Gene E Alexander

PMID: 15932949;PMCID: PMC1149416;Abstract:

Patients with Alzheimer's disease (AD) have abnormally low positron emission tomography (PET) measurements of the cerebral metabolic rate for glucose (CMRgI) in regions of the precuneus and the posterior cingulate, parietotemporal, and frontal cortex. Apolipoprotein E (APOE) ε4 gene dose (i.e., the number of ε4 alleles in a person's APOE genotype) is associated with a higher risk of AD and a younger age at dementia onset. We previously found that cognitively normal late-middle-aged APOE ε4 carriers have abnormally low CMRgl in the same brain regions as patients with probable Alzheimer's dementia. In a PET study of 160 cognitively normal subjects 47-68 years of age, including 36 ε4 homozygotes, 46 heterozygotes, and 78 ε4 noncarriers who were individually matched for their gender, age, and educational level, we now find that ε4 gene dose is correlated with lower CMRgl in each of these brain regions. This study raises the possibility of using PET as a quantitative presymptomatic endophenotype to help evaluate the individual and aggregate effects of putative genetic and nongenetic modifiers of AD risk. © 2005 by The National Academy of Sciences of the USA.

PMID: 8831432;Abstract:

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 skilled 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 function can occur in Alzheimer's disease, with differential involvement of cortical systems resulting in distinctive clinical subgroups.

PMID: 9619151;Abstract:

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]H20 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 ≤20), and 11 patients with moderate to severe Alzheimer's disease (mean age=73, SD=12; Mini-Mental State score ≤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.

PMID: 8621743;Abstract:

Normal aging is associated with the degeneration of specific neural systems. We used [¹⁸F]fluorodeoxyglucose (FDG)/positron emission tomography (PET) and a statistical model of regional covariation to explore the metabolic topography of this process. We calculated global and regional metabolic rates for glucose (GMR and rCMR(glc)) in two groups of normal subjects studied independently on different tomographs: Group 1-130 normal subjects (62 men and 68 women; range 21-90 years); Group 2-20 normal subjects (10 men and 10 women; range 24-78 years). In each of the two groups, the Scaled Subprofile Model (SSM) was applied to rCMR(glc) data to identify specific age-related profiles. The validity of these profiles as aging markers was assessed by correlating the associated subject scores with chronological age in both normal populations. SSM analysis disclosed two significant topographic profiles associated with aging. The first topographic profile, extracted in an analysis of group 1 normals, was characterized by relative frontal hypometabolism associated with covariate metabolic increases in the parietooccipital association areas, basal ganglia, midbrain, and cerebellum. Subject scores for this profile correlated significantly with age in both normal groups (R² = 0.48 and 0.33, p 0.0001 for groups 1 and 2, respectively). Because of clinical similarities between normal motoric aging and parkinsonism, we explored the possibility of shared elements in the metabolic topography of both processes. We performed a combined group SSM analysis of the 20 group 2 normals and 22 age-matched Parkinson's disease patients, and identified another aging-related topographic profile. This profile was characterized by relative basal ganglia hypermetabolism associated with covariate decreases in frontal premotor cortex. Subject scores for this profile also correlated significantly with age in both normal groups (group 1: R² = 0.30, p 0.00001; group 2: R² = 0.59, p 0.01). Healthy aging is associated with reproducible topographic covariation profiles associated with specific neural systems. FDG/PET may provide a useful metabolic marker of the normal aging process.

PMID: 8672604;Abstract:

Brain lesions have been reported with increasing frequency in the delusional misidentification syndromes (DMS). This is the first controlled study to describe DMS regional cerebral metabolic rates of glucose (rCMRglc). We compared rCMRglc (using positron emission tomography) and neuropsychological data in 9 patients with DMS and Alzheimer dementia (AD), 15 AD patients without DMS, and 17 healthy controls. The DMS group differed from the AD group without DMS in having significant hypometabolism in paralimbic (orbitofrontal and cingulate areas bilaterally) and left medial temporal areas, and significant bilateral normalized hypermetabolism in sensory association cortices (superior temporal and inferior parietal) without right left asymmetry. Compared to healthy controls, both AD groups had significant dorsolateral frontal hypometabolism bilaterally. No specific DMS neuropsychological profile was identified. Dysfunctional connections among multimodal association areas, paralimbic structures, and dorsolateral frontal cortex are proposed as the predisposing neural deficit underlying DMS, causing cognitive-perceptual-affective dissonance, which under specific conditions results in "positive" delusion formation. © 1995 Society of Biological Psychiatry.