RESUMO
BACKGROUND: Impulse control disorders (ICD) are a common and disrupting complication of Parkinson's disease (PD) treatment. Although their relationship with dopaminergic activity is well studied, their brain metabolic correlates are mostly unknown. METHODS: In this work we studied brain metabolism using brain 18F-FDG-PET. We performed a case-control study nested within a cohort of PD patients free of ICD at baseline to compare ICD patients right after ICD diagnosis and prior to any treatment modification with matched ICD-free patients. We also compared both PD groups with healthy controls. RESULTS: When compared with ICD-free PD patients, PD patients with recently diagnosed ICD showed higher glucose metabolism in widespread areas comprising prefrontal cortices, both amygdalae and default mode network hubs (p < 0.05, corrected). When compared to healthy controls, they did not show hypermetabolism, and the only hypometabolic region was the right caudate. In turn, ICD-free patients showed diffuse hypometabolism when compared to healthy controls. CONCLUSION: Our results suggest brain metabolism is more preserved in PD patients with ICD than patients without ICD. This metabolic preservation could be related to ICD development.
Assuntos
Transtornos Disruptivos, de Controle do Impulso e da Conduta , Doença de Parkinson , Encéfalo/diagnóstico por imagem , Estudos de Casos e Controles , Transtornos Disruptivos, de Controle do Impulso e da Conduta/diagnóstico por imagem , Transtornos Disruptivos, de Controle do Impulso e da Conduta/etiologia , Fluordesoxiglucose F18 , Humanos , Doença de Parkinson/diagnóstico por imagemRESUMO
Cognitive decline is a major disabling feature in Parkinson's disease (PD). Multimodal imaging studies have shown functional disruption in neurocognitive networks related to cognitive impairment. However, it remains unknown whether these changes are related to gray matter loss, or whether they outline network vulnerability in the early stages of cognitive impairment. In this work, we intended to assess functional connectivity and graph theoretical measures and their relation to gray matter loss in Parkinson's disease with mild cognitive impairment (PD-MCI). We recruited 53 Parkinson's disease patients and classified them for cognitive impairment using Level-1 Movement Disorders Society-Task Force Criteria. Voxel-based morphometry, functional connectivity and graph theoretical measures were obtained on a 3-Tesla MRI scanner. Loss of gray matter was observed in the default mode network (bilateral precuneus), without a corresponding disruption of functional or graph theoretical properties. However, functional and graph theoretical changes appeared in salience network nodes, without evidence of gray matter loss. Global cognition and executive scores showed a correlation with node degree in the right anterior insula. We also found a correlation between visuospatial scores and right supramarginal gyrus node degree. Our findings highlight the loss of functional connectivity and topological features without structural damage in salience network regions in PD-MCI. They also underline the importance of multimodal hubs in the transition to mild cognitive impairment. This functional disruption in the absence of gray matter atrophy suggests that the salience network is a key vulnerable system at the onset of mild cognitive impairment in PD.
Assuntos
Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Rede Nervosa/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Idoso , Cognição/fisiologia , Disfunção Cognitiva/psicologia , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/psicologiaRESUMO
Essential tremor (ET) is a common movement disorder with an estimated prevalence of 5% of the population aged over 65 years. In spite of intensive efforts, the genetic architecture of ET remains unknown. We used a combination of whole-exome sequencing and targeted resequencing in three ET families. In vitro and in vivo experiments in oligodendrocyte precursor cells and zebrafish were performed to test our findings. Whole-exome sequencing revealed a missense mutation in TENM4 segregating in an autosomal-dominant fashion in an ET family. Subsequent targeted resequencing of TENM4 led to the discovery of two novel missense mutations. Not only did these two mutations segregate with ET in two additional families, but we also observed significant over transmission of pathogenic TENM4 alleles across the three families. Consistent with a dominant mode of inheritance, in vitro analysis in oligodendrocyte precursor cells showed that mutant proteins mislocalize. Finally, expression of human mRNA harboring any of three patient mutations in zebrafish embryos induced defects in axon guidance, confirming a dominant-negative mode of action for these mutations. Our genetic and functional data, which is corroborated by the existence of a Tenm4 knockout mouse displaying an ET phenotype, implicates TENM4 in ET. Together with previous studies of TENM4 in model organisms, our studies intimate that processes regulating myelination in the central nervous system and axon guidance might be significant contributors to the genetic burden of this disorder.
