Avaliação breve do défice executivo em pessoas idosas com Acidente Vascular Cerebral: Validação da Bateria de Avaliação Frontal

RESUMO Objetivos: O Acidente Vascular Cerebral (AVC) potencia o desenvolvimento de disfunção executiva, conduzindo a défice no desempenho das tarefas do quotidiano. A avaliação neuropsicológica das funções executivas é importante para desenvolver estratégias de reabilitação adequadas. Assim, são objetivos descrever os dados normativos, precisão de diagnóstico, propriedades psicométricas e análise fatorial da Bateria de Avaliação Frontal (FAB), instrumento breve e de rápida administração, numa amostra de idosos com AVC. Métodos: Inserida no projeto Trajetórias do Envelhecimento de Idosos em Resposta Social, esta investigação conta com uma amostra de 112 pessoas idosas com diagnóstico médico de AVC e 157 pessoas idosas de um subgrupo de controlo sem AVC. Os sujeitos apresentam idades compreendidas entre os 60 e os 100 anos (M = 78,20; DP = 7,57) sendo maioritariamente do sexo feminino (n = 194). A avaliação inclui entrevistas e testes neuropsicológicos agrupados em medidas de funcionamento executivo, medidas cognitivas de referência e medidas clínicas de controlo. Resultados: As variáveis idade e escolaridade interferiram nas pontuações obtidas na amostra clínica, não sendo verificado impacto da variável sexo. Para um ponto de corte de 7, a FAB teve uma sensibilidade de 83,4% e especificidade de 66,1 % (AUC = 0,64); revelou um alfa de Cronbach de 0,79 e correlações fortes com os testes executivos (teste de Stroop, Figura Complexa de Rey, fator Atencional-Executivo do Montreal Cognitive Assessment e Alternância nos testes de Fluência verbal). A análise fatorial confirmatória apontou uma estrutura com um fator. Conclusões: A FAB apresenta boa consistência interna, validade convergente e validade de constructo, aparentando ser uma escala útil para avaliar o défice executivo em pessoas idosas com AVC. Dadas algumas limitações do estudo, que poderão explicar a fraca precisão diagnóstica da FAB, são incentivadas investigações futuras pois a FAB revelou-se um instrumento com propriedades psicométricas promissoras. ABSTRACT Goals: Stroke potentiates the development of executive dysfunction, leading to impairment in performance of daily activities. The neuropsychological assessment of executive functions is important to develop adequate rehabilitation strategies. Thus, describing the normative data, diagnostic accuracy, psychometric properties and factor analysis of the Frontal Assessment Battery (FAB), a brief and easy to administer instrument, in a clinical sample with stroke are objectives of this study. Methods: Being part of the Aging Trajectories of Institutionalized Elderly, this research has a sample 112 elderly people with a medical diagnosis of stroke and a control subgroup of 157 elderly people. The subjects have ages between 60 and 100 years old (M = 78.20, SD = 7.57), mostly females (n = 194). The measurements used include interviews and neuropsychological tests grouped in executive functioning measures, cognitive measures of reference and clinical measures of control. Results: The variables age and education affect the scores obtained in the clinical subgroup, having the variable gender no impact on these. Using a cutoff score of 7, the FAB had a sensitivity of 83.4% and a specificity of 66.1% for screening stroke (AUC = 0.64); showed a Cronbach's α of 0.79, and strong correlations with executive tests (Stroop test, Rey Complex Figure, Attentional-Executive factor of Montreal Cognitive Assessment and Switching in the verbal fluency tests). The confirmatory factor analysis supported a one-factor structure. Conclusions: The FAB presents good internal consistency, convergent, and construct when used for elderly with stroke. Due to some limitations of the study, which may explain the weak discriminant validity, further investigations are encouraged because FAB has showed promising psychometric properties.

