Oxiracetam ameliorates cognitive deficits in vascular dementia rats by regulating the expression of neuronal apoptosis/autophagy-related genes associated with the activation of the Akt/mTOR signaling pathway

Oxiracetam (ORC) is a commonly used nootropic drug for improving cognition and memory impairments. The therapeutic effect and underlying mechanism of ORC in vascular dementia (VaD) treatment remain unknown. In this study, 3-month-old male Sprague-Dawley rats with permanent bilateral common carotid artery occlusion-induced VaD were treated orally with low (100 mg/kg) or high (200 mg/kg) dose ORC once a day for 4 weeks. The results of the Morris water maze test and Nissl staining showed that ORC treatment significantly alleviated learning and memory deficits and neuronal damage in rats with VaD. Mechanistically, the protein levels of a panel of genes associated with neuronal apoptosis (Bcl-2, Bax) and autophagy (microtubule-associated protein 1 chain 3, Beclin1, p62) were significantly altered by ORC treatment compared with VaD, suggesting a protective role of ORC against VaD-induced neuronal apoptosis and autophagy. Moreover, the Akt/mTOR pathway, which is known to be the upstream signaling governing apoptosis and autophagy, was found to be activated in ORC-treated rats, suggesting an involvement of Akt/mTOR activation in ORC-rendered protection in VaD rats. Taken together, this study demonstrated that ORC may alleviate learning and memory impairments and neuronal damage in VaD rats by altering the expression of apoptosis/autophagy-related genes and activation of the Akt/mTOR signaling pathway in neurons.

Diferenciación clínica del déficit cognitivo del CADASIL con respecto a otras demencias vasculares / Clinical differentiation of the cognitive deficit of CADASIL whit respect to the other vascular dementias

En el mundo hay unos 47 millones de personas que padecen demencia, y cada año se registran cerca de 10 millones de nuevos casos. La demencia es una de las principales causas de discapacidad y dependencia entre las personas mayores de 65 años. La demencia vascular constituye la segunda causa de demencia en adultos mayores y en ocasiones su diagnóstico es poco asertivo por la variedad y similitud de síntomas entre las diferentes enfermedades que originan demencia vascular, incluyendo CADASIL (acrónimo inglés de Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy); particularmente el déficit cognitivo es de los síntomas más complejos de diagnóstico, teniendo en cuenta que su manifestación clínica depende de la magnitud y localización de la lesión. La enfermedad de CADASIL, aunque se constituye como una infrecuente causa de demencia vascular de naturaleza hereditaria a nivel mundial, representa una patología de gran importancia en el ámbito nacional, dado que en familias colombianas se ha reportado mutaciones que conllevan a dicha patología. Por lo tanto, su diagnóstico y tratamiento constituyen un reto para el personal clínico, sabiendo que la identificación temprana y precisa es la mejor estrategia para evitar la progresión precoz de la enfermedad y el mejoramiento de la calidad de vida del paciente. De acuerdo con lo anterior, se realizó una revisión de la diferenciación clínica del déficit cognitivo del CADASIL con respecto a las demás demencias vasculares, con el fin de generar una herramienta que apoye la diferenciación clínica de dicha patología.

In the world, there are approximately 47 million people who have dementia, and every year they register near 10 million new cases. The dementia is one of the principal reasons for disability and dependence between people older than 65 years old. Vascular dementia constitutes the second reason of dementia in the elders, and sometimes the diagnosis is slightly assertive because of the variety and similarity of symptoms between the different diseases that originate vascular dementia, including CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy). Particularly, the cognitive deficit is one of the most complex symptoms of diagnosis, bearing in mind that its clinical manifestation depends on the magnitude and location of the injury. CADASIL disease, though it constituted as an infrequent reason of vascular dementia of hereditary nature worldwide, represents a pathology of great importance in the national area, because, in Colombian families, there have been reported mutations that carry to the above-mentioned pathology. Therefore, its diagnosis and treatment constitute a challenge for the clinical personnel, knowing that the early and precise identification is the best strategy to avoid the rapid progression of the disease and the improvement of the quality of life of the patient. In agreement with the previous information, there was made a review of the clinical differentiation of the cognitive deficit of CADASIL regarding other vascular dementias, to generate a tool that supports the clinical differentiation of the pathology mentioned above.

