Susceptibility to neurofibrillary tangles: role of the PTPRD locus and limited pleiotropy with other neuropathologies.

Tauopathies, including Alzheimer's disease (AD) and other neurodegenerative conditions, are defined by a pathological hallmark: neurofibrillary tangles (NFTs). NFT accumulation is thought to be closely linked to cognitive decline in AD. Here, we perform a genome-wide association study for NFT pathologic burden and report the association of the PTPRD locus (rs560380, P=3.8 × 10-8) in 909 prospective autopsies. The association is replicated in an independent data set of 369 autopsies. The association of PTPRD with NFT is not dependent on the accumulation of amyloid pathology. In contrast, we found that the ZCWPW1 AD susceptibility variant influences NFT accumulation and that this effect is mediated by an accumulation of amyloid ß plaques. We also performed complementary analyses to identify common pathways that influence multiple neuropathologies that coexist with NFT and found suggestive evidence that certain loci may influence multiple different neuropathological traits, including tau, amyloid ß plaques, vascular injury and Lewy bodies. Overall, these analyses offer an evaluation of genetic susceptibility to NFT, a common end point for multiple different pathologic processes.

A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.

The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10(-8)). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

Genetic variation in the HLA region is associated with susceptibility to herpes zoster.

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.

Effect of estrogen replacement therapy on the specificity and sensitivity of screening mammography.

BACKGROUND: Previous studies have demonstrated that mammographic breast density increases following the initiation of estrogen replacement therapy (ERT). The effect, if any, that this increase in density has on the specificity (related to false-positive readings) and the sensitivity (related to false-negative readings) of screening mammography is unknown. PURPOSE: Using a retrospective cohort study design, we assessed the effects of ERT on the specificity and the sensitivity of screening mammography. METHODS: Participants (n = 8779) were postmenopausal women, aged 50 years or older, who were enrolled in a health maintenance organization located in western Washington state and who entered a breast cancer screening program between January 1988 and June 1993. Two-view mammography was performed as part of a comprehensive breast cancer screening visit. Menopausal status, as well as demographic and risk-factor information, was recorded via self-administered questionnaires. Hormonal replacement therapy type and use were determined from questionnaire data and from an automated review of pharmacy records. Individuals diagnosed with breast cancer within 12 months of their first screening-program mammograms were identified through use of a regional cancer registry. Risk ratios (RRs) plus 95% confidence intervals (CIs) of false-positive as well as false-negative examinations among current and former ERT users (with never users as the reference group) were calculated. Reported P values are two-sided. RESULTS: The specificity of mammographic screening was lower for current users of ERT than for never users or former users. Defining a positive mammographic reading as any non-normal reading (either suspicious for cancer or indeterminate), the adjusted RR (95% CI) of a false-positive reading for current users versus never users was 1.33 (1.15-1.54) (P < .001); for former users versus never users, the RR (95% CI) was 1.00 (0.87-1.15). The adjusted mammographic specificities (95% CIs) for never users, former users, and current users of ERT were 86% (84%-88%), 86% (84%-87%), and 82% (80%-84%), respectively. Defining a positive reading more rigorously (i.e., as suspicious for cancer only), the adjusted RRs (95% CIs) of false-positive readings for current users and former users (versus never users) were 1.71 (1.37-2.14) (P < .001) and 1.16 (0.93-1.45), respectively. Sensitivity was also lower in women currently receiving ERT. The unadjusted RR (95% CI) of a false-negative reading for current users versus never users was 5.23 (1.09-25.02) (P = .04); for former users versus never users, the RR (95% CI) was 1.06 (0.10-10.87). The unadjusted mammographic sensitivities (95% CI) for never users, former users, and current users of ERT were 94% (80%-99%), 94% (69%-99%), and 69% (38%-91%), respectively. CONCLUSIONS AND IMPLICATIONS: Current use of ERT is associated with lower specificity and lower sensitivity of screening mammography. Lower specificity could increase the cost of breast cancer screening, and lower sensitivity may decrease its effectiveness.