Assuntos
Axônios/patologia , Tremor Essencial/genética , Glicoproteínas de Membrana/genética , Mutação de Sentido Incorreto , Oligodendroglia/patologia , Adulto , Animais , Análise Mutacional de DNA , Tremor Essencial/metabolismo , Tremor Essencial/fisiopatologia , Exoma , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Pessoa de Meia-Idade , Linhagem , Transporte Proteico , Adulto Jovem , Peixe-Zebra/metabolismoRESUMO
OBJECTIVES: The description of minor hallucinatory phenomena (presence, passage hallucinations) has widened the spectrum of psychosis in Parkinson's disease (PD). Minor hallucinatory phenomena seem to antedate the development of more severe hallucinations. Early detection of minor hallucinations may be useful for screening patients with more severe endophenotypes. Motivated by the observation of "de novo," drug-naive PD patients reporting minor hallucinations, we aimed to prospectively identify "de novo" untreated PD patients experiencing hallucinatory phenomena, and to compare their clinico-demographic characteristics with those of untreated PD patients without hallucinations and healthy controls. METHODS: Screening and description of psychosis was assessed by the Movement Disorders Society Unified Parkinson's Disease Rating Scale-Part I and a structured interview covering all types of psychotic phenomena reported in PD. Clinical, neuropsychological, and demographic data of PD patients with and without psychotic phenomena were compared with those of age- and education-matched healthy controls. RESULTS: Fifty drug-naive, "de novo" PD patients and 100 controls were prospectively included. Minor hallucinations were experienced in 42% (21 of 50) PD patients and 5% controls (P < 0.0001). Coexistence of passage and presence hallucinations was the most common finding. Unexpectedly, 33.3% of patients with minor hallucinations manifested these as a pre-motor symptom, starting 7 months to 8 years before first parkinsonian motor symptoms. The presence of minor hallucinations was significantly associated with presence of rapid eye movement sleep behavior disorder. CONCLUSIONS: In this first study to prospectively analyze the frequency of minor hallucinatory phenomena in incident, untreated PD patients, hallucinations appeared as a frequent early non-motor symptom that may even predate the onset of parkinsonism.
Assuntos
Alucinações/etiologia , Doença de Parkinson/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Estatísticas não ParamétricasRESUMO
The pathophysiology and the exact anatomy of essential tremor (ET) is not well known. One of the pillars that support the cerebellum as the main anatomical locus in ET is neurochemistry. This review examines the link between neurochemical abnormalities found in ET and cerebellum. The review is based on published data about neurochemical abnormalities described in ET both in human and in animal studies. We try to link those findings with cerebellum. γ-aminobutyric acid (GABA) is the main neurotransmitter involved in the pathophysiology of ET. There are several studies about GABA that clearly points to a main role of the cerebellum. There are few data about other neurochemical abnormalities in ET. These include studies with noradrenaline, glutamate, adenosine, proteins, and T-type calcium channels. One single study reveals high levels of noradrenaline in the cerebellar cortex. Another study about serotonin neurotransmitter results negative for cerebellum involvement. Finally, studies on T-type calcium channels yield positive results linking the rhythmicity of ET and cerebellum. Neurochemistry supports the cerebellum as the main anatomical locus in ET. The main neurotransmitter involved is GABA, and the GABA hypothesis remains the most robust pathophysiological theory of ET to date. However, this hypothesis does not rule out other mechanisms and may be seen as the main scaffold to support findings in other systems. We clearly need to perform more studies about neurochemistry in ET to better understand the relations among the diverse systems implied in ET. This is mandatory to develop more effective pharmacological therapies.
