Association between Alzheimer's disease and a functional polymorphism in the Myeloperoxidase gene.

A polymorphism in the Myeloperoxidase gene (MPO) has previously been demonstrated to be associated with gender-specific risk in an Alzheimer's Disease (AD) autopsy sample. We have investigated this polymorphism in our own samples of 226 Caucasian cases and 166 controls and 59 Hispanic cases and 75 controls. In Caucasians we find a significant association between MPO genotype and AD (P = 0.03), although we do not observe any effects of gender or any interaction with the APOE gene. Specifically, the MPO GG genotype contributes a 1.57-fold increased risk for AD. In Hispanics there was no effect of MPO genotype, or of MPO genotype in interaction with age or gender, on diagnosis of AD.

Cerebral ventricles are smaller in Hispanic than non-Hispanic patients with Alzheimer's disease.

MRI scans were compared between 71 Hispanic and 73 white non-Hispanic patients with National Institute of Neurological Disorders and Stroke probable AD. Analysis of covariance controlled for age, sex, education, and Mini-Mental State Examination scores indicated that ventricular size was smaller in Hispanic than white non-Hispanic patients (p = 0.0003). There was no difference in cortical atrophy and T2-weighted white matter hyperintense signals between groups.

The genetic association between Cathepsin D and Alzheimer's disease.

The aspartyl protease Cathepsin D has previously been suggested to play a role in the Alzheimer's disease (AD) process because of its ability to cleave the beta-amyloid precursor protein and the possibility that it may be one of the 'secretase' enzymes. A functional C-->T polymorphism in the Cathepsin D gene (CATD) has been reported to be associated with increased risk for AD in Caucasian case-control studies; specifically, the T-carrying genotypes confer increased risk. We have examined this association in our own Caucasian dataset of 210 AD cases and 120 controls, and in an additional Hispanic dataset comprising 79 AD cases and 112 controls. In Hispanics we find a modest interaction between CATD genotype and age of onset on risk for AD, such that the non-T-carrying genotype confers increased risk. In our Caucasian dataset we find no evidence for association between the CATD polymorphism and AD, although we do observe a small tendency towards an increase in the T-carrying genotypes in the case group, consistent with previous studies. We conducted an aggregate analysis of the published Caucasian datasets and found evidence that this CATD polymorphism (or another locus in linkage disequilibrium) does contribute significant, but small (<2%) risk for AD.

Apolipoprotein-E epsilon 4 allele frequency and conferred risk for Cuban Americans with Alzheimer's disease.

The authors compared Apo-E epsilon 4 frequencies for Cuban American and white non-Hispanic persons with and without Alzheimer's disease (AD). The Apo-E epsilon 4 allele conferred as large a risk for AD in Cuban Americans as for white non-Hispanics, a finding that differs from those for Hispanic subjects as a whole.

Relationship between denial of memory deficit and dementia severity in Alzheimer disease.

OBJECTIVE: To assess the relationship between denial of memory deficit and dementia severity in patients with Alzheimer disease (AD). Additionally, to introduce a new instrument, the Awareness of Memory Impairment Scale (AMIS), devised to minimize biases present in previous studies, especially those attributable to the use of difference scores and clinical ratings. BACKGROUND: Estimates of the magnitude of denial in patients with AD, and of its relationship with disease progression, have varied across studies. Part of this variability may have resulted from differences in the way investigators measured denial. In this study, the AMIS was used to obtain a relatively unbiased assessment of the relationship between denial and disease severity in patients with AD. METHOD: Two hundred three patients with AD were studied, 106 longitudinally, and 40 age-matched control subjects were evaluated. Multiple regression analysis, controlled for age, sex, education, and duration of illness, was used to compare AMIS scores with disease severity cross-sectionally and to determine whether AMIS scores change over time. A similar analysis was performed using difference scores and clinical ratings to determine whether introduction of a new assessment instrument was warranted. RESULTS: Cross-sectionally, a small but statistically significant correlation between AD denial and dementia severity was found. Upon direct longitudinal assessment, no change in denial was noted after a mean interval of 1 year and 3 months. As expected, use of difference scores and clinical ratings yielded inflated correlations relative to those obtained with the AMIS. CONCLUSIONS: Denial of memory deficit correlates minimally with dementia severity in cross-sectional analysis but is independent of disease progression when assessed longitudinally.

Platelet activation in Alzheimer disease.