The association of statin therapy with the risk of recurrent venous thrombosis.

UNLABELLED: Essentials A lowered risk of recurrent venous thrombosis (VT) with statin treatment is controversial. Among observational inception cohort of 2,798 adults with incident VT, 457 had recurrent VT. Time-to-event models with time-varying statin use and adjustment for potential confounders was used for analysis. Compared to nonuse, current statin use was associated with 26% lower risk of recurrent VT. Click to hear Prof. Büller's perspective on Anticoagulant Therapy in the Treatment of Venous Thromboembolism SUMMARY: Background Meta-analyses of randomized controlled trials suggest that treatment with hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) lowers the risk of incident venous thrombosis (VT), particularly among those without prevalent clinical cardiovascular disease (CVD). Whether this is true for the prevention of recurrent VT is debated. We used an observational inception cohort to estimate the association of current statin use with the risk of recurrent VT. Methods and Results The study setting was a large healthcare organization with detailed medical record and pharmacy information at cohort entry and throughout follow-up. We followed 2798 subjects 18-89 years of age who experienced a validated incident VT between January 1, 2002, and December 31, 2010, for a first recurrent VT, validated by medical record review. During follow-up, 457 (16%) developed a first recurrent VT. In time-to-event models incorporating time-varying statin use and adjusting for potential confounders, current statin use was associated with a 26% lower risk of recurrent VT: hazard ratio 0.74, 95% confidence interval 0.59-0.94. Among cohort members free of CVD (n = 2134), current statin use was also associated with a lower risk (38%) of recurrent VT: hazard ratio 0.62, 95% confidence interval 0.45-0.85. We found similar results when restricting to new users of statins and in subgroups of different statin types and doses. Conclusions In a population-based cohort of subjects who had experienced an incident VT, statin use, compared with nonuse, was associated with a clinically relevant lower risk of recurrent VT. These findings suggest a potential secondary benefit of statins among patients who have experienced an incident VT.

Genetic variation among 82 pharmacogenes: The PGRNseq data from the eMERGE network.

Genetic variation can affect drug response in multiple ways, although it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, collaborating with the Pharmacogenomics Research Network, began eMERGE-PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of "precision medicine." The February 2015 eMERGE-PGx data release includes sequence-derived data from ∼5,000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function. We found 95.12% of genes have variants with a scaled Combined Annotation-Dependent Depletion score above 20, and 96.19% of all samples had one or more Clinical Pharmacogenetics Implementation Consortium Level A actionable variants. These data highlight the distribution and scope of genetic variation in relevant pharmacogenes, identifying challenges associated with implementing clinical sequencing for drug treatment at a broader level, underscoring the importance for multifaceted research in the execution of precision medicine.

Health benefits of exercise in an aging society.

The effects of regular aerobic exercise are important to an aging society increasingly preoccupied with exercise. Traditionally, most attention has been directed to the relationship between a physically active life-style and cardiovascular mortality. In an aging society, however, active life expectancy and maintenance of independence may be as important as effects of regular exercise on longevity. Regular exercise results in increased maximum aerobic capacity due to peripheral changes in muscle (increased capacity for aerobic metabolism and improved substrate and oxygen extraction with a widened arteriovenous oxygen difference) and also due to cardiovascular changes with increased stroke volume and cardiac output in normal persons. "Therapeutic benefits" of conditioning probably occur at submaximal work loads common to everyday activity, when cardiac work and myocardial oxygen consumption are less for any given work load, muscles are more efficient, and relative oxygen requirements are less. Aging is associated with a linear decline in maximum aerobic capacity. The rate of decline is twofold greater when comparing sedentary with physically active middle-aged men. Thus, regular exercise could conceivably lower functional aerobic age by slowing this functional decline. Exercise, particularly excessive exercise, is also associated with serious hazards, including sudden death, nonfatal myocardial infarction, excessive fatigue, hyperthermia, and significant musculoskeletal problems. Accounts of the health effects of exercise should consider a wide range of risks and benefits, especially those related to improving function, minimizing disability, and prolonging independent living.