Perfil cognoscitivo de adultos mayores de 60 años con y sin deterioro cognoscitivo / Cognitive profile of adults over 60 years with and without cognitive impairment

Introducción: En el envejecimiento, las funciones cognoscitivas se caracterizan por un decremento y variabilidad en sus procesos, discernir si se trata de un envejecimiento normal o un deterioro patológico es clínicamente difícil; los límites no son precisos, además, intervienen variables como la edad, escolaridad y las diferencias poblacionales. Con el objetivo de caracterizar el perfil neuropsicológico de adultos mayores de 60 años con y sin deterioro cognoscitivo se estudió una muestra de 536 adultos mayores de 60 años con queja subjetiva o de familiares en los proceso de memoria, los cuales, fueron pacientes del Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán” de la Ciudad de México, entre los años 2006 a 2010. Por consenso interdisciplinario de especialistas con énfasis en la evaluación neuropsicológica, se dividió la muestra en: Envejecimiento Normal (EN), Deterioro cognitivo Leve (DCL), Enfermedad de Alzheimer (EA), Demencia Vascular (DV) y Demencia Mixta (DM). Con puntajes Z se calculó estadística descriptiva y un ANOVA de medidas repetidas. Resultados: Se encontraron diferencias estadísticas en el rendimiento de la evaluación neuropsicológica entre los grupos. El 29 por ciento de la muestra fue EN que no presenta alteraciones objetivas de funciones cognoscitivas. El más alto porcentaje fue el 46 por ciento del grupo DCL, que mostraron alteraciones en memoria y atención. La EA con el 12 por ciento, presenta alteraciones severas en memoria, funciones ejecutivas y lenguaje. El 7 por ciento del grupo DV la atención, la visuoconstructivo, el cálculo y la coordinación motora fueron las funciones afectadas. Por su parte, en el perfil de DM que representa el 6 por ciento, mostro mayor severidad en las alteraciones cognoscitivas afectadas.

Introduction: During aging cognitive function processes may decrease and fluctuate. This makes the task of distinguishing between normal aging and pathological deterioration clinically difficult. Variables such as age, academic level and social demographics combine to impede an objective analysis. The goal of the study was to characterize the neuropsychological profile of Mexican senior citizens who expressed a subjective complaint regarding memory. Method: A sample of 536 people over the age of 60 was studied. Each had reported memory issues between2006 and 2010 at the Salvador Zubiran National Institute of Medical Science and Nutrition. For interdisciplinary consensus the sample was divided into: Normal Aging (NA), Slight Cognitive Deterioration (SCD), Alzheimer Disease (AL), Vascular Dementia (VA) and Mixed Dementia (MD). Z points were used to calculate ANOVA with repeated measurements. Results: The population yielded statistical differences stemming from neuropsychological evaluations. 29 percent of the sample were classified NA with no current objective alterations in cognitive functions. The largest group, 46 percent, were classified as SCD, manifesting some alterations in memory and attention. AL was found in 12 percent with severe alterations in memory, executive functions and language. A similar cognitive profile was shared with the 6 percent of the group with MD, with only difference in the severity of cognitive alterations. Those with a VA profile manifested affected functions for attention, visual construction, calculation and motor coordination.

Neuropsychological performance in patients with subcortical stroke / Perfil neuropsicológico em pacientes com lesões vasculares subcorticais

Vascular cognitive impairment (VCI) is characterized by cognitive compromise predominantly of executive dysfunction. OBJECTIVES: To assess cognitive functions in VCI, focusing on executive functions, to observe functional losses in relation to activities of daily living (ADLs) and to detect early symptoms prior to the onset of dementia. METHODS: We evaluated healthy subjects matched for gender, education and age to patients with diagnosis of subcortical vascular disease who had a stroke classified into three groups: 1) vascular lesions and no impairment; 2) vascular cognitive impairment with no dementia (VCIND); 3) vascular dementia (VaD). RESULTS AND DISCUSSION: The performance on neuropsychological tests differed among groups, worsening with increased impairment level. The probable VaD group demonstrated impaired performance in memory, processing speed and verbal production, while the VCIND group showed attention deficits. CONCLUSION: Impairment in executive functions and difficulties in ADLs allow us to differentiate levels of impairment in groups of subcortical vascular disease.

