RESUMO
Recently, an intronic biallelic (AAGGG)n repeat expansion in RFC1 was shown to be a cause of CANVAS and adult-onset ataxia in multiple populations. As the prevalence of the RFC1 repeat expansion in Dutch cases was unknown, we retrospectively tested 9 putative CANVAS cases and two independent cohorts (A and B) of 395 and 222 adult-onset ataxia cases, respectively, using the previously published protocol and, for the first time optical genome mapping to determine the size of the expanded RFC1 repeat. We identified the biallelic (AAGGG)n repeat expansion in 5/9 (55%) putative CANVAS patients and in 10/617 (1.6%; cohorts A + B) adult-onset ataxia patients. In addition to the AAGGG repeat motif, we observed a putative GAAGG repeat motif in the repeat expansion with unknown significance in two adult-onset ataxia patients. All the expanded (AAGGG)n repeats identified were in the range of 800-1299 repeat units. The intronic biallelic RFC1 repeat expansion thus explains a number of the Dutch adult-onset ataxia cases that display the main clinical features of CANVAS, and particularly when ataxia is combined with neuropathy. The yield of screening for RFC1 expansions in unselected cohorts is relatively low. To increase the current diagnostic yield in ataxia patients, we suggest adding RFC1 screening to the genetic diagnostic workflow by using advanced techniques that attain long fragments.
Assuntos
Ataxia Cerebelar , Doenças do Sistema Nervoso Periférico , Adulto , Ataxia , Ataxia Cerebelar/genética , Humanos , Prevalência , Estudos RetrospectivosRESUMO
PURPOSE: Chronic traumatic encephalopathy refers to a neurodegenerative disease resulting from repetitive head injury of participants in contact sports. Similar to other neurodegenerative diseases, neuroinflammation is thought to play a role in the onset and progression of the disease. Limited knowledge is available regarding the neuroinflammatory consequences of repetitive head injury in currently active contact sports athletes. PET imaging of the 18-kDa translocator protein (TSPO) allows quantification of microglial activation in vivo, a marker of neuroinflammation. METHODS: Eleven rank A kickboxers and 11 age-matched controls underwent TSPO PET using [11C]-PK11195, anatomical MRI, diffusion tensor imaging, and neuropsychological testing. Relevant imaging parameters were derived and correlated with the outcomes of the neuropsychological testing. RESULTS: On a group level, no statistically significant differences were detected in non-displaceable binding potential (BPND) using PET. Individually, 3 kickboxers showed increased BPNDs in widespread regions of the brain without a correlation with other modalities. Increased FA was observed in the superior corona radiata bilaterally. DTI parameters in other regions did not differ between groups. CONCLUSION: Despite negative results on a group level, individual results suggest that neuroinflammation may be present as a consequence of repetitive head injury in active kickboxers. Future studies using a longitudinal design may determine whether the observed TSPO upregulation is related to the future development of neuropsychiatric symptoms.
Assuntos
Traumatismos em Atletas , Traumatismos Craniocerebrais , Doenças Neurodegenerativas , Doenças Neuroinflamatórias , Traumatismos em Atletas/diagnóstico por imagem , Encéfalo/metabolismo , Traumatismos Craniocerebrais/diagnóstico por imagem , Traumatismos Craniocerebrais/metabolismo , Imagem de Tensor de Difusão , Humanos , Artes Marciais/lesões , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neuroinflamatórias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Receptores de GABA/metabolismoRESUMO
Pornographic addiction refers to an addiction model associated with compulsive and repeated use of pornographic material. Whether the use of pornography may indeed become addictive remains a matter of debate. The current study investigated whether compulsive pornography use (CPU) is accompanied by reduced D2/3 receptor availability in the striatum and frontal hypofunctionality. Male subjects between 18 and 50 years of age with and without CPU were recruited using online and newspaper advertisements. Questionnaires were used to the assess the severity of compulsive pornography use (CIUS) and symptoms of depression, impulsivity and sensation seeking. Dopaminergic imaging was performed using [11C]-raclopride PET. Striatal binding potentials (BPND) and regional frontal cerebral influx values (R1) of [11C]-raclopride were calculated. Arterial Spin Labeling (ASL) MRI was performed to assess regional cerebral blood flow. No group differences between striatal BPND's of [11C]-raclopride in subjects with (n = 15) and without (n = 10) CPU were detected. In CPU subjects, no correlation was found between the CIUS score and striatal BPND's. Cerebral R1 values in frontal brain regions and cerebral blood flow measurements did not differ between groups. The current study fails to provide imaging support for sharing similar neurobiological alterations as previously has been reported in other addictive modalities.