How much is too much? Advising patients about safe levels of alcohol consumption.

United States physicians are increasingly encouraged to advise patients about health-related behaviors, such as smoking, but there is minimal discussion in the US medical literature about the need to advise patients about safe levels of alcohol consumption. Several factors likely contribute to this lack of focus on safe drinking practices. These include the complex relationship between drinking and health, limitations in the available epidemiologic data, misinterpretation of the disease model of alcoholism, and physician attitudes. Nevertheless, epidemiologic evidence clearly relates increasing levels of alcohol consumption to increased morbidity and mortality, and research has shown that physician advice can reduce both alcohol consumption and alcohol-related problems. We propose that physicians thoroughly assess patients' alcohol consumption and advise patients who drink about safe levels of consumption.

The effectiveness of cerebral imaging in the diagnosis of chronic headache.

OBJECTIVE: The increasing availability of high-resolution cerebral imaging scanners has fueled enthusiasm for their use to "rule out" brain tumor and other serious neurologic conditions in patients with headache. The effectiveness of this practice, however, has not been tested since the advent of newer scanning equipment. Our objective was to measure the usefulness of cerebral imaging in patients with chronic isolated headache. DESIGN: A retrospective study with a 15- to 27-month follow-up period. SETTING: A group-model health maintenance organization. PATIENTS: Adult patients, 100,800, in a health maintenance organization and an enriched sample of 63 patients with neurosurgical conditions from other health maintenance organization hospitals. RESULTS: During 1990, 1083 cerebral computed tomographic scans were performed on 863 adults (0.9% of health maintenance organization adults). Eighty-nine patients were scanned for chronic isolated headache; none of the scans provided important new information (95% confidence interval, 0%, 3%). Long-term patient follow-up confirmed that this low yield could not be attributed to diagnostic work-up bias. Further attempts to support a policy of imaging patients with isolated headache were also unsuccessful. Review of an enriched sample of patients with malignant brain tumor and patients requiring craniotomy for other reasons (n = 40) demonstrated that no patient had headache alone at the time of diagnosis (95% confidence interval, 0%, 8%) and that only 5% (95% confidence interval, 0%, 12%) of these patients sought medical attention for headache alone. Sampling a second enriched sample of patients who were referred from other hospitals (n = 63) because of conditions requiring neurosurgical procedures demonstrated that only 6% of patients presented with chronic isolated headache alone (95% confidence interval, 0%, 12%). Uncertainty regarding the appropriateness of imaging patients with headache was illustrated by the extreme interphysician variability of this practice. CONCLUSION: Our study demonstrates the large potential cost and low (although not zero) yield associated with nonselectively imaging patients with chronic isolated headache.

Diagnostic tests in the evaluation of dementia. A prospective study of 200 elderly outpatients.

We studied the components of the diagnostic evaluation in 200 patients older than 60 years of age with suspected dementia who received standardized diagnostic evaluation and follow-up. The most common dementia diagnoses were Alzheimer's-type dementia (74.5%) and dementia due to toxic effects of drugs (9.5%). Eleven patients with hypothyroidism, metabolic encephalopathies due to hyponatremia, hyperparathyroidism, and hypoglycemia required laboratory tests for diagnosis, whereas the other dementia diagnoses were made primarily on the basis of data available on the history and physical and neurologic examinations. The complete blood cell count, blood chemistry battery (especially sodium, calcium, and glucose concentrations), and thyroid function tests were of definite value for the diagnosis of unsuspected disease and were useful as routine tests in evaluating patients for dementia. A careful history and physical examination accompanied by complete blood cell count, chemistry battery, and a thyroid function test would have been effective in diagnosing treatable illnesses causing cognitive impairment. Other diagnostic tests could have been used selectively based on results of the examination and screening tests. Estimated diagnostic charges from a selective approach would be 25% to 34% of those for the "routine" evaluation.

