Ranjan Duara

Relations between Neuropsychological and Cerebral Metabolic Asymmetries in Early Alzheimer's Disease

Regional CMRglc (rCMRglc) values were determined with positron emission tomography (PET) in 10 patients with mild to moderate clinically diagnosed Alzheimers disease (AD) and in 26 healthy controls. rCMRglc in frontal, parietal, and temporal association cortices were significantly more laterally asymmetrical in AD patients than in controls (p < 0.05). Furthermore, lateral asymmetry of rCMRglc in AD patients but not in the control subjects correlated significantly with asymmetry of language and visuospatial functions such that lower left than right rCMRglc was associated with relatively greater impairment of language and vice versa. The results demonstrate that discrepancies between language and visuospatial deficits in patients with early AD are related to asymmetrical reductions in cerebral cortical glucose metabolism.

Intercorrelations of Glucose Metabolic Rates between Brain Regions: Application to Healthy Males in a State of Reduced Sensory Input

We use a correlational analysis of regional metabolic rates to characterize relations among different brain regions. Starting with rates of local glucose metabolism (rCMRglc) obtained by positron emission tomography using [18F]fluorodeoxyglucose, we propose that pairs of brain regions whose rCMRglc values are significantly correlated are functionally associated, and that the strength of the association is proportional to the magnitude of the correlation coefficient. Partial correlation coefficients, controlling for whole brain glucose metabolism, are used in the analysis. We also introduce a graphical technique to display simultaneously all the correlations, allowing us to examine patterns of relations among them. The method was applied to 40 very healthy males under conditions of reduced auditory and visual inputs (the “resting state”). Dividing the brain into 59 regions, and keeping only those partial correlation coefficients significant to p < 0.01, we found the following: (a) All regions were significantly correlated with their contralateral homologues. For the most part, the largest partial correlation coefficients were between homologous brain regions. (b) Generally, the pattern of significant correlations between any two lobes in the left hemisphere did not differ statistically from the corresponding pattern in the right hemisphere. (c) Strong correlations were observed between primary somatosensory areas and premotor association areas. Correlations between these association areas and primary visual and auditory regions were not statistically significant. (d) Significant correlations between inferior occipital and temporal areas were found. Metabolic rates in the superior part of the occipital lobe were not correlated significantly with metabolic rates in regions of the temporal lobe, nor with metabolism in the parietal lobe. (e) As a whole, there were numerous correlations among frontal and parietal lobe regions, on the one hand, and among temporal and occipital lobe regions, on the other, but few statistically significant correlations between these two domains. We relate our results to various aspects of known brain anatomy, physiology, and cognitive functioning.

Intercorrelations of regional cerebral glucose metabolic rates in Alzheimer's disease.

Patterns of cerebral metabolic correlations were compared between 21 Alzheimers disease patients and 21 healthy age-matched controls in the resting state. Cerebral metabolic rates for glucose were determined by positron emission tomography using [18F]2-fluoro-2-deoxy-D-glucose. Partial correlation coefficients, controlling for whole brain glucose metabolism, were evaluated between pairs of regional glucose metabolic rates in 59 brain regions. Reliable correlation coefficients were obtained with the jackknife and bootstrap statistical procedures. Compared with healthy controls, the Alzheimer patients had significantly fewer reliable partial correlation coefficients between frontal and parietal lobe regions, and more reliable correlations between the cerebellum and temporal lobe. The number of reliable correlations between many bilaterally symmetric brain regions was reduced in the Alzheimer patients, as compared with controls. These results suggest that in the early stages of Alzheimers disease there is a breakdown of the organized functional activity between the two cerebral hemispheres, and between parietal and frontal lobe structures.

Relation of measured brain glucose utilisation and cerebral atrophy in man.