Assuntos
Literatura Erótica , Tomografia por Emissão de Pósitrons , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Humanos , Masculino , Racloprida , Receptores de Dopamina D2/metabolismoRESUMO
AIM: L -3,4-dihydroxy-6-18F-fluorophenylalanine (18F-DOPA PET may be used to distinguish subjects with Parkinsonism from those with symptoms not originating from impaired dopaminergic transmission. However, it is not routinely utilized to discriminate Idiopathic Parkinson's disease (IPD) from Atypical Parkinsonian Disorders (APD). We investigated the potential of FDOPA PET to discriminate between IPD and APD, with a focus on the anterior-to-posterior decline in het striatum, considered to be more specific for IPD. MATERIALS AND METHODS: 18F-DOPA PET data from a total of 58 subjects were retrospectively analyzed. 28 subjects had idiopathic Parkinson's disease (14 male, 14 female; age at scan 61 +- 11,5), 13 atypical Parkinsonian disease (7 male, 6 females; age at scan: 69,6 +- 6,4) and 17 were controls (6 male, 11 female; age at scan 65,3 +-8,6). Regional striatal-to-occipital ratio's (RSOR's) were calculated, as well as multiple in-line VOI's from the caudate nucleus to the posterior part of the putamen. The linearity of anteroposterior decline was determined by a linear regression fit and associated R squared values. ROC curves were calculated to assess the diagnostic performance of these measurements. Data contralateral to the clinically most affected side were used for analysis. RESULTS: ROC curve analysis for differentiation between controls and Parkinsonism patients showed the highest AUC for the caudate nucleus-to-posterior putamen ratio (AUC = 0.930; p < 0.00) and for the R squared value for the linear regression fit (AUC = 0.948; p = 0.006). For discrimating IPD from APD, the highest AUC was found for the caudate nucleus-to-anterior putamen ratio (0.824; p < 0.001) CONCLUSIONS: Subregional analysis of the striatum in F-DOPA PET scans may provide additional diagnostic information in patients screened for a presynaptic dopaminergic deficit. A more linear decrease from the head of the caudate nucleus to the posterior putamen was present in patients with IPD, although this feature did not have additional diagnostic value over the RSOR analysis.
Assuntos
Corpo Estriado/diagnóstico por imagem , Di-Hidroxifenilalanina/análogos & derivados , Neuroimagem/métodos , Transtornos Parkinsonianos/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Idoso , Núcleo Caudado/diagnóstico por imagem , Diagnóstico Diferencial , Di-Hidroxifenilalanina/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Putamen/diagnóstico por imagem , Estudos RetrospectivosRESUMO
PURPOSE: People with neuromuscular disease experience lower quality of life levels than people from the general population. We examined the prevalence and severity of a broad range of neuromuscular disease-related disabilities and their impact on health-related quality of life. MATERIALS AND METHODS: A cross-sectional postal survey study was conducted among patients diagnosed with neuromuscular disease. Patients completed the Neuromuscular Disease Impact Profile, a disease-related disability impact questionnaire, and two generic health-related quality of life questionnaires: the medical outcome study Short Form Questionnaire and the World Health Organization Quality of Life-bref. The impact of disabilities on quality of life was estimated using multiple regression analyses. RESULTS: Six hundred sixty two patients (68% response rate) completed the questionnaires. There were no differences in quality of life between diagnosis-based subgroups. 'Impairments in muscle functions' had the highest prevalence and severity scores in the total sample and diagnosis-based subgroups. Neuromuscular disease-related disabilities showed strong and independent associations with all aspects of health-related quality of life. 'Impairments in mental functions and pain' was the most important predictor of health-related quality of life followed by 'restrictions in participation in life situations'. CONCLUSIONS: Although 'impairment in muscle functions' is the most prevalent and severe disability, the 'impairments in mental functions and pain' have a strong association with health-related quality of life in patients with a neuromuscular disease. Implications for rehabilitation Disease-related disabilities have a strong and independent associations with all aspects of health-related quality of life. Although health-related domains of quality of life are affected by the neuromuscular disease, the general quality of life is quite good. The most prevalent and severe disability in total group and diagnosis-based subgroups is 'impairments in muscle functions'. The most significant predictor in health-related quality of life is 'impairments in mental functions and pain'.
