Longitudinal Changes in Serum Glucose Levels are Associated with Metabolic Changes in Alzheimer's Disease Related Brain Regions.

BACKGROUND: The association between longitudinal changes in serum glucose level and longitudinal changes in [18F] Fluorodeoxyglucose-PET (FDG PET) measurements of Alzheimer's disease (AD) risk are unknown. OBJECTIVE: To investigate whether variation in serum glucose levels across time are associated with changes in FDG PET measurements of cerebral metabolic rate for glucose (rCMRgl) in brain regions preferentially affected by Alzheimer's disease (AD). METHODS: Participants are a subset of a prospective cohort study investigating FDG PET, apolipoprotein E (APOE) ɛ4, and risk for AD which includes data from baseline, interim, and follow up visits over 4.4±1.0-years. An automated brain-mapping algorithm was utilized to characterize and compare associations between longitudinal changes in serum glucose levels and longitudinal changes in rCMRgl. RESULTS: This study included 80 adults aged 61.5±5 years, including 38 carriers and 42 non-carriers of the APOE ɛ4 allele. Longitudinal increases in serum glucose levels were associated with longitudinal CMRgl decline in the vicinity of parietotemporal, precuneus/posterior cingulate, and prefrontal brain regions preferentially affected by AD (p < 0.05, corrected for multiple comparisons). Findings remained significant when controlled for APOE ɛ4 status and baseline and advancing age. CONCLUSIONS: Additional studies are needed to clarify and confirm the relationship between longitudinal changes in peripheral glucose and FDG PET measurements of AD risk. Future findings will set the stage on the use of FDG PET in the evaluation of possible interventions that target risk factors for the development of AD.

Improved power for characterizing longitudinal amyloid-ß PET changes and evaluating amyloid-modifying treatments with a cerebral white matter reference region.

UNLABELLED: In this article, we describe an image analysis strategy with improved power for tracking longitudinal amyloid-ß (Aß) PET changes and evaluating Aß-modifying treatments. METHODS: Our aims were to compare the power of template-based cerebellar, pontine, and cerebral white matter reference regions to track 24-mo florbetapir standardized uptake value (SUV) ratio (SUVR) changes; to relate those changes to 24-mo clinical declines; and to evaluate Aß-modifying treatments in Aß-positive (Aß+) and Aß-negative (Aß-) patients with probable Alzheimer dementia (pAD), in patients with mild cognitive impairment (MCI), in cognitively normal controls (NCs), and in cognitively normal apolipoprotein E4 (APOE4) carriers and noncarriers. We used baseline and follow-up (∼24 mo) florbetapir PET scans from 332 Aß+ and Aß- subjects participating in the multicenter Alzheimer's Disease Neuroimaging Initiative. Each of the proposed analyses included 31 pAD patients, 187 MCI patients, and 114 NCs. Cerebral-to-white matter, cerebellar, and pontine SUVRs were characterized in terms of their longitudinal variability; their power to track longitudinal fibrillar Aß increases in Aß+ and Aß- subgroups and cognitively normal APOE4 carriers and noncarriers; the sample sizes needed to detect attenuated accumulation of or clearance of fibrillar Aß accumulation in randomized clinical trials; and their ability to relate 24-mo fibrillar Aß increases to clinical declines. RESULTS: As predicted, cerebral-to-white matter SUVR changes were significantly less variable and had significantly greater power to detect 24-mo fibrillar Aß increases and evaluate Aß-modifying treatment effects in Aß+ pAD, MCI, and NC subjects and cognitively normal APOE4 carriers. They were also distinguished by the ability to detect significant associations between 24-mo Aß increases and clinical declines. CONCLUSION: A cerebral white matter reference region may improve the power to track longitudinal fibrillar Aß increases, to characterize their relationship to longitudinal clinical declines, and to evaluate Aß-modifying treatments in randomized clinical trials.

Posterior cingulate glucose metabolism, hippocampal glucose metabolism, and hippocampal volume in cognitively normal, late-middle-aged persons at 3 levels of genetic risk for Alzheimer disease.

