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Objective: To investigate with fluorodeoxyglucose positron emission tomography whether regional reductions in the cerebral metabolic rate for glucose (CMRgl) previously found in cognitively healthy late-middle-aged apolipoprotein E (APOE) epsilon4 carriers extend to members of the Latino Mexican American community., Design: Prospective cohort study., Setting: Banner Alzheimer's Institute, Phoenix, Arizona., Patients or Other Participants: Eleven APOE epsilon4 carriers and 16 noncarriers from Arizona's Latino community (mean [SD] age, 54.6 [6.4] years) matched for sex, mean age, and educational level and who were predominantly of self-designated Mexican origin., Main Outcome Measure: A brain mapping algorithm was used to compare cross-sectional regional CMRgl in Latino APOE epsilon4 carriers vs noncarriers., Results: Participant groups had similar distributions for age, sex, education, family history of dementia, clinical ratings, and neuropsychological test scores. Latino APOE epsilon4 carriers had lower CMRgl than the noncarriers in the posterior cingulate, precuneus, and parietal regions previously found to be preferentially affected in patients with Alzheimer disease (AD) and cognitively healthy non-Latino APOE epsilon4 carriers. Additionally, the Latino APOE epsilon4 carriers had lower CMRgl in the middle and anterior cingulate cortex, hippocampus, and thalamus., Conclusions: This study provides support for the relationship between APOE epsilon4 and risk of AD in Latino individuals. It illustrates the role of positron emission tomography as a presymptomatic endophenotype for the assessment of AD risk factors and supports the inclusion of Latino APOE epsilon4 carriers in proof-of-concept studies using fluorodeoxyglucose PET to evaluate promising presymptomatic treatments in cognitively healthy carriers of this common AD susceptibility gene.

Background: Before symptomatic memory loss, healthy apolipoprotein E epsilon4 (APOE epsilon4) (OMIM 104310) carriers demonstrate accelerated longitudinal decline on memory tests, suggesting the existence of a transitional state between normal aging and mild cognitive impairment (MCI), which we have called amnestic pre-MCI., Objective: To support our neuropsychological construct of pre-MCI by characterizing and comparing the relationship between measurements of baseline regional hypometabolism and subsequent rates of memory decline in a group of individuals with neuropsychologically defined asymptomatic memory decline (pre-MCI group) and in nondecliners after controlling for APOE epsilon4 gene dose., Design: Longitudinal study., Setting: Academic medical center., Participants: Of 139 healthy individuals in the Arizona APOE Cohort aged 50 to 69 years who underwent longitudinal neuropsychological testing and fludeoxyglucose F 18-positron emission tomography (FDG-PET) since 1994, 10 met our criteria for amnestic pre-MCI, and 15 showed no decline., Main Outcome Measures: Correlations between lower regional cerebral metabolic rates for glucose (CMRgl) and rates of verbal memory test decline that occurred at a mean of 41 months after baseline FDG-PET using an automated brain mapping algorithm (SPM5)., Results: The pre-MCI and nondecliner groups did not differ in mean (SD) age (56.8 [4.8] years), education (16.5 [2.3] years), sex (19 women [76%]), or APOE epsilon4 carrier status (12 epsilon4 carriers [48%)]. After controlling for APOE epsilon4 gene dose, the pre-MCI group had significant correlations between lower baseline CMRgl in the posterior cingulate, bilateral parietal, and left prefrontal regions (known to be preferentially affected by Alzheimer disease) and subsequent verbal memory decline. Nondecliners had significant correlations bilaterally in the posterior and midcingulate cortices. Correlations in the left parietal, left temporal, and bilateral frontal regions were significantly greater in the pre-MCI group than those in the nondecliner group., Conclusion: Individuals with amnestic pre-MCI showed significantly greater correlations between cerebral hypometabolism and subsequent long-term memory decline than nondecliners in Alzheimer disease-affected brain regions.