Assuntos
Pessoas com Deficiência , Doenças Neuromusculares/fisiopatologia , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Índice de Gravidade de Doença , Inquéritos e Questionários , Adulto JovemRESUMO
The autosomal dominant cerebellar ataxias, referred to as spinocerebellar ataxias in genetic nomenclature, are a rare group of progressive neurodegenerative disorders characterized by loss of balance and coordination. Despite the identification of numerous disease genes, a substantial number of cases still remain without a genetic diagnosis. Here, we report five novel spinocerebellar ataxia genes, FAT2, PLD3, KIF26B, EP300, and FAT1, identified through a combination of exome sequencing in genetically undiagnosed families and targeted resequencing of exome candidates in a cohort of singletons. We validated almost all genes genetically, assessed damaging effects of the gene variants in cell models and further consolidated a role for several of these genes in the aetiology of spinocerebellar ataxia through network analysis. Our work links spinocerebellar ataxia to alterations in synaptic transmission and transcription regulation, and identifies these as the main shared mechanisms underlying the genetically diverse spinocerebellar ataxia types.
Assuntos
Redes Reguladoras de Genes/genética , Ataxias Espinocerebelares/genética , Animais , Células COS , Caderinas/genética , Chlorocebus aethiops , Proteína p300 Associada a E1A/genética , Exoma/genética , Feminino , Células HEK293 , Humanos , Cinesinas/genética , Masculino , Linhagem , Fosfolipase D/genética , Plasmídeos , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , TransfecçãoRESUMO
Spinocerebellar ataxia type 13 (SCA13) is an autosomal dominantly inherited neurodegenerative disorder of the cerebellum caused by mutations in the voltage gated potassium channel KCNC3. To identify novel pathogenic SCA13 mutations in KCNC3 and to gain insights into the disease prevalence in the Netherlands, we sequenced the entire coding region of KCNC3 in 848 Dutch cerebellar ataxia patients with familial or sporadic origin. We evaluated the pathogenicity of the identified variants by co-segregation analysis and in silico prediction followed by biochemical and electrophysiological studies. We identified 19 variants in KCNC3 including 2 non-coding, 11 missense and 6 synonymous variants. Two missense variants did not co-segregate with the disease and were excluded as potentially disease-causing mutations. We also identified the previously reported p.R420H and p.R423H mutations in our cohort. Of the remaining 7 missense variants, functional analysis revealed that 2 missense variants shifted Kv3.3 channel activation to more negative voltages. These variations were associated with early disease onset and mild intellectual disability. Additionally, one other missense variant shifted channel activation to more positive voltages and was associated with spastic ataxic gait. Whereas, the remaining missense variants did not change any of the channel characteristics. Of these three functional variants, only one variant was in silico predicted to be damaging and segregated with disease. The other two variants were in silico predicted to be benign and co-segregation analysis was not optimal or could only be partially confirmed. Therefore, we conclude that we have identified at least one novel pathogenic mutation in KCNC3 that cause SCA13 and two additionally potential SCA13 mutations. This leads to an estimate of SCA13 prevalence in the Netherlands to be between 0.6% and 1.3%.