OBJECTIVE: To characterize and compare measurements of the posterior cingulate glucose metabolism, the hippocampal glucose metabolism, and hippocampal volume so as to distinguish cognitively normal, late-middle-aged persons with 2, 1, or 0 copies of the apolipoprotein E (APOE) ε4 allele, reflecting 3 levels of risk for late-onset Alzheimer disease. DESIGN: Cross-sectional comparison of measurements of cerebral glucose metabolism using 18F-fluorodeoxyglucose positron emission tomography and measurements of brain volume using magnetic resonance imaging in cognitively normal ε4 homozygotes, ε4 heterozygotes, and noncarriers. SETTING: Academic medical center. PARTICIPANTS: A total of 31 ε4 homozygotes, 42 ε4 heterozygotes, and 76 noncarriers, 49 to 67 years old, matched for sex, age, and educational level. MAIN OUTCOME MEASURES: The measurements of posterior cingulate and hippocampal glucose metabolism were characterized using automated region-of-interest algorithms and normalized for whole-brain measurements. The hippocampal volume measurements were characterized using a semiautomated algorithm and normalized for total intracranial volume. RESULTS: Although there were no significant differences among the 3 groups of participants in their clinical ratings, neuropsychological test scores, hippocampal volumes (P = .60), or hippocampal glucose metabolism measurements (P = .12), there were significant group differences in their posterior cingulate glucose metabolism measurements (P = .001). The APOE ε4 gene dose was significantly associated with posterior cingulate glucose metabolism (r = 0.29, P = .0003), and this association was significantly greater than those with hippocampal volume or hippocampal glucose metabolism (P < .05, determined by use of pairwise Fisher z tests). CONCLUSIONS: Although our findings may depend in part on the analysis algorithms used, they suggest that a reduction in posterior cingulate glucose metabolism precedes a reduction in hippocampal volume or metabolism in cognitively normal persons at increased genetic risk for Alzheimer disease.

Higher serum glucose levels are associated with cerebral hypometabolism in Alzheimer regions.

OBJECTIVE: To investigate whether higher fasting serum glucose levels in cognitively normal, nondiabetic adults were associated with lower regional cerebral metabolic rate for glucose (rCMRgl) in brain regions preferentially affected by Alzheimer disease (AD). METHODS: This is a cross-sectional study of 124 cognitively normal persons aged 64 ± 6 years with a first-degree family history of AD, including 61 APOEε4 noncarriers and 63 carriers. An automated brain mapping algorithm characterized and compared correlations between higher fasting serum glucose levels and lower [(18)F]-fluorodeoxyglucose-PET rCMRgl measurements. RESULTS: As predicted, higher fasting serum glucose levels were significantly correlated with lower rCMRgl and were confined to the vicinity of brain regions preferentially affected by AD. A similar pattern of regional correlations occurred in the APOEε4 noncarriers and carriers. CONCLUSIONS: Higher fasting serum glucose levels in cognitively normal, nondiabetic adults may be associated with AD pathophysiology. Findings suggest that the risk imparted by higher serum glucose levels may be independent of APOEε4 status. This study raises additional questions about the role of the metabolic process in the predisposition to AD and supports the possibility of targeting these processes in presymptomatic AD trials.

Gray matter network associated with risk for Alzheimer's disease in young to middle-aged adults.

The apolipoprotein E (APOE) ε4 allele increases the risk for late-onset Alzheimer's disease (AD) and age-related cognitive decline. We investigated whether ε4 carriers show reductions in gray matter volume compared with ε4 non-carriers decades before the potential onset of AD dementia or healthy cognitive aging. Fourteen cognitively normal ε4 carriers, aged 26 to 45 years, were compared with 10 age-matched, ε4 non-carriers using T1-weighted volumetric magnetic resonance imaging (MRI) scans. All had reported first- or second-degree family histories of dementia. Group differences in gray matter were tested using voxel-based morphometry (VBM) and a multivariate model of regional covariance, the Scaled Subprofile Model (SSM). A combination of the first two SSM MRI gray matter patterns distinguished the APOE ε4 carriers from non-carriers. This combined pattern showed gray matter reductions in bilateral dorsolateral and medial frontal, anterior cingulate, parietal, and lateral temporal cortices with covarying relative increases in cerebellum, occipital, fusiform, and hippocampal regions. With these gray matter differences occurring decades before the potential onset of dementia or cognitive aging, the results suggest longstanding, gene-associated differences in brain morphology that may lead to preferential vulnerability for the later effects of late-onset AD or healthy brain aging.

Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons.