A critical appraisal of ticlopidine, a new antiplatelet agent. Effectiveness and clinical indications for prophylaxis of atherosclerotic events.

BACKGROUND: Recommendations are broadening for the prophylaxis of atherosclerotic disorders, but aspirin is the only widely used agent. Ticlopidine hydrochloride, a new antiplatelet medication, has recently been approved for prescription in North America. We reviewed the major clinical trials of ticlopidine and derived guidelines for its use. METHODS: Studies of ticlopidine were sought through MEDLINE for 1980 to 1990 and through bibliographies of retrieved articles. All published, randomized trials of ticlopidine were appraised if they reported major morbidity and mortality as primary end points. All eligible studies were formally reviewed by an expert panel according to published principles for critical appraisal of the medical literature. Both benefits and risks were quantified. RESULTS: Four randomized trials reported major clinical end points. In these, ticlopidine was more effective than placebo for preventing recurrences after completed stroke; was more effective than aspirin for patients with transient ischemic attacks and partial strokes; and reduced vascular death and nonfatal myocardial infarction in an open trial among patients with unstable angina. For patients with intermittent claudication ticlopidine, was not significantly better than placebo for preventing myocardial infarction or stroke. Side effects were more common with ticlopidine than with aspirin or placebo. CONCLUSIONS: Ticlopidine should be prescribed in place of aspirin for stroke prophylaxis or unstable angina if the patient is unable to tolerate aspirin. Ticlopidine may also benefit patients who experience new ischemic events while taking aspirin or, probably, patients with peripheral vascular disease. A complete blood cell count should be performed every 2 weeks during the first 3 months of therapy to check for leukopenia.

The knowledge base of certified internists. Relationships to training, practice type, and other physician characteristics.

A written examination was used to assess the knowledge base of 183 practicing certified internists. Analyses of the examination scores showed that performance on the initial American Board of Internal Medicine certification examination taken 7.6 years previously was the major factor predicting current knowledge base. By developing regression models, the unique contribution of different variables to prediction of current examination scores was determined. Prior American Board of Internal Medicine certification examination performance accounted for 70.9% of the explained variance, and demographic and practice variables were responsible for 17.8%. Among the demographic and practice variables studied, community size and subspecialty practice were the only variables that contributed significantly to the regression equations. Examination scores were highest for certified internists practicing in smaller communities. General internists received higher scores than subspecialists. Although statistically significant, the apparent adverse influence of subspecialty practice and larger community size on examination performance was modest. Further study is needed to determine if longer periods in practice might produce different relationships between variables such as these and examination performance.

Postmenopausal estrogen and estrogen-progestin use and 2-year rate of cognitive change in a cohort of older Japanese American women: The Kame Project.

BACKGROUND: The relation between estrogen and cognition among postmenopausal women remains controversial. Also uncertain is whether the proposed association varies between women taking unopposed estrogen and those taking estrogen combined with progestin. OBJECTIVE: To determine whether unopposed estrogen and combined estrogen-progestin use were associated with the rate of cognitive change in a cohort of older, Japanese American, postmenopausal women. METHODS: A prospective observational study in a population-based cohort of older Japanese Americans (aged > or =65 years) living in King County, Washington. Cognitive performance was measured in 837 women at baseline (1992-1994) and 2-year follow-up (1994-1997) examinations using the 100-point Cognitive Abilities Screening Instrument (CASI). Least squares means general linear models were used to estimate the 2-year rate of cognitive change according to categories of postmenopausal estrogen use. RESULTS: Approximately half of this cohort (n=455) had never used estrogen at any time since menopause, 186 were past users, 132 were current unopposed estrogen users, and 64 were current estrogen-progestin users. The majority of current estrogen users were taking conjugated estrogens, and all women receiving combined therapy were taking medroxyprogesterone acetate. After adjusting for age, education, language spoken at the interview, surgical menopause, and baseline CASI score, women who had never used postmenopausal estrogen improved slightly on the CASI scale (mean adjusted change, 0.79; SEM, 0.19). This change was significantly greater for current unopposed estrogen users (mean adjusted change, 1.68; SEM, 0.36; P=.04) and significantly worse for current estrogen-progestin users (mean adjusted change, -0.41; SEM, 0.50; P =.02) compared with never users. The improvement observed in past users (mean adjusted change, 1.12; SEM, 0.29) was intermediate between the changes for never users and current unopposed estrogen users and not significantly greater than that for never users (P=.35). CONCLUSIONS: Our findings support a modest beneficial association between current unopposed estrogen use and the rate of cognitive change. We also observed a modest detrimental association between current estrogen-progestin use and the rate of cognitive change. The clinical significance of these modest differences, however, is uncertain. Data from large, long-term randomized trials are required before applying this information to the clinical setting.

