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BackgroundGlutamate is the principal excitatory neurotransmitter in the central nervous system which acts by the activation of either ionotropic (AMPA, NMDA and kainate receptors) or G-protein coupled metabotropic receptors. Glutamate is widely accepted to play a major role in the path physiology of migraine as implicated by data from animal and human studies. Genes involved in synthesis, metabolism and regulation of both glutamate and its receptors could be, therefore, considered as potential candidates for causing/predisposing to migraine when mutated.MethodsThe association of polymorphic variants of GRIA1-GRIA4 genes which encode for the four subunits (GluR1-GluR4) of the alpha-amino-3- hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor for glutamate was tested in migraineurs with and without aura (MA and MO) and healthy controls.ResultsTwo variants in the regulative regions of GRIA1 (rs2195450) and GRIA3 (rs3761555) genes resulted strongly associated with MA (P = 0.00002 and P = 0.0001, respectively), but not associated with MO, suggesting their role in cortical spreading depression. Whereas the rs548294 variant in GRIA1 gene showed association primarily with MO phenotype, supporting the hypothesis that MA and MO phenotypes could be genetically related. These variants modify binding sites for transcription factors altering the expression of GRIA1 and GRIA3 genes in different conditions.ConclusionsThis study represents the first genetic evidence of a link between glutamate receptors and migraine.

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Cerebrospinal fluid (CSF) levels of rT(3) were evaluated in 21 euthyroid patients with overt Alzheimer's disease (AD) and 18 matched healthy controls. The assessment also included transthyretin and total T(3) and T(4) CSF concentrations. Despite normal circulating thyroid hormone levels, AD subjects showed significantly increased rT(3) levels and an increased rT(3) to T(4) ratio in the face of unchanged CSF total T(4) and transthyretin levels. These results suggest an abnormal intracerebral thyroid hormone metabolism and possibly the occurrence of brain hypothyroidism, either as a secondary consequence of the ongoing process or as a cofactor in the progression of the disease.