallidus internus (GPi) DBS) is the best therapeutic option for disabling isolated idiopathic (IID) and inherited (INH) dystonia. Acquired dystonia (AD) may also benefit from GPi DBS. Efficacy and safety in the long-term remained to be established. OBJECTIVE: To retrospectively assess long-term clinical outcomes and safety in dystonic patients who underwent GPi DBS. METHODS: Patients were videotaped and assessed preoperatively and postoperatively (1-year and at last available follow-up) using the Burke-Fahn-Marsden Dystonia Rating Scale (motor score (BFMDRS-M); disability score (BFMDRS-D)). RESULTS: Sixty-one patients were included (follow-up 7.9±5.9 years; range 1-20.7). In IID and INH (n=37), the BFMDRS-M improved at first (20.4±24.5; p<0.00001) and last (22.2±18.2; p<0.001) follow-ups compared with preoperatively (50.5±28.0). In AD (n=19), the BFMDRS-M ameliorated at 1-year (40.8±26.5; p<0.02) and late follow-ups (44.3±24.3; p<0.04) compared with preoperatively (52.8±24.2). In INH dystonia with other neurological features (n=4) there was no motor benefit. In IID and INH, the BFMDRS-D improved at 1-year (9.5±7.5; p<0.0002) and late follow-ups (10.4±7.8; p<0.016) compared with preoperatively (13.3±6.9). In AD, the BFMDRS-D reduced at 1-year (12.0±8.1; p<0.01) and late follow-ups (12.7 ±6.1; p=0.2) compared with preoperatively (14.35±5.7). Most adverse events were hardware related. CONCLUSIONS: GPi DBS is an effective and safe treatment in most patients with dystonia.


Assuntos
Estimulação Encefálica Profunda , Distúrbios Distônicos/terapia , Globo Pálido/fisiopatologia , Adulto , Distúrbios Distônicos/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
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