The effect of cerebral atrophy on measured cerebral metabolic rates for glucose (CMRglc), as determined with positron emission tomography (PET), was examined in 49 healthy males aged 21-83 years. Global CMRglc and regional CMRglc for 34 grey matter regions parallel to and from 30 to 80 mm above the inferior orbital meatal (IOM) line were measured under resting conditions, using [18F]-fluorodeoxyglucose and an ECAT II positron emission tomograph. Using a GE 8800 CT/T scanner, slices parallel to and from 30 to 80 mm above the IOM line were analysed for CSF volume. Cerebral atrophy, indicated by increased CSF volume, was correlated significantly with global CMRglc, but accounted for no more than 13% of the variance in the CMRglc measurements. Methods for correcting for inter-subject variation in CSF volume were proposed. Global values for CMRglc, uncorrected or corrected for CSF volume, were found to be age invariant. These findings indicate that (a) cerebral atrophy has a small, but statistically significant effect on CMRglc as measured with PET; (b) CMRglc is age invariant in healthy males.

Relations among age, visual memory, and resting cerebral metabolism in 40 healthy men

Visual memory, as measured by the Benton Visual Retention Test (BVRT), and resting regional cerebral metabolic rates for glucose (rCMRglc), as measured by positron emission tomography (PET) and [18-F]fluorodeoxyglucose, were examined in 40 very healthy men, aged 21 to 83 years. Age-related differences in visual memory were found but were significantly smaller than differences reported in the general population. This discrepancy is attributable to our rigorous health screening. The age-related differences found in this sample are estimates of the lower limit of population differences unconfounded by disease. Age-related differences on undistracted delayed visual memory were greater than differences on immediate visual memory, suggesting age-related differences in spontaneous elaborative visual information processing. No relation between visual memory and resting rCMRglc was found, supporting the hypothesis that mental abilities are unrelated to resting brain metabolism unless both functions are influenced by disease.

Decline in cerebral glucose utilisation and cognitive function with aging in Down's syndrome.

The cerebral metabolic rate for glucose (CMRglc) was measured with positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose in 14 healthy subjects with Downs syndrome, 19 to 33 years old, and in six healthy Downs syndrome subjects over 35 years, two of whom were demented. Dementia was diagnosed from a history of mental deterioration, disorientation and hallucinations. All Downs syndrome subjects were trisomy 21 karyotype. CMRglc also was examined in 15 healthy men aged 20-35 years and in 20 healthy men aged 45-64 years. All subjects were at rest with eyes covered and ears plugged. Mean hemispheric CMRglc in the older Downs syndrome subjects was significantly less, by 23%, than in the young Downs syndrome group; statistically significant decreases in regional metabolism (rCMRglc) also were present in all lobar regions. Comparison of the younger control group with the older control group showed no difference in CMRglc or any rCMRglc (p greater than 0.05). Assessment of language, visuospatial ability, attention and memory showed significant reductions in test scores of the old as compared with the young Downs syndrome subjects. These results show that significant age differences in CMRglc and rCMRglc occur in Downs syndrome but not in healthy controls, and that, although only some older Downs syndrome subjects are demented, significant age reductions in neuropsychologic variables occur in all of them.

Brain Imaging: Aging and Dementia

The brain imaging techniques of positron emission tomography using [18F]-fluoro-2-deoxy-D-glucose, and computed tomography, together with neuropsychological tests, were used to examine overall brain function and anatomy in three study populations: healthy men at different ages, patients with presumptive Alzheimers disease, and adults with Downs syndrome. Brain glucose use did not differ with age, whereas an age-related decrement in gray matter volume was found on computed tomographic assessment in healthy subjects. Memory deficits were found to precede significant reductions in brain glucose utilization in mild to moderate Alzheimers dementia. Furthermore, differences between language and visuoconstructive impairments in patients with mild to moderate Alzheimers disease were related to hemispheric asymmetry of brain metabolism. Brain glucose utilization was found to be significantly elevated in young adults with Downs syndrome, compared with controls. The importance of establishing strict criteria for selecting control subjects and patients is explained in relation to the findings.

Cerebral Glucose Metabolism in Aging, Dementia, and Down Syndrome

Aging in animals and man is accompanied by many changes in morphometric and neurochemical measures of the brain. In pathologic conditions such as Alzheimer’s disease and Down syndrome (DS), furthermore, these alterations have been shown to be greatly accelerated; however, the functional significance of these changes remains to be determined.