Genetic determinants of neuroglobin transcription.

Neuroglobin (NGB) is a neuron-specific vertebrate globin shown to protect against hypoxia, ischemia, oxidative stress and the toxic effects of Amyloid-beta. Following on our and others' results highlighting the importance of NGB expression in disease, we searched for genetic determinants of its expression. We found that a microRNA expressed with the NGB transcript shows significant target enrichments in the angiogenesis pathway and the Alzheimer disease/presenilin pathway. Using reporter constructs we identified potential promoter/enhancer elements between the transcription start site and 1,142 bp upstream. Using 184 post-mortem temporal lobe samples we replicated the reported negative effect of age, and after genotyping tagging SNPs we found one (rs981471) showing a significant correlation with the gene's expression and another (rs8014408) showing an interaction with age, the rare C allele being correlated with higher expression and faster decline. The two SNPs are towards the 3' end of NGB within the same LD block, 52 Kb apart and modestly correlated (r (2) = 0.5). Next generation sequencing of the same 184 temporal lobe samples and 79 confirmed AD patients across the entire gene region (including >12 Kb on the 3' and 5' flank) revealed limited coding variation, suggesting purifying selection of NGB, but did not identify regulatory or disease associated rare variants. A dinucleotide repeat in intron 1 with extensive evidence of functionality showed interesting but inconclusive results, as it was not amenable to further molecular analysis.

Alzheimer's risk variants in the clusterin gene are associated with alternative splicing.

Genetic variation in CLU encoding clusterin has been associated with Alzheimer's disease (AD) through replicated genome-wide studies, but the underlying mechanisms remain unknown. Following earlier reports that tightly regulated CLU alternative transcripts have different functions, we tested CLU single nucleotide polymorphisms (SNPs) including those associated with AD for quantitative effects on individual alternative transcripts. In 190 temporal lobe samples without pathology we found that the risk allele of the AD associated SNP rs9331888 increases the relative abundance of transcript NM_203339 (P=4.3×10(-12)). Using an independent set of 115 AD and control samples, we replicated this result (p=0.0014) and further observed that multiple CLU transcripts are at higher levels in AD compared to controls. The AD SNP rs9331888 is located in the first exon of NM_203339 and therefore, it is a functional candidate for the observed effects. We tested this hypothesis by in vitro dual luciferase assays using SK-N-SH cells and mouse primary cortical neurons and found allelic effects on enhancer function, consistent with our results on post-mortem human brain. These results suggest a biological mechanism for the genetic association of CLU with AD risk and indicate that rs9331888 is one of the functional DNA variants underlying this association.

Intelligence and medial temporal lobe function in older adults: a functional MR imaging-based investigation.

BACKGROUND AND PURPOSE: The influence of general intelligence and formal education on functional MR imaging (fMRI) activation has not been thoroughly studied in older adults. Although these factors could be controlled for through study design, this approach makes sample selection more difficult and reduces power. This study was undertaken to examine our hypothesis that intelligence and education would impact medial temporal lobe (MTL) fMRI responses to an episodic memory task in healthy elderly subjects. MATERIALS AND METHODS: Thirty-six women and 38 men, 50-83 years of age (mean, 63.4 +/- 7.9 years), completed an auditory paired-associates paradigm in a 1.5T magnet. The amplitude and volume of fMRI activation for both the right and left MTLs and MTL subregions were correlated with the intelligence quotients (IQs) and educational levels by using Pearson correlation coefficient tests and regression analyses. RESULTS: The participants' mean estimated full scale IQ and verbal IQ scores were 110.4 +/- 7.6 (range, 92-123) and 108.9 +/- 8.7 (range, 88-123), respectively. The years of education showed a mean of 16.1 +/- 3.2 years (range, 8-25 years). The paradigm produced significant activation in the MTL and subregions. However, the volume and amplitude of activation were unrelated to either IQ or years of schooling in men and/or women. CONCLUSIONS: We found no evidence of an effect of IQ or education on either the volume or amplitude of fMRI activation, suggesting that these factors do not necessarily need to be incorporated into study design or considered when evaluating other group relationships with fMRI.

Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease: the NIMH Alzheimer Disease Genetics Initiative.

Tumor necrosis factor (TNF), a proinflammatory cytokine, may be involved in the pathogenesis of Alzheimer disease (AD) based on observations that senile plaques have been found to upregulate proinflammatory cytokines. Additionally, nonsteroidal anti-inflammatory drugs have been found to delay and prevent the onset of AD. A collaborative genome-wide scan for AD genes in 266 late-onset families implicated a 20 centimorgan region at chromosome 6p21.3 that includes the TNF gene. Three TNF polymorphisms, a -308 TNF promoter polymorphism, whose TNF2 allele is associated with autoimmune inflammatory diseases and strong transcriptional activity, the -238 TNF promoter polymorphism, and the microsatellite TNFa, whose 2 allele is associated with a high TNF secretion, were typed in 145 families consisting of 562 affected and unaffected siblings. These polymorphisms formed a haplotype, 2-1-2, respectively, that was significantly associated with AD (P = 0.005) using the sibling disequilibrium test. Singly, the TNFa2 allele was also significantly associated (P = 0.04) with AD in these 145 families. This TNF association with AD lends further support for an inflammatory process in the pathogenesis of AD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:823-830, 2000.

Genomic structure, expression pattern, and chromosomal localization of the human calsenilin gene: no association between an exonic polymorphism and Alzheimer's disease.

Calsenilin is a recently-identified member of the neuronal calcium sensor family. Like other members of this family, it is found in the brain and binds calcium. Calsenilin was discovered by virtue of its interaction with both presenilin-1 and -2, proteins that are involved in the etiology of Alzheimer's disease. Because calsenilin may play a role in Alzheimer's disease and other disease with alterations in calcium homeostasis, we characterized the human gene. The gene, which we localized to chromosome 2, extends over a region of at least 74 kb and includes nine exons. Interestingly, the ninth exon of calsenilin contains a highly polymorphic CA repeat, adjacent to the stop codon. In a study of Alzheimer patients and their unaffected siblings, there was no evidence of association of AD with any calsenilin allele. This CA repeat will be useful for linkage and linkage disequilibrium studies to determine whether calsenilin variants contribute to risk in other diseases.

Attention: neuropsychological predictor of competency in Alzheimer's disease.

This study was undertaken to examine the relationship between two different competencies, financial and medical decision making, and explore whether neuropsychological testing can identify a common underlying cognitive operation impaired in patients with AD. The objective was to examine the neuropsychological predictors of financial and medical decision-making competencies in patients with Alzheimer's disease (AD). Twenty individuals with mild to moderate AD and 20 control subjects matched for age and education were evaluated at a university medical center. All participants were administered a financial competency questionnaire, a competency test for medical decision making, and a set of standardized neuropsychological tests selected to reflect cognitive processes theoretically related to competency. In addition, an informant provided information regarding banking history for each participant. AD patients performed more poorly on all measures, including both measures of competency, which were highly related (R = .718, P < .001). Two tests, Trails A and Word List Recall, were significantly correlated with both competency measures, with Trails A predicting over 85% of the variance in competency scores. Trails A discriminated competent from not competent participants with an accuracy ranging from 77% to 82%. Measures of financial and medical decision-making competency were significantly correlated among patients with AD. One brief neuropsychological test of attention, Trails A, proved to be highly predictive of performance on both competency measures and useful in the discrimination of competent performance on these measures and by informant report.

Alpha-2 macroglobulin is genetically associated with Alzheimer disease.

