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Objective: The purpose of this study was to characterize the relationship between whole brain atrophy rates and three levels of genetic risk for Alzheimer's disease in cognitively normal persons. The authors previously found accelerated whole brain atrophy rates in patients with probable Alzheimer's disease by computing changes in brain volume from sequential magnetic resonance images (MRIs)., Methods: The authors assessed 36 late-middle-aged persons from three genetic groups: those with two, one, and no copies of the apolipoprotein E (APOE) epsilon4 allele, a common Alzheimer's disease susceptibility gene. The participants had clinical ratings, neuropsychological tests, and volumetric T1-weighted MRIs during a baseline visit and again approximately 2 years later. Two different image-analysis techniques, brain boundary shift integration and iterative principal component analysis, were used to compute whole brain atrophy rates., Results: While there were no baseline, follow-up, or between-visit differences in the clinical ratings or neuropsychological test scores among the three subject groups, whole brain atrophy rates were significantly greater in the epsilon4 homozygote group than in noncarriers and were significantly correlated with epsilon4 gene dose (i.e., the number of epsilon4 alleles in a person's APOE genotype)., Conclusion: Since APOE epsilon4 gene dose is associated with an increased risk of Alzheimer's disease and a younger median age at dementia onset, this study suggests an association between the risk of Alzheimer's disease and accelerated brain atrophy rates before the onset of cognitive impairment.

Objective: Aging in Down's syndrome is accompanied by amyloid and neurofibrillary pathology, the regional and laminar distribution of which resembles pathological changes seen in Alzheimer's disease. Previous studies using magnetic resonance imaging (MRI) demonstrated age-related atrophy of medial temporal lobe structures in nondemented older subjects with Down's syndrome, reflecting early allocortical pathology. Corpus callosum atrophy has been established as a marker of neocortical neuronal loss in Alzheimer's disease. This study investigated whether atrophy of the corpus callosum and hippocampus occurs in nondemented subjects with Down's syndrome and compared the degree of age-related atrophy between these structures., Method: Hippocampus and corpus callosum measures were obtained from volumetric T(1)-weighted MRI scans of 34 nondemented Down's syndrome adults (mean age=41.6 years, 17 women) and 31 healthy comparison subjects (mean age=41.8 years, 14 women)., Results: Down's syndrome subjects had smaller corpus callosum areas and hippocampal volumes relative to age-matched healthy comparison subjects, even after age and total intracranial volume were controlled. There was an age-related decrease of corpus callosum area (most prominent in posterior regions) and hippocampal volume in the Down's syndrome group. The degree of the age effect was comparable between the total corpus callosum and hippocampus, and corpus callosum size was correlated with cognitive performance in the Down's syndrome subjects. There was no correlation between age and corpus callosum or hippocampal size in the comparison group., Conclusions: Comparable decrease of corpus callosum and hippocampal size with age in nondemented subjects with Down's syndrome suggests that neocortical neuronal alterations accompany allocortical changes in the predementia phase of Down's syndrome.

Objective: It is well established that regional cerebral metabolic rates for glucose assessed by [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in patients with Alzheimer's disease in the mental resting state (eyes and ears covered) provide a sensitive, in vivo metabolic index of Alzheimer's disease dementia. Few studies, however, have evaluated longitudinal declines in regional cerebral glucose metabolism in patients with dementia caused by Alzheimer's disease. In addition, the available studies have not used recently developed brain mapping algorithms to characterize the progression of Alzheimer's disease throughout the brain, and none considered the statistical power of regional cerebral glucose metabolism in testing the ability of treatments to attenuate the progression of dementia., Method: The authors used FDG PET and a brain mapping algorithm to investigate cross-sectional reductions in regional cerebral glucose metabolism, longitudinal decline in regional cerebral glucose metabolism after a 1-year follow-up, and the power of this method to evaluate treatments for Alzheimer's disease in patients with mild to moderate dementia. PET scans were initially acquired in 14 patients with Alzheimer's disease and 34 healthy comparison subjects of similar age and sex. Repeat scans were obtained in the patients 1 year later. Power analyses for voxels showing maximal decline over the 1-year period in regional cerebral glucose metabolism (mg/100 g per minute) were computed to estimate the sample sizes needed to detect a significant treatment response in a 1-year, double-blind, placebo-controlled treatment study., Results: The patients with Alzheimer's disease had significantly lower glucose metabolism than healthy comparison subjects in parietal, temporal, occipital, frontal, and posterior cingulate cortices. One year later, the patients with Alzheimer's disease had significant declines in glucose metabolism in parietal, temporal, frontal, and posterior cingulate cortices. Using maximal glucose metabolism reductions in the left frontal cortex, we estimated that as few as 36 patients per group would be needed to detect a 33% treatment response with one-tailed significance of p