Background: Memory declines more rapidly with age in apolipoprotein E (APOE) epsilon4 carriers than in APOE epsilon4 noncarriers, and APOE epsilon4 homozygotes' cognitive performances correlate with stressors. These changes could represent presymptomatic disease in some, despite their youth., Objective: To show that presymptomatic APOE epsilon4 homozygotes experience greater psychometric decline at a younger age than APOE epsilon4 heterozygotes and noncarriers before the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD)., Design: Prospective observational study, Setting: Academic medical center., Participants: A total of 43 APOE epsilon4 homozygotes, 59 APOE epsilon4 heterozygotes, and 112 APOE epsilon4 noncarriers aged 50 to 69 years were cognitively healthy and matched at entry according to age, educational level, and sex., Intervention: Neuropsychological battery given every 2 years., Main Outcome Measures: Predefined test and cognitive domain decline criteria applied to consecutive epochs., Results: Of 214 participants, 48 showed no decline on any test, 126 showed decline on only 1 test in 1 or more domains, and 40 showed decline on 2 or more tests in 1 or more domains. Cognitive domain decline occurred in 4 of 10 APOE epsilon4 homozygotes 60 years and older at entry (40.0%) compared with 5 of 66 APOE epsilon4 heterozygotes and noncarriers (7.6%) (P = .02) and was more predictive of subsequent decline than nondomain decline (17 of 24 [70.8%] vs 29 of 70 [41.4%]; P = .01). Decline on any memory test was predictive of further decline (P < .001), as was memory domain decline (P = .006) in all genetic subgroups. Seven participants developed MCI (in 6) or AD (in 1), of whom 5 were APOE epsilon4 homozygotes (P = .008). Retrospective comparison showed that those who experienced multidomain, memory, and language domain decline had lower spatial and memory scores at entry than those who experienced no decline., Conclusions: APOE epsilon4 homozygotes in their 60s have higher rates of cognitive domain decline than APOE epsilon4 heterozygotes or noncarriers before the diagnosis of MCI and AD, thus confirming and characterizing the existence of a pre-MCI state in this genetic subset.

Background: Atrophy of the corpus callosum in the absence of primary white matter degeneration reflects loss of intracortical projecting neocortical pyramidal neurons in Alzheimer disease (AD)., Objectives: To determine individual rates of atrophy progression of the corpus callosum in patients with AD and to correlate rates of atrophy progression with clinical disease severity and subcortical disease., Methods: Magnetic resonance imaging-derived measurements of corpus callosum size were studied longitudinally in 21 patients clinically diagnosed as having AD (mean observation time, 17.0 +/- 8.5 months) and 10 age- and sex-matched healthy controls (mean observation time, 24.1 +/- 6.8 months)., Results: Corpus callosum size was significantly reduced in AD patients at baseline. Annual rates of atrophy of total corpus callosum, splenium, and rostrum were significantly larger in AD patients (-7.7%, -12.1%, and -7.3%, respectively) than in controls (-0.9%, -1.5%, and 0.6%, respectively). Rates of atrophy of the corpus callosum splenium were correlated with progression of dementia severity in AD patients (rho = 0.52, P<.02). The load of subcortical lesions at baseline (P<.05) predicted rate of anterior corpus callosum atrophy in healthy controls. Rates of atrophy of corpus callosum areas were independent of white matter hyperintensity load in patients with AD., Conclusions: Measurement of corpus callosum size allows in vivo mapping of neocortical neurodegeneration in AD over a wide range of clinical dementia severities and may be used as a surrogate marker for evaluation of drug efficacy.