Alpha-2-macroglobulin (alpha-2M; encoded by the gene A2M) is a serum pan-protease inhibitor that has been implicated in Alzheimer disease (AD) based on its ability to mediate the clearance and degradation of A beta, the major component of beta-amyloid deposits. Analysis of a deletion in the A2M gene at the 5' splice site of 'exon II' of the bait region (exon 18) revealed that inheritance of the deletion (A2M-2) confers increased risk for AD (Mantel-Haenzel odds ratio=3.56, P=0.001). The sibship disequilibrium test (SDT) also revealed a significant association between A2M and AD (P=0.00009). These values were comparable to those obtained for the APOE-epsilon4 allele in the same sample, but in contrast to APOE-epsilon4, A2M-2 did not affect age of onset. The observed association of A2M with AD did not appear to account for the previously published linkage of AD to chromosome 12, which we were unable to confirm in this sample. A2M, LRP1 (encoding the alpha-2M receptor) and the genes for two other LRP ligands, APOE and APP (encoding the amyloid beta-protein precursor), have now all been genetically linked to AD, suggesting that these proteins may participate in a common neuropathogenic pathway leading to AD.

Disability and psychiatric disorders in an urban community: measurement, prevalence and outcomes.

BACKGROUND: The purpose of this analysis was to examine: (1) the prevalence of psychiatric disorders among disabled people, using seven different measures of disability; (2) variation in disability between and within psychiatric diagnostic categories; and (3) relationship of diagnosis and disability to health service utilization. METHOD: Data were drawn from Phase I and Phase II of the Eastern Baltimore Mental Health Survey, part of the Epidemiologic Catchment Area Program (ECA) conducted in 1980-1 to survey mental morbidity within the adult population. A total of 810 individuals received both a household interview and a standardized clinical psychiatric evaluation. Estimated prevalence rates were computed using appropriate survey sampling weights. RESULTS: Prevalence of disability ranged from 2.5 to 19.5%, varying with specific disability measure. Among those classified as disabled by any of the measures examined, 56 to 92% had a psychiatric disorder and serious chronic medical conditions were present in the majority of these cases (54 to 78%). Disability was expressed differently among the various diagnostic groups. Diagnostic category and disability were significant independent predictors of medical service utilization and receipt of disability payments. CONCLUSIONS: The majority of disabled adults living in the community have diagnosable psychiatric disorders, with the majority of these individuals suffering from significant chronic medical conditions as well, thus making co-morbidity the norm.

ApoE-4 and age at onset of Alzheimer's disease: the NIMH genetics initiative.

OBJECTIVE: To explore the impact of apoE-4 on Alzheimer's disease (AD) and its age at onset. DESIGN: A genetic linkage study using affected relative pairs, predominantly siblings. SETTING: Three academic medical centers ascertained subjects from memory disorder clinics, nursing homes, and the local community. SUBJECTS: 310 families including 679 subjects with AD by NINCDS/ADRDA and/or Khachaturian criteria and 231 unaffected subjects. OUTCOME MEASURE: ApoE genotype. ANALYTIC METHODS: Association, affected pedigree member, sibling pair, and lod score analyses. RESULTS: ApoE-4 was strongly associated with AD in this sample (allele frequency = 0.46 vs. 0.14 in controls, p < 0.000001). Results of lod score, affected pedigree member analysis, and sib-pair analysis also supported apoE-4 as a risk factor for AD. When the sample was stratified on family mean age at onset, the risk conferred by apoE-4 was most marked in the 61 to 65 age group. Individuals with two copies of apoE-4 had a significantly lower age at onset than those with one or no copies (66.4 vs. 72.0, p < 0.001), but individuals with one copy did not differ from those with none. Within families, the individual with the earliest age at onset had, on average, significantly more apoE-4 alleles (p < 0.0001) than the individual with the latest onset. DISCUSSION: This work supports previous reports of an association between apoE-4 and the development of AD and demonstrates that apoE-4 exerts its maximal effect before age 70. These findings have important implications for the potential use of apoE genotyping for diagnosis and prediction of disease. They also underscore the need to identify additional genetic factors involved in AD with onset beyond age 70 years.

Development and validation of a Structured Telephone Interview for Dementia Assessment (STIDA): the NIMH Genetics Initiative.

