RESUMEN
Copper/zinc superoxide dismutase 1 (SOD1) scavenges free radicals that may otherwise damage brain parenchyma. Impaired SOD1 activity drives Alzheimer's disease (AD) neuropathology in animal models and postmortem AD brains. Yet, it is unknown how cerebrospinal fluid (CSF) SOD1 is related in vivo to AD-relevant cognitive, neuroimaging, and CSF neurotoxic factors, and what potential mechanisms underlie these associations. We found that higher CSF SOD1 correlated with better global cognition scores, yet less gray matter (GM) and glucose metabolism in AD-sensitive parietal and frontal regions. Higher CSF SOD1 was also associated with more CSF total tau and phosphorylated tau-181, but not beta-amyloid 1-42. Through mediation analyses, higher total tau largely mitigated higher CSF SOD1 and better global cognition associations, and it fully accounted for less predicted regional GM but not glucose metabolism. Among participants who developed AD over 2 years or had AD at baseline, higher CSF SOD1 was initially related to more regional GM. This association became nonsignificant with full mediation via higher CSF total tau, through which higher CSF SOD1 predicted more total tau and in turn less GM. Our observations lead to the hypothesis that SOD1 antioxidation reflects tau but not amyloid accumulation, which may lead to pro-oxidant-based neurodegeneration and cognitive dysfunction. Antioxid. Redox Signal. 31, 572-578.
Asunto(s)
Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/metabolismo , Amiloide/metabolismo , Biomarcadores , Superóxido Dismutasa-1/metabolismo , Proteínas tau/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Cognición , Susceptibilidad a Enfermedades , Femenino , Fluorodesoxiglucosa F18/metabolismo , Humanos , Imagen por Resonancia Magnética , Masculino , Memoria , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Tomografía de Emisión de Positrones , Superóxido Dismutasa-1/líquido cefalorraquídeoRESUMEN
Cholecystokinin (CCK) is a satiety hormone that is highly expressed in brain regions like the hippocampus. CCK is integral for maintaining or enhancing memory and thus may be a useful marker of cognitive and neural integrity in participants with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD). Cerebrospinal fluid (CSF) CCK levels were examined in 287 subjects from the Alzheimer's Disease Neuroimaging Initiative. Linear or voxelwise regression was used to examine associations between CCK, regional gray matter, CSF AD biomarkers, and cognitive outcomes. Briefly, higher CCK was related to a decreased likelihood of having mild cognitive impairment or AD, better global and memory scores, and more gray matter volume primarily spanning posterior cingulate cortex, parahippocampal gyrus, and medial prefrontal cortex. CSF CCK was also strongly related to higher CSF total tau (R2 = 0.342) and p-tau-181 (R2 = 0.256) but not Aß1-42. Tau levels partially mediated CCK and cognition associations. In conclusion, CCK levels may reflect compensatory protection as AD pathology progresses.