Rehabilitation of executive dysfunction: A controlled trial of an attention and problem solving treatment group

In this study, the effectiveness of a group-based attention and problem solving (APS) treatment approach to executive impairments in patients with frontal lobe lesions was investigated. Thirty participants with lesions in the frontal lobes, 16 with left frontal (LF) and 14 with right frontal (RF) lesions, were allocated into three groups, each with 10 participants. The APS treatment was initially compared to two other control conditions, an information/education (IE) approach and treatment-as-usual or traditional rehabilitation (TR), with each of the control groups subsequently receiving the APS intervention in a crossover design. This design allowed for an evaluation of the treatment through assessment before and after treatment and on follow up, six months later. There was an improvement on some executive and functional measures after the implementation of the APS programme in the three groups. Size, and to a lesser extent laterality, of lesion affected baseline performance on measures of executive function, but there was no apparent relationship between size, laterality or site of lesion and level of benefit from the treatment intervention. The results were discussed in terms of models of executive functioning and the effectiveness of domain specific interventions in the rehabilitation of executive dysfunction.

Executive dysfunction in children and adolescents with temporal lobe epilepsy: Is the Wisconsin Card Sorting Test enough?

The Wisconsin Card Sorting Test (WCST) is the gold standard in the evaluation of executive dysfunction (ED) in patients with temporal lobe epilepsy (TLE). We evaluated 35 children with TLE and 25 healthy controls with the WCST and with a more comprehensive battery. Among the children with TLE, 77.14% showed impairment on the WCST. On other tests (Wechsler Intelligence Scale for Children-Digit Forward, Matching Familiar Figures Test, Trail Making Test, Word Fluency, Finger Windows, and Number-Letter Memory), impairment was demonstrated in 94.29%. The authors concluded that the WCST is a good paradigm to measure executive impairment in children with TLE: however, it may be not enough. Evaluation performed only with the WCST not only underestimated the number of patients with ED, but also missed relevant information regarding the type of ED. (C) 2009 Elsevier Inc. All rights reserved.

Executive dysfunction correlates with impaired functional status in older adults with varying degrees of cognitive impairment

Background: Previous studies have reported an association between executive dysfunction and the ability to perform activities of daily living (ADL)s among older adults. This study aims to examine the association between executive functions and functional status in a cross-section of older adults with varying degrees of cognitive impairment. Methods: 89 individuals (mean age 73.8 years) were recruited at a memory clinic in Sao Paulo, Brazil. Subjects underwent evaluation, and were allocated into three diagnostic groups according to cognitive status: normal controls (NC, n = 32), mild cognitive impairment (MCI, n = 3 1) and mild Alzheimer`s disease (AD, n=26). Executive functions were assessed with the 25-item Executive Interview (EXIT25), and functional status was measured with the Direct Assessment of Functional Status test (DAFS-R). Results: Significantly different total DAFS-R scores were observed across the three diagnostic groups. Patients with AD performed significantly worse in EXIT25 compared with subjects without dementia, and no significant differences were detected between NC and MCI patients. We found a robust negative correlation between the DAFS-R and the EXIT25 scores (r=-0.872, p < 0.001). Linear regression analyses suggested a significant influence of the EXIT-25 and the CAMCOG on the DAFS-R scores. Conclusion: Executive dysfunction and decline in general measures of cognitive functioning are associated with a lower ability to undertake instrumental ADLs. MCI patients showed worse functional status than NC subjects. MCI patients may show subtle changes in functional status that may only be captured by objective measures of ADLs.

Use of the frontal assessment battery in evaluating executive dysfunction in patients with Huntington`s disease

The frontal assessment battery (FAB) is a bedside cognitive scale designed to measure executive functions. Huntington`s disease (HD) is a neurodegenerative disorder characterized by motor, behavioral, and cognitive dysfunction. The aim of this study was to check the validity of the FAB for the evaluation of cognitive impairment in patients with HD. Forty-one patients diagnosed with HD and 53 healthy controls matched by education, sex and age were evaluated with a validated Brazilian version of the UHDRS, the VFT, the SDMT, the SIT, the MMSE, and the FAB. The diagnosis of HD was made by DNA analysis. FAB scores were lower in patients than in the controls (p < 0.001) and had significant correlations with the VFT (r = 0.79; p < 0.05), the SDMT (r = 0.80; p < 0.05), the SIT (r = 0.72; p < 0.05), the MMSE (r = 0.83; p < 0.05), the FCS (r = 0.79; p < 0.05) and the motor section of the UHDRS (r = -0.80; p < 0.05). The FAB differentiated between HD patients in the initial and later stages of the disease. The one-year longitudinal evaluation revealed a global trend toward a worsening in the second score of the FAB. The results demonstrate that the FAB presents good internal consistency and also convergent and discriminative validity; therefore it is a useful scale to assess executive functions and to evaluate cognitive impairment in patients with HD.