As part of the NIMH Genetics Initiative Alzheimer's Disease (AD) Study Group, a brief structured telephone interview to distinguish individuals with normal cognitive functioning from those with changes in cognition and daily functioning suggestive of early AD was developed. The Structured Telephone Interview for Dementia Assessment (STIDA), yields a dementia score between 0 and 81 (higher scores indicating greater impairment). Subscales corresponding to the subscales of the Clinical Dementia Rating Scale (CDR) can be derived. The STIDA performed well as a screening instrument for mildly demented individuals. When a score of 10 or more (based on informant interview and subject testing) was used to identify mildly impaired individuals, the STIDA had a sensitivity of .93 and a specificity of .92 for a clinician-derived CDR of 0.5 or more. The STIDA was also capable of accurately assessing the level of dementia. STIDA-derived CDR ratings agreed with clinician-derived CDR scores in 23 of 28 cases, corresponding to an unweighted kappa of.71 and a weighted kappa of.81. A much-abbreviated short STIDA that could be administered directly to the subject was able to detect possible impairment with a sensitivity of .93 and a specificity of.77. These results suggest that the short STIDA provides a sensitive and fairly specific telephone screen for dementia, and that the full STIDA, consisting of an interview with a knowledgeable informant and subject testing, approximates the success of a face-to-face clinical interview, and provides reliable and valid screening and staging of dementia over the telephone.

Long-term treatment of girls with ornithine transcarbamylase deficiency.

BACKGROUND: Ornithine transcarbamylase is an X-linked mitochondrial enzyme that catalyzes the synthesis of citrulline from carbamoyl phosphate and ornithine. A deficiency of this enzyme leads to hyperammonemia and hyperglutaminemia. In boys the disease is often fatal when its onset occurs during the neonatal period, but it is milder when onset occurs later in childhood. Heterozygous girls may be normal or may have episodes of hyperammonemic encephalopathy and decline in cognitive function. We report here on the long-term outcome in girls with ornithine transcarbamylase deficiency enrolled in studies of treatments designed to activate new pathways of waste-nitrogen excretion. METHODS: We studied 32 girls (age, 1 to 17 years) with ornithine transcarbamylase deficiency who had had at least one episode of encephalopathy. The patients were assigned to treatment that consisted of sodium benzoate, alone or in combination with sodium phenylacetate or sodium phenylbutyrate, or sodium phenylbutyrate alone. Collaborating physicians provided clinical, metabolic, and developmental data at specified intervals. RESULTS: Patients treated according to these protocols had greater than 90 percent survival at five years and maintained appropriate weight for height. The frequency of hyperammonemic episodes decreased with increasing age and with sodium phenylacetate or sodium phenylbutyrate treatment. Although the mean IQ before treatment was in the low average range, 19 of the 23 girls in whom intelligence was tested longitudinally had stable test scores. CONCLUSIONS: Girls with symptomatic ornithine transcarbamylase deficiency who are treated with drugs that activate new pathways of waste-nitrogen excretion have fewer hyperammonemic episodes and a reduced risk of further cognitive decline.

Use of proxies to measure health and functional status in epidemiologic studies of community-dwelling women aged 65 years and older.

Proxy and subject responses to survey questions about chronic conditions, health symptoms, and physical and instrumental functioning were compared to determine the extent of disagreement, the direction of nonrandom discrepancies (i.e., bias), and how disagreement and bias vary by proxy and subject characteristics. Subjects included 538 community-dwelling women aged 65 years and older who participated in the third home interview of a health survey in Baltimore, Maryland, 1986, and a self-designated proxy for each. The authors observed kappa values of > 0.6 (i.e., substantial to almost perfect agreement) for five of nine chronic conditions, no health symptoms, six of seven physical tasks of daily living, and seven of seven instrumental tasks of daily living. With few exceptions, proxies were more likely than subjects to report the presence of a condition, symptom, or functional problem. Variations in agreement and bias were noted by subject and proxy characteristics, with different patterns observed for different measurement areas. When using proxy reports in place of self-reports, it is important to evaluate the impact that using proxies has on study results.

