Effects of Vascular Risk Factors on the Association of Blood-Based Biomarkers with Alzheimer's Disease.

Background: Comorbidities may influence the levels of blood-based biomarkers for Alzheimer's disease (AD). We investigated whether differences in risk factors or comorbid conditions might explain the discordance between clinical diagnosis and biomarker classifications in a multi-ethnic cohort of elderly individuals. Aims: To evaluate the relationship of medical conditions and other characteristics, including body mass index (BMI), vascular risk factors, and head injury, with cognitive impairment and blood-based biomarkers of AD, phosphorylated tau (P-tau 181, P-tau 217), in a multi-ethnic cohort. Methods: Three-hundred individuals, aged 65 and older, were selected from a prospective community-based cohort for equal representation among three racial/ethnic groups: non-Hispanic White, Hispanic/Latino and African American/Black. Participants were classified into four groups based on absence (Asym) or presence (Sym) of cognitive impairment and low (NEG) or high (POS) P-tau 217 or P-tau 181 levels, determined previously in the same cohort: (Asym/NEG, Asym/POS, Sym/NEG, Sym/POS). We examined differences in individual characteristics across the four groups. We performed post-hoc analysis examining the differences across biomarker and cognitive status. Results: P-tau 217 or P-tau 181 positive individuals had lower BMI than P-tau negative participants, regardless of symptom status. Symptomatic and asymptomatic participants did not differ in terms of BMI. BMI was not a mediator of the effect of P-tau 217 or P-tau 181 on dementia. Frequencies of other risk factors did not differ between the four groups of individuals. Conclusions: Participants with higher levels of P-tau 217 or P-tau 181 consistent with AD had lower BMI regardless of whether the individual was symptomatic. These findings suggest that weight loss may change with AD biomarker levels before onset of cognitive decline. They do not support BMI as a confounding variable. Further longitudinal studies could explore the relationship of risk factors with clinical diagnoses and biomarkers.

Piperidine enhances sleep-related and insulin-induced growth hormone secretion: further evidence for a cholinergic secretory mechanism.

Piperidine, a nicotinic cholinergic receptor stimulator, was used in paired design studies of sleep-related and insulin-induced GH and PRL secretion. For the sleep studies, 100 mg piperidine or an equal volume of saline were infused for 30 min starting at sleep onset in eight normal volunteers. The same dose of piperidine was infused for 30 min (beginning 15 min before insulin injection) in an additional eight volunteers undergoing insulin tolerance tests. After piperidine administration, there was a significant (P less than 0.01) enhancement of sleep-related GH secretion, abut no change in PRL. GH concentrations during the first 2 h of sleep were 7.2 +/- 1.2 ng/ml after saline and 15.2 +/-2.9 ng/ml after piperidine (P less than 0.01). No alteration in any measured sleep parameter was noted with the drug. Piperidine did not affect the daytime insulin-induced secretion of either GH or PRL, as assessed by an analysis of variance. However, paired analysis of increments and areas under the response curves indicated a statistically significant effect for GH but not PRL. The maximum GH increment with piperidine was 48.0 +/- 4.3 ng/ml, compared to 36.8 +/- 3.6 ng/ml with saline (P less than 0.01). Piperidine given alone did not influence daytime concentrations of GH. These data are consistent with the view proposed by us, on the bass of methoscopolamine inhibition of nocturnal GH secretion, that cholinergic pathways play a facilitatory role in sleep-related and insulin-induced GH secretion. Thus, cholinergic mechanisms stimulate GH secretion. Nicotinic as well as muscarinic pathways appear to be involved, although the quantitative nicotinic contribution seems to be smaller than the associated with muscarinic sites.

Errors in potassium balance.

Six overweight adult subjects given a low calorie diet containing adequate amounts of nitrogen but subnormal amounts of potassium (K) were observed on the Clinical Research Center for periods of 29 to 40 days. Metabolic balance of potassium was measured together with frequent assays of total body K by 40K counting. Metabolic K balance underestimated body K loses by 11 to 87% (average 43%); the intersubject variability is such as to preclude the use of a single correction value for unmeasured losses in K balance studies.

Diagnosis of dementia in a heterogeneous population. Development of a neuropsychological paradigm-based diagnosis of dementia and quantified correction for the effects of education.