Intracellular calcium response is reduced in CD4+ lymphocytes in Alzheimer's disease and in older persons with Down's syndrome.

Abnormalities in intracellular free calcium ([Ca2+]i) regulation are likely to play a role in brain aging and have been described in cells from patients with Alzheimer's disease (AD). [Ca2+]i acts as a second messenger in transmembrane signaling and regulates diverse functions in many cell types. Therefore, abnormalities in [Ca2+]i response may have far-ranging effects. Using flow cytometric assay for [Ca2+]i, we examined whether mitogen-induced increases in [Ca2+]i are abnormal in CD4+ T-lymphocytes from patients with familial AD (FAD), other AD, and Down's syndrome (DS) compared to age-matched controls. We observed that the peak [Ca2+]i responses were significantly decreased in CD4+ cells from 6 FAD patients (59% of control), 34 other AD patients (69% of age-matched control), and 6 older persons with DS (> 25 years old, 47% of control), after stimulation with 10 micrograms/ml anti-CD3 monoclonal antibody (mAb). The number of CD3 receptors on T lymphocytes of the AD patients was not decreased. In contrast, lymphocytes from subjects with FAD, other AD and older DS patients had no decrease in response to phytohemagglutinin (30 micrograms/ml). CD3 and related classes of membrane receptors are present on many cells of the central nervous system. Therefore, receptor signaling defects via this receptor in T lymphocytes of AD patients may be relevant to the central nervous system pathology seen in AD and DS.

Relationship between serum alpha 1-antichymotrypsin and Alzheimer's disease.

We obtained serum samples and measured alpha 1-antichymotrypsin (ACT) levels in 36 pairs of consecutive probable Alzheimer's disease (AD) patients and age- and sex-matched, cognitively intact control subjects. Serum ACT was measured by radial immunodiffusion. Unique to this study, we found that ACT levels rose significantly with age within controls (but not within AD cases), thus ACT may be related to the aging process. Consistent with other reports, we found that AD cases had greater serum ACT in 27 of 36 pairs [mean difference = 135.5 (SE = 50.8) mg/l (p < 0.05)]. Severity and duration of AD were not significantly associated with the observed difference. The ACT increase observed in AD is not sufficient to recommend ACT's use as a diagnostic marker for AD. Because adult Down's syndrome (DS) persons are known to have pathologic features of AD, we also measured serum ACT levels in 11 adult, noninstitutionalized, DS persons paired with 11 age- and sex-matched, volunteer control subjects; we found no statistically significant difference. The unexpected age-associated increase in ACT among normal controls could be an indicator of early amyloid plaque formation. Future studies comparing ACT levels in both serum and cerebrospinal fluid should help to clarify the origin of ACT found in amyloid plaques and its value as a diagnostic marker for AD.

Adult Still's disease. Evolution of a clinical syndrome and diagnosis, treatment, and follow-up of 17 patients.

