Susan Spear Bassett

ApoE-4 and Age at Onset of Alzheimer's Disease The NIMH Genetics Initiative

Objective: To explore the impact of apoE-4 on Alzheimers 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. NEUROLOGY 1997;48: 139-147

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.

Clinical features associated with impulse control disorders in Parkinson disease.

In patients with Parkinson disease (PD), impulse control disorders (ICDs) such as hypersexuality and pathologic gambling and shopping can be devastating complications of antiparkinsonian treatment. To improve their detection, we investigated clinical features associated with ICDs. Subjects were participants in a longitudinal study of PD. ICDs were associated with use of dopamine agonists and depressed mood, disinhibition, irritability, and appetite disturbance.

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.

Past adult lead exposure is linked to neurodegeneration measured by brain MRI

Objective: To determine whether cumulative lead dose in former organolead workers was associated with MRI measures of white matter lesions (WML) and global and structure-specific brain volumes. Methods: MRIs, tibia lead, and other measures were obtained from 532 former organolead workers with a mean age of 56 years and a mean of 18 years since last occupational exposure to lead. Cumulative lead dose was measured by tibia lead, obtained by X-ray fluorescence, and expressed as μg lead per gram of bone mineral (μg Pb/g). WML were evaluated using the Cardiovascular Health Study grading scale. A total of 21 global and specific brain regions were evaluated. Results: A total of 36% of individuals had WML grade of 1 to 7 (0 to 9 scale). Increasing peak tibia lead was associated with increasing WML grade (p = 0.004). The adjusted OR for a 1 μg Pb/g increase in tibia lead was 1.042 (95% CI = 1.021, 1.063) for a CHS grade of 5+ (≥5 vs <5). In linear regression, the coefficient for tibia lead was negative for associations with all structures. Higher tibia lead was significantly related to smaller total brain volume, frontal and total gray matter volume, and parietal white matter volume. Of nine smaller specific regions of interest, higher tibia lead was associated with smaller volumes for the cingulate gyrus and insula. Conclusions: These data suggest that cumulative lead dose is associated with persistent brain lesions, and may explain previous findings of a progressive decline in cognitive function.

Repeat Expansion in C9ORF72 in Alzheimer's Disease

A hexanucleotide repeat expansion in the gene C9ORF72 has been implicated in the development of amyotrophic lateral sclerosis and frontotemporal dementia. The variant has also been found in a small percentage of patients with probable late-onset Alzheimers disease.

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.

Functional brain changes in presymptomatic Huntington's disease.

Evidence suggests early structural brain changes in individuals with the Huntingtons disease (HD) genetic mutation who are presymptomatic for the movement symptoms of the illness. The aim of this study was to investigate the presence of functional brain changes in this same population using functional magnetic resonance imaging. Subjects and matched controls underwent an functional magnetic resonance imaging “interference” protocol, a task known to be mediated in part by corticostriatal circuitry. In the setting of normal cognitive performance, presymptomatic HD subjects had significantly and specifically less activation in the left anterior cingulate cortex (BA 24, 32) compared with matched controls. Ann Neurol 2004;55:879–883

Regional white matter change in pre-symptomatic Huntington's disease : A diffusion tensor imaging study

The pathology of Huntingtons disease (HD) is characterized by diffuse brain atrophy, with the most substantial neuronal loss occurring in the caudate and putamen. Recent evidence suggests that there may be more widespread neuronal degeneration with significant involvement of extrastriate structures, including white matter. In this study of pre-symptomatic carriers of the HD genetic mutation, we have used diffusion tensor imaging to examine the integrity and organization of white matter in a group of individuals who previously demonstrated abnormalities in response to a functional magnetic resonance imaging paradigm. Our results indicate that, before the onset of manifest HD, there are regional decreases in fractional anisotropy, indicating early white matter disorganization.

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.