RESUMO
BACKGROUND: Parkinson's disease (PD) is associated with various non-motor symptoms, including cognitive deterioration. OBJECTIVE: Here, we used data from the DEMPARK/LANDSCAPE cohort to describe the association between progression of cognitive profiles and the PD motor phenotypes: postural instability and gait disorder (PIGD), tremor-dominant (TR-D), and not-determined (ND). METHODS: Demographic, clinical, and neuropsychological six-year longitudinal data of 711 PD-patients were included (age: Mâ=â67.57; 67.4% males). We computed z-transformed composite scores for a priori defined cognitive domains. Analyses were controlled for age, gender, education, and disease duration. To minimize missing data and drop-outs, three-year follow-up data of 442 PD-patients was assessed with regard to the specific role of motor phenotype on cognitive decline using linear mixed modelling (age: Mâ=â66.10; 68.6% males). RESULTS: Our study showed that in the course of the disease motor symptoms increased while MMSE and PANDA remained stable in all subgroups. After three-year follow-up, significant decline of overall cognitive performance for PIGD-patients were present and we found differences for motor phenotypes in attention (ß=â-0.08, SEâ=â0.003, pâ<â0.006) and memory functions showing that PIGD-patients deteriorate per months by -0.006 compared to the ND-group (SEâ=â0.003, pâ=â0.046). Furthermore, PIGD-patients experienced more often difficulties in daily living. CONCLUSION: Over a period of three years, we identified distinct neuropsychological progression patterns with respect to different PD motor phenotypes, with early executive deficits yielding to a more amnestic profile in the later course. Here, in particular PIGD-patients worsened over time compared to TR-D and ND-patients, highlighting the greater risk of dementia for this motor phenotype.
Assuntos
Disfunção Cognitiva , Transtornos Neurológicos da Marcha , Doença de Parkinson , Disfunção Cognitiva/complicações , Feminino , Transtornos Neurológicos da Marcha/diagnóstico , Humanos , Masculino , Testes Neuropsicológicos , Doença de Parkinson/diagnóstico , Fenótipo , Equilíbrio Postural , Tremor/diagnósticoRESUMO
Ataxin-2 (human gene symbol ATXN2) acts during stress responses, modulating mRNA translation and nutrient metabolism. Ataxin-2 knockout mice exhibit progressive obesity, dyslipidemia, and insulin resistance. Conversely, the progressive ATXN2 gain of function due to the fact of polyglutamine (polyQ) expansions leads to a dominantly inherited neurodegenerative process named spinocerebellar ataxia type 2 (SCA2) with early adipose tissue loss and late muscle atrophy. We tried to understand lipid dysregulation in a SCA2 patient brain and in an authentic mouse model. Thin layer chromatography of a patient cerebellum was compared to the lipid metabolome of Atxn2-CAG100-Knockin (KIN) mouse spinocerebellar tissue. The human pathology caused deficits of sulfatide, galactosylceramide, cholesterol, C22/24-sphingomyelin, and gangliosides GM1a/GD1b despite quite normal levels of C18-sphingomyelin. Cerebellum and spinal cord from the KIN mouse showed a consistent decrease of various ceramides with a significant elevation of sphingosine in the more severely affected spinal cord. Deficiency of C24/26-sphingomyelins contrasted with excess C18/20-sphingomyelin. Spinocerebellar expression profiling revealed consistent reductions of CERS protein isoforms, Sptlc2 and Smpd3, but upregulation of Cers2 mRNA, as prominent anomalies in the ceramide-sphingosine metabolism. Reduction of Asah2 mRNA correlated to deficient S1P levels. In addition, downregulations for the elongase Elovl1, Elovl4, Elovl5 mRNAs and ELOVL4 protein explain the deficit of very long-chain sphingomyelin. Reduced ASMase protein levels correlated to the accumulation of long-chain sphingomyelin. Overall, a deficit of myelin lipids was prominent in SCA2 nervous tissue at prefinal stage and not compensated by transcriptional adaptation of several metabolic enzymes. Myelination is controlled by mTORC1 signals; thus, our human and murine observations are in agreement with the known role of ATXN2 yeast, nematode, and mouse orthologs as mTORC1 inhibitors and autophagy promoters.