Background: Brain glucose metabolic rates measured by positron emission tomography can be more affected by partial volume effects in Alzheimer disease (AD) than in healthy aging because of disease-associated brain atrophy., Objective: To determine whether the distinct distribution of cerebral metabolic lesions in patients with the visual variant of AD (AD + VS) represents a true index of neuronal/synaptic dysfunction or is the consequence of brain atrophy., Setting: Government research hospital., Design: Resting cerebral metabolic rate for glucose was measured with positron emission tomography in a cross-sectional study of AD and AD + VS groups and in healthy control subjects. Segmented magnetic resonance images were used to correct for brain atrophy., Patients: Patients with AD + VS had prominent visual and visuospatial symptoms. There were 15 patients with AD, 10 with AD + VS, and 37 age-matched control subjects., Main Outcome Measure: Measurement of the rate of cerebral glucose metabolism., Results: Before atrophy correction, the AD + VS group, compared with the control subjects, showed hypometabolism in primary and extrastriate visual areas and in parietal and superior temporal cortical areas. Compared with the AD group, the AD + VS group showed hypometabolism in visual association areas. After atrophy correction, hypometabolism remained significantly different between patients and controls and between the 2 AD groups., Conclusions: The reductions in cerebral hypometabolism represent a true loss of functional activity and are not simply an artifact caused by brain atrophy. The different patterns of hypometabolism indicate the differential development of the lesions between the AD and AD + VS groups.

Background: Positron emission tomographic studies of patients with Alzheimer disease (AD) suggest a loss of metabolic functional interactions between different cortical regions. Atrophy of the corpus callosum as the major tract of intracortical connective fibers may reflect decreased cortical functional integration in AD., Objectives: To investigate whether regional atrophy of the corpus callosum is correlated with regional reductions of cortical glucose metabolism, as shown by positron emission tomography, and whether primary white matter degeneration is a possible cofactor of corpus callosum atrophy in AD., Patients and Methods: We measured total and regional cross-sectional areas of the corpus callosum on midsagittal magnetic resonance imaging scans from 12 patients with AD and 15 age-matched control subjects. Regional cerebral metabolic rates for glucose in cortical lobes were measured by positron emission tomography using fludeoxyglucose F 18. White matter hyperintensities were rated in T2-weighted magnetic resonance imaging scans., Results: The total cross-sectional area of corpus callosum was significantly reduced in patients with AD, with the most prominent changes in the rostrum and splenium and relative sparing of the body of the corpus callosum. Frontal and parietal lobe metabolism was correlated with the truncal area of the corpus callosum in AD. The ratios of frontal to parietal and of frontal to occipital metabolism were correlated with the ratio of anterior to posterior corpus callosum area in the group with AD. White matter hyperintensities did not correlate with corpus callosum atrophy in the patients with AD., Conclusion: The regional pattern of corpus callosum atrophy correlated with reduced regional glucose metabolism independently of primary white matter degeneration in the patients with AD.

Background: Pathological studies in Alzheimer disease indicate the specific loss of layer III and V large pyramidal neurons in association cortex. These neurons give rise to long corticocortical connections within and between the cerebral hemispheres., Objective: To evaluate the corpus callosum as an in vivo marker for cortical neuronal loss., Method: Using a new imaging technique, we measured region-specific corpus callosum atrophy in patients with Alzheimer disease and correlated the changes with neuropsychological functioning. Total cross-sectional area of the corpus callosum and areas of 5 callosal subregions were measured on midsagittal magnetic resonance imaging scans of 14 patients with Alzheimer disease (mean age, 64.4 years; Mini-Mental State Examination score, 11.4) and 22 healthy age- and sex-matched control subjects (mean age, 66.6 years; Mini-Mental State Examination score, 29.8). All subjects had minimal white matter changes., Results: The total callosal area was significantly reduced in the patients with Alzheimer disease, with the greatest changes in the rostrum and splenium and relative sparing of the callosal body. Regional callosal atrophy correlated significantly with cognitive impairment in the patients with Alzheimer disease, but not with age or the white matter hyperintensities score., Conclusions: Callosal atrophy in patients with Alzheimer disease with only minimal white matter changes may indicate loss of callosal efferent neurons in corresponding regions of the cortex. Because these neurons are a subset of corticocortical projecting neurons, region-specific callosal atrophy may serve as a marker of progressive neocortical disconnection in Alzheimer disease.