Prediabetes Is Associated With Structural Brain Abnormalities: The Maastricht Study

Type 2 diabetes is associated with dementia, and also with more slight cognitive decrements. In this Review we discuss trajectories from normal cognition to dementia in people with type 2 diabetes, and explore opportunities for treatment. Slight diabetes-associated cognitive decrements and dementia affect different age groups and show a different evolution. These cognitive entities should therefore not be regarded as a continuum, although their effects might be additive. Vascular damage is a key underlying process in both entities. Glucose-mediated processes and other metabolic disturbances might also have a role. No treatment has been established, but management of vascular risk factors and optimisation of glycaemic control could have therapeutic benefit. We identify possible opportunities for intervention to improve cognitive outcomes in people with type 2 diabetes, and suggest how treatment can be tailored to individual risk profiles and comorbidities. Copyright © 2014 Elsevier Ltd. All rights reserved.

"Incidental" MRI white matter (WM) lesions, comprising periventricular lesions (PVLs) and deep subcortical lesions (DSCLs), are common in the aging brain. Direct evidence of ischemia associated with incidental WM lesions (WMLs) has been lacking, and their pathogenesis is unresolved. A population-based, postmortem cohort (n=456) of donated brains was examined by MRI and pathology. In a subsample of the whole cohort, magnetic resonance images were used to sample and compare WMLs and nonlesional WM for molecular markers of hypoxic injury. PVL severity was associated with loss of ventricular ependyma (P=0.004). For DSCLs, there was arteriolar sclerosis compared with normal WM (vessel wall thickness and perivascular enlargement; both P<0.001). Capillary endothelial activation (ratio of intercellular adhesion molecule to basement membrane collagen IV; P<0.001) and microglial activation (CD68 expression; P=0.002) were elevated in WMLs. Immunoreactivity for hypoxia-inducible factors (HIFs) HIF1alpha and HIF2alpha was elevated in DSCLs (P=0.003 and P=0.005). Other hypoxia-regulated proteins were also increased in WMLs: matrix metalloproteinase-7 (PVLs P<0.001; DSCLs P=0.009) and the number of neuroglobin-positive cells (WMLs P=0.02) reaching statistical significance. The severity of congophilic amyloid angiopathy was associated with increased HIF1alpha expression in DSCLs (P=0.04). The data support a hypoxic environment within MRI WMLs. Persistent HIF expression may result from failure of normal adaptive mechanisms. WM ischemia appears to be a common feature of the aging brain.

MRI segmentation and mapping techniques were used to assess evidence in support of categorical distinctions between periventricular white matter hyperintensities (PVWMH) and deep WMH (DWMH). Qualitative MRI studies generally identify 2 categories of WMH on the basis of anatomical localization. Separate pathophysiologies and behavioral consequences are often attributed to these 2 classes of WMH. However, evidence to support these empirical distinctions has not been rigorously sought. MRI analysis of 55 subjects included quantification of WMH volume, mapping onto a common anatomical image, and spatial localization of each WMH voxel. WMH locations were then divided into PVWMH and DWMH on the basis of distance from the lateral ventricles and correlations, with total WMH volume determined. Periventricular distance histograms of WMH voxels were also calculated. PVWMH and DWMH were highly correlated with total WMH (R2>0.95) and with each other (R2>0.87). Mapping of all WMH revealed smooth expansion from around central cerebrospinal fluid spaces into more distal cerebral white matter with increasing WMH volume. PVWMH, DWMH, and total WMH are highly correlated with each other. Moreover, spatial analysis failed to identify distinct subpopulations for PVWMH and DWMH. These results suggest that categorical distinctions between PVWMH and DWMH may be arbitrary, and conclusions regarding individual relationships between causal factors or behavior for PVWMH and DWMH may more accurately reflect total WMH volume relationships.