BACKGROUND: In light of recent reports of diminished platelet serotonin concentration and increased plasma serotonin levels in patients with Alzheimer disease (AD), we hypothesized that a state of heightened platelet activation might be present in AD. OBJECTIVE: To compare baseline activation of unstimulated platelets in patients with AD with that in control subjects. PATIENTS AND METHODS: Flow cytometry was used to measure platelet activation in 91 patients with probable AD and 40 age-matched control subjects. Groups were compared for percentage of circulating platelet aggregates, expression of CD62p, formation of leukocyte-platelet complexes, and presence of circulating platelet microparticles, controlling for effects of demographic, clinical, physiological, and logistical factors. RESULTS: Multiple analysis of covariance on ranked data revealed a 39.5% increase in percentage of platelet aggregates (P=.0001), a 59.3% increase in expression of CD62p (P=.001), and a 53.3% increase in leukocyte-platelet complexes (P=.0001) in the group with AD but no differences in the number of platelet microparticles, overall platelet count, plasma fibrinogen level, or plasma platelet factor 3. Activation was weakly correlated with sex, but was independent of age, severity of disease, duration of disease, depression, agitation, and family history of dementia. CONCLUSIONS: Platelets of patients with AD exhibit greater unstimulated activation than those of controls. Potential causes of such activation include possible stimulation of platelets by damaged cerebral endothelial cells or platelet activation induced by membrane abnormalities previously reported to be present in platelets of patients with AD. In light of recent evidence that platelets are the principal source of both amyloid precursor protein and beta-amyloid peptide in human blood, it is possible that AD platelet activation may reflect or even contribute to the pathogenesis of the disease.

No association between the intronic presenilin-1 polymorphism and Alzheimer's disease in clinic and population-based samples.

Mutations in the Presenilin 1 (PS1) gene on chromosome 14 cause most early-onset familial Alzheimer's disease (AD). An intronic polymorphism in the PS1 gene was recently identified and reported to be associated with late-onset AD [Wragg et al., Lancet 347: 509-512, 1996]. The authors found an excess of homozygotes for the more common allele (allele 1) in AD cases, associated with an approximate doubling of risk. In the present study, we report the PS1 polymorphism distributions in clinic and population-based samples. We were not able to replicate the findings of Wragg et al. [1996]. Our results are consistent with those of other researchers and do not support the conclusion that the PS1 polymorphism is associated with late-onset AD.

Familial and population-based studies of apolipoprotein E and Alzheimer's disease.

The finding of an association between the epsilon 4 allele of the APOE locus and the early expression of late-onset Alzheimer's disease (AD) is robust. However, the estimates of the proportion of AD cases carrying one or more copies of the epsilon 4 allele vary dramatically between studies (highest estimates being 180% of lowest ones). Here we compare the results of association studies in samples drawn from an epidemiologically based study design and samples drawn from families selected for linkage studies. The significant differences between results probably point to the unwitting selection of familial factors other than the APOE locus in the family history positive samples. We conclude that any selection procedure tending to enrich samples for positive family history will also tend to artificially increase APOE epsilon 4 allele frequencies in probands. This is of significance in samples drawn from clinical settings where referral may be influenced by previous known family history. Further work is needed to clarify the nature of the additional factors operating within families. We also report data showing an association between late-onset AD and a polymorphism in an adjacent locus to APOE-the APOCI locus. As no additional risk for AD can be attributed to the APOCI locus, the most likely explanation for the association between AD and APOCI is the disequilibrium between the APOCI and APOE loci. Therefore, there are likely to be other genetic markers in the area that can be used in the same way as APOE as a marker of risk for the disease.

Alzheimer's disease: interaction of apolipoprotein E genotype, family history of dementia, gender, education, ethnicity, and age of onset.

We evaluated 197 patients with predominantly late-onset Alzheimer's disease (AD) who belonged to several ethnic groups and analyzed the relationship of age of onset of AD to the presence or absence of several risk factors in this entire group of patients. The apolipoprotein E (apoE) epsilon 4 allele frequency, which was 29% in all patients (compared with the reported population mean of 13.7%, p < 0.001, did not vary significantly between ethnic groups but declined significantly with increasing age. The apoE epsilon 2 allele frequency was 3%, compared with the reported population mean of 7.4% (p = 0.001). The frequency of a positive family history of dementia in first-degree relatives (FH +) (overall 45%) did not vary significantly between ethnic groups. ApoE epsilon 4-positive (epsilon 4+) patients tended to have a higher FH + rate (58%) than apoE epsilon 4-negative (epsilon 4-) patients (40%) (p = 0.02). When the potential risk factors of gender, education, FH+ status, and epsilon 4+ status were examined together in a multiple linear-regression analysis, FH+ and epsilon 4+ status (but not gender or education) were significant (they were both associated with an earlier age of onset of AD). In a post-hoc analysis, we found a reduced age of onset in women, but not men, who were both FH + and epsilon 4+. Additionally, those probands who were epsilon 4+ were more likely to inherit the disease from their mothers than their fathers. The mechanism by which epsilon 4+ and FH+ status operate as risk factors may be by their effect on the age of onset of AD.

