Methylglyoxal, cognitive function and cerebral atrophy in older people.

BACKGROUND: The effects of advanced glycation endproducts on cognition and brain structure are poorly understood. We studied associations of the advanced glycation endproduct precursor methylglyoxal (MGO) with cognitive function and brain volumes in older people. METHODS: Nondemented participants in the Tasmanian Study of Cognition and Gait underwent cognitive testing and brain magnetic resonance imaging scans. Brain volumes were obtained by magnetic resonance imaging scan segmentation and statistical parametric mapping procedures. Serum MGO was measured after derivatization to methylquinoxaline by high pressure liquid chromatography and UV detection. Linear regression was used to examine associations of log-transformed MGO with cognitive scores and brain volumes adjusting for potential confounding by age, sex, education, mood, insulin resistance, history of stroke, vascular risk factors, alcohol intake, and psychoactive medication use. RESULTS: There were 378 participants, mean age 72.1 years (SD 7.1), 55% male. Greater MGO was associated with poorer memory (ß = -.12, 95% confidence interval: -0.22, -0.02, p = .02) and executive function, the latter being greater among those with a history of stroke (MGO × stroke ß = .48, 95% confidence interval: 0.17, 0.79, p = .002). Greater MGO was associated with lower grey matter volume (ß = -6.42, 95% confidence interval -11.82, -1.11, p = .02) but not with white matter volume, white matter lesion volume, or hippocampal volume. CONCLUSIONS: These results support the investigation of the role of the advanced glycation endproduct precursor methylglyoxal in cognitive decline and neurodegeneration in older people.

Advanced glycation endproducts and their pathogenic roles in neurological disorders.

Glycation is implicated in neurological disorders. In some cases it plays a key role in the pathogenesis, in others it plays a co-adjuvant role or it appears as a consequence of degenerative changes and protein accumulation stemming from other pathways. In this work, we attempt to provide a concise, updated review of the major recent findings concerning glycation in neurological diseases. After a short introduction covering advanced glycation endproducts (AGEs) and the receptor for AGEs (RAGE), we will discuss the impact of glycation in central nervous system disorders including Alzheimer's, Parkinson's and Creutzfeldt-Jakob disease, as well as peripheral diabetic polyneuropathies. Therapies directed at lowering the concentrations of RAGE ligands including AGEs, blocking RAGE signaling, preventing oxidative stress or lowering methylglyoxal (MGO) levels may significantly decrease the development of AGE-related pathologies in patients with neurological disorders. Many drugs are on the pipeline and the future clinical trials will reveal if the promising results translate into clinical application.

Advanced glycation endproducts and their receptor RAGE in Alzheimer's disease.

Alzheimer's disease (AD) is the most common dementing disorder of late life. Although there might be various different triggering events in the early stages of the disease, they seem to converge on a few characteristic final pathways in the late stages, characterized by inflammation and neurodegeneration. In this review, we revisit the hypothesis that advanced glycation endproducts (AGEs) and their receptor RAGE may play an important role in disease pathogenesis. Accumulation of AGEs in cells and tissues is a normal feature of aging, but is accelerated in AD. In AD, AGEs can be detected in pathological deposits such as amyloid plaques and neurofibrillary tangles. AGEs explain many of the neuropathological and biochemical features of AD such as extensive protein crosslinking, glial induction of oxidative stress and neuronal cell death. Oxidative stress and AGEs initiate a positive feedback loop, where normal age-related changes develop into a pathophysiological cascade. RAGE and its decoy receptor soluble RAGE, may contribute to or protect against AD pathogenesis by influencing transport of ß-amyloid into the brain or by manipulating inflammatory mechanisms. Targeted pharmacological interventions using AGE-inhibitors, RAGE-antagonists, RAGE-antibodies, soluble RAGE or RAGE signalling inhibitors such as membrane-permeable antioxidants may be promising therapeutic strategies to slow down the progression of AD.