Adult Still's Disease (SD) has evolved into a well-characterized nosologic entity. This categorization allows physicians to place a unifying label on the rare, puzzling patient who presents with a systemic illness characterized by high spiking fever of unknown cause associated with intense arthralgias or arthritis, an evanescent erythematous macular or maculopapular rash, and other less constant features of systemic illness including lymphadenopathy, hepatosplenomegaly, sore throat, leukocytosis, anemia and elevated concentration of hepatic enzymes. The diagnosis of Adult SD is syndromic, based solely on compatible clinical findings; serologic or other diagnostic tests do not aid in diagnosis. The diagnostic problem presented by these patients with such severe systemic illness and the insecurities inherent in diagnosis based solely on clinical features make the availability of the diagnosis, Adult SD, useful in patient care. The cause of Adult SD is unknown. Some have speculated that the disease has features of non-necrotizing immune complex vasculitis. Rubella infection has been reported to be associated with Adult SD, but no clear-cut etiologic relationship has been established. Neither rubella infection nor any other potential antigen has been identified consistently in association with the disease. Management of patients with the disease depends on the correct diagnosis. Diagnosis should include recognition of the syndrome as well as exclude other possible diseases. Control of systemic manifestations may require unusually high doses of aspirin, indomethacin or other non-steroidal anti-inflammatory drugs, prednisone or combinations of these drugs. Some adults appear to require both high-dose prednisone and indomethacin to control disease manifestations. Fortunately, systemic attacks are usually episodic; steroid toxicity can be minimized by use of alternate day doses and attempts to discontinue steroids between episodes. The current series and other reports of long-term follow-up indicate that Adult SD may be more disabling than was originally reported. At least three patterns of recurrences occur: 1) systemic attacks with or without arthritis, 2) pauciarticular disease, and 3) disabling deforming chronic arthritis, which may require surgery and long-term anti-inflammatory, gold, or cytotoxic therapy.

Hickman catheter infections in patients with malignancies.

The infectious complications associated with implantation of 1,088 Hickman catheters (HCs) in 992 patients reported in 18 published series are presented (including data on 129 previously unreported HCs from our own institution). HCs allow reliable long-term venous access (mean, 92.4 days) with low complication and infection rates (0.30 and 0.14 cases per 100 catheter days, respectively). Exit site infections were the most common form of infection encountered (45.5%), followed by septicemia alone (30.8%), tunnel infections (20.3%), and septic thrombophlebitis (3.5%). Staphylococcus epidermidis (54.1%) and S. aureus (20.0%) were the most common pathogens responsible for catheter infections. HC infections were associated with a low mortality rate (maximum rate of 0.5%). Risk factor analysis of 129 HCs demonstrated that catheter thrombosis was the major risk factor associated with development of catheter infection. Presence of fever, distant infection, neutropenia or antibiotic administration on the day of catheter insertion was not significantly associated with HC infection in this series (although there was a trend suggesting an increased risk of infection of HCs inserted during febrile episodes). Based on observations at our institution and from a review of the literature, tentative recommendations for management of the various types of HC infections are outlined.

A door-to-door survey of Parkinson's disease in a Chinese population in Kinmen.

BACKGROUND: Most published studies have shown lower prevalence rates of Parkinson's disease (PD) in Asian and black African than in Western countries, leading to the hypothesis that Asians and blacks might be protected from PD. OBJECTIVE: To investigate the prevalence of PD in a Chinese population. DESIGN: Community-based survey. SETTING: Registered residents 50 years of age or older (N = 5061) on the islet of Kinmen located off the southeastern coast of China [corrected]. METHOD: Single-phase door-to-door survey by neurologists. All participants were administered a questionnaire and received motor examinations of the Unified Parkinson's Disease Rating Scale. RESULTS: The participation rate was 96% (N = 3915) among 4158 contacted individuals. Twenty-three cases of PD were identified, including three cases with dementia. The crude prevalence rate of PD was 587 (95% confidence interval (CI), 373 to 884) per 100,000 persons 50 years of age or older. Assuming no case of PD among individuals under 50 years of age, the prevalence rate was 119 (95% CI, 80 to 169) per 100,000 for the total population. CONCLUSIONS: The prevalence rates of PD in Kinmen were much higher than those reported from mainland China, but slightly lower than those reported from more developed countries. The present findings suggest that, instead of genetic factors, differences in case-ascertainment, life expectancy, and the length of survival with PD may be more important contributors to the variations in observed PD prevalence rates.