Disfunção executiva como uma medida de funcionalidade em adultos com TDAH

Este artigo aborda a presença e a apresentação clínica da disfunção executiva em pacientes com TDAH. Na medida em que sintomas de disfunção executiva determinam as alterações de funcionamento desses pacientes nas atividades do dia-a-dia, torna-se relevante o estudo das relações entre alterações em testes neuropsicológicos formais de funções executivas e a ocorrência desses sintomas. A constatação relativamente recente do papel da disfunção executiva no TDAH tem impulsionado a pesquisa neuropsicológica, mas os dados até agora disponíveis são ainda pouco consistentes. Uma visão atualizada dessas questões sugere que a semiologia neuropsicológica disponível ainda não alcança plenamente a constelação de sintomas práticos do TDAH no dia-a-dia, mostrando a necessidade de avanços na pesquisa dessas relações.

Executive dysfunction and memory impairment in schizoaffective disorder: a comparison with bipolar disorder, schizophrenia and healthy controls.

BACKGROUND: Deficits in memory and executive performance are well-established features of bipolar disorder and schizophrenia. By contrast, data on cognitive impairment in schizoaffective disorder are scarce and the findings are conflicting. METHOD: We used the Wechsler Memory Scale (WMS-III) and the Behavioural Assessment of the Dysexecutive Syndrome (BADS) to test memory and executive function in 45 schizophrenic patients, 26 schizomanic patients and 51 manic bipolar patients in comparison to 65 healthy controls. The patients were tested when acutely ill. RESULTS: All three patient groups performed significantly more poorly than the controls on global measures of memory and executive functioning, but there were no differences among the patient groups. There were few differences in memory and executive function subtest scores within the patient groups. There were no differences in any test scores between manic patients with and without psychotic symptoms. CONCLUSIONS: Schizophrenic, schizomanic and manic patients show a broadly similar degree of executive and memory deficits in the acute phase of illness. Our results do not support a categorical differentiation across different psychotic categories with regard to neuropsychological deficits.

The social consequences of mild head injury and executive dysfunction /

Mild head injury (MHI) is a serious cause of neurological impairment as is evident by the substantial percentage (15%) of individuals who remain symptomatic at least 1-year following "mild" head trauma. However, there is a paucity of research investigating the social consequences following a MHI. The first objective of this study was to examine whether measures of executive functioning were predictive of specific forms of antisocial behaviour, such as reactive aggression, impulsive antisocial behaviour, behavioural disinhibition, and deficits in social awareness after controlling for the variance accounted for by sex differences. The second objective was to investigate whether a history of MHI was predictive of these same social consequences after controlling for both sex differences and executive functioning. Ninety university students participated in neuropsychological testing and filled out self-report questionnaires. Fifty-two percent of the sample self-reported experiencing a MHI. As expected, men were more reactively aggressive and antisocial than women. Furthermore, executive dysfunction predicted reactive aggression and impulsive antisocial behaviour after controlling for sex differences. Finally, as expected, MHI status predicted reactive aggression, impulsive antisocial behaviour, and behavioural disinhibition after controlling for sex and executive fimctioning. MHI status and executive functioning did not predict social awareness or sensitivity to reward or punishment. These results suggest that incurring a MHI has serious social consequences that mirror the neurobehavioural profile following severe cases of brain injury. Therefore, the social sequelae after MHI imply a continuum of behavioural deficits between MHI and more severe forms of brain injury.

Memory in children with temporal lobe epilepsy is at least partially explained by executive dysfunction

An association between memory and executive dysfunction (ED) has been demonstrated in patients with mixed neurological disorders. We aimed to investigate the impact of ED in memory tasks of children with temporal lobe epilepsy (TLE). We evaluated 36 children with TLE and 28 controls with tests for memory, learning, attention, mental flexibility, and mental tracking. Data analysis was composed of comparison between patients and controls in memory and executive function; correlation between memory and executive function tests; and comparison between patients with mild and severe ED in memory tests. Children with TLE had worse performance in focused attention, immediate and delayed recall, phonological memory, mental tracking, planning, and abstraction. Planning, abstraction, and mental tracking were correlated with visual and verbal memory. Children with severe ED had worse performance in verbal and visual memory and learning tests. This study showed that ED was related to memory performance in children with TLE. (C) 2012 Elsevier Inc. All rights reserved.

