Improving CSF biomarker accuracy in predicting prevalent and incident Alzheimer disease.

OBJECTIVE: To investigate factors, including cognitive and brain reserve, which may independently predict prevalent and incident dementia of the Alzheimer type (DAT) and to determine whether inclusion of identified factors increases the predictive accuracy of the CSF biomarkers Aß(42), tau, ptau(181), tau/Aß(42), and ptau(181)/Aß(42). METHODS: Logistic regression identified variables that predicted prevalent DAT when considered together with each CSF biomarker in a cross-sectional sample of 201 participants with normal cognition and 46 with DAT. The area under the receiver operating characteristic curve (AUC) from the resulting model was compared with the AUC generated using the biomarker alone. In a second sample with normal cognition at baseline and longitudinal data available (n = 213), Cox proportional hazards models identified variables that predicted incident DAT together with each biomarker, and the models' concordance probability estimate (CPE), which was compared to the CPE generated using the biomarker alone. RESULTS: APOE genotype including an ε4 allele, male gender, and smaller normalized whole brain volumes (nWBV) were cross-sectionally associated with DAT when considered together with every biomarker. In the longitudinal sample (mean follow-up = 3.2 years), 14 participants (6.6%) developed DAT. Older age predicted a faster time to DAT in every model, and greater education predicted a slower time in 4 of 5 models. Inclusion of ancillary variables resulted in better cross-sectional prediction of DAT for all biomarkers (p < 0.0021), and better longitudinal prediction for 4 of 5 biomarkers (p < 0.0022). CONCLUSIONS: The predictive accuracy of CSF biomarkers is improved by including age, education, and nWBV in analyses.

Alzheimer disease identification using amyloid imaging and reserve variables: proof of concept.

OBJECTIVE: Several factors may influence the relationship between Alzheimer disease (AD) lesions and the expression of dementia, including those related to brain and cognitive reserve. Other factors may confound the association between AD pathology and dementia. We tested whether factors thought to influence the association of AD pathology and dementia help to accurately identify dementia of the Alzheimer type (DAT) when considered together with amyloid imaging. METHODS: Participants with normal cognition (n = 180) and with DAT (n = 25), aged 50 years or older, took part in clinical, neurologic, and psychometric assessments. PET with the Pittsburgh compound B (PiB) tracer was used to measure brain amyloid, yielding a mean cortical binding potential (MCBP) reflecting PiB uptake. Logistic regression was used to generate receiver operating characteristic curves, and the areas under those curves (AUC), to compare the predictive accuracy of using MCBP alone vs MCBP together with other variables selected using a stepwise selection procedure to identify participants with DAT vs normal cognition. RESULTS: The AUC resulting from MCBP alone was 0.84 (95% confidence interval [CI] = 0.73-0.94; cross-validated AUC = 0.80, 95% CI = 0.68-0.92). The AUC for the predictive equation generated by a stepwise model including education, normalized whole brain volume, physical health rating, gender, and use of medications that may interfere with cognition was 0.94 (95% CI = 0.90-0.98; cross-validated AUC = 0.91, 95% CI = 0.85-0.96), an improvement (p = 0.025) over that yielded using MCBP alone. CONCLUSION: Results suggest that factors reported to influence associations between AD pathology and dementia can improve the predictive accuracy of amyloid imaging for the identification of symptomatic AD.

Cancer linked to Alzheimer disease but not vascular dementia.

OBJECTIVE: To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD). METHODS: Cox proportional hazards models were used to test associations between prevalent dementia and risk of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study-Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer. RESULTS: The presence of any AD (pure AD + mixed AD/VaD; hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.20-0.84) and pure AD (HR = 0.31, 95% CI = 0.12-0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95% CI = 0.52-0.997) and pure AD (HR = 0.57; 95% CI = 0.36-0.90) among white subjects after adjustment for demographics, number of APOE epsilon4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD. CONCLUSIONS: In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration.

A common biological mechanism in cancer and Alzheimer's disease?

Cancer and Alzheimer's disease (AD) are two common disorders for which the final pathophysiological mechanism is not yet clearly defined. In a prospective longitudinal study we have previously shown an inverse association between AD and cancer, such that the rate of developing cancer in general with time was significantly slower in participants with AD, while participants with a history of cancer had a slower rate of developing AD. In cancer, cell regulation mechanisms are disrupted with augmentation of cell survival and/or proliferation, whereas conversely, AD is associated with increased neuronal death, either caused by, or concomitant with, beta amyloid (Abeta) and tau deposition. The possibility that perturbations of mechanisms involved in cell survival/death regulation could be involved in both disorders is discussed. Genetic polymorphisms, DNA methylation or other mechanisms that induce changes in activity of molecules with key roles in determining the decision to "repair and live"- or "die" could be involved in the pathogenesis of the two disorders. As examples, the role of p53, Pin1 and the Wnt signaling pathway are discussed as potential candidates that, speculatively, may explain inverse associations between AD and cancer.

