In late middle age, cognitively normal subjects who are homozygous for the epsilon 4 allele for apolipoprotein E have reduced glucose metabolism in the same regions of the brain as in patients with probable Alzheimer's disease. These findings provide preclinical evidence that the presence of the epsilon 4 allele is a risk factor for Alzheimer's disease. PET may offer a relatively rapid way of testing future treatments to prevent Alzheimer's disease.

Fluorodeoxyglucose positron emission tomography (PET) studies have found that patients with Alzheimer's dementia (AD) have abnormally low rates of cerebral glucose metabolism in posterior cingulate, parietal, temporal, and prefrontal cortex. We previously found that cognitively normal, late-middle-aged carriers of the apolipoprotein E 4 allele, a common susceptibility gene for late-onset Alzheimer's dementia, have abnormally low rates of glucose metabolism in the same brain regions as patients with probable AD. We now consider whether 4 carriers have these regional brain abnormalities as relatively young adults. Apolipoprotein E genotypes were established in normal volunteers 20 -39 years of age. Clinical ratings, neuropsychological tests, magnetic resonance imaging, and PET were performed in 12 4 heterozygotes, all with the 3͞ 4 genotype, and 15 noncarriers of the 4 allele, 12 of whom were individually matched for sex, age, and educational level. An automated algorithm was used to generate an aggregate surface-projection map that compared regional PET measurements in the two groups. The young adult 4 carriers and noncarriers did not differ significantly in their sex, age, educational level, clinical ratings, or neuropsychological test scores. Like previously studied patients with probable AD and late-middleaged 4 carriers, the young 4 carriers had abnormally low rates of glucose metabolism bilaterally in the posterior cingulate, parietal, temporal, and prefrontal cortex. Carriers of a common Alzheimer's susceptibility gene have functional brain abnormalities in young adulthood, several decades before the possible onset of dementia.apolipoprotein E ͉ positron emission tomography ͉ glucose metabolism ͉ brain mapping ͉ surrogate markers A lzheimer's dementia (AD) afflicts Ϸ10% of those over the age of 65 and almost half of those over the age of 85 (1). To develop and test effective primary prevention therapies, it would be helpful to characterize brain changes associated with the susceptibility to AD as early as possible before the onset of cognitive impairment (2).Fluorodeoxyglucose positron emission tomography (PET) studies have found that patients with AD have abnormally low cerebral metabolic rates for glucose (CMRgl) in posterior cingulate, parietal, temporal, and prefrontal cortex and a progressive decline in these rates over time (3-8). We (2, 9, 10) and others (11, 12) have been using PET to detect and track these functional brain abnormalities before the onset of dementia in carriers of the apolipoprotein E (APOE) 4 allele, a common Alzheimer's susceptibility gene associated with up to half of cases of late-onset AD (13-15). Previously, we found that cognitively normal 50-to 65-year-old 4 carriers have abnormally low CMRgl in each of the same regions as patients with probable AD and abnormal rates of regional CMRgl decline over time (2, 9, 10). We now consider whether 4 carriers have these regional brain abnormalities as relatively young adults, several decades before the possible onset of dementia. Our a...

Temperature sensation is regarded as a submodality of touch, but evidence suggests involvement of insular cortex rather than parietal somatosensory cortices. Using positron emission tomography (PET), we found contralateral activity correlated with graded cooling stimuli only in the dorsal margin of the middle/posterior insula in humans. This corresponds to the thermoreceptive- and nociceptive-specific lamina I spinothalamocortical pathway in monkeys, and can be considered an enteroceptive area within limbic sensory cortex. Because lesions at this site can produce the post-stroke central pain syndrome, this finding supports the proposal that central pain results from loss of the normal inhibition of pain by cold. Notably, perceived thermal intensity was well correlated with activation in the right (ipsilateral) anterior insular and orbitofrontal cortices.

Fibrillar amyloid-beta (A␤) is found in the brains of many cognitively normal older people. Whether or not this reflects a predisposition to Alzheimer's disease (AD) is unknown. We used Pittsburgh Compound B (PiB) PET to characterize the relationship between fibrillar A␤ burden and this predisposition in cognitively normal older people at 3 mean levels of genetic risk for AD. Dynamic PiB PET scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest (ROIs) were used to characterize and compare cerebral-to-cerebellar PIB distribution volume ratios, reflecting fibrillar A␤ burden, in 28 cognitively normal persons (mean age, 64 years) with a reported family history of AD and 2 copies, 1 copy, and no copies of the apolipoprotein E (APOE) 4 allele. The 8 4 homozygotes, 8 heterozygotes, and 12 noncarriers did not differ significantly in terms of age, sex, or cognitive scores. Fibrillar A␤ was significantly associated with APOE 4 carrier status and 4 gene dose in AD-affected mean cortical, frontal, temporal, posterior cingulate-precuneus, parietal, and basal ganglia ROIs, and was highest in an additional homozygote who had recently developed mild cognitive impairment. These findings suggest that fibrillar A␤ burden in cognitively normal older people is associated with APOE 4 gene dose, the major genetic risk factor for AD. Additional studies are needed to track fibrillar A␤ accumulation in persons with different kinds and levels of AD risk; to determine the extent to which fibrillar A␤, alone or in combination with other biomarkers and risk factors, predicts rates of cognitive decline and conversion to clinical AD; and to establish the role of fibrillar A␤ imaging in primary prevention trials.apolipoprotein E ͉ Pittsburgh Compound B PET

The central role of the hypothalamus in the origination and͞or processing of feeding-related stimuli may be modulated by the activity of other functional areas of the brain including the insular cortex (involved in enteroceptive monitoring) and the prefrontal cortex (involved in the inhibition of inappropriate response tendencies). Regional cerebral blood f low (rCBF), a marker of neuronal activity, was measured in 11 healthy, normal-weight men by using positron emission tomography in a state of hunger (after 36-h fast) and a state of satiation (after a liquid meal). Hunger was associated with significantly increased rCBF in the vicinity of the hypothalamus and insular cortex and in additional paralimbic and limbic areas (orbitofrontal cortex, anterior cingulate cortex, and parahippocampal and hippocampal formation), thalamus, caudate, precuneus, putamen, and cerebellum. Satiation was associated with increased rCBF in the vicinity of the ventromedial prefrontal cortex, dorsolateral prefrontal cortex, and inferior parietal lobule. Changes in plasma insulin concentrations in response to the meal were negatively correlated with changes in rCBF in the insular and orbitofrontal cortex. Changes in plasma free fatty acid concentrations in response to the meal were negatively correlated with changes in rCBF in the anterior cingulate and positively correlated with changes in rCBF in the dorsolateral prefrontal cortex. In conclusion, these findings raise the possibility that several regions of the brain participate in the regulation of hunger and satiation and that insulin and free fatty acids may be metabolic modulators of postprandial brain neuronal events. Although exploratory, the present study provides a foundation for investigating the human brain regions and cognitive operations that respond to nutritional stimuli.

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Background-This is a progress report of the Alzheimer's Disease Neuroimaging Initiative (ADNI) PET Core.