Reliability and validity of NINCDS-ADRDA criteria for Alzheimer's disease. The National Institute of Mental Health Genetics Initiative.

OBJECTIVE: To assess interrater reliability and validity of NINCDS-ADRDA (National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association) criteria for Alzheimer's disease (AD). DESIGN: A multisite reliability and validity study in which clinicians from each site diagnosed 60 case summaries yielding a preconsensus estimate of reliability and validity. A consensus conference was conducted for each disagreement, leading to a postconsensus estimate of validity. The criterion standard was a diagnosis of AD by autopsy. SETTING: Three academic medical centers. SUBJECTS: A convenience sample of 60 detailed case summaries, 40 with AD and 20 with other dementing disorders. MAIN OUTCOME MEASURES: The kappa coefficient, sensitivity, and specificity. RESULTS: The kappa coefficient for preconsensus agreement on a diagnosis of probable or possible AD vs non-AD was 0.51; the sensitivity of a diagnosis of probable or possible AD for a pathological diagnosis of AD was 0.81, and the specificity was 0.73. The postconsensus sensitivity was 0.83, and the specificity was 0.84. CONCLUSIONS: The results support the reliability and validity of NINCDS-ADRDA criteria and show that the consensus process may improve diagnostic accuracy. The cases are reviewed with a focus on the sources of diagnostic disagreements and errors and possible changes that might improve the accuracy of the criteria.

Population-based norms for the Mini-Mental State Examination by age and educational level.

OBJECTIVE: To report the distribution of Mini-Mental State Examination (MMSE) scores by age and educational level. DESIGN: National Institute of Mental Health Epidemiologic Catchment Area Program surveys conducted between 1980 and 1984. SETTING: Community populations in New Haven, Conn; Baltimore, Md; St Louis, Mo; Durham, NC; and Los Angeles, Calif. PARTICIPANTS: A total of 18,056 adult participants selected by probability sampling within census tracts and households. MAIN OUTCOME MEASURES: Summary scores for the MMSE are given in the form of mean, median, and percentile distributions specific for age and educational level. RESULTS: The MMSE scores were related to both age and educational level. There was an inverse relationship between MMSE scores and age, ranging from a median of 29 for those 18 to 24 years of age, to 25 for individuals 80 years of age and older. The median MMSE score was 29 for individuals with at least 9 years of schooling, 26 for those with 5 to 8 years of schooling, and 22 for those with 0 to 4 years of schooling. CONCLUSIONS: Cognitive performance as measured by the MMSE varies within the population by age and education. The cause of this variation has yet to be determined. Mini-Mental State Examination scores should be used to identify current cognitive difficulties and not to make formal diagnoses. The results presented should prove to be useful to clinicians who wish to compare an individual patient's MMSE scores with a population reference group and to researchers making plans for new studies in which cognitive status is a variable of interest.

Memory complaint, memory performance, and psychiatric diagnosis: a community study.

This study examined the prevalence of memory complaint and poor memory performance on brief screening measures within a community sample of 810 adults. All individuals received an extensive household interview and a clinical psychiatric evaluation. Overall, 22% indicated that they currently had trouble with their memory. This percentage increased with age, rising to 43% for those 65 to 74 years old, 51% for those 75 to 84 years old, and 88% for those 85 years of age and older; the percentage indicating memory problems decreased with educational attainment. The prevalence of poor memory performance was 11%, also increasing with less education and increased age, rising to 26% for those 65 to 74 years old and to 40% for those older then 75. Those who complained of memory trouble were twice as likely to show poor memory performance (29%) compared with those who did not complain (15%). Multivariate analysis found age, emotional distress, and physical illness to be independent predictors of memory complaint; age, functional disability, education, and physical illnesses proved to be independently associated with poor memory performance. A higher prevalence of complaints of memory trouble was found not only for those with affective disorders, as might be expected, but also among those with schizophrenic, cognitive, anxiety, and adjustment disorders. However, only individuals with cognitive disorders showed a higher prevalence of poor memory performance.