Epidemiological studies suggest that elevated blood pressure (BP) in midlife is associated with increased risk of Alzheimer's disease (AD) in late life. In this preliminary study, we investigated the extent to which BP measurements are related to positron emission tomography (PET) measurements of fibrillar amyloid-beta burden using Pittsburgh Compound-B (PiB) and fluorodeoxyglucose (FDG) PET measures of cerebral metabolic rate for glucose metabolism (CMRgl) in cognitively normal, late middle-aged to older adult apolipoprotein E (APOE) ε4 homozygotes, heterozygotes and noncarriers. PiB PET results revealed that systolic BP (SBP) and pulse pressure (PP) were each positively correlated with cerebral-to-cerebellar PiB distribution volume ratio (DVR) in frontal, temporal, and posterior-cingulate/precuneus regions, whereas no significant positive correlations were found between PiB distribution volume ratios and diastolic BP (DBP). FDG PET results revealed significant inverse correlations between each of the BP measures and lower glucose metabolism in frontal and temporal brain regions. These preliminary findings provide additional evidence that higher BP, likely a reflection of arterial stiffness, during late midlife may be associated with increased risk of presymptomatic AD.

Association between GAB2 haplotype and higher glucose metabolism in Alzheimer's disease-affected brain regions in cognitively normal APOEε4 carriers.

In a genome-wide association study (GWAS) of late-onset Alzheimer's disease (AD), we found an association between common haplotypes of the GAB2 gene and AD risk in carriers of the apolipoprotein E (APOE) ε4 allele, the major late-onset AD susceptibility gene. We previously proposed the use of fluorodeoxyglucose positron emission tomography (FDG-PET) measurements as a quantitative pre-symptomatic endophenotype, more closely related to disease risk than the clinical syndrome itself, to help evaluate putative genetic and non-genetic modifiers of AD risk. In this study, we examined the relationship between the presence or absence of the relatively protective GAB2 haplotype and PET measurements of regional-to-whole brain FDG uptake in several AD-affected brain regions in 158 cognitively normal late-middle-aged APOEε4 homozygotes, heterozygotes, and non-carriers. GAB2 haplotypes were characterized using Affymetrix Genome-Wide Human SNP 6.0 Array data from each of these subjects. As predicted, the possibly protective GAB2 haplotype was associated with higher regional-to-whole brain FDG uptake in AD-affected brain regions in APOEε4 carriers. While additional studies are needed, this study supports the association between the possibly protective GAB2 haplotype and the risk of late-onset AD in APOEε4 carriers. It also supports the use of brain-imaging endophenotypes to help assess possible modifiers of AD risk.

Hypometabolism in Alzheimer-affected brain regions in cognitively healthy Latino individuals carrying the apolipoprotein E epsilon4 allele.

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.

Evidence for an association between KIBRA and late-onset Alzheimer's disease.

We recently reported evidence for an association between the individual variation in normal human episodic memory and a common variant of the KIBRA gene, KIBRA rs17070145 (T-allele). Since memory impairment is a cardinal clinical feature of Alzheimer's disease (AD), we investigated the possibility of an association between the KIBRA gene and AD using data from neuronal gene expression, brain imaging studies, and genetic association tests. KIBRA was significantly over-expressed and three of its four known binding partners under-expressed in AD-affected hippocampal, posterior cingulate and temporal cortex regions (P<0.010, corrected) in a study of laser-capture microdissected neurons. Using positron emission tomography in a cohort of cognitively normal, late-middle-aged persons genotyped for KIBRA rs17070145, KIBRA T non-carriers exhibited lower glucose metabolism than did carriers in posterior cingulate and precuneus brain regions (P<0.001, uncorrected). Lastly, non-carriers of the KIBRA rs17070145 T-allele had increased risk of late-onset AD in an association study of 702 neuropathologically verified expired subjects (P=0.034; OR=1.29) and in a combined analysis of 1026 additional living and expired subjects (P=0.039; OR=1.26). Our findings suggest that KIBRA is associated with both individual variation in normal episodic memory and predisposition to AD.

Higher serum total cholesterol levels in late middle age are associated with glucose hypometabolism in brain regions affected by Alzheimer's disease and normal aging.

