BsmI polymorphism in the vitamin D receptor gene is associated with 25-hydroxy vitamin D levels in individuals with cognitive decline.

OBJECTIVE: Elderly people are at a high risk of developing vitamin D (VitD) deficiency due to both decreased intake and cutaneous synthesis. Most of the biological actions of VitD are mediated by the vitamin D receptor (VDR), which is present in neurons and glial cells of the hippocampus, and in the cortex and subcortical nuclei, essential areas for cognition. It is known that VDR gene polymorphisms may decrease the VDR affinity for VitD. Objective: The present study aimed to investigate the influence of VitD levels on cognitive decline in patients with dementia due to Alzheimer's disease (AD, n = 32) and mild cognitive impairment (MCI, n = 15) compared to cognitively healthy elderly (n = 24). METHODS: We also evaluated the association of VDR gene polymorphisms with cognitive disturbance. Methods: Four polymorphisms on the VDR gene were studied, namely, BsmI, ApaI, FokI and TaqI, by polymerase chain reaction-restriction fragment length polymorphism. Serum levels of 25-hydroxy vitamin D (25(OH)D) were determined by high performance liquid chromatography. RESULTS: Results: No significant difference in 25(OH)D levels or genotypic/allelic frequencies was observed between the groups. Deficiency of 25(OH)D was more frequently observed in women. The AA/AG genotypes of the BsmI polymorphism was associated with sufficient 25(OH)D levels, while the GG genotype of this same polymorphism was associated to insufficient levels in the cognitively-impaired group (individuals with AD or MCI). CONCLUSIONS: Conclusions: The data obtained do not confirm the relationship between reductions of VitD levels, polymorphisms in the VDR gene, and altered cognitive function in this sample. However, the data indicate that BsmI polymorphism in the VDR gene is associated with the VitD levels in individuals with cognitive decline.

BsmI polymorphism in the vitamin D receptor gene is associated with 25-hydroxy vitamin D levels in individuals with cognitive decline / Polimorfismo BsmI no gene do receptor de vitamina D está associado aos níveis de 25-hidroxi vitamina D em indivíduos com declínio cognitivo

ABSTRACT Elderly people are at a high risk of developing vitamin D (VitD) deficiency due to both decreased intake and cutaneous synthesis. Most of the biological actions of VitD are mediated by the vitamin D receptor (VDR), which is present in neurons and glial cells of the hippocampus, and in the cortex and subcortical nuclei, essential areas for cognition. It is known that VDR gene polymorphisms may decrease the VDR affinity for VitD. Objective: The present study aimed to investigate the influence of VitD levels on cognitive decline in patients with dementia due to Alzheimer's disease (AD, n = 32) and mild cognitive impairment (MCI, n = 15) compared to cognitively healthy elderly (n = 24). We also evaluated the association of VDR gene polymorphisms with cognitive disturbance. Methods: Four polymorphisms on the VDR gene were studied, namely, BsmI, ApaI, FokI and TaqI, by polymerase chain reaction-restriction fragment length polymorphism. Serum levels of 25-hydroxy vitamin D (25(OH)D) were determined by high performance liquid chromatography. Results: No significant difference in 25(OH)D levels or genotypic/allelic frequencies was observed between the groups. Deficiency of 25(OH)D was more frequently observed in women. The AA/AG genotypes of the BsmI polymorphism was associated with sufficient 25(OH)D levels, while the GG genotype of this same polymorphism was associated to insufficient levels in the cognitively-impaired group (individuals with AD or MCI). Conclusions: The data obtained do not confirm the relationship between reductions of VitD levels, polymorphisms in the VDR gene, and altered cognitive function in this sample. However, the data indicate that BsmI polymorphism in the VDR gene is associated with the VitD levels in individuals with cognitive decline.

RESUMO Idosos apresentam risco elevado de desenvolverem deficiência de Vitamina D (VitD) devido à diminuição da ingestão e da síntese na pele. A maioria das ações biológicas da VitD é mediada pelo receptor da vitamina D (VDR), que está presente nos neurônios e células gliais do hipocampo, e no córtex e em núcleos subcorticais, áreas essenciais para a cognição. Sabe-se que polimorfismos do gene VDR podem diminuir a afinidade do VDR pela VitD. Objetivo: O presente estudo teve como objetivo investigar a influência dos níveis de VitD no declínio cognitivo em pacientes com demência devida à doença de Alzheimer (DA, n = 32) e comprometimento cognitivo leve (CCL, n = 15) em comparação a um grupo de idosos cognitivamente saudáveis (n = 24). Nós também avaliamos a associação entre polimorfimos no gene do receptor de VitD e as alterações cognitivas. Métodos: Quatro polimorfismos no gene VDR foram estudados, sendo BsmI, ApaI, FokI e TaqI, por PCR-RFLP. Os níveis séricos de 25-hidroxi vitamina D (25(OH)D) foram determinados por HPLC. Resultados: Não houve diferença significativa nos níveis de 25(OH)D ou nas frequências genotípicas / alélicas entre os grupos. Níveis deficientes de 25(OH)D foram mais frequentes nas mulheres. Os genótipos AA / AG do polimorfismo BsmI foram associados a níveis suficientes de 25(OH)D, enquanto o genótipo GG deste mesmo polimorfismo foi associado a níveis insuficientes no grupo com comprometimento cognitivo (em indivíduos com DA ou CCL). Conclusões: Os resultados obtidos não confirmam a relação entre redução dos níveis de VitD, polimorfismos no gene VDR e função cognitiva alterada nesta amostra. No entanto, os dados indicam que o polimorfismo BsmI no gene VDR está associado aos níveis de VitD em indivíduos com declínio cognitivo.