O comprometimento cognitivo vascular (CCV) é caracterizado por comprometimento cognitivo predominantemente sob a forma de disfunção executiva. OBJETIVOS: Avaliar as funções cognitivas no CCV, enfocando as funções executivas, observar as perdas funcionais em relação às atividades cotidianas (AVDs) e detectar os primeiros sintomas antes do início da demência. MÉTODOS: Foram avaliados indivíduos controles saudáveis pareados por sexo, escolaridade e idade com pacientes com diagnóstico de doença vascular subcortical que sofreram derrame classificados em três grupos: 1) lesões vasculares sem déficit; 2) comprometimento cognitivo vascular sem demência (CCVSD); 3) demência vascular (DV). RESULTADOS E DISCUSSÃO: O desempenho em testes neuropsicológicos diferiu entre os grupos, sendo o desempenho tanto pior quanto maior o comprometimento. O grupo DV provável demonstrou desempenho prejudicado na memória, velocidade de processamento e produção verbal, enquanto o grupo CCVSD apresentou déficit de atenção. CONCLUSÃO: Prejuízos nas funções executivas e dificuldades em AVDs permitem diferenciar os níveis de comprometimento nos grupos de doença vascular subcortical.

Impaired abstract thinking may discriminate between normal aging and vascular mild cognitive impairment / O pensamento abstrato comprometido pode diferenciar o envelhecimento normal do comprometimento cognitivo leve vascular

OBJECTIVE: Cerebrovascular disease (CVD) is associated with cognitive deficits. This cross-sectional study examines differences among healthy elderly controls and patients with vascular mild cognitive impairment (VaMCI) and vascular dementia (VaD) in performances on CAMCOG subscales. METHOD: Elderly individuals (n=61) were divided into 3 groups, according to cognitive and neuroimaging status: 16 controls, 20 VaMCI and 25 VaD. VaMCI and VaD individuals scored over 4 points on the Hachinski Ischemic Scale. RESULTS: Significant differences in total CAMCOG scores were observed across the three groups (p<0.001). VaD subjects performed worse than those with VaMCI in most CAMCOG subscales (p<0.001). All subscales showed differences between controls and VaD (p<0.001). Performance on abstract thinking showed difference between VaMCI and controls (p<0.001). CONCLUSION: CAMCOG discriminated controls from VaMCI and VaD. Assessment of abstract thinking may be useful as a screening item for diagnosis of VaMCI.

OBJETIVO: A doença cerebrovascular (DCV) associa-se a déficits cognitivos. Este estudo transversal objetiva examinar diferenças entre controles saudáveis idosos e pacientes com comprometimento cognitivo leve vascular (CCLV) e demência vascular (DV) nas subescalas do CAMCOG. MÉTODO: Indivíduos idosos (n=61) foram divididos em 3 grupos, de acordo com o perfil cognitivo e com a neuroimagem: 16 controles, 20 CCLV e 25 DV. Pacientes com CCLV e DV pontuaram acima de 4 pontos no Escore Isquêmico de Hachinski. RESULTADOS: Diferenças significativas foram observadas entre os três grupos no resultado final do CAMCOG. Pacientes com DV obtiveram escores inferiores àqueles dos indivíduos com CCLV em quase todas as subescalas. Todas as subescalas mostraram diferenças entre DV e controles. O desempenho no item pensamento abstrato mostrou diferenças entre CCLV e controles. CONCLUSÃO: O CAMCOG diferenciou controles de pacientes com CCLV e DV. A avaliação do pensamento abstrato pode ser útil para discriminar CCLV de controles.

Clinical characteristics in subcortical ischemic white matter disease / Características clínicas na doença isquêmica da substância branca subcortical

BACKGROUND: Vascular white matter lesions (WML) represent one of the main neuroimage findings in individuals older than 65 years and its clinical significance is still partially understood. OBJECTIVE: To describe and analyze the clinical profile of a high severity sample with WML focusing on the frontal executive control. METHOD: Outpatients (n=20) with high severity WML evaluated with magnetic resonance imaging were selected using the Fazekas scale. RESULTS: Most patients (n=17; 85 percent) presented an altered Trail Making Test ratio (section B/section A); on verbal fluency, 15 individuals (75 percent) performed below the cutoff score. Apathy (5.9 ± 4.65) and depression (3.05±3.67) were frequent as assessed by the Neuropsychiatric Inventory. The impairment in functional activities strongly correlated with apathy (r=0.814, p<0.001) and verbal fluency (r=0.744, p<0.001). CONCLUSION: Executive dysfunction, apathy, and ratio depression were the main characteristics found. Extension of WML may have distinct impact on the clinical picture, but further studies with methodological adjustments are necessary to provide more definitive conclusions.