South Florida Program on Aging and Health. Assessing the prevalence of Alzheimer's disease in three ethnic groups.

The South Florida Program on Aging and Health was initiated in 1992 with the aim to assess physical and mental health of the elderly in Dade County and provide a basis for public health policy. This report describes the methodology applied in the study and preliminary screening results in a probability sample of 2,400 African American, Cuban American and white non-Hispanic American elderly men and women. Of 2,013 participants screened by May 1995, 11.5% had cognitive impairment. An increase in prevalence from 4-7% to 25-36% with advancing age was found among men and women of each group, from the youngest (65-74) to the oldest (85+ years). Male and female prevalences were similar but vary by ethnic group and age.

Serotonin uptake and its kinetics in platelets of women with Alzheimer's disease.

The uptake of serotonin (14C-5-hydroxytryptamine, 5HT) in platelets and its kinetic characteristics were investigated in a group of women (n = 20) with probable Alzheimer's Disease (mean age = 76.0, years, SD = 8.27, range = 63-88) and in healthy normal women (n = 18, mean age = 72.6 years, SD = 7.24, range = 61-84). Both the apparent affinity of binding of 5HT to the platelet membrane (Km) and the maximum velocity (Vmax) of the rate of transport of 14C-5HT into platelets were significantly higher in the Alzheimer's Disease group than in the normal comparison group. Initial velocity of 14C-5HT uptake not passive diffusion (nonspecific uptake of 14C-5HT at 4 degrees C) differed significantly in the two groups. Our findings suggest abnormalities in the kinetic mechanisms involved in the uptake of 14C-5HT by platelets in women with Alzheimer's Disease.

Clinicopathologic study of probable Alzheimer disease: assessment of criteria for excluding cerebrovascular disease.

The National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer Disease and Related Disorders Association criteria for probable Alzheimer disease (AD) require exclusion of non-AD dementia-producing conditions but do not specify how the non-AD conditions are to be identified. We addressed this issue for the case of cerebrovascular disease (CVD) by defining exclusion rules based on commonly described clinical features: (a) history of strokelike episodes; (b) history of stepwise cognitive decline; (c) focal deficits on neurological examination; and (d) evidence of significant CVD on neuroimaging. We applied these rules retrospectively to clinical records for 92 cognitively impaired patients who otherwise met criteria for probable AD and whose brains were subsequently available for postmortem examination. We used Fisher's exact test to assess the effectiveness of the exclusion rules in predicting the presence of CVD on autopsy. Prediction was better than chance when all four clinical features were used together (p = 0.0008) and when the stepwise decline or neuroimaging criteria were used alone (p = 0.03 and p = 0.05, respectively). Overall, the CVD exclusion rules were deficient because of low accuracy (50.0%) and low sensitivity (52.6%). These results support provisional use of the CVD criteria chosen for this study but suggest that modifications are needed for acceptable diagnostic accuracy and sensitivity to be achieved.

Peripheral serotonin in Alzheimer's disease.

The platelet has been suggested to be a peripheral model of the central serotonergic neuron. This investigation was carried out in order to test the hypothesis that levels of serotonin (5-HT) in the platelet will be decreased in Alzheimer's disease (AD) since neurochemical studies suggest that levels of 5-HT are decreased in the brain of AD patients. We investigated platelet and plasma 5-HT in a group of AD patients (n = 22) as well as in age-matched normal control subjects (n = 20). The results show that the platelet level of 5-HT was significantly reduced in AD (65.7 +/- 28.41 ng/10(8) platelets in AD vs. 112.9 +/- 35.11 ng/10(8) platelets in controls; p = 0.0001). There was no effect on the levels of its metabolite 5-hydroxyindoleacetic acid. These findings suggest that the peripheral serotonergic system in AD is adversely affected.

Apraxia due to a pathologically documented thalamic infarction.

We report a pathologically documented case of infarction of the dominant thalamus with extensive involvement of the ventral lateral, ventral posterolateral, and lateral posterior nuclei and some involvement of the pulvinar. This patient exhibited linguistic impairment with features fairly typical for thalamic lesions. He also demonstrated a severe ideomotor apraxia. The preservation of repetition, syntax, and implicit memory despite severe naming deficits in patients with thalamic lesions suggests the possibility that thalamic involvement in cognitive function involves processes underlying declarative as opposed to nondeclarative (eg, implicit or procedural) memory. The occurrence of apraxia with thalamic lesions may be consistent with this hypothesis if it is accepted that only actual tool use approaches a pure skill that involves only nondeclarative memory, while other aspects of praxis implicate declarative memories.

Evaluation of the demented patient.

Approaching the patient with Alzheimer's disease often requires the participation of a team of collaborating physicians and psychologists as well as others both for diagnosis and for management. This article describes the approach to the disease by a neurologist, geriatrician, psychiatrist, and psychologist. Each describes a specific diagnostic approach, and the reader can appreciate the incremental value to assessment and care that emerges from the aggregate.