Assuntos
Canais de Potássio Shaw/genética , Canais de Potássio Shaw/metabolismo , Ataxias Espinocerebelares/genética , População Branca/genética , Adulto , Idoso , Simulação por Computador , Estudos de Associação Genética , Predisposição Genética para Doença , Células HeLa , Humanos , Pessoa de Meia-Idade , Mutação , Países Baixos , Análise de Sequência de DNA , Ataxias Espinocerebelares/metabolismo , Adulto JovemRESUMO
BACKGROUND: Down syndrome (DS) is the most prevalent genetic cause of intellectual disability. Early-onset Alzheimer's disease (AD) frequently develops in DS and is characterized by progressive memory loss and behavioral and psychological signs and symptoms of dementia (BPSD). Predicting and monitoring the progression of AD in DS is necessary to enable adaptive caretaking. OBJECTIVE: Reliable blood biomarkers that aid the prediction of AD are necessary, since cerebrospinal fluid sampling is rather burdensome, particularly for people with DS. Here, we investigate serum levels of eight biogenic amines and their metabolites in relation to dementia staging and probable BPSD items. METHODS: Using RP-HPLC with electrochemical detection, (nor)adrenergic (NA/A and MHPG), serotonergic (5-HT and 5-HIAA), and dopaminergic (DA, HVA, and DOPAC) compounds were quantified in the serum of DS subjects with established AD at baseline (n = 51), DS subjects without AD (n = 50), non-demented DS individuals that converted to AD over time (n = 50), and, finally, healthy non-DS controls (n = 22). RESULTS: Serum MHPG levels were significantly lower in demented and converted DS subjects (p < 0.0001) compared to non-demented DS individuals and healthy controls. Those subjects with MHPG levels below median had a more than tenfold increased risk of developing dementia. Furthermore, significant correlations were observed between monoaminergic serum values and various probable BPSD items within each DS group. CONCLUSION: Decreased serum MHPG levels show great potential as biomarker to monitor and predict conversion to AD in DS. Moreover, significant monoaminergic alterations related to probable BPSD items, suggesting that monoaminergic dysregulation is an underlying biological mechanism, and demonstrating the need to develop a validated rating scale for BPSD in DS.
Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/sangue , Síndrome de Down/sangue , Metoxi-Hidroxifenilglicol/sangue , Fragmentos de Peptídeos/sangue , Doença de Alzheimer/sangue , Biomarcadores/sangue , Progressão da Doença , Dopamina/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Norepinefrina/sangueRESUMO
BACKGROUND: Several studies have suggested that language impairment can be observed in patients with cerebellar pathology. The aim of this study was to investigate language performance in patients with spinocerebellar ataxia type 6 (SCA6). METHODS: We assessed speech and language in 29 SCA6 patients with standardized linquistic tests and correlated this with the severity of ataxia, as quantified by the Scale of Assessment and Rating of Ataxia. RESULTS: Individual patients show mild-to-moderate linguistic impairment. Linguistic abnormalities were most distinct on the writing and comprehension subtests. A strong correlation between severity of ataxia and linguistic performance was consistently found. CONCLUSIONS: This study confirms the occurrence of linguistic impairments in patients with cerebellar degenerative diseases, such as SCA6. The relation between linguistic abnormalities and severity of ataxia provides further evidence for a role of the cerebellum in linguistic processing.
Assuntos
Ataxia Cerebelar/complicações , Transtornos da Linguagem/etiologia , Idoso , Idoso de 80 Anos ou mais , Canais de Cálcio/genética , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Feminino , Humanos , Transtornos da Linguagem/diagnóstico , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Índice de Gravidade de DoençaRESUMO
OBJECTIVES: National guidelines recommend mobilisation in bed as early as possible after acute stroke. Little is known about the influence of upright positioning on real-time cerebral flow variables in patients with stroke. We aimed to assess whether cerebral blood flow velocity (CBFV) changes significantly after upright positioning in bed in the acute stroke phase. DESIGN: Observational study. PARTICIPANTS: 47 patients with acute ischaemic stroke measured in the subacute phase after symptom onset and 20 healthy controls. PRIMARY AND SECONDARY OUTCOME MEASURES: We recorded postural changes in bilateral transcranial Doppler (primary outcome) and simultaneously recorded near-infrared spectroscopy, end-tidal CO2, non-invasive blood pressure data and changes in neurological status (secondary outcomes). METHODS: Postures included the supine, half sitting (45°), sitting (70°) and Trendelenburg (-15°) positions. Using multilevel analyses, we compared postural changes between hemispheres, outcome groups (using modified Rankin Scale) as well as between patients and healthy controls. RESULTS: The mean patient age was 62±15 years and median National Institute of Health Stroke Scale score on admission was 7 (IQR 5-14). Mean proportional CBFV changes on sitting were not significantly different between healthy controls and affected hemispheres in patients with stroke. No significant differences were found between affected and unaffected stroke hemispheres and between patients with unfavourable and favourable outcomes. During upright positioning, no neurological worsening or improvement was observed in any of the patients. CONCLUSIONS: No indications were found that upright positioning in bed in mild to moderately affected patients with stroke compromises flow and (frontal)oxygenation significantly during the subacute phase of stroke. Supine or Trendelenburg positioning does not seem to augment real-time flow variables.