Assuntos
Cerebelo/metabolismo , Tremor Essencial/metabolismo , Animais , Humanos , Neurônios/metabolismoRESUMO
BACKGROUND: To date, antidepressant drugs show limited efficacy, leaving a large number of patients experiencing severe and persistent symptoms of major depression. Previous open-label clinical trials have reported significant sustained improvements with deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) in patients with severe, chronic treatment-resistant depression (TRD). This study aimed to confirm the efficacy and measure the impact of discontinuation of the electrical stimulation. METHODS: We conducted a 6-month double-blind, randomized, sham-controlled crossover study in implanted patients with previous severe TRD who experienced full remission after chronic stimulation. After more than 3 months of stable remission, patients were randomly assigned to 2 treatment arms: the ON-OFF arm, which involved active electrode stimulation for 3 months followed by sham stimulation for 3 months, and the OFF-ON arm, which involved sham stimulation for 3 months followed by active stimulation for 3 months. The primary outcome measure was the difference in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score between sham and active stimulation. RESULTS: We enrolled 5 patients in our trial. A Friedman repeated-measures analysis of variance revealed a significant effect of treatment (χ(2)1 = 5.0, p = 0.025) in patients with higher depression scores during sham stimulation. At the end of active stimulation, depression was remitted in 4 of 5 patients and none of them had experienced a relapse, whereas at the end of sham stimulation, 2 patients remained in remission, 2 relapsed and 1 showed a progressive worsening without reaching relapse criteria. LIMITATIONS: The small sample size limited the statistical power and external validity. CONCLUSION: These preliminary findings indicate that DBS of the SCG is an effective and safe treatment for severe forms of TRD and that continuous electrical stimulation is required to maintain therapeutic effects. TRIAL REGISTRATION: NCT01268137 (ClinicalTrials.gov).
Assuntos
Estimulação Encefálica Profunda/métodos , Transtorno Depressivo Maior/terapia , Transtorno Depressivo Resistente a Tratamento/terapia , Giro do Cíngulo , Adulto , Estudos Cross-Over , Transtorno Depressivo Maior/patologia , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Resistente a Tratamento/patologia , Transtorno Depressivo Resistente a Tratamento/fisiopatologia , Método Duplo-Cego , Feminino , Giro do Cíngulo/patologia , Giro do Cíngulo/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Escalas de Graduação Psiquiátrica , Prevenção Secundária/métodos , Resultado do TratamentoRESUMO
In the last decades there has been progress in the treatment of essential tremor (TE) especially in the surgical field and to a lesser extent in the pharmacological field. We carry out a review of the currently available treatments. The first intervention is the use of non-pharmacological and non-surgical strategies (general advice, occupational therapy, speech therapy, psychotherapy). With discrete advances, the pharmacological treatment is not very satisfactory. Only 30-60% of patients have a positive response, and in these the anti-tremor effectiveness is 40-60%. The first-line drugs are still propranolol and primidone. In cases with severe tremor we will consider a surgical option, the method of choice being thalamotomy using high-intensity focused ultrasound. In the future we must continue to study the pathophysiology of TE, develop drugs specifically designed for TE and improve the technology of available invasive techniques.
Assuntos
Tremor Essencial , Tremor Essencial/terapia , Tremor Essencial/tratamento farmacológico , Humanos , Propranolol/uso terapêutico , Primidona/uso terapêutico , Ablação por Ultrassom Focalizado de Alta Intensidade , Anticonvulsivantes/uso terapêutico , Tálamo , Antagonistas Adrenérgicos beta/uso terapêuticoRESUMO
OBJECTIVE: The effects of stimulation frequency on verbal fluency (VF) following subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) are not well understood. The present study examines the impact stimulation frequency has on VF following bilateral STN-DBS in PD. METHODS: Prospective study of 38 consecutive patients with PD with low frequency STN-DBS (LFS) (n = 10) and high frequency STN-DBS (HFS) (n = 14), and a non-operated PD control group consisting of patients with fluctuating response to dopaminergic medication (n = 14) homogeneous in age, education, disease duration, and global cognitive function. Patients were evaluated on VF tasks (letter, semantic, action verbs, alternating). A one-way analysis of variance (ANOVA) was conducted to assess distinctions between groups. Pre- and post-surgical comparisons of fluencies were performed for operated groups. A mixed ANOVA was applied to the data to evaluate the interaction between treatment (HFS vs. LFS) and time (pre- vs. post-surgery). Strategy use (clustering and switching) was evaluated. RESULTS: Semantic and letter fluency performance revealed significant differences between HFS and LFS groups. Pre- and post-surgical comparisons revealed HFS negatively affected letter, semantic, and action fluencies, but LFS had no effect on VF. No interaction effect or main effect of treatment was found. Main effect of time was significant for semantic and action fluencies indicating a decrease in postoperative fluency performance. Patients with LFS produced larger average cluster sizes than patients with HFS. CONCLUSION: LFS may be less detrimental to VF, but these findings suggest that VF decline following STN-DBS is not caused by stimulation frequency alone.
