Gene E Alexander

PMID: 23137948;Abstract:

Background: We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's disease. To gain further knowledge on the preclinical phase of Alzheimer's disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimer's disease. Methods: Between January and August, 2010, 18-26-year-old presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the Colombian Alzheimer's Prevention Initiative Registry in Medellín Antioquia, Colombia, had structural MRI, functional MRI during associative memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations, regional grey matter reductions, CSF Aβ1-42, total tau and phospho-tau181 concentrations, and plasma Aβ1-42 concentrations and Aβ1-42:Aβ1-40 ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to Alzheimer's disease. Cognitive and fluid biomarkers were compared using Mann-Whitney tests. Findings: 44 participants were included: 20 PSEN1 E280A mutation carriers and 24 non-carriers. The carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) e{open}4 carriers. Compared with non-carriers, carriers had greater right hippocampal and parahippocampal activation (p=0·001 and p0·014, respectively, after correction for multiple comparisons), less precuneus and posterior cingulate deactivation (all p0·010 after correction), and less grey matter in several parietal regions (all p0·002 uncorrected and corrected p=0·009 in the right parietal search region). In the 20 participants (ten PSEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures and venepunctures, mutation carriers had higher CSF Aβ1-42 concentrations (p=0·008) and plasma Aβ1-42 concentrations (p=0·01) than non-carriers. Interpretation: Young adults at genetic risk for autosomal dominant Alzheimer's disease have functional and structural MRI findings and CSF and plasma biomarker findings consistent with Aβ1-42 overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimer's disease. Funding: Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the State of Arizona. © 2012 Elsevier Ltd.

PMID: 10924775;Abstract:

To assess age-related differences in cortical activation during form perception, two classes of visual textures were shown to young and older subjects undergoing positron emission tomography (PET). Subjects viewed even textures that were rich in rectangular blocks and extended contours and random textures that lacked these organized form elements. Within-group significant increases in regional cerebral blood flow (rCBF) during even stimulation relative to random stimulation in young subjects were seen in occipital, inferior and medial temporal regions, and cerebellum, and in older subjects, in posterior occipital and frontal regions. Group by texture type interactions revealed significantly smaller rCBF increases in older subjects relative to young in occipital and medial temporal regions. These results indicate that young subjects activate the occipitotemporal pathway during form perception, whereas older subjects activate occipital and frontal regions. The between-group differences suggest that age-related reorganization of cortical activation occur during early visual processes in humans. (C) 2000 Elsevier Science Inc.

PMID: 12028246;Abstract:

OBJECTIVES: To determine whether apolipoprotein E (apo E) genotype influences intellectual achievement in cognitively normal individuals. DESIGN: Between 1994 and 1999 we performed apo E testing on 1,000 self-described cognitively normal residents of Maricopa County and detailed neuropsychological testing on a subset of 250. SETTING: Tertiary care academic medical center. PARTICIPANTS: Cognitively normal adults genotyped for apo E. MEASUREMENTS: Measures of intellectual background included years of education and a demographically based estimate of intellectual capacity (demographic intellectual quotient (DIQ)). Measures of intellectual achievement, which included Wechsler Adult Intelligence Scale revised (WAIS-R), information (WAISI), and vocabulary (WAISV) scores, occupational intellectual requirements (OIR), and census-derived estimates of household income, were compared between apo E genetic subgroups while adjusting for intellectual background and demographic variables. RESULTS: WAISI, WAISV, OIR, and income correlated with age, sex, education, and DIQ, but after controlling for these variables there were no clinically significant differences between apo E-e4 homozygotes and noncarriers on any measure. CONCLUSIONS: No clinically significant differences between genotypes were observed for the effects of education and DIQ on WAISI, WAISV, OIR, or income, although a larger sample size would be required to exclude smaller, clinically insignificant differences.

Article providing findings on the first application of regional network analysis to non-human primate model of healthy aging.;Your Role: First author.;Full Citation: Alexander GE, Chen K, Aschenbrenner M, Merkley TL, Santerre-Lemmon LE, Shamy JL, Skaggs WE, Buonocore MH, Rapp P, & Barnes C.A. (2008). Age-related regional network pattern of MRI gray matter in the rhesus macaque. Journal of Neuroscience, 28, 2710-8.;Collaborative with faculty member in unit: Yes;

PMID: 11694153;Abstract:

Context: Deficits in cerebral glucose utilization have been identified in patients with cognitive dysfunction attributed to various disease processes, but their prognostic and diagnostic value remains to be defined. Objective: To assess the sensitivity and specificity with which cerebral metabolic patterns at a single point in time forecast subsequent documentation of progressive dementia. Design, Setting, and Patients: Positron emission tomography (PET) studies of [¹⁸F]fluorodeoxyglucose in 146 patients undergoing evaluation for dementia with at least 2 years' follow-up for disease progression at the University of California, Los Angeles, from 1991 to 2000, and PET studies in 138 patients undergoing evaluation for dementia at an international consortium of facilities, with histopathological diagnoses an average of 2.9 years later, conducted from 1984 to 2000. Main Outcome Measures: Regional distribution of [¹⁸F]fluorodeoxyglucose in each patient, classified by criteria established a priori as positive or negative for presence of a progressive neurodegenerative disease in general and of Alzheimer disease (AD) specifically, compared with results of longitudinal or neuropathologic analyses. Results: Progressive dementia was detected by PET with a sensitivity of 93% (191/ 206) and a specificity of 76% (59/78). Among patients with neuropathologically based diagnoses, PET identified patients with AD and patients with any neurodegenerative disease with a sensitivity of 94% and specificities of 73% and 78%, respectively. The negative likelihood ratio of experiencing a progressive vs nonprogressive course over the several years following a single negative brain PET scan was 0.10 (95% confidence interval, 0.06-0.16), and the initial pattern of cerebral metabolism was significantly associated with the subsequent course of progression overall (P.001). Conclusion: In patients presenting with cognitive symptoms of dementia, regional brain metabolism was a sensitive indicator of AD and of neurodegenerative disease in general. A negative PET scan indicated that pathologic progression of cognitive impairment during the mean 3-year follow-up was unlikely to occur.