The AD8: a brief informant interview to detect dementia.

BACKGROUND: Brief measures that accurately discriminate normal cognitive aging from very mild dementia are lacking. Cognitive tests often are insensitive to very mild dementia. Informant-based measures may be more sensitive in detecting early dementia. OBJECTIVE: To identify informant-reported clinical variables that differentiate cognitively normal individuals from those with very mild dementia. METHODS: A 55-item battery of informant queries regarding an individual's cognitive status was derived from a semistructured interview and a consensus panel of dementia experts. The battery was evaluated with informants for 189 consecutive participants of a longitudinal study of memory and aging and compared with an independently obtained Clinical Dementia Rating (CDR) score for the participant. Multiple regression and receiver operator characteristic curves assessed subsets of the items to discriminate between CDR 0 (no dementia) and CDR 0.5 (very mild dementia). RESULTS: The final version (AD8) querying memory, orientation, judgment, and function was administered to an additional sample of 112 CDR 0 and 68 CDR 0.5 participants. Using a cut-off of two items endorsed, the area under the curve was 0.834, suggesting good to excellent discrimination, sensitivity was 74%, and specificity was 86% (prevalence of 0.38 for very mild dementia). Inclusion of 56 additional individuals with mild to severe dementia (increasing dementia prevalence to 0.53) increased sensitivity to 85%. CONCLUSIONS: The AD8 is a brief, sensitive measure that reliably differentiates between nondemented and demented individuals. Use of the AD8 in conjunction with a brief assessment of the participant could improve diagnostic accuracy in general practice.

The pathology of the substantia nigra in Alzheimer disease with extrapyramidal signs.

BACKGROUND: Extrapyramidal signs (EPS) are common in Alzheimer disease (AD) and increase in prevalence as AD advances. The neuropathologic substrate responsible for EPS in AD remains to be fully characterized. METHODS: Subjects had a clinical diagnosis of AD confirmed by neuropathologic examination. EPS during life were documented by clinical methods assessing bradykinesia, cogwheel rigidity, rest tremor, and parkinsonian gait. Subjects with EPS and previous neuroleptic exposure were excluded. Twenty-eight subjects were in the EPS group and 104 subjects were without EPS. Neuron loss, alpha-synuclein (ASYN)-labeled pathology, and tau-labeled pathology in the substantia nigra were measured using semiquantitative techniques such that higher scores represented increased pathologic burden. RESULTS: Presence of nigral ASYN-labeled pathology was more common (50 vs 28.9%; p < 0.05) in the EPS group than in those without EPS. There was more nigral neuron loss in the EPS group (1.50 vs 1.11 in no-EPS group; p < 0.05). Tau-labeled burden was not different by group comparisons; however, EPS onset at later stages of dementia severity was associated with increased tau-labeled pathology (Kendall tau-B = 0.48, p < 0.01) and this association remained after controlling for dementia severity at death. Additionally, moderate to severe tau burden was more common in the subgroup with "pure AD" (definite AD without other neuropathology) with EPS (81.8%) than cases without EPS (49.0%; p < 0.05). Four subjects with EPS (14.3%) had little to no significant nigral pathologic changes. CONCLUSIONS: Clinically detected extrapyramidal signs (EPS) in Alzheimer disease (AD) are associated with substantia nigra pathology including alpha-synuclein aggregation, hyperphosphorylated tau accumulation, and neuron loss that may account for the increasing prevalence of EPS as AD progresses. In some cases, limited nigral pathology suggests extranigral factors in the clinical symptoms of EPS.

Alzheimer disease and cancer.

Cross-sectional studies raise the possibility of protective relationships between, or a common mechanism underlying, the development of dementia of the Alzheimer type (DAT) and cancer. Using a prospective longitudinal design, the authors found that the risk of developing cancer is less among participants with DAT vs nondemented participants (p < 0.001) and that the risk of developing DAT may be less for participants with a history of cancer (p = 0.060).

Compliance with and dosing of angiotensin-converting-enzyme inhibitors before and after hospitalization.