Do executive dysfunction and freezing of gait in Parkinson's disease share the same neuroanatomical correlates?

Current hypotheses postulate a relationship between executive dysfunction and freezing of gait (FOG) in Parkinson's disease (PD). Hitherto, most evidence comes from entirely clinical approaches, while knowledge about this relationship on the morphological level is sparse. The aim of this study was therefore to assess the overlap of gray matter atrophy associated with FOG and executive dysfunction in PD. We included 18 PD patients with FOG and 20 without FOG in our analysis. A voxel-based morphometry approach was used to reveal voxel clusters in the gray matter which were associated with FOG and executive dysfunction as measured by the Frontal Assessment Battery, respectively. Conjunction analysis was applied to detect overlaps of the associated patterns. FOG correlated with different cortical clusters in the frontal and parietal lobes, whereas those associated with the FAB scores were, although widespread, widely confined to the frontal lobe. Conjunction analysis revealed a significant cluster of gray matter loss in the right dorsolateral prefrontal cortex. We could show that the patterns of neurodegeneration associated with FOG and executive dysfunction (as measured by the FAB) share atrophic changes in the same cortical areas. However, there is also a considerable number of cortical areas where neurodegenerative changes are only unique for either sign. Particularly, the involvement of parietal lobe areas seems to be more specific for FOG.

Impaired sustained attention and executive dysfunction:bipolar disorder versus depression-specific markers of affective disorders

Objective - To identify neurocognitive measures that could be used as objective markers of bipolar disorder. Methods - We examined executive function, sustained attention and short-term memory as neurocognitive domains in 18 participants with bipolar disorder in euthymic state (Beuth), 14 in depressed state (Bdep), 20 with unipolar depression (Udep) and 28 healthy control participants (HC). We conducted four-group comparisons followed by relevant post hoc analyses. Results - Udep and Bdep, but not Beuth showed impaired executive function (p = 0.045 and p = 0.046, respectively). Both Bdep and Beuth, but not Udep, showed impaired sustained attention (p = 0.001 and p = 0.045, respectively). The four groups did not differ significantly on short-term memory. Impaired sustained attention and executive dysfunction were not associated with depression severity, duration of illness and age of illness onset. Only a small number of abnormal neurocognitive measures were associated with medication in Bdep and Beuth. Conclusion - Impaired sustained attention appears specific to bipolar disorder and present in both Beuth and Bdep; it may represent an objective marker of bipolar disorder. Executive dysfunction by contrast, appears to be present in Udep and Bdep and likely represents a marker of depression.

A contribuição de défices mnésicos e disfunção executiva nas memórias falsas/confabulação provocada em pacientes com rutura de aneurisma da artéria comunicante anterior (ACoA)

Dissertação de Mestrado, Neurociências Cognitivas e Neuropsicologia, Faculdade de Ciências Humanas e Sociais, Universidade do Algarve, 2014