RESUMO
Background: We describe our experience of using perampanel to treat essential tremor (ET) over 12 months. Methods: We enrolled 50 ET patients in an open-label trial. Perampanel was titrated to 4 mg/day as adjuvant therapy. The main outcome measures were baseline, +1, +3, +6, and + 12 month scores of the Tremor Clinical Rating Scale (TCRS) and the Glass scale (GS). Results: Twenty patients withdrew because of adverse effects. At +1 month, 27 of 30 patients improved: 68% reduction in both TCRS 1 + 2 (P < 0.001) and TCRS 3 (P < 0.001); TCRS 4 + 1.8 and GS 1.1 point reduction. By +12 months non-persistence of therapeutic effect occurred in 70% of patients: the mean reduction in TCRS 1 + 2 was 33% (P = 0.03), TCRS 3 (0.04), TCRS 4 + 0.8, GS 0.2 points reduction. Conclusions: We report important peramapanel acute tremorolytic effects, but poor tolerance to adverse effects and a non-sustained therapeutic effect in most patients.
RESUMO
Deep brain stimulation (DBS) is currently tested as an experimental therapy for patients with treatment-resistant depression (TRD). Here we report on the short- and long-term (1 yr) clinical outcomes and tolerance of DBS in eight TRD patients. Electrodes were implanted bilaterally in the subgenual cingulate gyrus (SCG; Broadman areas 24-25), and stimulated at 135 Hz (90-µs pulsewidth). Voltage and active electrode contacts were adjusted to maximize short-term responses. Clinical assessments included the 17-item Hamilton Depression Rating Scale (HAMD17; primary measure), the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI) Scale. In the first week after surgery, response and remission (HAMD ⩽7) rates were, respectively 87.5% and 50%. These early responses were followed by an overall worsening, with a response and remission rates of 37.5% (3/8) at 1 month. From then onwards, patients showed a progressive improvement, with response and remission rates of 87.5% and 37.5%, respectively, at 6 months. The corresponding figures at 1 yr were 62.5% and 50%, respectively. Clinical effects were seen in all HAMD subscales without a significant incidence of side-effects. Surgical procedure and post-operative period were well-tolerated for all patients. This is the second independent study on the use of DBS of the SCG to treat chronic depression resistant to current therapeutic strategies. DBS fully remitted 50% of the patients at 1 yr, supporting its validity as a new therapeutic strategy for TRD.
Assuntos
Estimulação Encefálica Profunda/métodos , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/terapia , Transtorno Depressivo Resistente a Tratamento/fisiopatologia , Transtorno Depressivo Resistente a Tratamento/terapia , Giro do Cíngulo/fisiopatologia , Adolescente , Adulto , Idoso , Estimulação Encefálica Profunda/efeitos adversos , Humanos , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Frontal subcortical cognitive defects are predominant in Parkinson's disease (PD). Temporal lobe dysfunction seems more relevant for progression to dementia. We aimed to study the relative importance of temporal lobe defects versus executive impairment in the progression to dementia in PD by using proton magnetic resonance spectroscopy ((1)H-MRS). The (1)H-MRS features of PD patients with intact cognition (PD-CgInt; n = 16), mild cognitive impairment (MCI; n = 15) and dementia (PDD; n = 15) were compared, to delineate the metabolic alterations correlating with cognitive status. Metabolite concentrations were acquired from voxels localized to the hippocampus and dorsolateral prefrontal cortex (DL-PFC). Cognitive status was established following the Movement Disorder Society PDD criteria, administering the Clinical Dementia Rating Scale and Mattis Dementia Rating Scale. The Parkinson's Disease Cognitive Rating Scale (PD-CRS) was used to correlate (1)H-MRS with neuropsychology. N-acetylaspartate (NAA) concentrations in the right DL-PFC were decreased in PD-MCI compared with PD-CgInt patients (p = 0.002), and correlated with frontal subcortical tasks. Decreased NAA concentrations in the left hippocampus in PDD compared to PD-MCI (p = 0.03) correlated with confrontation naming. The present findings support that executive impairment is related to dorsolateral prefrontal dysfunction from the early stages, while progression to dementia is linked to the additional impairment of temporal lobe structures. The PD-CRS was able to capture the differential impairment of prefrontal versus temporal cortical areas.