RESUMO
BACKGROUND: Ongoing growth in health care expenditures and changing patterns in the demand for health care challenge societies worldwide. The Chronic Care Model (CCM), combined with classification for care needs based on Kaiser Permanente (KP) Triangle, may offer a suitable framework for change. The aim of the present study is to investigate the effectiveness of Embrace, a population-based model for integrated elderly care, regarding patient outcomes, service use, costs, and quality of care. METHODS/DESIGN: The CCM and the KP Triangle were translated to the Dutch setting and adapted to the full elderly population living in the community. A randomized controlled trial with balanced allocation was designed to test the effectiveness of Embrace. Eligible elderly persons are 75 years and older and enrolled with one of the participating general practitioner practices. Based on scores on the INTERMED-Elderly Self-Assessment and Groningen Frailty Indicator, participants will be stratified into one of three strata: (A) robust; (B) frail; and (C) complex care needs. Next, participants will be randomized per stratum to Embrace or care as usual. Embrace encompasses an Elderly Care Team per general practitioner practice, an Electronic Elderly Record System, decision support instruments, and a self-management support and prevention program - combined with care and support intensity levels increasing from stratum A to stratum C. Primary outcome variables are patient outcomes, service use, costs, and quality of care. Data will be collected at baseline, twelve months after starting date, and during the intervention period. DISCUSSION: This study could provide evidence for the effectiveness of Embrace. TRIAL REGISTRATION: The Netherlands National Trial Register NTR3039.
Assuntos
Custos de Cuidados de Saúde/normas , Assistência ao Paciente/economia , Assistência ao Paciente/normas , Qualidade da Assistência à Saúde/economia , Qualidade da Assistência à Saúde/normas , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Países Baixos/epidemiologia , Assistência ao Paciente/estatística & dados numéricos , Qualidade da Assistência à Saúde/estatística & dados numéricos , Resultado do TratamentoRESUMO
Cerebral vessels can keep cerebral perfusion more or less constant. This process is called cerebral vasoregulation and can be measured using different neuromonitoring techniques, which will be discussed in this overview. Cerebral perfusion deficits after brain damage caused by a cerebrovascular accident (CVA), subarachnoid haemorrhage (SAH) or severe traumatic skull and brain injury (TSBI) can be detected early and better understood by using these techniques. In current clinical guidelines on the treatment of CVA, SAB and TSBI, impaired cerebral vasoregulation is often assumed. However, there is a need to measure cerebral vasoregulation status at the individual level, with follow-up over time. Some vasoregulation techniques inform the clinician about subtle local regulation disorders ('snapshot' assessment). Other techniques are suitable for the global long-term monitoring of vasoregulation ('monitoring' assessment) where the results could serve as feedback for treatment interventions. Appropriate use of the techniques in daily clinical practice requires standardisation of the methods available for the monitoring of cerebral vasoregulation. Presently, use is mostly restricted to the research setting.