Avaliação clínica na disfunção fronto-estriatal : movimento e cognição

RESUMO: Os circuitos fronto-estriatais constituem um sistema em ansa fechada que une diversas regiões do lobo frontal aos gânglios da base, participando, com outras áreas cerebrais, no controlo do movimento, cognição e comportamento. As Distonias Primárias, a Doença de Parkinson e a Hidrocefalia de Pressão Normal, são doenças do movimento caracterizadas por disfunção do circuito fronto-estriatal motor. A conectividade funcional entre as diversas ansas do sistema fronto-estriatal, permite prever que as doenças do movimento possam também acompanhar-se de sintomas da esfera cognitiva e comportamental, cuja avaliação seria importante no manejo diagnóstico e terapêutico dos doentes. Objectivos Os nossos objectivos foram avaliar, por estudos clínicos, a relação entre sintomas motores, cognitivos e comportamentais em três doenças do movimento com fisiopatologias diversas - distonias Primárias, Doença de Parkinson e Hidrocefalia de Pressão Normal - analisando os dados sob a perspectiva teórica fornecida pelo conhecimentos dos vários circuitos frontoestriatais. Os nossos objectivos específicos para cada doença foram: a) Distonias Primárias: avaliação de disfunção executiva em doentes com Distonia Primária e relação com a gravidade dos sintomas motores b) Doença de Parkinson: 1. avaliação breve das funções mentais nas fases iniciais da doença, incluindo análise longitudinal para determinação de factores preditivos para declínio cognitivo; 2. relação entre a função motora e cognitiva e a Perturbação do Comportamento do sono REM, incluindo análise longitudinal; 3.avaliação de sintomas psiquiátricos, de um ponto de vista global e especificamente com incidência sobre as Perturbações do Controlo do Impulso (PCI). c) Hidrocefalia de Pressão Normal: 1. caracterização das alterações da marcha, incluindo comparação com a Doença de Parkinson; 2. caracterização das alterações cognitivas e da relação entre estas e a disfunção da marcha; 3. estudo evolutivo das alterações da marcha e cognitiva em doentes submetido a cirurgia e doentes não submetidos a cirurgia. Métodos: A Distonia Primária, a Doença de Parkinson e a Hidrocefalia de Pressão Normal foram diagnosticadas segundo critérios clínicos validados. Sempre que justificado, foram recrutados grupos de controlo, com indivíduos sem doença, emparelhados para idade, sexo e grau de escolaridade. Os doentes foram avaliados com instrumentos de aplicação clinica directa, incluindo escalas de função motora, testes neuropsicológicos globais e dirigidos às funções executivas e escalas de avaliação psiquiátrica. Testes aplicados nas Distonias Primárias: Unified Dystonia Rating Scale, Wisconsin Card Sorting Test, teste de Stroop, teste de cubos da WAIS, Teste de Retenção Visual de Benton; na Doença de Parkinson: Unified Parkinson's Disease Rating Scale, Frontal Assessment Battery (FAB), Mini-Mental State Examination (MMSE), REM-sleep behaviour disorder Questionnaire; Symptom Chek-list 90-R, Brief Psychiatric Rating Scale, FAS (fluência verbal lexical) Nomeação de Animais (Fluência verbal semântica), prova de repetição de dígitos (WAIS), Rey auditory verbal learning test, teste de Stroop, matrizes progressivas de Raven, Questionnaire for Impulsive-Compulsive Disorders; na HPN: prova cronometrada de marcha,MMSE, prova de memória imediata da WAIS, prova de repetição de dígitos (WAIS), FAB, desenho complexo de Rey, teste de Stroop, cancelamento de letras, teste Grooved Pegboard. Os doentes com HPN foram também submetidos a estudo imagiológico. A avaliação estatística foi adaptada às características de cada um dos estudos.Resultados Distonias Primárias: encontrámos défices de função executiva, envolvendo dificuldade na mudança entre sets cognitivos, bem como correlação significativa entre as pontuações nos testes cronometrados e a gravidade dos sintomas motores. Doença de Parkinson: os doentes com DP obtiveram pontuações significativamente inferiores na FAB e em sub-testes do MMSE (memória e função visuo-espacial). A pontuação no MMSE encontrava-se significativamente correlacionada com itens da função motora não relacionados com o tremor. A disfunção da marcha, a disartria, o fenótipo não tremorígeno, a presença de alucinações e pontuação abaixo do ponto de corte na MMSE, foram factores preditivos de demência na avaliação longitudinal. A rigidez e a disartria foram factores preditivos de declínio nas funções frontais. A disfunção frontal foi factor preditivo de declínio na pontuação do MMSE. Encontrámos uma prevalência elevada de RBD nas fases iniciais da DP, que o estudo longitudinal mostrou ser factor preditivo de declínio motor, nomeadamente por agravamento da bradicinésia. Encontrámos também uma prevalência elevada de sintomas psiquiátricos, nomeadamente psicose, depressão, ansiedade, somatização e sintomas obsessivo-compulsivos. As PCI não se encontravam relacionadas com o fenótipo motor, com as complicações motoras do tratamento dopaminérgico ou com a disfunção cognitiva. HPN: os doentes com HPN e os DP apresentaram um padrão disfunção da marcha semelhante, caraterizado por passos curtos, lentidão e dificuldades