A brief diagnostic battery of neuropsychological tests was developed for a large-scale epidemiological study of dementia. We operationally defined dementia as defective memory and defective performance in at least two other areas, including orientation, abstract reasoning, construction, and language. Criterion scores for defining defective performance on each test were developed. In a pilot study that used 51 different subjects with a working diagnosis based on physicians' assessment (ie, 32 demented and 29 nondemented subjects), the test-based diagnosis agreed with the working diagnosis in all but two cases. The test battery was then applied to 430 healthy elderly subjects. Eighteen percent of those with 8 or less years of education met criteria for dementia compared with 5% of those with more than 8 years of education. We computed education-corrected scores for each test with the use of residuals from the regression of each test score on education. Based on corrected scores, 12 subjects were reclassified as nondemented and 11 as demented. Subjects who were reclassified as demented were significantly more impaired in activities of daily living than nondemented subjects who were not reclassified. Activities of daily living in subjects who were reclassified as nondemented did not differ from those in demented subjects who were not reclassified. These findings suggest that the neuropsychological battery may have utility in the diagnosis of dementia. However, neuropsychological performance may be influenced by education, and some form of adjustment, such as correction for activities of daily living, may be required in epidemiological studies.

No association between a presenilin 1 polymorphism and Alzheimer disease.

BACKGROUND: Homozygosity of allele 1 of a presenilin 1 intron 8 polymorphism (PS1-1) has been associated with doubling of the risk of sporadic late-onset Alzheimer disease (LOAD), in some, but not all studies. OBJECTIVE: To genotype the PS1 intron 8 polymorphism in predominantly Hispanic families with LOAD to test for association and for linkage between this polymorphism and LOAD. DESIGN: A family-based, case-control, genetic-linkage study. SETTING: Predominantly Hispanic families were selected from probands who were part of a random sample of 2128 Medicare beneficiaries aged 65 years or older who were residing in the community of Washington Heights, which is located in the northern part of Manhattan, NY. PARTICIPANTS: Fifty-one families with 103 affected family members, 67 unaffected family members, and 7 family members with other diagnoses were genotyped for the PS1 polymorphism. All patients met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for either probable or possible Alzheimer disease. Age was truncated at 55 years or older. MAIN OUTCOME MEASURES: Association analyses, conditional logistic regression, and traditional linkage methods were applied to the families for the PS1 polymorphism and for the presence of the gene for apolipoprotein E (APOE). Results of the association and conditional logistic regression analyses of PS1 intron 8 polymorphism were subsequently adjusted for the effect of APOE-epsilon4, sex, age, and education of each sibling. RESULTS: No association between the PS1 intron 8 polymorphism and LOAD was observed (relative risk, 0.99; 95% confidence interval, 0.3-3.4). An association between presence of the APOE-epsilon4 allele and LOAD (relative risk 4.05; 95% confidence interval, 1.3-12.5) was observed. CONCLUSION: We could not confirm the relationship between the PS1 intron 8 polymorphism and LOAD in this collection of families.

Differences in the prevalence of essential tremor among elderly African Americans, whites, and Hispanics in northern Manhattan, NY.

BACKGROUND: Until now there has been only one community-based study to examine interethnic differences in the prevalence of essential tremor (ET). The study suggested a higher prevalence among whites than African Americans. The present study is the first to examine differences in the prevalence of ET among Hispanics, African Americans, and whites. OBJECTIVE: To estimate the prevalence of essential tremor (ET) in a cohort of community-dwelling elderly of mixed ethnic background. METHODS: A random sample of 2117 Medicare recipients residing in Washington Heights-Inwood in northern Manhattan, NY, were interviewed. A standardized neurological assessment was performed on those who had neurological complaints and on a random sample of those who did not. Essential tremor was defined as a postural or kinetic tremor of the head or limbs. Diagnoses were independently confirmed by two neurologists based on videotaped examination. RESULTS: After age adjustment to the 1990 Washington Heights-Inwood census, the prevalence of ET was 40.2 per 1000 (95% confidence interval, 31.8 to 48.6). Among 46 cases with ET, ET was significantly more prevalent in men than in women (chi 2 = 5.0, P = .03). Prevalence increased significantly with age. The prevalence was higher in whites than African Americans. The prevalence in Hispanics was intermediate. CONCLUSION: The prevalence of ET increases with age and may be higher among men and whites. Prospective studies are needed to further examine these associations.