Objective: In Down's syndrome (trisomy 21), a dementia syndrome occurs that is phenotypically similar to Alzheimer's disease; the initial phase is characterized by memory loss. The authors used an in vivo structural technique in the predementia stage of Alzheimer's disease in adults with Down's syndrome to investigate whether atrophy of medial temporal lobe structures occurs in these subjects and whether volumes of these structures correlate specifically with performance on memory tests., Method: The subjects were 34 nondemented Down's syndrome adults (mean age=41.6 years, 17 women and 17 men) and 33 healthy comparison subjects (mean age=41.3, 15 women and 18 men). By using T(1)-weighted magnetic resonance imaging slices taken perpendicular to the Sylvian fissure, volumes of the hippocampus, amygdala, anterior and posterior parahippocampal gyrus, and temporal pole CSF were measured in both hemispheres. These data were normalized to the total intracranial volume., Results: For Down's syndrome, smaller volumes of the right and left amygdala, hippocampus, and posterior parahippocampal gyrus were significantly associated with greater age; this association was not seen in the anterior parahippocampal gyrus. The amygdala and hippocampus volumes were positively correlated with memory measures. For the comparison group, there was no relationship between volume and age in any region., Conclusions: In the predementia phase of Down's syndrome, significant volume changes in medial temporal lobe structures occur with age and are related to memory. These structures are affected early in Alzheimer's disease in Down's syndrome, and their evaluation may help identify people in the preclinical stages of Alzheimer's disease.

Objective: An extra portion of chromosome 21 in Down's syndrome leads to a dementia in later life that is phenotypically similar to Alzheimer's disease. Down's syndrome therefore represents a model for studying preclinical stages of Alzheimer's disease. Markers that have been investigated in symptomatic Alzheimer's disease are myoinositol and N-acetyl-aspartate. The authors investigated whether abnormal brain levels of myo-inositol and other metabolites occur in the preclinical stages of Alzheimer's disease associated with Down's syndrome., Method: The authors used 1H magnetic resonance spectroscopy (MRS) with external standards to measure absolute brain metabolite concentrations in 19 nondemented adults with Down's syndrome and 17 age- and sex-matched healthy comparison subjects., Results: Concentrations of myoinositol and choline-containing compounds were significantly higher in the occipital and parietal regions of the adults with Down's syndrome than in the comparison subjects. Within the Down's syndrome group, older subjects (42-62 years, N = 11) had higher myo-inositol levels than younger subjects (28-39 years, N = 8). Older subjects in both groups had lower N-acetylaspartate levels than the respective younger subjects, although this old-young difference was not greater in the Down's syndrome group., Conclusions: The approximately 50% higher level of myo-inositol in Down's syndrome suggests a gene dose effect of the extra chromosome 21, where the human osmoregulatory sodium/myo-inositol cotransporter gene is located. The even higher myoinositol level in older adults with Down's syndrome extends to the predementia phase earlier findings of high myoinositol levels in symptomatic Alzheimer's disease.