de equilíbrio, sendo os sintomas mais graves na HPN. Os doentes de Parkinson com maior duração de doença, maior dose de dopaminérgicos e fenótipo motor acinético-rígido apresentaram um padrão de disfunção da marcha de gravidade semelhante ao encontrado na HPN. As alterações vasculares da substância branca, em particular as encontradas na região frontal, encontravam-se negativamente correlacionadas com a melhoria da marcha após PL. O estudo das funções cognitivas mostrou um padrão de atingimento global, com valores mais baixos na cópia do desenho complexo de Rey. Os resultados nas provas de função cognitiva não se encontravam significativamente correlacionados com os resultados na prova da marcha. A progressão na disfunção da marcha encontrava-se relacionada com o tratamento não cirúrgico, idade superior na primeira avaliação, presença de lesões da substância branca, e presença de factores de risco vascular, ao passo que não foram encontrados factores que predissessem de modo significativo o agravamento da função cognitiva. Conclusões: Os resultados dos diversos estudos, evidenciam a presença de alterações cognitivas e comportamentais nas três doenças de movimento. O padrão destas alterações e o modo como estas se relacionaram com os sintomas motores variou de doença para doença. Nas Distonias primárias, a perseveração cognitiva poderá ser o sintoma correspondente à perseveração motora própria da doença, sugerindo disfunção no circuito dorso-lateral frontoestriatal. A correlação entre a gravidade motora da doença e o resultado nos testes cognitivos cronometrados, poderá ser o efeito da relação entre bradicinésia e bradifrenia. Na Doença de Parkinson, o espectro de alterações é mais acentuado, espelhando a disseminação do processo degenerativo no SNC. Para além dos sintomas de disfunção executiva, sugerindo disfunção das tês ansas não motoras, existem sinais de disfunção cognitiva global, estas com uma influência mais significativa no desenvolvimento da demência. A relação entre os diferentes sintomas motores e cognitivos é também complexa, embora se evidencie uma dissociação significativa entre o tremor, sem relação com os sintomas não motores, e os sintomas motores não tremorígenos, relacionados com o declínio cognitivo. Enquanto que a presença de RBD parece ser um factor preditivo de agravamento motor, os sintomas psiquiátricos, também muito frequentes, apresentam uma relação menos clara com a função motora. Destes, os sintomas obsessivo-compulsivos são aqueles que com mais frequência se atribuem a disfunção do sistema fronto-estriatal, nomeadamente da ansa orbito-frontal. As PCI também não mostraram ter relação com os sintomas motores ou cognitivos. Na HPN, é patente o carácter fronto-estriatal das alterações da marcha, demonstrado tanto na sua caracterização quanto no efeito deletério das lesões vasculares da substância branca do lobo frontal na recuperação da marcha após PL. As alterações cognitivas parecem ter um padrão mais difuso, o que talvez explique a falta de correlação com os sintomas motores - esta dissociação pode ser causada quer por diferença nos mecanismos fisiopatológicos quer por presença de comorbilidades cognitivas. --------- ABSTRACT: Fronto-striatal circuits constitute a closed loop system which connects different parts of the frontal lobes to the basal ganglia. They are engaged in motor, cognitive and behavioural control. Primary Dystonia, Parkinson's Disease and Normal-Pressure Hydrocephalus are movement disorders caused by disturbance of the motor fronto-striatal circuit. The existence of cognitive and behavioural dysfunction in these movement disorders is predictable, given the functional connectivity between the several distinct loops of the circuit. Evaluation of cognitive and behavioural dysfunction in these three disorders is thus both of clinical and theoretical relevance. Objectives Our objectives were to evaluate, by clinical means, the relation between motor, cognitive and behavioural symptoms in three movement disorders with different pathophysiological backgrounds - Primary Dystonia, Parkinson's Disease and Normal-Pressure Hydrocephalus - and to analyse the study results under the theoretical framework formed by present knowledge of the fronto-estriatal system. Specific objectives: a) Primary Dystonia: executive dysfunction assessment and correlation analysis with motor dysfunction severity; b) Parkinson's Disease: 1. brief cognitive assessment in the early stages of disease, including a longitudinal analysis for determination of predictive factors for cognitive decline; 2. to investigate the relation between RBD and cognitive and motor dysfunction, including a longitudinal analysis; 3. psychiatric symptom assessment, with particular incidence on Impulse Control Disorders; c) Normal-Pressure Hydrocephalus: 1. gait dysfunction characterization and comparison with Parkinson's Disease patients; 2. determination of cognitive dysfunction profile and its relation with gait dysfunction; 3. follow-up study of cognitive and motor outcome in patients submitted and not submitted to shunt surgery. Methods: Primary Dystonia, Parkinson's Disease and Normal Pressure Hydrocephalus