Assuntos
Circulação Cerebrovascular/fisiologia , Homeostase/fisiologia , Monitorização Fisiológica/métodos , Pressão Sanguínea/fisiologia , Lesões Encefálicas/fisiopatologia , Isquemia Encefálica/fisiopatologia , Humanos , Monitorização Fisiológica/instrumentação , Perfusão , Acidente Vascular Cerebral/fisiopatologia , Hemorragia Subaracnóidea/fisiopatologiaRESUMO
INTRODUCTION: Psychosis is a common and difficult to treat symptom in Alzheimer's disease (AD). It is a cause of diminished quality of life and caregiver distress. Atypical antipsychotics are frequently used for the treatment of dementia-related psychosis, despite FDA warnings because of increased mortality associated with the use of these medications in dementia patients. Aripiprazole is a newer atypical antipsychotic drug with partial agonist activity at dopamine receptors and antagonist activity at 5-HT(2A) receptors, with a low side-effect profile. AREAS COVERED: This descriptive review gives a short overview of the pathology and epidemiology of AD, including psychotic symptoms, and describes the mode of action of aripiprazole and results of preclinical studies. Finally, randomized controlled trials evaluating the use of aripiprazole in AD-related psychosis and agitation are discussed. Whenever relevant, meta-analytical data from literature are referred to. EXPERT OPINION: In randomized placebo-controlled clinical trials, aripiprazole shows modest efficacy in the treatment of AD-related psychosis. Neuropsychiatric symptoms alleviated were predominantly psychotic features and agitation. In individual trials, aripiprazole was generally well tolerated, serious side effects were seldom reported and included accidental injury and somnolence. Meta-analyses however demonstrated increased mortality as a class effect for atypical, but also for typical antipsychotics. No increased cardiovascular outcomes, cerebrovascular accidents, increased appetite or weight gain were demonstrated in meta-analyses for aripiprazole-treated patients with psychosis of dementia. Aripiprazole was found to induce sedation. Aripiprazole should only be used in selected patient populations resistant to non-pharmacological treatment with persisting or severe psychotic symptoms and/or agitation, and in which symptoms lead to significant morbidity, patient suffering and potential self-harm. The indication for continuing treatment should be revised regularly.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Antipsicóticos/uso terapêutico , Agonistas de Dopamina/uso terapêutico , Piperazinas/uso terapêutico , Transtornos Psicóticos/tratamento farmacológico , Quinolonas/uso terapêutico , Antagonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Aripiprazol , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/efeitos adversos , Humanos , Metanálise como Assunto , Uso Off-Label , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Transtornos Psicóticos/epidemiologia , Transtornos Psicóticos/metabolismo , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor 5-HT2A de Serotonina/metabolismo , Receptores Dopaminérgicos/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Antagonistas do Receptor 5-HT2 de Serotonina/efeitos adversosRESUMO
BACKGROUND: The prognostic value of serum uric acid (UA) in acute ischemic stroke is controversial. The aim of this study is to further analyse the relation between UA and outcome after acute ischemic stroke. METHODS: We analysed UA levels in blood samples collected within 6h of stroke onset from patients included in the placebo arm of the US and Canadian Lubeluzole Ischemic Stroke Study (LUB-INT-9). We compared mean serum UA levels in patients with and without early neurological improvement (≥ 4 versus <4 points improvement on NIHSS after 5 days) and in patients with good functional and poor functional outcome (mRS 0-2 versus mRS 3-6). Multivariable logistic regression analyses were performed to adjust for possible confounders. RESULTS: UA levels of 226 patients were available for analysis. Mean serum UA levels were not significantly higher in patients with than without early neurological improvement (0.33 mmol/L versus 0.30 mmol/L, p=0.070). The difference between patients with good and patients with poor functional outcome was borderline statistically significant (0.34 mmol/L versus 0.31 mmol/L, p=0.050). After adjustment for confounders, higher serum UA levels were neither associated with early neurological improvement OR (1.30, 95% CI 0.98-1.73, p=0.069), nor with a good functional outcome (OR 1.09, 95% CI 0.72-1.65, p=0.690). CONCLUSION: We found no association between admission serum UA levels and both short- and long-term outcome in acute ischemic stroke.