The relationship of hypertension in the elderly to AD, vascular dementia, and cognitive function.

BACKGROUND: Hypertension at the age of 45 to 50 years may predispose to AD later in life. It is not known whether hypertension after age 65 years also contributes to AD risk, and its effect on cognitive function is also not fully understood. METHODS: Data were analyzed from 1,259 Medicare recipients free of dementia in a longitudinal study covering a 7-year period (1991 to 1998). The effect of hypertension was first examined in relationship to the risk for incident AD and then to incident vascular dementia (VaD) using Cox proportional hazards models. Changes in performance over time on tasks of memory, language, and visuospatial/cognitive function were compared in those with and without hypertension using generalized estimating equations. RESULTS: Of the 1,259 subjects, 731 (58.1%) had a history of hypertension associated with diabetes, stroke, and heart disease. A history of hypertension was not associated with an increased risk for AD (rate ratio [RR] 0.9, 95% CI 0.7 to 1.3) but was associated with an increased risk for VaD (1.8 [1.0 to 3.2]). Hypertension was not associated with changes in memory, language, and general cognitive function in normal individuals over time. Compared with individuals with neither hypertension nor heart disease, those with hypertension or heart disease alone had no increase in risk for VaD. However, when both were present, there was a threefold increase in risk for VaD. A sixfold increase in risk was observed when both hypertension and diabetes were present. CONCLUSIONS: Hypertension after age 65 years is not associated with AD and does not adversely affect memory, language, or general cognitive function. A history of hypertension may be an antecedent to VaD, particularly in the presence of heart disease or diabetes.

Consistency of clinical diagnosis in a community-based longitudinal study of dementia and Alzheimer's disease.

We evaluated the consistency of the diagnosis of dementia in a multicultural, longitudinal community-based study of cognitive impairment and dementia. We diagnosed dementia using a fixed neuropsychological paradigm; the diagnosis also required historical evidence of functional impairment. In a sample of 656 subjects with at least one annual follow-up examination, dementia was confirmed at 1 year in 89% of the 304 subjects initially demented, and in 90% of the 136 subjects with the initial diagnosis of probable Alzheimer's disease (AD). The 34 initially demented subjects who failed to meet criteria for dementia at follow-up included 13 with an initial diagnosis of probable AD. All 34 still had evidence of cognitive impairment; this group was more likely to have a history of pulmonary disease, multiple medication use, or chronic alcohol use than other demented patients. Consistency of dementia diagnosis did not vary according to educational attainment or ethnic background. The use of a neuropsychological paradigm such as ours in large longitudinal studies of dementia may minimize interobserver diagnostic variability or diagnostic drift over time while contributing the benefits of a comprehensive cognitive evaluation to the diagnostic process.

Incidence of AD in African-Americans, Caribbean Hispanics, and Caucasians in northern Manhattan.

OBJECTIVE: To compare the incidence rates for AD among elderly African-American, Caribbean Hispanic, and white individuals and to determine whether coincident cerebrovascular disease contributes to the inconsistency in reported differences among ethnic groups. METHODS: This was a population-based, longitudinal study over a 7-year period in the Washington Heights and Inwood communities of New York City. Annual incidence rates for AD were calculated and compared by ethnic group, and cumulative incidence adjusted for differences in education, diabetes, cardiovascular risk factors, and stroke was calculated. RESULTS: The age-specific incidence rate for probable and possible AD was 1.3% (95% CI, 0.8 to 1.7) per person-year between the ages of 65 and 74 years, 4.0% (95% CI, 3.2 to 4.8) per person-year between ages 75 and 84 years, and 7.9% (95% CI, 5.5 to 10.5) per person-year for ages 85 and older. Compared to white individuals, the cumulative incidence of AD to age 90 years was increased twofold among African-American and Caribbean Hispanic individuals. Adjustment for differences in number of years of education, illiteracy, or a history of stroke, hypertension, heart disease, or diabetes did not change the disproportionate risks among the three ethnic groups. CONCLUSION: The incidence rate for AD was significantly higher among African-American and Caribbean Hispanic elderly individuals compared white individuals. The presence of clinically apparent cardiovascular or cerebrovascular disease did not contribute to the increased risk of disease. Because the proportion of African-American and Caribbean Hispanic individuals reaching ages 65 and older in the United States is increasing more rapidly than the proportion of white individuals, it is imperative that this disparity in health among the elderly be understood.