were diagnosed according to clinically validate criteria. Where warranted, we recruited control groups formed by healthy individuals, matched for age, sex and educational level. Patients were evaluated with instruments of direct clinical application, including motor function scales, neuropsychological tests aimed at global and executive functions and psychiatric rating scales. Tests used in Primary Dystonia: Unified Dystonia Rating Scale, Wisconsin Card Sorting Test, Stroop Test, Cube Assembly test (WAIS), Benton’s Visual Retention Test; in Parkinson's Disease: Unified Parkinson's Disease Rating Scale, Frontal Assessment Battery (FAB) , Mini-mental State Examination (MMSE), REM-sleep behavior disorder Questionnaire, Symptom Check-list 90- R, Brief Psychiatric Rating Scale, FAS (phonetic verbal fluency), semantic verbal fluency test, digit span test (WAIS), auditory verbal learning test,Stroop test, Raven's progressive Matrices, Questionnaire for Impulsive-Compulsive Disorders; in NPH: timed walking test, MMSE, immediate memory task (WAIS), digit span test (WAIS), FAB, Rey’s Complex Figure test, Stroop test, letter cancellation test, Perdue Pegboard test. NPH patients were also subjected to an imaging study. Statistics were adapted to the characteristics of each study.Results: Primary Dystonia: we found set-shifting deficits as well as significant correlation between timed neuropsychological tests and dystonia severity. Parkinson's Disease: PD patients had significantly lower scores on the FAB and on the memory and visuo-spatial tests of the MMSE; MMSE scores were significantly correlated to non-tremor motor scores; gait dysfunction and speech scores, non-tremor motor phenotype, hallucinations and scores bellow cut-off on the MMSE were predictive of dementia at follow-up; speech and rigidity scores were predictive of frontal type decline; frontal dysfunction was predictivy of decline in MMSE scores; RBD bradykinesia worsening; psychiatric symptoms were prevalent, particularly Psychosis, Depression, Anxiety, Somatisation and Obsessive-Compulsive Symptoms; Impulse Control Disorders were unrelated to motor phenotype,motor side effects of dopamine treatment and executive function; NPH: gait dysfunction was worse in NPH when compared to PD patients, although the pattern was similarly characterized by slowness, short steps and disequilibrium; PD patients whose gait disturbance was as severe as that of NPH patients were characterized by longer disease duration, predominance of non-tremor motor scores, more advanced disease stage and higher dopamine dose; frontal white matter lesions correlated negatively with improvement after LP; cognitive function assessment revealed wide spread deficits, with lower results on the drawing of the complex figure of Rey, which were not significantly correlated to gait dysfunction; older age, white matter lesions and the presence of vascular risk factors were predictive factors for motor but not cognitive function worsening. Conclusion: Results from our studies highlight the presence of cognitive and behavioural dysfunction in all three movement disorders. Symptom pattern and the relation with ovement derangement varied according to the disease. In Primary Dystonia, set-shifting difficulties could be the cognitive counterpart of motor perseveration characteristic of this disorder, suggesting dysfunction of the dorso-lateral circuit. The relation between timed tests and dystonia severity could suggest a relation between bradyphrenia and bradykinesia in Primary Dystonia. In Parkinson's Disease patients, the spectrum of non-motor symptoms is wider, probably reflecting the spread of neurodegeneration beyond the fronto-striatal circuits. While frontal type deficits predominate, suggestive of dorso-lateral and orbito-frontal dysfunction, non-frontal deficits were also apparent in the initial stages of disease, and were predictive of dementia at follow-up. The relationship between cognitive and motor symptoms is complex, although the results strongly suggest a dissociation between tremor symptoms, which bore no relation with non-motor symptoms, and non-tremor symptoms,whichwas frequent, and a predictive factor for which were related with cognitive decline. While RBD was found to be a predictive factor for bradykinesia worsening, psychiatric symptoms, which were also frequent, showed no apparent relation with motor dysfunction. Relevant to our theoretical consideration was the high prevalence of OCS, which have been attributed to orbito-frontal dysfunction. As to the particular case of ICD, we found no relation either with motor or cognitive dysfunction. The fronto-striatal nature of gait dysfunction in NPH is suggest by the clinical characterization study and by the effects of frontal white matter lesions on gait recovery after LP, whereas cognitive dysfunction presented a more diffuse pattern, which could explain the lack or relation with gait assessment results and also the different outcome on the longitudinal study - this dissociation could be caused by a real difference in pathophysiological mechanisms or, in alternative, be due to the existence of cognitive comorbidities.