Assuntos
Química Encefálica/fisiologia , Disfunção Cognitiva/metabolismo , Demência/metabolismo , Doença de Parkinson/metabolismo , Idoso de 80 Anos ou mais , Ácido Aspártico/análogos & derivados , Ácido Aspártico/química , Ácido Aspártico/metabolismo , Cognição/fisiologia , Interpretação Estatística de Dados , Demência/etiologia , Progressão da Doença , Função Executiva , Feminino , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/complicações , Córtex Pré-Frontal/química , Córtex Pré-Frontal/metabolismo , Escalas de Graduação Psiquiátrica , Desempenho Psicomotor/fisiologia , Lobo Temporal/química , Lobo Temporal/metabolismo , Tomografia Computadorizada por Raios XRESUMO
Multiple system atrophy (MSA) is a sporadic alpha-synucleinopathy clinically characterized by variable degrees of parkinsonism, cerebellar ataxia and autonomic dysfunction. The histopathological hallmark of MSA is glial cytoplasmic inclusion (GCI). It is considered to represent the earliest stage of the degenerative process in MSA and to precede neuronal degeneration. Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal, rapidly progressive dementia generally associated with ataxia, pyramidal and extrapyramidal symptoms and myoclonus. Definite diagnosis needs neuropathological demonstration of variable degrees of spongiform degeneration of neuropil, neuronal loss, astro- and microgliosis, and the presence of abnormal deposits of the misfolded prion protein PrP(res) . Both diseases, CJD and MSA are infrequent among neurodegenerative diseases. In the present report we describe clinical and neuropathological findings of a previously healthy 64-year-old woman who developed symptoms of classical CJD. At post mortem examination, the brain showed in addition to classical methionine/methionine PrP(res) type 1 (MM1) sCJD changes and moderate Alzheimer-type pathology, features of "preclinical" MSA with minimal histopathological changes. These were characterized by discrete amounts of alpha-synuclein immunoreacive glial cytoplasmic inclusions in the striato-nigral system, isolated intraneuronal inclusions in pigmented neurons of the substantia nigra, as well as some vermiform intranuclear inclusions. To our knowledge, this is the first report on the coexistence of definite sCJD and "minimal changes" MSA in the same patient.
Assuntos
Síndrome de Creutzfeldt-Jakob/complicações , Síndrome de Creutzfeldt-Jakob/diagnóstico , Atrofia de Múltiplos Sistemas/complicações , Atrofia de Múltiplos Sistemas/diagnóstico , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Dysfunction in gamma-aminobutyric acid (GABA) neurotransmission has emerged as a prime suspect for the underlying neurochemical dysfunction in essential tremor (ET). This dysfunction has been termed the GABA hypothesis. We review findings to date supporting the 4 steps in this hypothesis in studies of cerebrospinal fluid, pathology, genetics, animal models, imaging, computational models, and human drugs, while not overlooking the evidence of negative studies and controversies. It remains to be elucidated whether reduced GABAergic tone is a primary contributing factor to ET pathophysiology, a consequence of altered Purkinje cell function, or even a result of Purkinje cell death. More studies are clearly needed to confirm both the neurodegenerative nature of ET and the reduction in GABA activity in the cerebellum. Also necessary is to test further therapies to enhance GABA transmission specifically focused on the cerebellar area.
Assuntos
Tremor Essencial , Animais , Cerebelo/metabolismo , Cerebelo/patologia , Humanos , Transmissão Sináptica , Ácido gama-Aminobutírico/metabolismoRESUMO
Background: For specialists in charge of Parkinson's disease (PD), one of the most time-consuming tasks of the consultations is the assessment of symptoms and motor fluctuations. This task is complex and is usually based on the information provided by the patients themselves, which in most cases is complex and biased. In recent times, different tools have appeared on the market that allow automatic ambulatory monitoring. The MoMoPa-EC clinical trial (NCT04176302) investigates the effect of one of these tools-Sense4Care's STAT-ON-can have on routine clinical practice. In this sub-analysis the agreement between the Hauser diaries and the STAT-ON sensor is analyzed. Methods: Eighty four patients from MoMoPa-EC cohort were included in this sub-analysis. The intraclass correlation coefficient was calculated between the patient diary entries and the sensor data. Results: The intraclass correlation coefficient of both methods was 0.57 (95% CI: 0.3-0.73) for the OFF time (%), 0.48 (95% CI: 0.17-0.68) for the time in ON (%), and 0.65 (95% CI%: 0.44-0.78) for the time with dyskinesias (%). Furthermore, the Spearman correlations with the UPDRS scale have been analyzed for different parameters of the two methods. The maximum correlation found was -0.63 (p < 0.001) between Mean Fluidity (one of the variables offered by the STAT-dON) and factor 1 of the UPDRS. Conclusion: This sub-analysis shows a moderate concordance between the two tools, it is clearly appreciated that the correlation between the different UPDRS indices is better with the STAT-ON than with the Hauser diary. Trial Registration: https://clinicaltrials.gov/show/NCT04176302 (NCT04176302).
