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Eric M Reiman

Publications and source records attributed to Eric M Reiman.

At least 37 records · Page 2Linked to original sources
PubMed2006

Preliminary demonstration of an allelic association of the IREB2 gene with Alzheimer's disease.

The role of iron metabolism in Alzheimer's disease (AD) is well documented. Regulation of the proteins that maintain cellular iron metabolism is mediated by two cytoplasmic RNA-binding proteins, the Iron Regulatory Proteins (IRP1 and IRP2), that function through post-transcriptional interactions with RNA stem loop structures called iron-responsive elements. As the primary mediator of iron homeostasis in neuronal cells, IRP2 is a strong candidate for polymorphisms that could impact AD pathogenesis. Thus, we performed a pilot study to assess polymorphisms in the gene encoding IRP2 (IREB2) on clinically well-characterized, post-mortem samples (50 AD and 50 controls). DNA sequence analysis of the IREB2 gene region revealed 14 polymorphisms. Two (rs2656070 and rs13180) showed statistically significant skewing of allelic and genotypic distributions between AD patients and controls. In silico analyses revealed that rs2656070 lies within a probable promoter and disrupts the binding sites of at least two known transcription factors. Though silent and likely not functionally relevant, rs13180 is in complete LD with rs2656070 (D' > 0.999), creating an IREB2-haplotype that is significantly associated with AD. Confirmation of this association in a larger cohort of cases and controls would further support the role of iron regulation in the pathogenesis of this catastrophic and increasingly common neurodegenerative disorder.

Aged↗
PubMed2006

Genetics, transcriptomics, and proteomics of Alzheimer's disease.

OBJECTIVE: To provide an updated overview of the methods used in genetic, transcriptomic, and proteomic studies in Alzheimer's disease and to demonstrate the importance of those methods for the improvement of the current diagnostic and therapeutic possibilities. DATA SOURCES: MEDLINE-based search of 233 peer-reviewed articles published between 1975 and 2006. DATA SYNTHESIS: Alzheimer's disease is a genetically heterogeneous disorder. Rare mutations in the amyloid precursor protein, presenilin 1, and presenilin 2 genes have shown the importance of the amyloid metabolism for its development. In addition, converging evidence from population-based genetic studies, gene expression studies, and protein profile studies in the brain and in the cerebrospinal fluid suggest the existence of several pathogenetic pathways such as amyloid precursor protein processing, beta-amyloid degradation, tau phosphorylation, proteolysis, protein misfolding, neuroinflammation, oxidative stress, and lipid metabolism. CONCLUSIONS: The development of high-throughput genotyping methods and of elaborated statistical analyses will contribute to the identification of genetic risk profiles related to the development and course of this devastating disease. The integration of knowledge derived from genetic, transcriptomic, and proteomic studies will greatly advance our understanding of the causes of Alzheimer's disease, improve our capability of establishing an early diagnosis, help define disease subgroups, and ultimately help to pave the road toward improved and tailored treatments.

Alzheimer Disease↗
PubMed2006

Alzheimer's disease a century later.

OBJECTIVE: To provide a current survey of the clinical and pathologic features, known genetic and suggested pathogenic contributions, diagnosis, and treatment of Alzheimer's disease (AD) and related forms of dementia. DATA SOURCES: PubMed was searched for specific indexing terms identified by the authors as relevant to the topic. Also included were diagnostic and consensus criteria and classic references long standing in the Alzheimer's disease literature. DATA SYNTHESIS: AD is the most common form of disabling cognitive impairment in older persons, and its prevalence is rapidly growing as people live to older ages. Clinically, the disorder is characterized by a gradual but progressive decline in memory and other cognitive domains and the frequent occurrence of noncognitive behavioral symptoms. Neuropathologically, the cardinal features of AD include neuritic plaques, neuro-fibrillary tangles, and the loss of synapses and neurons. The clinical evaluation of AD includes a history and physical examination, laboratory tests, and structural brain imaging to exclude less common forms of dementia. The clinical management of AD includes medication and nonmedication strategies for addressing cognitive, behavioral, and other commonly associated symptoms of patients as well as lifestyle changes such as driving cessation and residential care. Genetic causes of familial Alzheimer's disease as well as genes that predispose to late-onset and sporadic Alzheimer's disease have led to greater understanding of the pathophysiology of the neurodegenerative process. CONCLUSIONS: While there has been great promise in the scientific understanding, early detection, and tracking of AD and in the discovery of promising disease-slowing treatments, there remains an unmet urgent need to identify effective primary and secondary prevention therapies in order to avert a financially overwhelming public health problem.