Estudo de associação entre disfunção neurocognitiva, estresse oxidativa e polimorfismos em pacientes jovens com Transtornos Bipolar tipo I

O Transtorno Bipolar (TB) tipo I é uma doença caracterizada por episódios de mania e depressão recorrentes com importante prejuízo do funcionamento global e comprometimento das funções cognitivas. Além disso, sabe-se que o número de episódios de humor patológico ao longo da vida pode também influenciar o funcionamento cognitivo destes sujeitos. Neste cenário, ocorreu a necessidade de se investigar marcadores genéticos para disfunção cognitiva no TB com o objetivo de estudar este fenômeno. Dentre os potenciais genes responsáveis por influenciar a cognição destacam-se os polimorfismos funcionais do fator neurotrófico derivado do cérebro (BDNF), da catecol-O-metiltransferase (COMT), da apolipoproteína-E (APOE) e do canal de cálcio de baixa voltagem subunidade 1-C (CACNA1C). Sabe-se, também, que no TB os marcadores de estresse oxidativo estão aumentados durante todas as fases da doença, entretanto, não é claro qual impacto destes na disfunção cognitiva de indivíduos com TB. O objetivo dessa tese foi avaliar o desempenho cognitivo de pacientes jovens com bipolaridade tipo I e sua associação com o genótipo de BDNF, COMT, APOE e CACNA1C e também com os níveis plasmáticos de oxidação da guanosina (8-OHdG) e citosina (5-Mec) durante os episódios de humor, eutimia e em controles. Para investigar essa associação foram incluídos 116 pacientes (79 em episódio de humor patológico e 37 eutímicos) com diagnóstico de TB tipo I (DSMIV-TR); 97 controles saudáveis foram submetidos à avaliação neuropsicológica e coleta de sangue para extração de DNA visando genotipagem para BDNF (rs6265), COMT (rs4680; rs165599), APOE (rs429358 e rs7412), CACNA1C (rs1006737), 8-OhdG e 5-Mec. A análise dos dados obtidos revelou que pacientes portadores do genótipo Met/Met rs4680/rs165599 do COMT apresentam comprometimento cognitivo mais grave (função executiva, fluência verbal, memória e inteligência) comparado ao genótipo Val/Met ou Val/Val durante episódios maníacos ou mistos. Na mesma direção destes resultados, verificou-se que pacientes portadores do alelo Met rs4680 do COMT apresentam comprometimento do reconhecimento de emoções faciais em episódios de mania e depressão. Nenhum efeito do COMT foi observado em controles. O alelo de risco Met do CACNA1C se associou a um pior comprometimento executivo independente dos sintomas maníacos ou depressivos no TB, porém nenhum efeito se observou nos controles. O alelo Met do BDNF rs6265 ou a presença do alelo 4 da APOE não representa um fator que identifique um grupo com desempenho cognitivo diferenciado durante as fases do TB ou em controles. Sujeitos com TB apresentaram níveis mais elevados de 8-OHdG e tais níveis eram diretamente proporcionais ao número de episódios maníacos ao longo da vida, sugerindo um papel dos episódios hiperdopaminérgicos na oxidação das bases de DNA. Concluiu-se que a genotipagem para COMT e CACNA1C em pacientes com TB pode identificar um grupo de pacientes associados a pior disfunção cognitiva durante as fases maníacas e mistas do TB. Tal dado pode ser um indicador do envolvimento do sistema dopaminérgico e dos canais de cálcio de baixa voltagem na fisiopatologia da disfunção cognitiva no TB e deve ser explorado em outros estudos