Epidemiological studies suggest that higher midlife serum total cholesterol levels are associated with an increased risk of Alzheimer's disease (AD). Using fluorodeoxyglucose positron emission tomography (PET) in the study of cognitively normal late middle-aged people, we demonstrated an association between apolipoprotein E (APOE) epsilon4 gene dose, the major genetic risk factor for late-onset AD, and lower measurements of the cerebral metabolic rate for glucose (CMRgl) in AD-affected brain regions, we proposed using PET as a pre-symptomatic endophenotype to evaluate other putative AD risk modifiers, and we then used it to support an aggregate cholesterol-related genetic risk score in the risk of AD. In the present study, we used PET to investigate the association between serum total cholesterol levels and cerebral metabolic rate for glucose metabolism (CMRgl) in 117 cognitively normal late middle-aged APOE epsilon4 homozygotes, heterozygotes and non-carriers. Higher serum total cholesterol levels were associated with lower CMRgl bilaterally in precuneus, parietotemporal and prefrontal regions previously found to be preferentially affected by AD, and in additional frontal regions previously found to be preferentially affected by normal aging. The associations were greater in APOE epsilon4 carriers than non-carriers in some of the AD-affected brain regions. We postulate that higher midlife serum total cholesterol levels accelerate brain processes associated with normal aging and conspire with other risk factors in the predisposition to AD. We propose using PET in proof-of-concept randomized controlled trials to rapidly evaluate the effects of midlife cholesterol-lowering treatments on the brain changes associated with normal aging and AD.

Linking functional and structural brain images with multivariate network analyses: a novel application of the partial least square method.

In this article, we introduce a multimodal multivariate network analysis to characterize the linkage between the patterns of information from the same individual's complementary brain images, and illustrate its potential by showing its ability to distinguish older from younger adults with greater power than several previously established methods. Our proposed method uses measurements from every brain voxel in each person's complementary co-registered images and uses the partial least square (PLS) algorithm to form a combined latent variable that maximizes the covariance among all of the combined variables. It represents a new way to calculate the singular value decomposition from the high-dimensional covariance matrix in a computationally feasible way. Analyzing fluorodeoxyglucose positron emission tomography (PET) and volumetric magnetic resonance imaging (MRI) images, this method distinguished 14 older adults from 15 younger adults (p=4e-12) with no overlap between groups, no need to correct for multiple comparisons, and greater power than the univariate Statistical Parametric Mapping (SPM), multimodal SPM or multivariate PLS analysis of either imaging modality alone. This technique has the potential to link patterns of information among any number of complementary images from an individual, to use other kinds of complementary complex datasets besides brain images, and to characterize individual state- or trait-dependent brain patterns in a more powerful way.

Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease.

Fibrillar amyloid-beta (Abeta) 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 Abeta 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 Abeta 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) epsilon4 allele. The 8 epsilon4 homozygotes, 8 heterozygotes, and 12 noncarriers did not differ significantly in terms of age, sex, or cognitive scores. Fibrillar Abeta was significantly associated with APOE epsilon4 carrier status and epsilon4 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 Abeta burden in cognitively normal older people is associated with APOE epsilon4 gene dose, the major genetic risk factor for AD. Additional studies are needed to track fibrillar Abeta accumulation in persons with different kinds and levels of AD risk; to determine the extent to which fibrillar Abeta, 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 Abeta imaging in primary prevention trials.

Cholesterol-related genetic risk scores are associated with hypometabolism in Alzheimer's-affected brain regions.

We recently implicated a cluster of nine single nucleotide polymorphisms from seven cholesterol-related genes in the risk of Alzheimer's disease (AD) in a European cohort, and we proposed calculating an aggregate cholesterol-related genetic score (CREGS) to characterize a person's risk. In a separate study, we found that apolipoprotein E (APOE) epsilon4 gene dose, an established AD risk factor, was correlated with fluorodeoxyglucose (FDG) positron emission tomography (PET) measurements of hypometabolism in AD-affected brain regions in a cognitively normal American cohort, and we proposed using PET as a presymptomatic endophenotype to help assess putative modifiers of AD risk. Thus, the objective in the present study is to determine whether CREGS is related to PET measurements of hypometabolism in AD-affected brain regions. DNA and PET data from 141 cognitively normal late middle-aged APOE epsilon4 homozygotes, heterozygotes and noncarriers were analyzed to evaluate the relationship between CREGS and regional PET measurements. Cholesterol-related genetic risk scores were associated with hypometabolism in AD-affected brain regions, even when controlling for the effects of APOE epsilon4 gene dose. The results support the role of cholesterol-related genes in the predisposition to AD and support the value of neuroimaging in the presymptomatic assessment of putative modifiers of AD risk.