Assuntos
Isquemia Encefálica/sangue , Recuperação de Função Fisiológica/fisiologia , Acidente Vascular Cerebral/sangue , Ácido Úrico/sangue , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder caused by mutations in the SACS gene (13q12) encoding the protein sacsin. It is characterized by early-onset cerebellar ataxia, lower limb spasticity, sensorimotor axonal polyneuropathy, and atrophy of the superior cerebellar vermis. Cerebellar disorders in general may be accompanied by the cerebellar cognitive affective syndrome (CCAS) which presents with disturbances of executive functioning, spatial cognition, linguistic capacities, and affect. SAMPLING AND METHODS: Two middle-aged brothers with ARSACS, one of whom was referred for behavioral disinhibition, are described. A detailed neuropsychiatric and neuropsychological assessment was performed. RESULTS: Apart from motor symptoms, motivational deficits along with cognitive and behavioral dysfunctions were present; these were much more pronounced in the older sib. CONCLUSIONS: These observations add to the literature which suggests that the cerebellum, apart from its significance for motor behavior, plays a functional role in human cognition and affect. The nonmotor symptoms of ARSACS are discussed in terms of the CCAS.
Assuntos
Encéfalo/patologia , Doenças Cerebelares/diagnóstico , Transtornos Cognitivos/diagnóstico , Transtornos do Humor/diagnóstico , Espasticidade Muscular/diagnóstico , Ataxias Espinocerebelares/congênito , Atrofia , Doenças Cerebelares/genética , Doenças Cerebelares/patologia , Transtornos Cognitivos/genética , Transtornos Cognitivos/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/genética , Transtornos do Humor/patologia , Espasticidade Muscular/genética , Espasticidade Muscular/patologia , Testes Neuropsicológicos , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologiaRESUMO
Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder with multisystem involvement and cancer predisposition, caused by mutations in the A-T mutated (ATM) gene. To study genotype-phenotype correlations, we evaluated the clinical and laboratory data of 51 genetically proven A-T patients, and additionally measured ATM protein expression and kinase activity. Patients without ATM kinase activity showed the classical phenotype. The presence of ATM protein, correlated with slightly better immunological function. Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X-ray hypersensitivity in lymphocytes, and extended lifespan. In these patients, cancer occurred later in life and generally consisted of solid instead of lymphoid malignancies. The genotypes of severely affected patients generally included truncating mutations resulting in total absence of ATM kinase activity, while patients with milder phenotypes harbored at least one missense or splice site mutation resulting in expression of ATM with some kinase activity. Overall, the phenotypic manifestations in A-T show a continuous spectrum from severe classical childhood-onset A-T to a relatively mild adult-onset disorder, depending on the presence of ATM protein and kinase activity. Each patient is left with a tremendously increased cancer risk.
Assuntos
Ataxia Telangiectasia/metabolismo , Ataxia Telangiectasia/patologia , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adolescente , Adulto , Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/genética , Criança , Proteínas de Ligação a DNA/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Adulto JovemRESUMO
OBJECTIVE: To identify the causative gene for the neurodegenerative disorder spinocerebellar ataxia type 19 (SCA19) located on chromosomal region 1p21-q21. METHODS: Exome sequencing was used to identify the causal mutation in a large SCA19 family. We then screened 230 ataxia families for mutations located in the same gene (KCND3, also known as Kv4.3) using high-resolution melting. SCA19 brain autopsy material was evaluated, and in vitro experiments using ectopic expression of wild-type and mutant Kv4.3 were used to study protein localization, stability, and channel activity by patch-clamping. RESULTS: We detected a T352P mutation in the third extracellular loop of the voltage-gated potassium channel KCND3 that cosegregated with the disease phenotype in our original family. We identified 2 more novel missense mutations in the channel pore (M373I) and the S6 transmembrane domain (S390N) in 2 other ataxia families. T352P cerebellar autopsy material showed severe Purkinje cell degeneration, with abnormal intracellular accumulation and reduced protein levels of Kv4.3 in their soma. Ectopic expression of all mutant proteins in HeLa cells revealed retention in the endoplasmic reticulum and enhanced protein instability, in contrast to wild-type Kv4.3 that was localized on the plasma membrane. The regulatory ß subunit Kv channel interacting protein 2 was able to rescue the membrane localization and the stability of 2 of the 3 mutant Kv4.3 complexes. However, this either did not restore the channel function of the membrane-located mutant Kv4.3 complexes or restored it only partially. INTERPRETATION: KCND3 mutations cause SCA19 by impaired protein maturation and/or reduced channel function.