Assuntos
Ataxina-2/genética , Ceramidas/metabolismo , Esfingomielinas/metabolismo , Ataxias Espinocerebelares/genética , Expansão das Repetições de Trinucleotídeos/genética , Animais , Ataxina-2/metabolismo , Modelos Animais de Doenças , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Humanos , Metabolismo dos Lipídeos/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Knockout , Esfingomielina Fosfodiesterase/genética , Esfingomielina Fosfodiesterase/metabolismo , Esfingosina N-Aciltransferase/genética , Esfingosina N-Aciltransferase/metabolismo , Ataxias Espinocerebelares/metabolismo , Ataxias Espinocerebelares/patologiaRESUMO
OBJECTIVES: Parkinson's disease (PD) is the second most common neurodegenerative disorder and is further associated with progressive cognitive decline. In respect to motor phenotype, there is some evidence that akinetic-rigid PD is associated with a faster rate of cognitive decline in general and a greater risk of developing dementia.The objective of this study was to examine cognitive profiles among patients with PD by motor phenotypes and its relation to cognitive function. METHODS: Demographic, clinical and neuropsychological cross-sectional baseline data of the DEMPARK/LANDSCAPE study, a multicentre longitudinal cohort study of 538 patients with PD were analysed, stratified by motor phenotype and cognitive syndrome. Analyses were performed for all patients and for each diagnostic group separately, controlling for age, gender, education and disease duration. RESULTS: Compared with the tremor-dominant phenotype, akinetic-rigid patients performed worse in executive functions such as working memory (Wechsler Memory Scale-Revised backward; p=0.012), formal-lexical word fluency (p=0.043), card sorting (p=0.006), attention (Trail Making Test version A; p=0.024) and visuospatial abilities (Leistungsprüfungssystem test 9; p=0.006). Akinetic-rigid neuropsychological test scores for the executive and attentive domain correlated negatively with non-tremor motor scores. Covariate-adjusted binary logistic regression analyses showed significant odds for PD-mild cognitive impairment for not-determined as compared with tremor-dominant (OR=3.198) and akinetic-rigid PD (OR=2.059). The odds for PD-dementia were significant for akinetic-rigid as compared with tremor-dominant phenotype (OR=8.314). CONCLUSION: The three motor phenotypes of PD differ in cognitive performance, showing that cognitive deficits seem to be less severe in tremor-dominant PD. While these data are cross-sectional, longitudinal data are needed to shed more light on these differential findings.
Assuntos
Disfunção Cognitiva/etiologia , Doença de Parkinson/fisiopatologia , Doença de Parkinson/psicologia , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/fisiopatologia , Estudos de Coortes , Função Executiva/fisiologia , Feminino , Alemanha , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Atividade Motora/fisiologia , Testes Neuropsicológicos , Doença de Parkinson/complicações , Fenótipo , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: Inconsistent results exist regarding the cognitive profile in patients with Parkinson's disease with mild cognitive impairment (PD-MCI). We aimed at providing data on this topic from a large cohort of patients with PD-MCI. METHODS: Sociodemographic, clinical and neuropsychological baseline data from patients with PD-MCI recruited in the multicentre, prospective, observational DEMPARK/LANDSCAPE study were analysed. RESULTS: 269 patients with PD-MCI (age 67.8±7.4, Unified Parkinson's Disease Rating Scale (UPDRS-III) scores 23.2±11.6) were included. PD-MCI subtypes were 39.4% non-amnestic single domain, 30.5% amnestic multiple domain, 23.4% non-amnestic multiple domain and 6.7% amnestic single domain. Executive functions were most frequently impaired. The most sensitive tests to detect cognitive dysfunctions were the Modified Card Sorting Test, digit span backwards and word list learning direct recall. Multiple stepwise regression analyses showed that global cognition, gender and age, but not education or disease-related parameters predicted PD-MCI subtypes. CONCLUSIONS: This study with the so far largest number of prospectively recruited patients with PD-MCI indicates that non-amnestic PD-MCI is more frequent than amnestic PD-MCI; executive dysfunctions are the most typical cognitive symptom in PD-MCI; and age, gender and global cognition predict the PD-MCI subtype. Longitudinal data are needed to test the hypothesis that patients with PD-MCI with specific cognitive profiles have different risks to develop dementia.
Assuntos
Amnésia/diagnóstico , Amnésia/epidemiologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Doença de Parkinson/diagnóstico , Doença de Parkinson/epidemiologia , Idoso , Amnésia/classificação , Amnésia/psicologia , Disfunção Cognitiva/classificação , Disfunção Cognitiva/psicologia , Estudos Transversais , Função Executiva , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/classificação , Doença de Parkinson/psicologia , Estudos ProspectivosRESUMO
Although antisaccadic task is a sensitive research tool in psychopathology, it has not been systematically studied in patients with spinocerebellar ataxia type 2 (SCA2). To identify putative biomarkers of executive dysfunction in SCA2 we assessed the antisaccade performance in 41 SCA2 patients and their sex-and-age matched controls using an electronystagmography device. We studied the relationship between findings in the antisaccade task and CAG repeat length and motor function as assessed using the Scale for the Assessment and Rating of Ataxia (SARA), Nine-Hole Pegboard Test and a validated battery for executive dysfunctions. SCA2 patients showed a significant increase of inhibition and omission antisaccadic error rates, decrease of corrected antisaccadic errors and prolongation of antisaccadic latency and antisaccadic correction latency. Multiple regression predictions identified the expanded CAG repeat as a significant contributing factor on inhibition antisaccadic error rate and percentage of corrected antisaccadic errors. Impaired antisaccadic performance was associated to higher Stroop interference task and verbal fluency test deficits. In conclusion, antisaccadic eye movement abnormalities are a newly recognized association with the genetic abnormality in SCA2 and correlate with executive dysfunction in SCA2. Antisaccade parameters are a promising source of cognitive biomarkers for exploring the disease pathophysiology, and assessing the efficacy of therapeutic options.