Alzheimer Disease↗
PubMed2005

Gene expression correlates of neurofibrillary tangles in Alzheimer's disease.

Neurofibrillary tangles (NFT) constitute one of the cardinal histopathological features of Alzheimer's disease (AD). To explore in vivo molecular processes involved in the development of NFTs, we compared gene expression profiles of NFT-bearing entorhinal cortex neurons from 19 AD patients, adjacent non-NFT-bearing entorhinal cortex neurons from the same patients, and non-NFT-bearing entorhinal cortex neurons from 14 non-demented, histopathologically normal controls (ND). Of the differentially expressed genes, 225 showed progressively increased expression (AD NFT neurons > AD non-NFT neurons > ND non-NFT neurons) or progressively decreased expression (AD NFT neurons < AD non-NFT neurons < ND non-NFT neurons), raising the possibility that they may be related to the early stages of NFT formation. Immunohistochemical studies confirmed that many of the implicated proteins are dysregulated and preferentially localized to NFTs, including apolipoprotein J, interleukin-1 receptor-associated kinase 1, tissue inhibitor of metalloproteinase 3, and casein kinase 2, beta. Functional validation studies are underway to determine which candidate genes may be causally related to NFT neuropathology, thus providing therapeutic targets for the treatment of AD.

Aged, 80 and over↗
PubMed2005

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.

Age of Onset↗
PubMed2005

Cerebral asymmetry in children when reading Chinese characters.

This study examined cerebral asymmetry, especially in the hierarchical visual system, when reading Chinese characters. Twelve right-handed Chinese children (mean age = 11.6 years) were scanned while performing semantic and phonological tasks. Strong leftward asymmetry was found in the left inferior frontal cortex (BA44/45/47), the parietal lobule (BA40), and the cingulate cortex (BA24/32). In the visual system, we found significant left-hemispheric dominance in the fusiform cortex (BA19/37), but no asymmetry was found in the primary visual cortex (BA17/18). The differential results for the primary visual cortex versus high-order visual cortex (i.e., the fusiform cortex) are discussed in terms of the contribution of the logographic nature of Chinese characters to the asymmetry pattern in the hierarchical visual system.

Brain Mapping↗
PubMed2005

Sensory experience of food and obesity: a positron emission tomography study of the brain regions affected by tasting a liquid meal after a prolonged fast.

The sensory experience of food is a primary reinforcer of eating and overeating plays a major role in the development of human obesity. However, whether the sensory experience of a forthcoming meal and the associated physiological phenomena (cephalic phase response, expectation of reward), which prepare the organism for the ingestion of food play a role in the regulation of energy intake and contribute to the development of obesity remains largely unresolved. We used positron emission tomography (PET) and 15O-water to measure changes in regional cerebral blood flow (rCBF) and to assess the brain's response to the oral administration of 2 ml of a liquid meal (Ensure Plus, 1.5 kcal/ml) after a 36-h fast and shortly before consuming the same meal. Twenty-one obese (BMI > 35 kg/m2, 10M/11F, age 28 +/- 6 years, body fat 40 +/- 6%) and 20 lean individuals (BMI < 25 kg/m2, 10M/10F, age 33 +/- 9 years, body fat 21 +/- 7%) were studied. Compared to lean individuals, obese individuals had higher fasting plasma glucose (83.3 +/- 6.2 vs. 75.5 +/- 9.6 mg/dl; P = 0.0003) and insulin concentrations (6.1 +/- 3.5 vs. 2.5 +/- 1.7 microU/ml; P < 0.0001) and were characterized by a higher score of dietary disinhibition (i.e., the susceptibility of eating behavior to emotional factors and sensory cues, 5.7 +/- 3.6 vs. 3.5 +/- 2.7; P = 0.01) assessed by the Three Factor Eating Questionnaire. In response to the sensory experience of food, differences in rCBF were observed in several regions of the brain, including greater increases in the middle-dorsal insula and midbrain, and greater decreases in the posterior cingulate, temporal, and orbitofrontal cortices in obese compared to lean individuals (P < 0.05, after small volume correction). In a multiple regression model, percentage of body fat (P = 0.04), glycemia (P = 0.01), and disinhibition (P = 0.07) were independent correlates of the neural response to the sensory experience of the meal in the middle-dorsal insular cortex (R2 = 0.45). We conclude that obesity is associated with an abnormal brain response to the sensory aspects of a liquid meal after a prolonged fast especially in areas of the primary gustatory cortex. This is only partially explained by the elevated glycemia and high level of disinhibition which characterize individuals with increased adiposity. These results provide a new perspective on the understanding of the neuroanatomical correlates of abnormal eating behavior and their relationship with obesity in humans.