Objective: This study tested the hypothesis that regional cerebral glucose metabolism during neuronal activation is a more sensitive index of neuronal dysfunction and clinical severity in Alzheimer's disease than is glucose metabolism at rest., Method: The subjects were 15 Alzheimer's disease patients with a wide range of Mattis Dementia Rating Scale scores (23-128). By using positron emission tomography, absolute glucose metabolism was measured in the parietal, occipital (visual areas), and temporal (auditory areas) cortical regions during rest (eyes/ears covered) and audiovisual stimulation., Results: In the parietal cortex, glucose metabolism correlated with dementia severity in both conditions. In contrast, in the relatively preserved visual and auditory cortical regions, glucose metabolism predicted dementia severity during stimulation but not at rest., Conclusions: These findings suggest that regional cerebral glucose metabolism during stimulation is a more sensitive index of the functional/metabolic failure of neuronal systems than is metabolism at rest.

Objective: The authors examined the interaction of Alzheimer's disease severity and visual stimulus complexity in relation to regional brain function., Method: Each subject had five positron emission tomography [15]H2O scans while wearing goggles containing a grid of red lights embedded into each lens. Regional cerebral blood flow (CBF) was measured at 0 Hz and while lights were flashed alternately into the two eyes at 1, 4, 7, and 14 Hz. Changes in regional CBF from the 0-Hz baseline were measured at each frequency in 19 healthy subjects (mean age = 65 years, SD = 11), 10 patients with mild Alzheimer's disease (mean age = 69, SD = 5; Mini-Mental State score > or = 20), and 11 patients with moderate to severe Alzheimer's disease (mean age = 73, SD = 12; Mini-Mental State score < or = 19)., Results: As pattern-flash frequency increased, CBF responses in the comparison group included biphasic rising then falling in the striate cortex, linear increase in visual association areas, linear decrease in many anterior areas, and a peak at 1 Hz in V5/MT. Despite equivalent resting CBF and CBF responses to low frequencies among all groups, the groups with Alzheimer's disease had significantly smaller CBF responses than the comparison group at the frequency producing the largest response in the comparison group in many brain regions. Also, patients with moderate/severe dementia had smaller responses at frequencies producing intermediate responses in comparison subjects., Conclusions: Functional failure was demonstrated in patients with mild dementia when large neural responses were required and in patients with moderate/severe dementia when large and intermediate responses were required.

Objective: Down's syndrome is characterized by the genetically programmed accumulation of substantial Alzheimer's disease neuropathology after age 40 and the development of early dementia years later, providing a unique human model to investigate the preclinical phases of Alzheimer's disease. Older nondemented adults with Down's syndrome show normal rates of regional cerebral glucose metabolism at rest before the onset of dementia, indicating that their neurons maintain function at rest. The authors hypothesized that an audiovisual stimulation paradigm, acting as a stress test, would reveal abnormalities in cerebral glucose metabolism before dementia in the neocortical parietal and temporal areas most vulnerable to Alzheimer's disease., Method: Regional cerebral glucose metabolism was assessed by means of positron emission tomography (PET) with [18F]fluorodeoxyglucose in eight younger (mean age = 35 years, SD = 2) and eight older (mean age = 50, SD = 7) healthy, nondemented adults with trisomy 21 Down's syndrome. PET scans were performed at rest and during audiovisual stimulation in the same scanning session. Levels of general intellectual functioning and compliance were similar in the two groups., Results: At rest the two groups showed no difference in glucose metabolism in any cerebral region. In contrast, during audiovisual stimulation the older subjects with Down's syndrome had significantly lower glucose metabolic rates in the parietal and temporal cortical areas., Conclusions: Abnormalities in cerebral metabolism during stimulation appeared in the first cortical regions typically affected in Alzheimer's disease. These results indicate that a stress test paradigm can detect metabolic abnormalities in the preclinical stages of Alzheimer's disease despite normal cerebral metabolism at rest.

