Advanced glycation end-products (AGEs) may contribute to the aetiology of many disease processes including Alzheimer's disease (AD) [1
] and the vascular complications of diabetes [10
]. The microvascular changes in diabetes bear some similarity to the microvascular disease observed in patients with vascular dementia (VD) [11
]. VD shares many risk factors with AD such as age, hypertension, diabetes mellitus and hyperhomocysteinemia [12
]. Hence, VD often co-occurs with Alzheimer's disease (AD). Previous work has shown that even in cases where AD pathology is only mild, VD may promote cognitive impairment [13
]. Hence, if AGEs contribute to microvascular damage, then they may also relate to cognitive impairment. The present study tested this hypothesis.
AGEs are adducts or crosslinks which can form non-enzymatically between reducing sugars such as glucose, and other moieties such as lipids, nucleic acids or proteins. The classical pathway of AGE formation, the Maillard (browning) reaction involves a glucose-protein condensation reaction to form Schiff base adducts, which are subject to Amadori rearrangement. Some Amadori products convert to AGEs, which are characteristically fluorescent, pigmented adducts that can cross link with proteins and persist for the lifetime of the modified substrate. Examples include Nε
-(carboxymethyl)-lysine (CML), pentosidine, pyrraline and crosslines A and B, all of which have been identified in brain using immunohistochemical methods [5
The degree of AGE accumulation in a tissue depends on the rates of AGE formation and degradation. Hyperglycemia and oxidative stress accelerate the former, while the latter depends on the rates of protein turnover, ligation to macrophage scavenger receptors (MSR) [15
] and renal clearance. Probably, the accumulation of AGEs during natural ageing [16
] is due to the time-dependent nature of advanced glycation coupled with increased oxidative stress and a progressive reduction in the capacity to neutralise oxidative stress. AGEs have diverse detrimental effects. They can damage proteins directly and enhance oxidative stress via specific receptors (RAGE).
CML is the most abundant AGE in vivo
]. It accumulates in vascular tissue and atherosclerotic and diabetic lesions [17
]. Levels of CML in serum are higher in diabetics with retinopathy and microalbuminaemia than in those without these complications [19
]. The amount of CML detectable in cortical neurons increases with ageing [4
] and even more so in AD [1
]. This increased accumulation of AGEs in the brains of AD patients [5
] may index neuronal damage due to glycation and oxidative stress.
Our present aim was to test if CML expression in the brain in elderly subjects with cerebrovascular disease relates to cognitive dysfunction. Accordingly, we analysed immunocytochemical expression of CML in cerebral neurons and blood vessel walls in autopsy samples from people with cerebrovascular disease with or without cognitive dysfunction and explored how CML expression related to presence of risk factors for vascular dementia. Since vascular and Alzheimer pathology often co-exist [13
], to clarify the relation of cognitive impairment to AGEs requires careful control of its relation to Alzheimer pathology. To this end, we studied only samples from individuals with minimal Alzheimer pathology and we covaried the severity of that pathology. Finally, to test whether cognitive impairment relates specifically to vascular AGE staining, we studied CML staining not only in vessel walls in subcortical white matter and basal ganglia but also in neurons.