FUNDAMENTO: Lesões vasculares em substância branca (LSB) são um dos principais achados de neuroimagem em indivíduos acima de 65 anos e sua importância em termos clínicos é ainda parcialmente conhecida. OBJETIVO: Descrever e analisar o perfil clínico de amostra com LSB grave enfocando as alterações do controle executivo frontal. MÉTODO: Pacientes ambulatoriais (n=20) avaliados pela ressonância nuclear magnética e com maior proporção de LSB foram selecionados através da escala de Fazekas. RESULTADOS: A maioria dos pacientes (n=17; 85 por cento) apresentou alteração na proporção teste das trilhas (seção B/A); na fluência verbal, 15 indivíduos (75 por cento) apresentaram desempenho abaixo do ponto de corte. Apatia (5,9±4,65) e depressão (3,05±3,67) foram freqüentes na avaliação pelo Inventário Neuropsiquiátrico. O prejuízo nas atividades funcionais correlacionou-se fortemente à apatia (r=0, 814, p<0,001) e à fluência verbal (r=0, 744, p< 0,001). CONCLUSÃO: Disfunção executiva, apatia e depressão foram as principais características encontradas. A extensão e localização das LSB parecem exercer um impacto distinto nas manifestações clínicas, porém estudos futuros com ajustes metodológicos são necessários para conclusões mais definitivas.

Patterns of single photon emission tomography (SPECT) among patients with dementia in the memory clinic at Siriraj Hospital.

OBJECTIVE: The authors hypothesized that there is a pattern difference in cerebralperfusion of the 99-Technitium L, L-ethyl cysteinate dimer Single Photon Emission Computer Tomography (99-Tc ECD SPECT) between mild and moderate to severe dementia. MATERIAL AND METHOD: The authors reported a retrospective study in the Memory Clinic, Siriraj Hospital between January 2001 and October 2003 including only patients with Alzheimer's disease, vascular dementia, and mixed dementia. Clinical dementia rating (CDR) was used to document dementia severity. Patterns of hypoperfusion were classified into no definite hypoperfusion, regional hypoperfusion, and diffused hypoperfusion. RESULTS: One hundred and seven patients were included in the present study. Only mean Thai Mental State Examination (TMSE) score was different between the two groups. There was no significant correlation between pattern of hypoperfusion in brain SPECT and severity of dementia. CONCLUSION: The authors cannot demonstrate the pattern of hypoperfusion of 99-Tc ECD SPECT among patients' difference in dementia severity.

Caracterizaçäo clínica da demência vascular: avaliaçäo retrospectiva de uma amostra de pacientes ambulatoriais / Clinical characterization of vascular dementia: retrospective evaluation of an outpatient sample

OBJETIVO: analisar as características clínicas e as condiçöes mórbidas (CM) associados em uma amostra de pacientes com demência vascular (DV). MÉTODOS: foram estudados retrospectivamente 25 pacientes com diagnóstico de DV, estabelecidos com base critérios do grupo State of California Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC). Os dados clínicos e de neuroimagem e os exames laboratoriais foram computados para caracterizaçäo da amostra. RESULTADOS: a média da faixa etária foi de 68,7 + ou - 14,6 anos (64,0 por cento homens), com escolaridade média de 5,2 + ou - 4,4 anos. A instalaçäo súbita do quadro foi observada em 48,0 por cento dos pacientes e a evoluçäo em degraus e o curso flutuante, em 4,0 por cento e 16,0 por cento dos casos, respectivamente. Apresentavam déficit neurológico focal como sintoma inicial 48,0 por cento, sendo constatado déficit ao exame em 80,0 por cento. As principais CM foram: hipertensäo arterial sistêmica (92,0 por cento); hipercolesterolemia (64,0 por cento); insuficiência coronariana (40,0 por cento); tabagismo (40,0 por cento); hipertrigliceridemia (36,0 por cento); diabete melito (32,0 por cento); doença de Chagas (8,0 por cento). CONCLUSÖES: observou-se forte correlaçäo entre DV e hipertensäo e hipercolesterolemia. A presença de dois pacientes com doença de Chagas sugere que esta doença possa constituir possível fator de risco regional