Leptin, hsCRP, TNF-α and IL-6 levels from normal aging to dementia: Relationship with cognitive and functional status.

Cognitive impairment, including mild cognitive impairment (MCI) and dementia, compromises the patients' cognitive abilities and, to different extents, to carry out daily activities, accompanied by personality and behavioral changes. Studies suggest that leptin, an adipokine, has a neuroprotective role against Alzheimer's disease (AD) and that cytokines are associated with inflammatory processes and dementia. This study aimed to evaluate serum leptin, hsCRP, IL-6 and TNF-α levels in a cognitive continuum group from normal to demential status, and to assess whether they correlates to Mini-Mental State Examination (MMSE) and Functional Assessment Staging (FAST) scores. Forty-three participants were included, of whom 12 with probable AD, 18 with MCI and 13 with no objective cognitive decline. Serum leptin and hsCRP levels were evaluated by immunoturbidimetric method, and IL-6 and TNF-α by ELISA. Higher TNF-α levels were found in individuals with FAST stages 1/2 and normal scores evaluated by MMSE. hsCRP levels were inversely correlated with FAST stages. No association with function or global cognition was observed for leptin and IL-6 levels. However, women presented higher leptin serum levels than men while lower leptin and IL-6 levels were observed in individuals aged ≥59 years. Our results suggest that TNF-α is associated with cognitive and functional decline and that inflammation could be a substrate of cognitive impairment at early clinical stages of dementia.

Cerebrospinal fluid biomarkers for the differential diagnosis of Alzheimer’s disease / Aplicação de biomarcadores do fluido cerebrospinal no diagnóstico diferencial da doença de Alzheimer

ABSTRACT Introduction: Several studies have been conducted in order to validate cerebrospinal fluid biomarkers for the diagnosis of Alzheimer’s disease (AD), aiming primarily to facilitate the early diagnosis. Objective: To evaluate CSF biomarkers on patients with probable AD and the applicability of the international references values in this population. Methods: 46 individuals were recruited and classified as probable AD (n = 19), mild cognitive impairment (MCI) (n = 5) and other dementias (n = 22). The cerebrospinal fluid (CSF) biomarkers were measured using the INNOTEST kits for enzyme-linked immunosorbent assay (ELISA). Higher Tau protein values and lower Aβand Innotest Amyloid Tau Index (IATI) values were observed in AD group when compared with MCI; higher levels of Tau and phosphorylated Tau (P-Tau), and lower Aβand IATI values were observed in AD group when compared to patients with other dementias. No biomarker or IATI was able to distinguish between MCI and other dementias. The kappa index between biomarkers and the clinical diagnosis was regular to Tau and IATI, and weak to Aβand P-tau. Conclusion: The cut-off values for each biomarker that showed better combined sensibility and specificity differ from the reference values suggested by the manufacturer. The CSF biomarkers represent important resources that can help with the AD diagnosis, although the results interpretation must be made based on the analysis of the three analytes together. The cut-off values must be established to address the specificities and characteristics of each population.

RESUMO Introdução: Estudos têm sido conduzidos no sentido de validar biomarcadores no liquor para o diagnóstico da doença de Alzheimer (DA), objetivando, sobretudo, facilitar o diagnóstico precoce. Objetivo: Avaliar os biomarcadores do liquor em indivíduos com provável DA, bem como a aplicabilidade dos valores de referência internacionais nesta população. Métodos: Foram recrutados 46 indivíduos, sendo classificados como provável DA (n = 19), comprometimento cognitivo leve (CCL) (n = 5) e outras demências (n = 22). Os biomarcadores foram dosados no liquor utilizando-se os kits INNOTEST por ensaio imunossorvente ligado à enzima (ELISA). Maiores valores de proteína Tau e menores valores de Aβ e índice Innotest Amiloide Tau Index (IATI) foram observados no grupo de DA quando comparados com o de CCL; maiores níveis de Tau e Tau fosforilada (Tau-P) e menores valores de Aβ e IATI foram observados no grupo de DA quando comparados com os pacientes que apresentavam outras demências. Nenhum biomarcador ou o IATI foi capaz de discernir entre CCL e outras demências. O índice kappa entre os biomarcadores e o diagnóstico clínico foi regular para a Tau e IATI, e fraco para Aβ e Tau-P. Conclusão: Os valores de cut-off para cada biomarcador que apresentou melhor sensibilidade e especificidade conjugadas diferiram dos valores de referência sugeridos pelo fabricante. Os biomarcadores do liquor representam importantes recursos que podem auxiliar no diagnóstico da DA, mas a interpretação dos resultados deve ser feita com base na análise dos três analitos em conjunto. Os valores de cut-off devem ser estabelecidos de modo a atender as especificidades e as características de cada população.