RESUMO
Mild cognitive impairment in Parkinson's disease (PD-MCI) is associated with consistent structural and functional brain changes. Whether different approaches for diagnosing PD-MCI are equivalent in their neural correlates is presently unknown. We aimed to profile the neuroimaging changes associated with the two endorsed methods of diagnosing PD-MCI. We recruited 53 consecutive non-demented PD patients and classified them as PD-MCI according to comprehensive neuropsychological examination as operationalized by the Movement Disorders Task Force. Voxel-based morphometry, cortical thickness, functional connectivity and graph theoretical measures were obtained on a 3-Tesla MRI scanner. 18 patients (32%) were classified as PD-MCI with Level-II criteria, 19 (33%) with the Parkinson's disease Cognitive Rating Scale (PD-CRS) and 32 (60%) with the Montreal Cognitive Assessment (MoCA) scale. Though regions of atrophy differed across classifications, reduced gray matter in the precuneus was found using both Level-II and PD-CRS classifications in PD-MCI patients. Patients diagnosed with the PD-CRS also showed extensive changes in cortical thickness, concurring with the MoCA in regions of the cingulate cortex, and again with Level-II regarding cortical thinning in the precuneus. Functional connectivity analysis found higher coherence within salience network regions of interest, and decreased anticorrelations between salience/central executive and default-mode networks in the PD-CRS classification for PD-MCI patients. Graph theoretical metrics showed a widespread decrease in node degree for the three classifications in PD-MCI, whereas betweenness centrality was increased in select nodes of the default mode network (DMN). Clinical and neuroimaging commonalities between the endorsed methods of cognitive assessment suggest a corresponding set of neural correlates in PD-MCI: loss of structural integrity in DMN structures, mainly the precuneus, and a loss of weighted connections in the salience network that might be counterbalanced by increased centrality in the DMN. Furthermore, the similarity of the results between exhaustive Level-II and screening Level-I tools might have practical implications in the search for neuroimaging biomarkers of cognitive impairment in Parkinson's disease.
Assuntos
Disfunção Cognitiva , Doença de Parkinson , Encéfalo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética/métodos , Testes NeuropsicológicosRESUMO
INTRODUCTION: Essential tremor (ET) is one of the most common movement disorders. Despite its high prevalence and heritability, its genetic etiology remains elusive with only a few susceptibility genes identified and poorly replicated. Our aim was to find novel candidate genes involved in ET predisposition through whole exome sequencing. METHODS: We studied eight multigenerational families (N = 40 individuals) with an autosomal-dominant inheritance using a comprehensive strategy combining whole exome sequencing followed by case-control association testing of prioritized variants in a separate cohort comprising 521 ET cases and 596 controls. We further performed gene-based burden analyses in an additional dataset comprising 789 ET patients and 770 healthy individuals to investigate whether there was an enrichment of rare deleterious variants within our candidate genes. RESULTS: Fifteen variants co-segregated with disease status in at least one of the families, among which rs749875462 in CCDC183, rs535864157 in MMP10 and rs114285050 in GPR151 showed a nominal association with ET. However, we found no significant enrichment of rare variants within these genes in cases compared with controls. Interestingly, MMP10 protein is involved in the inflammatory response to neuronal damage and has been previously associated with other neurological disorders. CONCLUSIONS: We prioritized a set of promising genes, especially MMP10, for further genetic and functional studies in ET. Our study suggests that rare deleterious coding variants that markedly increase susceptibility to ET are likely to be found in many genes. Future studies are needed to replicate and further infer biological mechanisms and potential disease causality for our identified genes.