Compliance with and dosing of angiotensin-converting-enzyme (ACE) inhibitors as they occur before and after hospitalization for heart failure were studied, and factors predictive of compliance with and dosing of ACE inhibitors after hospitalization were identified. Two hundred thirty-six patients hospitalized with heart failure between October 1, 1995, and April 30, 1996, were identified. Compliance with and use and dosing of ACE inhibitors were examined over the 180-day period before admission and the 180-day period after discharge using an integrated pharmacy and medical claims database. Use of an ACE inhibitor was defined as at least one claim for an ACE inhibitor over the period examined, and dosing was assessed by calculating the mean percentage of an adequate daily dose dispensed. Before hospitalization 109 patients (46.2%) used ACE inhibitors, and after hospitalization 148 (62.7%) used them--a significant increase. ACE inhibitor use before hospitalization was a predictor of postdischarge use. Younger patients were more likely to take ACE inhibitors after hospitalization than older ones, and men had better compliance after hospitalization than women. Additional analyses revealed that, among hospitalized patients, compliance was lower in individuals who also took an antidepressant. Dosing increased from 72% to 85% of an adequate daily dose after hospitalization among patients who took ACE inhibitors during both prehospitalization and posthospitalization periods. However, almost one third of hospitalized patients stopped taking their ACE inhibitor within six months of hospital discharge. The study found few significant predictors of patient compliance after hospitalization. Dosing of ACE inhibitors before and after hospitalization needs to be improved.

Angiotensin-converting enzyme inhibitor compliance and dosing among patients with heart failure.

BACKGROUND: The efficacy of angiotensin-converting enzyme (ACE) inhibitors in treating heart failure is well established, but there is concern that these agents are underutilized. Proper treatment is contingent both on appropriate medication dosing by the physician and on patient compliance with therapy. This study examined dosing and compliance with ACE inhibitors in routine clinical practice. METHODS AND RESULTS: Data were integrated medical and pharmacy claims from 869 patients with heart failure. Compliance and dosing of ACE inhibitors was examined for each patient over a 10- to 17-month period. Patients had ACE inhibitors available on 71% of the days assessed. At 180 days after their index prescription, 86% of patients continued to take an ACE inhibitor. The mean percentage of an adequate daily dose of ACE inhibitors dispensed per prescription was 79%, but only 34% of patients were dispensed >/=100% of an adequate daily dose. A number of variables were found to independently predict compliance and dosing levels in the multivariate analyses. CONCLUSIONS: Both physician-dependent and patient-dependent factors contributed significantly to ACE inhibitor underutilization. Each of these factors must be addressed to improve compliance and dosing of ACE inhibitors in routine clinical care.

Nitric oxide regulation of corticotropin-releasing hormone release from the human perfused placenta in vitro.

We have investigated the regulatory role of nitric oxide (NO) in corticotropin-releasing hormone (CRH) release from the human perfused placental lobule in vitro. The effects of the NO donor sodium nitroprusside, the NO synthase inhibitor N omega-nitro-L-arginine, and the NO substrate L-arginine on human (h) placental CRH secretion have been studied. Single lobules of term placentae were bilaterally perfused with Krebs solution (5 mL/min; 95% O2-5% CO2; 37 C; pH 7.3). Fetal and maternal perfusates were collected at 4 C every 30 min for 3 h. CRH immunoreactivity (CRH-IR) in perfusates was measured by RIA using the 41-residue synthetic CRH as standard, 125I-labeled Tyr-hCRH as tracer, and a rabbit anti-CRH antibody Y2BO. The sensitivity of the assay was 0.13 pmol/L. Under basal conditions, human perfused placentae in vitro continuously secreted CRH-IR, which diluted in parallel to a synthetic hCRH-(1-41) standard curve. Size-exclusion chromatography of placental perfusates using a Sephadex G-50 column indicated that placental CRH-IR predominately coeluted with hCRH-(1-41) standard. Basal maternal perfusate CRH-IR levels (27 +/- 4 pmol/L) released from perfused placental lobules were nearly 10-fold greater than fetal perfusate CRH-IR levels (3.4 +/- 0.7 pmol/L; P < 0.05). Infusion of sodium nitroprusside (30-100 mumol/L) into the maternal and fetal placental circulations inhibited CRH-IR release into maternal perfusate in a concentration-dependent manner, but did not inhibit CRH-IR release into the fetal perfusate. N omega-nitro-L-arginine (100 mumol/L) increased placental CRH-IR secretion into fetal perfusate, and this effect was reversed by the infusion of L-arginine (100 mumol/L), which also reduced release below basal levels. In contrast, maternal perfusate CRH-IR levels were not affected by N omega-nitro-L-arginine or L-arginine. These results indicate that the human perfused placenta in vitro releases a substance of similar mol wt and hCRH-IR. Moreover, modulators of the NO signaling pathway differentially affect placental secretion of CRH-IR into the maternal and fetal perfusates. These data are consistent with the involvement of NO in the regulation of placental CRH release during pregnancy.