Quantitative immunogold study of glucose transporter (GLUT-1) in five brain regions of scrapie-infected mice showing obesity and reduced glucose tolerance.

Distribution of glucose transporter (GLUT-1) in the microvascular endothelium of scrapie-infected SJL/J hyperglycemic mice showing clinical signs of scrapie, obesity and reduced glucose tolerance was studied in five brain regions: cerebral cortex, hippocampus, thalamus, cerebellum and olfactory bulb. Uninfected normoglycemic SJL/J mice showing normal glucose tolerance were used as a control. Ultrathin sections of brain samples embedded at low temperature in the hydrophilic resin Lowicryl K4M were exposed to anti-GLUT-1 antiserum followed by gold-labeled secondary antibodies. Labeling density was recorded over luminal and abluminal plasma membranes of microvascular endothelial cells. Ultrastructural observations revealed attenuation of the microvascular endothelial lining in numerous vascular profiles from brain samples of diabetic mice. Morphometric analysis revealed significant decreases of the labeling density for GLUT-1 in the microvasculature of the thalamus, cerebellum and, to a lesser degree, the hippocampus of diabetic mice. No significant differences between diabetic and non-diabetic, control mice were observed in the microvessels supplying cerebral cortex and olfactory bulb. These findings suggest that abnormal glucose metabolism, manifested by reduced glucose tolerance and hyperglycemia, leads to impaired transvascular glucose transport in some brain regions but not in others, presumably disturbing the function of those brain regions supplied by the affected blood microvessels.

Cerebellar atrophy in Alzheimer's disease-clinicopathological correlations.

Morphometry of the cerebellum of 11 subjects who died in the severe, final stage of Alzheimer's disease (AD) and of five age-matched subjects without dementia revealed significant atrophy in the AD group, with a decrease in the volume of the molecular layer by 24% and of the granular layer by 22% in comparison with controls. The 32% decrease in the total number of Purkinje cells that was observed correlates with the atrophy of the molecular layer, whereas the 30% reduction in the total number of granule cells correlates with the atrophy of the molecular and granular layers. A unique pattern of Alzheimer-type pathology was observed in the cerebellum: (1) there were no neurofibrillary changes in the cerebellum of either the control or the AD subjects, (2) there was almost the same extent of leptomeningeal and cortical amyloid angiopathy in the normal aged subjects and in the AD patients, and (3) the presence of plaques was noted in the AD group, but not in the control group. This pattern of pathology suggests that two factors might be considered in the etiopathogenesis of cerebellar atrophy: (1) transneuronal degeneration and neuronal loss resulting from primary pathologic changes in cerebral structures and (2) parenchymal cerebellar ss-amyloidosis. The correlation between the temporal duration of AD and both the decrease of the total number of granule cells (r=0.86, p<0.01) and the volumetric loss of the molecular (r=0.73, p<0.05) and granular (r=0.93, p<0.001) layers of the cerebellar cortex indicates that these cerebellar atrophic changes are likely to be related to the basic pathologic process of AD. Similarly, the correlation between the most complex parameter the atrophy of the cerebellar cortex and the Functional Assessment Staging (FAST) measure of the clinical severity of AD at the time of demise (r=0.63, p<0.05) as well as with the duration of AD (r=0.78, p<0.01) indicates that cerebellar pathology, when viewed holistically, evolves continuously in association with clinical changes throughout the clinically manifest course of AD.