RESUMEN
BACKGROUND: The C9ORF72 expansion is one of the most common causes of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The C9ORF72 expansion is associated with TDP-43 and p62 neuropathology, and amyloid plaques and neurofibrillary tangles are not common in patients with the C9ORF72 expansion. Therefore, we hypothesized that cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease [AD; Aß1-42, total tau (T-tau) and phospho-tau] are normal in these patients. METHODS: The CSF Aß1-42, T-tau and phospho-tau levels were measured in 40 Finnish patients with the C9ORF72 expansion (29 FTLD, 10 ALS and 1 FTLD-ALS) using ELISA. RESULTS: A decreased Aß1-42 level was found in 25% of cases, while there were only single cases with changes in the t-Tau or phospho-tau level. The patients with abnormal biomarkers fulfilled the clinical criteria of the behavioral variant frontotemporal dementia and expressed no clinical signs of AD. CONCLUSIONS: In clinical diagnostics, a decreased CSF Aß1-42 level does not exclude the C9ORF72 expansion associated with FTLD.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Expansión de las Repeticiones de ADN , Degeneración Lobar Frontotemporal/líquido cefalorraquídeo , Proteínas/genética , Edad de Inicio , Anciano , Enfermedad de Alzheimer/genética , Esclerosis Amiotrófica Lateral/genética , Biomarcadores/líquido cefalorraquídeo , Encéfalo/patología , Proteína C9orf72 , Estudios de Cohortes , Proteínas de Unión al ADN/genética , Femenino , Degeneración Lobar Frontotemporal/genética , Humanos , Masculino , Persona de Mediana Edad , Proteínas tau/genéticaRESUMEN
Genetic variants in the granulin (GRN) gene have been shown to increase the risk of Alzheimer's disease (AD). Here, we report that the A allele of rs5848 in GRN reduces plasma granulin levels in a dose-dependent manner in a clinically-defined AD sample cohort. Similarly, the mRNA levels of granulin were decreased with respect to A allele of rs5848 in the inferior temporal cortex of neuropathologically confirmed AD patients. Our findings suggest that the A allele of rs5848 is functionally relevant by reducing the expression of granulin.