Assuntos
Predisposição Genética para Doença , Mutação de Sentido Incorreto/genética , Canais de Potássio Shal/genética , Degenerações Espinocerebelares/genética , Idoso , Idoso de 80 Anos ou mais , Encéfalo/patologia , Estudos de Casos e Controles , Imunoprecipitação da Cromatina , Cicloeximida/farmacologia , Análise Mutacional de DNA , Progressão da Doença , Saúde da Família , Feminino , Estudos de Associação Genética , Genótipo , Células HEK293/metabolismo , Células HeLa/patologia , Humanos , Proteínas Luminescentes/genética , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/genética , Técnicas de Patch-Clamp , Inibidores da Síntese de Proteínas/farmacologia , Coloração pela Prata , Degenerações Espinocerebelares/patologia , Fatores de Tempo , TransfecçãoRESUMO
To assess the clinical spectrum of ataxia and cerebellar oculomotor deficits in the most common spinocerebellar ataxias (SCAs), we analysed the baseline data of the EUROSCA natural history study, a multicentric cohort study of 526 patients with either spinocerebellar ataxia type 1, 2, 3 or 6. To quantify ataxia symptoms, we used the Scale for the Assessment and Rating of Ataxia (SARA). The presence of cerebellar oculomotor signs was assessed using the Inventory of Non-Ataxia Symptoms (INAS). In a subgroup of patients, in which magnetic resonance images (MRIs) were available, we correlated MRI morphometric measures with clinical signs on an exploratory basis. The SARA subscores posture and gait (items 1-3), speech (item 4) and the limb kinetic subscore (items 5-8) did not differ between the genotypes. The scores of SARA item 3 (sitting), 5 (finger chase) and 6 (nose-finger test) differed between the subtypes whereas the scores of the remaining items were not different. In SCA1, ataxia symptoms were correlated with brainstem atrophy and in SCA3 with both brainstem and cerebellar atrophy. Cerebellar oculomotor deficits were most frequent in SCA6 followed by SCA3, whereas these abnormalities were less frequent in SCA1 and SCA2. Our data suggest that vestibulocerebellar, spinocerebellar and pontocerebellar circuits in SCA1, SCA2, SCA3 and SCA6 are functionally impaired to almost the same degree, but at different anatomical levels. The seemingly low prevalence of cerebellar oculomotor deficits in SCA1 and SCA2 is most probably related to the defective saccadic system in these disorders.
Assuntos
Tronco Encefálico/patologia , Cerebelo/patologia , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ataxia/diagnóstico , Ataxia/patologia , Atrofia , Estudos de Coortes , Feminino , Transtornos Neurológicos da Marcha/diagnóstico , Transtornos Neurológicos da Marcha/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Blood pressure (BP) is one of the major vital parameters monitored in the stroke unit. The accuracy of indirect BP measurement is strongly influenced by the position of both patient and arm during the measurement. Acute stroke patients are often nursed in lateral decubitus positions. The effect of these alternating body positions in relation to affected body side on the outcome and reliability of BP readings in acute stroke patients is unknown. METHODS: An automatic oscillometric BP device was used. BP was measured in both arms in the (back) supine and both lateral decubitus positions. RESULTS: In total, 54 consecutive acute stroke patients were included. Thirty-five patients had right-sided deficits and 19 patients had left-sided deficits. Supine BP readings were similar in the right and left arms regardless of side of deficit. Measurements of BP in the lateral decubitus positions resulted in significantly lower BP readings in the uppermost arm (around 12 mm Hg in both arms) and significantly higher readings in the right lowermost arm (around 6 mm Hg) compared to the supine position. This effect seemed less pronounced when the left lowermost arm was measured. There was no relation between change of BP readings in various lateral positions and side of stroke. CONCLUSIONS: Alternating lateral decubitus positions according to nursing standards in acute stroke patients lead to a mean 18 mm Hg BP fluctuation. This may largely be explained by hydrostatic pressure effects, partly by anatomic factors in the left lowermost arm, but not by the side of stroke.