Dementia: case ascertainment in a community survey.

The three-stage East Baltimore Mental Health Survey, conducted in 1981 as part of the Epidemiological Catchment Area Program, provided an opportunity to assess the prevalence of dementia and specific dementing disorders in a community-based, cross-sectional sample of the population. From the 3,841 households originally sampled, 810 individuals were selected for clinical psychiatric evaluation. Forty-one individuals were given a provisional diagnosis and referred to Stage 3 for differential diagnosis, with 32 individuals completing this evaluation. Thorough clinical evaluation of these cases resulted in an overall prevalence of dementia of 4.5% in those 65 years of age and older. The prevalence of specific dementing disorders was Alzheimer's disease (AD) (2.0%), Multi-Infarct Dementia (MID) (2.0%) and Mixed Dementia (MD) (0.5%). Prevalence increased with age for all dementias: Non-Whites had higher rates of dementia than Whites; females had higher rates of AD while males had higher rates of MID; and the prevalence of AD increased with increasing education, whereas the prevalence of MID decreased with increased education. Although this study includes only a small number of cases, necessitating some caution in interpreting the results, these figures do represent an estimate of the prevalence of severe dementing disorders and provide a basis for further community study.

Cognitive impairment and functional disability in the absence of psychiatric diagnosis.

Data from the 1981 East Baltimore Mental Health Survey were used to examine the relationship between cognitive impairment and psychiatric diagnosis in an adult population. The Mini-Mental State Examination was administered to 3841 household respondents and a subset of 810 received psychiatric evaluations. Of the 810, 23% were found to be cognitively impaired. Over one-third of those with cognitive impairment, however, did not meet DSM-III criteria for a psychiatric diagnosis. Education, geographical background, race and neurological status were predictive of cognitive performance. There was no linear effect of age on cognitive performance with disease status and education controlled. In addition to their cognitive impairment these individuals, who ranged in age from 19 to 89, were found to have significant functional disabilities. Cognitive performance itself, along with physical and emotional health, predicted total functional disability.

The epidemiology of delirium in the community: the Eastern Baltimore Mental Health Survey.

The 1981 East Baltimore Mental Health Survey, part of the Epidemiological Catchment Area (ECA) program, provided data for the examination of the prevalence of delirium in the general adult population. From an original 3,841 households surveyed, 810 individuals were selected for psychiatric evaluation and, of these, 6 individuals were diagnosed as suffering from delirium. The estimated prevalence of delirium in the population was .4% and 1.1% among those 55 years of age and over. A comparison of these cases with cases of diagnosed dementia and individuals of the same age range who did not receive a psychiatric diagnosis found that those with a diagnosis of delirium suffer from a greater number of medical conditions, take more prescribed medications, and have a higher level of physical disability.

Neuropsychological function in adolescents sustaining mild closed head injury.

Adolescents sustaining mild closed head injury were evaluated for mental functioning immediately following injury. Evaluation of their neuropsychological performance in comparison with healthy adolescents and adolescents sustaining severe closed head injury revealed a pattern distinct from the other two groups. Mildly injured patients exhibited some dysfunction in verbally based measures of learning, abstraction, and reasoning, while appearing unimpaired on measures of attention, motor speed, and visual memory.

Reliability of proxy response on mental health indices for aged, community-dwelling women.

The correspondence between respondent and proxy response was evaluated on 4 mental health measures (Affect Balance Scale, Center for Epidemiological Studies Depression Scale, Mental Status Questionnaire, and Mini-Mental State Examination) with a sample of 538 respondent-proxy pairs. Results indicated that respondent and proxy responses were strongly associated, particularly for the cognitive measures. This association was found even for respondents classified as depressed or cognitively impaired. Although there was evidence of proxy bias, with proxies underrating affective status and overrating cognitive status, the magnitude of the bias proved small for all scales but the Mental Status Questionnaire. Examination of response comparability by proxy characteristics showed that choice of proxy affected agreement and bias. Implications of these findings for survey research are discussed.