Correlations between apolipoprotein E epsilon4 gene dose and whole brain atrophy rates.

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.

Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism.

Patients with Alzheimer's disease (AD) have abnormally low positron emission tomography (PET) measurements of the cerebral metabolic rate for glucose (CMRgl) in regions of the precuneus and the posterior cingulate, parietotemporal, and frontal cortex. Apolipoprotein E (APOE) epsilon4 gene dose (i.e., the number of epsilon4 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 epsilon4 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 epsilon4 homozygotes, 46 heterozygotes, and 78 epsilon4 noncarriers who were individually matched for their gender, age, and educational level, we now find that epsilon4 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.

An automated algorithm for the computation of brain volume change from sequential MRIs using an iterative principal component analysis and its evaluation for the assessment of whole-brain atrophy rates in patients with probable Alzheimer's disease.

This article introduces an automated method for the computation of changes in brain volume from sequential magnetic resonance images (MRIs) using an iterative principal component analysis (IPCA) and demonstrates its ability to characterize whole-brain atrophy rates in patients with Alzheimer's disease (AD). The IPCA considers the voxel intensity pairs from coregistered MRIs and identifies those pairs a sufficiently large distance away from the iteratively determined PCA major axis. Analyses of simulated and real MRI data support the underlying assumption of a linear relationship in paired voxel intensities, identify an outlier distance threshold that optimizes the trade-off between sensitivity and specificity in the detection of small volume changes while accounting for global intensity changes, and demonstrate an ability to detect changes as small as 0.04% of brain volume without confounding effects of between-scan shifts in voxel intensity. In eight patients with probable AD and eight age-matched normal control subjects, the IPCA was comparable to the established but partly manual digital subtraction (DS) method in characterizing annual rates of whole-brain atrophy: resulting rates were correlated (Spearman rank correlation = 0.94, P < 0.0005) and comparable in distinguishing probable AD from normal aging (IPCA-detected atrophy rates: 2.17 +/- 0.52% per year in the patients vs. 0.41 +/- 0.22% per year in the controls [Wilcoxon-Mann-Whitney test P = 7.8 x 10(-4)]; DS-detected atrophy rates: 3.51 +/- 1.31% per year in the patients vs. 0.48 +/- 0.29% per year in the controls [P = 7.8 x 10(-4)]). The IPCA could be used in tracking the progression of AD, evaluating the disease-modifying effects of putative treatments, and investigating the course of other normal and pathological changes in brain morphology.

Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia.

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 epsilon4 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 epsilon4 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 epsilon4 heterozygotes, all with the epsilon3/epsilon4 genotype, and 15 noncarriers of the epsilon4 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 epsilon4 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-middle-aged epsilon4 carriers, the young epsilon4 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.

Positron emission tomography in three children with pleomorphic xanthoastrocytoma.

The pleomorphic xanthoastrocytoma is generally considered a low-grade neoplasm with favorable prognosis. These tumors, however, can demonstrate primary anaplastic features, undergo malignant transformation, disseminate, or progress with poor outcome. Currently, there are no histologic or clinical features that reliably predict recurrent tumor or tumor progression. We report three children with confirmed pleomorphic xanthoastrocytoma who were studied with positron emission tomography (PET) using [18F]fluorodeoxyglucose (FDG) coregistered with magnetic resonance imaging. One patient had decreased FDG metabolism and, despite a gross total resection and benign pathology, had early local recurrence. Subsequent to a second surgical resection and radiation therapy, he has remained stable for 8 years. One patient with significant FDG uptake had gross total resection of an anaplastic pleomorphic xanthoastrocytoma. Follow-up FDG studies showed no abnormal metabolic activity, and he has been stable without adjuvant treatment for 5 years. The last patient had intermediate FDG uptake and a moderate-grade pleomorphic xanthoastrocytoma by histopathology. She showed early tumor progression with spinal metastases. Following a near-total resection of the recurrent intracranial lesion and neuroaxis radiation, she has been stable for 4 years. Although there are still no reliable prognostic indicators for pleomorphic xanthoastrocytoma, PET with FDG correlates with histopathology, and increased uptake may be a marker for more malignant or aggressive tumors. The extent of surgical resection in regard to prognosis in our limited study is unclear but appears helpful in the anaplastic pleomorphic xanthoastrocytoma case. Adjuvant radiation therapy also may benefit certain patients. Further PET studies are warranted in this group of tumors.