Adverse effects of liquid protein fast on the handling of magnesium, calcium and phosphorus.

We have studied the effect of a vitamin- and potassium-supplemented liquid protein fast on mineral metabolism of six obese subjects (five women, 1 man) for 40 days. Each patient was admitted to a metabolic ward and was given daily 300 Kcal, 75 mg of calcium, 406 mg of phosphorus, 7 mg of magnesium, 33 meq of potassium, and 11.5 g of nitrogen. Urinary calcium, phosphorus and magnesium levels were greatest during the first week, but decreased as the fast continued to 21, 31 and 300 percent, respectively, above intake. Cumulative urinary losses of calcium, phosphorus and magnesium were 58, 75 and 500 percent greater, respectively, than the cumulative intake. Fecal losses for calcium, phosphorus and magnesium were less than urinary losses throughout the study. Cumulative fecal losses of magnesium were more than 30 percent greater than dietary intake. Mean daily balances were -104 mg (calcium), -48 mg (magnesium) and -363 mg (phosphorus). Serum phosphorus and magnesium levels did not change. However, serum calcium levels decreased (-0.5 mg/dl, p less than 0.05). Serum bicarbonate levels decreased 20 percent during the first 8 days of the fast, at which time urinary ammonium was maximal, but later returned to control values despite sustained increases in serum and urinary acids throughout the fast. Ammonium excretion was 260 to 300 percent above control values. Urinary titratable acid excretion was greatest early in the fast but subsequently decreased as the excretion of phosphorus declined. Titratable acid accounted for less of the excreted acid (7 to 21 percent) than did ammonia (70 to 90 percent). It is concluded that a liquid protein fast results in negative mineral balance that is not reflected by serum values and is due primarily to renal losses. The losses of magnesium were proportionally greater than those of calcium and phosphorus. These studies indicate that a liquid protein fast results in depletion of the intracellular and/or skeletal stores of these minerals.

Cancer education among primary care physicians in an underserved community.

INTRODUCTION: Urban minority groups, such as those living in north Manhattan, are generally underserved with regard to cancer prevention and screening practices. Primary care physicians are in a critical position to counsel their patients on these subjects and to order screening tests for their patients. METHODS: Eighty-four primary care physicians in two intervention communities who received educational visits about cancer screening and prevention were compared with 38 physicians in a nearby community who received no intervention. With pre- and post-test interviews over an 18-month period, the physicians were asked about their attitudes toward, knowledge of (relative to American Cancer Society guidelines), and likelihood of counseling and screening for breast, cervical, colorectal, and prostate cancers. RESULTS: Comparison of the two surveys of physicians indicated no statistically significant differences in knowledge of cancer prevention or screening. At post-test, however, intervention group physicians identified significantly fewer barriers to practice than control physicians (p<0.05). While overall, the educational visits to inner-city primary care physicians did not appear to significantly alter cancer prevention practices, there was a positive dose-response relationship among the subgroup of participants who received three or more project contacts. CONCLUSIONS: We uncovered significant changes in attitude due to academic detailing among urban primary care physicians practicing in north Manhattan. A significant pre-test sensitization effect and small numbers may have masked overall changes in cancer prevention and screening behaviors among physicians due to the intervention.

Cancer screening and prevention practices of inner-city physicians.

INTRODUCTION: Effective preventive services are needed most in underserved, inner-city settings that suffer disproportionately from morbidity and mortality. Primary care physicians can play an important role in the provision of efficacious cancer prevention and screening services to patients in these communities. METHOD: We surveyed 122 primary care physicians about their cancer prevention and screening knowledge, attitudes, and practices. RESULTS: Relative to the findings from national and local surveys, sample physicians were not as knowledgeable about national guidelines for preventive care, were less likely to counsel on smoking cessation, and were less likely to advise diet modification. Although physician practices reflected national cancer prevention and screening guidelines in general, a significant proportion of physicians suggested lung and prostate cancer screening tests that were inconsistent with national recommendations. CONCLUSIONS: Systematic efforts are needed to increase the knowledge and practices of inner-city physicians concerning cancer prevention and screening.