Adipose Tissue↗
PubMed2004

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.

Aged↗
PubMed2004

A distinctive interaction between chronic anxiety and problem solving in asymptomatic APOE e4 homozygotes.

We correlated measures of problem solving (Wisconsin Card Sorting Test [WCST] categories, total errors, and perseverative errors) and chronic anxiety (Personality Assessment Inventory Anxiety Scale [ANX]) in asymptomatic apolipoprotein E (APOE) e4 homozygotes (HMZs), heterozygotes, and noncarriers (NC) (n = 42 in each group) matched for age, education, and gender. Differences between HMZ and NC in the slope of the regression of WCST scores on ANX reached statistical significance on all three WCST measures. Chronic anxiety adversely affects cognitive skills in all groups, and is associated with significantly greater decline in problem solving skills in cognitively normal APOE e4 HMZ.

Anxiety Disorders↗
PubMed2003

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.

Adult↗
PubMed2002

Tasting a liquid meal after a prolonged fast is associated with preferential activation of the left hemisphere.

We used positron emission tomographic scanning of the brain and measures of regional cerebral blood flow to investigate the response of 44 right-handed people to the oral administration of 2 ml of a liquid formula meal after a 36 h fast (and shortly before the administration of a satiating amount of the same meal). Several areas of the left hemisphere were significantly more activated than the contralateral, including the frontal operculum, ventral insula, and piriform cortex. In contrast with reports of right-hemisphere dominance in chemosensory perception in non-hungry individuals, our study reveals a preferential activation of the left hemisphere when people who are very hungry are briefly exposed to the chemical and physical properties of a liquid meal. This raises the possibility that the physiological context in which perception takes place (i.e. extreme vs moderate vs no hunger) may importantly affect the brain representation of chemosensory stimuli.

Adult↗
PubMed2002

A distinctive interaction between memory and chronic daytime somnolence in asymptomatic APOE e4 homozygotes.

STUDY OBJECTIVES: To correlate memory measures with a trait measure of chronic daytime somnolence in cognitively normal individuals with different gene doses of the apolipoprotein E (APOE) e4 allele, a common Alzheimer's disease susceptibility gene. DESIGN: Cross-sectional, exploratory study of cognitive abilities in APOE e4 homozygotes (HMZ) (n=42), heterozygotes (HTZ), (n=42) and noncarriers (NC) (n=42) who are matched for age, gender, educational level, and family history of dementia. SETTING: Tertiary care academic medical center. PARTICIPANTS: Cognitively normal residents of Maricopa County, Arizona who are 30-70 years of age, genotyped for APOE, and have no history of a sleep disorder INTERVENTIONS: N/A. MEASUREMENTS: Epworth Sleepiness Scale (ESS) and a battery of neuropsychological tests RESULTS: Age, education, gender, and insomnia complaints did not significantly differ among groups. Despite normal baseline memory scores, memory declined with increasing ESS on all eight memory measures in the HMZ, two of eight in the HTZ, and one of eight in the NC. Differences between HMZ and NC on the slope of memory decline with increasing ESS reached statistical significance on two verbal memory measures, AVLT Long-Term Memory (p=0.048) and Percent Delayed Recall (p=0.035). CONCLUSIONS: Chronic daytime somnolence is associated with a distinctive decline in verbal memory in cognitively normal APOE e4 HMZ, a group at particularly high risk of Alzheimer's disease. Additional studies are needed to confirm these exploratory findings and to determine the effects of acute somnolence on cognition in these genetic subgroups.

Adult↗
PubMed2002

Apolipoprotein E and intellectual achievement.

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.

Apolipoproteins E↗