Assuntos
Tremor Essencial/genética , Predisposição Genética para Doença , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Metaloproteinase 10 da Matriz/genética , Pessoa de Meia-Idade , Linhagem , Sequenciamento do Exoma , Adulto JovemRESUMO
The diagnosis of Parkinson's disease with dementia (PDD) is currently based on clinical criteria (DSM-IV, MDS-Task Force). In daily practice and research studies, these criteria still depend on the subjective impression of the examiner. Brief screening tests (BST) are helpful in identifying patients with PD with dementia, which can be difficult in patients with advanced PD. We aimed to develop a BST for PD, the PDD-Short Screen (PDD-SS), to accurately and quickly screen for PDD. In this prospective study, 70 patients with nondemented (age 73.8 +/- 4.4) and 32 demented (age 73.8 +/- 4.4) PD regularly attending a Movement Disorders Clinic were included. Diagnosis of dementia was based on DSM-IV criteria, CDR score >or=1, and PD-CRS total score Assuntos
Transtornos Cognitivos/diagnóstico
, Transtornos Cognitivos/epidemiologia
, Demência/diagnóstico
, Demência/epidemiologia
, Programas de Rastreamento/métodos
, Testes Neuropsicológicos
, Doença de Parkinson/epidemiologia
, Idoso
, Feminino
, Humanos
, Masculino
, Índice de Gravidade de Doença
RESUMO
The development of visual hallucinations (VH) is a frequent complication of Parkinson's disease (PD). Presence of hallucinations is one of the main risk factors associated with dementia, and severity progression of VH mainly contributes to impaired quality of life in PD. The neuropsychological features associated with severity progression of VH are unknown and might help to detect patients at risk of a more severe outcome. We aimed to explore the neuropsychological deficits associated with the different types of VH observed in PD, from minor hallucinations to well-formed VH with loss of insight. Prospective study of 57 PD patients with (n = 29) and without VH (n = 28) matched for age, education, antiparkinsonian medications, and disease duration. Description of VH was assessed by the Hallucinations and Psychosis item of the MDS-UPDRS. Cognition was assessed with the Parkinson's Disease-Cognitive Rating Scale (PD-CRS) and the Mattis Dementia Rating Scale (MDRS). Patients with minor VH did not differ from patients without VH in any cognitive domain. PD patients with major VH and insight retained performed worse on the action verbal fluency task (P < 0.04), and patients with VH and loss of insight showed a greater impairment on the PD-CRS posterior cortical score (P = 0.021) and the clock copying item (P = 0.01). A double dissociation was found in the neuropsychological profile of patients with VH with and without loss of insight. While the presence of major VH with insight retained appeared related to a predominant frontal-striatal impairment, loss of insight was characterized by further impairment of cognitive functions related to posterior cortical areas. A comprehensible continuum pattern of clinical relationships emerged among VH and cognitive functioning in PD.
Assuntos
Alucinações/complicações , Alucinações/psicologia , Doença de Parkinson/complicações , Qualidade de Vida , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Cognição , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/psicologia , Humanos , Testes Neuropsicológicos , Doença de Parkinson/psicologia , Estudos Prospectivos , Fatores de RiscoRESUMO
We assessed the effects of deep brain stimulation of the subthalamic nucleus (STN-DBS) or internal pallidum (GPi-DBS) on health-related quality of life (HrQoL) in patients with advanced Parkinson's disease participating in a previously reported multicenter trial. Sickness Impact Profile (SIP) questionnaires were available for analysis in a subgroup of n = 20/20 patients with GPi-DBS and n = 45/49 patients with STN-DBS at baseline, 6 and 36 months. The SIP provides a physical dimension and a psychosocial dimension sum score and 12 category scores: Alertness/Intellectual Behavior (AIB), Ambulation (A), Body Care and Movement (BCM), Communication (C), Eating (E), Emotional Behavior (EB), Home Management (HM), Mobility (M), Recreation and Pastimes (RP), Sleep and Rest (SR), Social Interaction (SI), and Work (W). Motor functioning was assessed by means of the Unified Parkinson's Disease Rating Scale and diaries. At 6 months significant improvements in off-period motor symptoms and activities of daily living were paralleled by significant reductions in the total, physical, and psychosocial SIP score in both treatment groups. At 3 years, sustained improvements were observed in the physical dimension score, BCM, E, M, RP after STN-DBS and M, SI after GPi-DBS. All other SIP subscores approached baseline values, but were still the same or better (except C) whereas motor functioning remained stable after 36 months. STN-DBS and GPi-DBS led to significant early improvements in HrQoL. Despite sustained motor improvements many of these initial benefits were lost after 3 years. This may reflect either progression of the disease or adaptive changes in the subjective perception of health-related wellbeing over time.