The deletion polymorphism and Val1000Ile in alpha-2-macroglobulin and Alzheimer disease in Caribbean Hispanics.

The association between polymorphisms in the alpha-2-macroglobulin (a2m) gene and Alzheimer's disease remains in doubt because of conflicting results in independent case-control and family studies. We examined the association between Alzheimer's disease and alpha2m polymorphisms in Caribbean Hispanic families. The odds of having the alpha2m deletion/insertion polymorphism was increased 3-fold for family members with Alzheimer's disease compared to healthy family members, rising to 5-fold after adjusting for APOE-epsilon4. In contrast, there was no relationship between the alpha2m Val1000Ile polymorphism and Alzheimer's disease in these families. The inconsistencies in studies cited above and the modest association between alpha2m and Alzheimer's disease found in the Caribbean Hispanic families reported here, suggest that the overall effect of this gene on susceptibility is small and may be limited to certain populations or families.

Differences in functional status of Hispanic versus non-Hispanic White elders: data from the Medical Expenditure Panel Survey.

OBJECTIVES: Few national studies have focused specifically on the functional status of Hispanic elders. We examined the prevalence of functional limitations and disabilities among Hispanic and Black elders compared to non-Hispanic Whites. METHODS: We analyzed seven measures of functional limitations, disabilities, and dependencies. Logistic regression was used to examine racial and ethnic group differences adjusting for age, gender, and education. RESULTS: Compared to non-Hispanic Whites, Hispanics tended to report greater instrumental activities of daily living (IADL) dependencies and cognitive disabilities. Blacks were more likely to have activities of daily living (ADL) and IADL dependencies and require use of assistive devices compared to non-Hispanic Whites. Further adjustment for respondent status reduced differences between groups, but these models may overadjust for functional status differences. DISCUSSION: Given the projected growth of minority elders, policymakers and planners will need to consider race and ethnic differentials in functional status in determining future medical and social service needs.

Familial Alzheimer disease in Latinos: interaction between APOE, stroke, and estrogen replacement.

BACKGROUND: Factors that modify risk related to APOE variants have been examined primarily in unrelated patients and controls, but seldom in family-based studies. Stroke, vascular risk factors, estrogen replacement therapy (ERT), head injury (HI), and smoking have been reported to influence risk of sporadic but not familial Alzheimer disease (AD). OBJECTIVES: To examine the potential relationship between these risk factors and APOE, the authors used a family study design in a population in which the APOE-epsilon4 variant is strongly associated with risk of AD. METHODS: Latino families primarily from the Caribbean Islands in which two or more living relatives had dementia were identified in the New York City metropolitan area, the Dominican Republic, and Puerto Rico. A total of 1,498 participants from 350 families underwent a clinical interview, medical and neurologic examinations, neuropsychological testing, and APOE genotyping. Diagnosis was made by consensus using research criteria for AD. RESULTS: APOE-epsilon4 was associated with a nearly twofold increased risk of AD. A history of stroke was also associated with a fourfold increased risk. A statistical interaction between APOE-epsilon4 and stroke was observed. Women with an APOE-epsilon4 who took ERT did not have an increased risk of AD, but in women with a history of stroke ERT was a deleterious effect modifier. CONCLUSIONS: APOE-epsilon4 and stroke independently increase risk of familial Alzheimer disease (AD) among Latinos, and may interact to further increase AD risk. Among women, the risk of AD associated with APOE-epsilon4 may be attenuated by a history of ERT.

Hispanic patients in an academic group practice: measurement issues and comparisons with non-Hispanics.

Health services researchers face a challenge when analyzing populations that include patients of Hispanic cultural heritage. Definitions of Hispanic have changed over the past 25 years. Methods of ascertaining race and ethnicity are flawed, particularly within health care institutions. This study was designed to address these problems by applying a new and unique methodology for identifying Hispanics in a clinical practice. Physicians in a hospital-based academic group practice were asked to identify all Hispanics in their patient panels. A random sample of patients identified as Hispanics were then surveyed by telephone to establish country of origin, length of time in the United States, and bilinguality. This demonstrated a great diversity of country of origin among Hispanics. The 2630 Hispanic patients identified by these methods were compared with non-Hispanics in terms of demographics, case mix, and health care utilization. Health services researchers should consider identification by physicians as a useful method for identifying Hispanics in clinical practice settings.