RESUMEN
OBJECTIVE: We investigated whether HIV brain latency was associated with brain injury in virally suppressed HIV infection. DESIGN: Observational cross-sectional and longitudinal study. METHODS: The study included 26 virally suppressed HIV-infected men (61.5% with HIV-associated neurocognitive disorder) who undertook cerebrospinal fluid (CSF) analyses at baseline. They also completed a proton magnetic resonance spectroscopy (1H MRS) and neuropsychological assessments at baseline and 18 months. To quantify whether there was residual brain HIV transcription, we measured CSF HIV-tat. As an HIV brain latency biomarker, we used concentrations of CSF BcL11b - a microglia transcription factor that inhibits HIV transcription. Concurrently, we assessed neuroinflammation with CSF neopterin, neuronal injury with CSF neurofilament light-chain (NFL), and in-vivo neurochemistry with 1H MRS of N-acetyl aspartate (NAA), choline (Cho), creatine, myo-inositol (MI), glutamine/glutamate (Glx) in the frontal white matter (FWM), posterior cingulate cortex (PCC), and caudate nucleus area. RESULTS: Baseline adjusted regression models for neopterin, NFL, and tat showed that a higher CSF BcL11b was consistently associated with lower FWM creatine (when adjusted for neopterin: ßâ=â-0.30, Pâ=â0.15; when adjusted for NFL: ßâ=â-0.47, Pâ=â0.04; and when adjusted for tat: ßâ=â-0.47, Pâ=â0.02). In longitudinal analyses, we found no time effect, but a consistent BcL11b altering effect on FWM creatine. The effect reached a significant moderate effect size range when corrected for CSF NFL (ßâ=â-0.36, Pâ=â0.02) and CSF tat (ßâ=â-0.34, Pâ=â0.02). CONCLUSIONS: Reduced frontal white matter total creatine may indicate subclinical HIV brain latency-related injury. H MRS may offer a noninvasive option to measure HIV brain latency.
Asunto(s)
Complejo SIDA Demencia/patología , Encéfalo/virología , Infecciones por VIH/complicaciones , Proteínas Represoras/líquido cefalorraquídeo , Proteínas Supresoras de Tumor/líquido cefalorraquídeo , Complejo SIDA Demencia/diagnóstico por imagen , Anciano , Biomarcadores/líquido cefalorraquídeo , Encéfalo/diagnóstico por imagen , Estudios Transversales , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas NeuropsicológicasRESUMEN
Clinical diagnosis of Alzheimer's disease (AD) relying on symptomatic features has a low specificity, emphasizing the importance of the pragmatic use of neurochemical biomarkers. The most advanced and reliable markers are amyloid-ß (Aß42), total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) with relatively high levels of sensitivity, specificity, and diagnostic accuracy. Recent advances within the field of proteomics offer the potential to search for novel biomarkers in CSF by using modern methods, such as microarrays. The purpose of this study was to identify pathognostic proteins in CSF obtained from patients whose clinical AD diagnosis was confirmed by the "core" biomarkers. CSF samples were obtained from 25 AD patients and 25 control individuals. The levels of Aß42, t-tau, and p-tau were measured by ELISA. In the microarray experiments, ultrasensitive slides representing of 653 antigens were used. Apolipoprotein E genotyping was also determined. A decrease of seven CSF proteins in AD were found, four of them (POLG, MGMT, parkin, and ApoD) have a protective function against neuronal death, while the remaining three proteins (PAR-4, granzyme B, Cdk5) trigger multiple pathways facilitating neuronal cell death. Since these proteins from CSF samples could not be identified by western blot, their decreased levels in AD patients were not verified. Our results provide new information of pathognostic importance of POLG and granzyme B in AD. Although the function of MGMT, parkin, ApoD, PAR-4, and Cdk5 was previously known in AD, the findings presented here provide novel evidence of the significance of CSF analysis in the mapping of the AD pathomechanism.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteómica , Proteínas tau/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Apolipoproteínas D/líquido cefalorraquídeo , Apolipoproteínas E/genética , Metilasas de Modificación del ADN/líquido cefalorraquídeo , ADN Polimerasa gamma , Enzimas Reparadoras del ADN/líquido cefalorraquídeo , ADN Polimerasa Dirigida por ADN/líquido cefalorraquídeo , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Análisis por Matrices de Proteínas , Sensibilidad y Especificidad , Tomógrafos Computarizados por Rayos X , Proteínas Supresoras de Tumor/líquido cefalorraquídeo , Ubiquitina-Proteína Ligasas/líquido cefalorraquídeoRESUMEN
Reissner's fibre (RF) is formed by the polymerization of the glycoprotein secreted by the subcommissural organ (SCO). The SCO also secretes soluble glycoprotein into the cerebrospinal fluid (CSF); variations in RF and SCO have been reported in hydrocephalus. On the other hand, hydrocephalus and other brain alterations have been described in p73 mutant mice. The p73 belongs to the tumour suppressor p53 protein family and has two isoforms: the TAp73 with apoptotic activity and DeltaNp73 with anti-apoptotic function. Moreover, the TAp73 isoform is glycosylated and secreted into the CSF. In the present work, we analysed the variations in RF and p73 proteins in the CSF and SCO of spontaneously hydrocephalic rats. Brains from control rats and spontaneously hydrocephalic rats of 12 months of age were used. The SCO sections were immunohistochemically processed with anti-TAp73 and anti-Reissner fibre (AFRU). The spontaneous hydrocephalus presents a decrease in the AFRU immunoreactive material in the SCO and an absence of RF. The anti-TAp73 was also present, slightly decreased, in the hydrocephalic SCO. AFRU and p73 bands were also detected in the CSF by western blot and six AFRU and p73 protein bands of a similar molecular weight were found in the CSF of the control rats. The number of AFRU and p73 bands was lower in the hydrocephalic rats than in the control rats. In conclusion, hydrocephalus produces a decrease in the secretions of the SCO and an absence of RF and a decrease in p73 and RF proteins in the CSF.