Objective: Clinical heterogeneity in Alzheimer's disease has been widely observed. One factor that may influence the expression of dementia in Alzheimer's disease is premorbid intellectual ability. It has been hypothesized that premorbid ability, as measured by educational experience, reflects a cognitive reserve that can affect the clinical expression of Alzheimer's disease. The authors investigated the relation between estimates of premorbid intellectual function and cerebral glucose metabolism in patients with Alzheimer's disease to test the effect of differing levels of premorbid ability on neurophysiological dysfunction., Method: In a resting state with eyes closed and ears occluded, 46 patients with Alzheimer's disease were evaluated with positron emission tomography and [18F]-2-fluoro-2-deoxy-D-glucose to determine cerebral metabolism. Premorbid intellectual ability was assessed by a demographics-based IQ estimate and performance on a measure of word-reading ability., Results: After the authors controlled for demographic characteristics and dementia severity, both estimates of premorbid intellectual ability were inversely correlated with cerebral metabolism in the prefrontal, pre-motor, and left superior parietal association regions. In addition, the performance-based estimate (i.e., reading ability) was inversely correlated with metabolism in the anterior cingulate, paracentral, right orbitofrontal, and left thalamic regions, after demographic and clinical variables were controlled for., Conclusions: The results suggest that higher levels of premorbid ability are associated with greater pathophysiological effects of Alzheimer's disease among patients of similar dementia severity levels. These findings provide support for a cognitive reserve that can alter the clinical expression of dementia and influence the neurophysiological heterogeneity observed in Alzheimer's disease.

Objective: A subgroup of patients with Alzheimer's disease present with visual disturbances at onset. This study investigated whether specific cortical networks associated with visual processes are preferentially affected in this subgroup and determined the clinical implications of such abnormalities., Method: Regional cerebral glucose metabolic rates were assessed with positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose, and general intellectual functions, memory, and visual skills were measured with cognitive tests in patients with probable Alzheimer's disease-10 with and 22 without prominent visual symptoms-and in 25 healthy comparison subjects., Results: Both patient groups showed reduced glucose metabolism in parietal regions and in middle and superior temporal regions in comparison with the healthy subjects. The Alzheimer's disease patients without visual symptoms also showed reductions in inferior temporal, frontal, and limbic structures, as is typical of Alzheimer's disease. In contrast, the patients with visual symptoms had larger metabolic deficits than the patients without visual symptoms in the parietal and occipital cortices (including the primary visual cortex), with a relative sparing of inferior temporal, frontal, and limbic regions. Consistently, the patients with visual symptoms had significantly greater visuospatial deficits and less severe memory impairments than the patients without visual symptoms., Conclusions: Alzheimer's disease patients with visuospatial deficits who are studied while alive have a distinctive regional distribution of cerebral metabolic impairment that is related to specific cognitive deficits and that distinguishes them from patients with typical Alzheimer's disease. These findings imply that regional variations in brain dysfunction can occur in Alzheimer's disease, with differential involvement of cortical systems resulting in distinctive clinical subgroups.

Objective: Visual-processing abnormalities commonly contribute to typical Alzheimer's disease symptoms, but their detailed pathophysiology remains unknown. To investigate why patients with Alzheimer's disease have greater difficulty performing visuoconstructive (magnocellular-dominated) tasks than face- or color-perception (parvocellular-dominated) tasks, the authors measured brain activation in response to a temporally graded visual stimulus (neural stress test) during positron emission tomography., Method: The stress test measured regional cerebral blood flow (CBF) in response to a patterned flash stimulus in the resting state (0 Hz in the dark) and at frequencies of 1, 2, 4, 7, and 14 Hz. Ten patients with Alzheimer's disease and 12 age- and sex-matched comparison subjects were studied., Results: The striate response at 7 Hz and 14 Hz (the degree of regional CBF increase from that at 0 Hz) was significantly less in the patients than in the comparison subjects, whereas the change in regional CBF at the lower frequencies did not differ between groups. In bilateral middle temporal association areas activated by motion and dominated by magnocellular input, regional CBF at 1 Hz (the frequency with maximal apparent motion) was significantly greater than at 0 Hz in the comparison subjects but not in the patients., Conclusions: The magnocellular visual system normally responds to high-frequency input and motion; the failure of response in the striate cortex at high but not low frequencies in the Alzheimer's patients suggests greater magnocellular than parvocellular dysfunction at these levels. Activation failure in the middle temporal areas in the patients supports magnocellular dysfunction. The finding that the Alzheimer's disease group had abnormal visual cortical function emphasizes the importance of clinical visuospatial evaluation of patients with Alzheimer's disease to fully understand symptom production and to plan interventions.