Denial of memory deficit in Alzheimer's disease.

OBJECTIVE: Patients with probable Alzheimer's disease often deny or underestimate the severity of their memory impairment. The authors examined the relationships between denial and severity of cognitive impairment and between denial and the presence of depressed mood and sad affect in 128 patients with probable Alzheimer's disease. METHOD: Denial of memory deficit was evaluated by structured interview. Cognition was evaluated with a quantitative examination that assessed performance on 16 subtests. Depression was rated by using a scale that included patients' self-ratings as well as caregivers' and examiners' assessments of the patient's mood and affect. Pearson correlation coefficients were used to quantify the relationship between denial and demographic, cognitive, and depression variables. Stepwise multiple regression analysis was used to further examine the relationship between denial and individual cognitive subset scores. RESULTS: Denial did not correlate with age at onset of Alzheimer's disease, duration of illness, or educational background. It did correlate with gender: women exhibited greater denial than men. A significant correlation was found between denial and overall severity of cognitive deficit and particularly with impairment in object naming. A negative correlation was found between denial and depression. CONCLUSIONS: The association between denial and cognitive impairment may suggest that denial of probable Alzheimer's disease results from disruption of cognitive abilities needed for awareness of illness. The negative association between denial and depression may suggest that depression in Alzheimer's disease is in part reactive in nature.

Age at disease onset and pattern of cognitive impairment in probable Alzheimer's disease.

Factor analysis of cognitive scores from 150 patients with Alzheimer's disease yielded two orthogonal factors: one (Factor 1) loading high on spontaneous speech, repetition, comprehension, reading, writing, digit span, and left/right discrimination; the other (Factor 2) loading high on long-term memory, orientation, object naming, and abstraction. Regression analysis, controlled for education and disease duration, showed Factor 1 scores to be lower in early-onset patients and Factor 2 scores to be lower in late-onset patients. These data corroborate results reported by previous investigators and suggest that Alzheimer's disease is age-dependent and heterogeneous in nature.

Improved verbal learning after outpatient oral physostigmine therapy in patients with dementia of the Alzheimer type.

BACKGROUND: Previous investigators have reported improvements in verbal learning in outpatients suffering from dementia of the Alzheimer type (DAT) when they were treated daily with oral physostigmine for periods of days to months. Questions remain, however, regarding both the specificity of the induced cognitive changes and the time course of the biological activity of the drug when physostigmine was used to treat DAT patients. We examined both of these parameters in an outpatient, double-blind, placebo-controlled study that examined the effect of physostigmine on memory and other cognitive functions. METHOD: Eight DAT patients were treated for 3 weeks with oral physostigmine administered four times daily in a double-blind, crossover, placebo-controlled study. An auditory verbal learning test (AVLT) was administered to assess verbal learning. Digit span, word fluency, and frequency of intrusions served as controls for nonspecific changes in attention and verbal responsiveness. RESULTS: AVLT scores improved after drug administration compared with scores for baseline and placebo performances (p = .04). Other measures were unchanged. Improvement was unrelated to the time interval between memory testing and last ingested dose. CONCLUSIONS: These results indicate a longer period of biological activity for physostigmine than previously considered and extend previous reports of improved verbal learning after oral physostigmine treatment to a more convenient dosing schedule. These results suggest further that the improvements induced by physostigmine result specifically from enhancement of long-term memory processes.

Positron emission tomographic studies during serial word-reading by normal and dyslexic adults.

Positron-emission tomography (PET) was used to study regional cerebral metabolic activity during oral reading in right-handed adult males with, and without a childhood and family history of developmental dyslexia. Significant group differences in normalized regional metabolic values were revealed in prefrontal cortex and in the lingual (inferior) region of the occipital lobe. Lingual values were bilaterally higher for dyslexic than normal readers. In contrast to the asymmetry observed in prefrontal and lingual regions in nondyslexic subjects during reading, the dyslexic pattern was more symmetric. These results demonstrate that individuals who suffered from familial developmental dyslexia as children, activate different brain regions during reading as adults, as compared to individuals without such childhood history.

Positional dyslexia.

Position-specific errors in word reading are usually associated with neglect or visual extinction on the same side as the reading problem. In this study, two patients with left-hemisphere lesions showed visual extinction on the right but reading difficulty on the left side of words and pseudowords. Further study of one patient revealed that he also had problems reading the beginning of words presented tachistoscopically or in vertical orientation. In addition, the positional difficulty was apparent when he named the letters in words. The pattern of results indicates that the positional dyslexia in these patients was not likely attributable to general deficits in visual perception or attention but may have reflected a disorder at a later stage of letter processing.