The utility of apolipoprotein E genotyping in the diagnosis of Alzheimer disease in a community-based case series.

CONTEXT: A recent collaborative study found that apolipoprotein E (APOE) genotype, in conjunction with the clinical diagnosis of Alzheimer disease (AD), was useful in improving diagnostic specificity (correctly not diagnosing AD) relative to the clinical diagnosis alone. Since these samples are particularly enriched with patients with AD and the APOE epsilon4 allele, results may not be generalizable to patients seen in the general medical community. OBJECTIVE: To evaluate the diagnostic utility of the APOE genotype in diagnosing AD in a community-based case series from the largest health maintenance organization in an urban area. DESIGN: We examined the effect of including APOE genotype on the diagnosis of AD in a community-based case series of patients presenting with memory complaints. PATIENTS: Clinical and neuropathologic diagnoses and APOE genotype were obtained from 132 patients who underwent evaluation for dementia and subsequent autopsy. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values given various combinations of clinical diagnoses and the presence of an APOE epsilon4 allele. RESULTS: Of the 132 patients, 94 had neuropathologically confirmed AD, yielding a prevalence of 71%. The clinical diagnosis alone yielded a sensitivity of 84%, an estimated specificity of 50%, and positive and negative predictive values of 81% and 56%, respectively. The presence of an epsilon4 allele alone was associated with an estimated sensitivity of 59%, specificity of 71%, and positive and negative predictive values of 83% and 41%, respectively. Using the presence of clinical AD and an epsilon4 allele decreased the sensitivity to 49% and increased the specificity to 84%. The positive and negative predictive values were 88% and 40%, respectively. Alternatively, the clinical diagnosis of AD or the presence of an epsilon4 allele in individuals not meeting clinical criteria for AD increases the estimated sensitivity to 94% but decreases the specificity to 37%. The positive and negative predictive values were 79% and 70%, respectively. The changes in the sensitivity and specificity for the combined tests relative to clinical diagnosis alone offset each other. For lower prevalence communities, the positive predictive value will be much lower than those observed herein. CONCLUSIONS: Our findings do not support the use of APOE genotyping alone in the diagnosis of AD in the general medical community. Although the presence of an epsilon4 allele in older persons with clinical AD increased the probability of having AD and the absence of an epsilon4 allele in this group decreased the probability of having AD, the association is not strong enough in the differential diagnosis of non-Alzheimer dementia and AD.

Increased platelet membrane fluidity as a diagnostic marker for Alzheimer's disease: a test in population-based cases and controls.

To test whether increased platelet membrane fluidity as measured by decreased steady state fluorescence anisotropy (rs) of diphenylhexatriene is a biologic/diagnostic marker for Alzheimer's disease (AD), we enrolled 95 clinically diagnosed, probable AD cases from our Alzheimer's Disease Patient Registry and 133 control subjects of similar age and sex randomly selected from the same population base as the cases. We measured rs in platelet membranes following published assay procedures. Laboratory personnel and investigators were blind to the identity of the samples; cases and controls were assayed in random order. Our analyses showed that the distributions of rs values were unimodal and similar for cases and controls. The overall mean differences (control mean-case mean) for the two established assay methods tested were 0.0011 and 0.0003. A nonparametric Wilcoxon rank sum test also showed no difference between cases and controls. Multivariate analysis adjusted for the significant effects of the processing date and analysis platelet recovery led to a final model with the adjusted mean difference of 0.0007 for the principal method. Increased platelet membrane fluidity is not an antemortem diagnostic or biologic marker for AD in our population.