Vitamin B12 status and rate of brain volume loss in community-dwelling elderly.

OBJECTIVES: To investigate the relationship between markers of vitamin B(12) status and brain volume loss per year over a 5-year period in an elderly population. METHODS: A prospective study of 107 community-dwelling volunteers aged 61 to 87 years without cognitive impairment at enrollment. Volunteers were assessed yearly by clinical examination, MRI scans, and cognitive tests. Blood was collected at baseline for measurement of plasma vitamin B(12), transcobalamin (TC), holotranscobalamin (holoTC), methylmalonic acid (MMA), total homocysteine (tHcy), and serum folate. RESULTS: The decrease in brain volume was greater among those with lower vitamin B(12) and holoTC levels and higher plasma tHcy and MMA levels at baseline. Linear regression analysis showed that associations with vitamin B(12) and holoTC remained significant after adjustment for age, sex, creatinine, education, initial brain volume, cognitive test scores, systolic blood pressure, ApoE epsilon4 status, tHcy, and folate. Using the upper (for the vitamins) or lower tertile (for the metabolites) as reference in logistic regression analysis and adjusting for the above covariates, vitamin B(12) in the bottom tertile (<308 pmol/L) was associated with increased rate of brain volume loss (odds ratio 6.17, 95% CI 1.25-30.47). The association was similar for low levels of holoTC (<54 pmol/L) (odds ratio 5.99, 95% CI 1.21-29.81) and for low TC saturation. High levels of MMA or tHcy or low levels of folate were not associated with brain volume loss. CONCLUSION: Low vitamin B(12) status should be further investigated as a modifiable cause of brain atrophy and of likely subsequent cognitive impairment in the elderly.

Elevated serum cardiac troponin I in older patients with hip fracture: incidence and prognostic significance.

INTRODUCTION: Cardiovascular complications are the main causes of morbidity and mortality in patients with osteoporotic hip fracture (HF). The aim of this prospective study was to evaluate the incidence and prognostic significance of elevated cardiac troponin I (cTnI) in the early peri-operative period in older patients with HF. MATERIALS AND METHODS: A blind evaluation of myocardial injury as detected by cTnI elevation in 238 consecutive older patients with low-trauma HF (mean age 81.9 +/- 7.8 (SD) years; 72% females). Data on demographic and clinical characteristics, in-hospital mortality, hospital length of stay and discharge destination were collected prospectively. Serum cTnI level was analysed from blood collected routinely in the first 72 h of hospital admission. RESULTS: Sixty-nine (29%) patients had elevated cTnI (>0.06 microg/l) but myocardial injury was clinically recognised in only 23 (33%) and only 24 (34.8%) had a history of coronary artery disease (CAD). Patients with elevated cTnI were significantly older, more often had American Society of Anaesthesiologist status score >or=3, a history of CAD or stroke and more often were current smokers than the patients without cTnI elevation. In multivariate regression analysis only age was an independent predictor of cTnI elevation. Patients with cTnI release were twice as likely to have a length of stay >or=20 days (P = 0.047) and 2.7 times more likely to be discharged to a long-term residential care facility (RCF) (P = 0.013). cTnI level >or=1 microg/l was a strong independent predictor of all-cause mortality with 98.3% specificity and 89.1% negative predictive value. CONCLUSION: Peri-operative myocardial injury is common in older HF patients but is frequently unrecognised clinically. Elevated blood cTnI level is an independent predictor of prolonged length of hospital stay (>or=20 days), need for long-term RCF and mortality (if cTnI >or=1 microg/l).

Outcomes for older patients with hip fractures: the impact of orthopedic and geriatric medicine cocare.

OBJECTIVES: To assess the impact of a specifically designed model of orthopedic-geriatric cocare on hip fracture (HF) outcomes. SETTING: Tertiary teaching hospital (level I trauma center). DESIGN: Prospective observational study with a retrospective (historical) control. Data on 951 consecutive patients 60 years of age or older admitted to the authors' institution with a nonpathologic HF over a 7-year period (1995 to 2002) were analyzed. Between 1995 and 1997, medical problems were managed by a geriatric medicine (GM) consultation-only service (retrospective audit). In 1998, a GM registrar began overseeing daily medical care with weekly geriatrician consultant review (prospective study). Outcomes for 2 time periods were compared: a 3-year period before (no GM; 504 patients) and a 4-year period after (GM; 447 patients) the introduction of GM cocare. MAIN OUTCOME MEASUREMENTS: Postoperative medical complications, mortality, length of stay, discharge destination, use of thromboprophylaxis, and antiosteoporotic treatment. RESULTS: While comparing 2 periods (GM and no GM), significant reductions in postoperative medical complications and comorbid conditions (in total 49.5% vs. 71.0%, P<0.001) and mortality (4.7% vs. 7.7%, P<0.01) occurred and rehospitalization to medical wards within 6 months decreased (28% vs. 7.6%). However, no differences were observed in median length of hospital stay (10.8 vs. 11.0 days) or in discharge destination. Antiosteoporotic treatment (12% to 69%) and specific thromboprophylaxis (63% to 94%) increased in the GM period. CONCLUSIONS: Orthopedic-geriatric cocare for the older patients with HF was associated with significant reductions in morbidity and mortality, and increases in optimal postoperative care. Options for further improvement of orthopedic-GM cocare need to be investigated.

Cases with mild cognitive impairment and Alzheimer's disease fail to benefit from repeated exposure to episodic memory tests as compared with controls.

Memory tests may be predictive for cognitive decline. We investigated the sensitivity and change in performance over time of the Hopkins Verbal Learning Test (HVLT) and the Mini-Mental Status Examination (MMSE) for Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD) when compared to cognitively healthy controls. Participants included elderly controls (n = 54), MCI (n = 19) and AD cases (n = 28) from OPTIMA. The MMSE and the HVLT (version 1) were administered twice to all subjects with an interval of 2-3 years.MCI and AD cases had poorer performance than controls on the HVLT and MMSE at both testing episodes (p < 0.05). The HVLT profile over time showed a learning effect in the control group (P < 0.0001), a trend to decline in the AD group (p = 0.09) and no change in the MCI group (P = 0.8). A subgroup of MCI subjects had lower HVLT scores at follow-up. The MMSE profile showed no significant change over time for all three groups (P > 0.05). The HVLT had better sensitivity and specificity compared to the MMSE for detecting MCI and AD. The HVLT is not only valuable for cross-sectional designs but has also proved to be valuable in a longitudinal design. Cognitively healthy controls showed evidence of learning strategies on the HVLT after a 2-3 year interval, with improved scores at the second testing episode. By contrast, an MCI group showed no benefits of previous exposure to this test. Lack of use of learning strategies on the HVLT may be an important marker of the likelihood of cognitive decline to MCI or dementia.

Sensitivity and specificity of neuropsychological tests for mild cognitive impairment, vascular cognitive impairment and Alzheimer's disease.

BACKGROUND: Early diagnosis of dementia is important for those who might benefit from treatment. We designed a brief comprehensive neuropsychological test battery to help differentiate control subjects from patients with mild cognitive impairment (MCI) and dementia. METHOD: The battery included tests of memory, attention, executive function, speed, perception and visuospatial skills. It was administered to subjects from the OPTIMA cohort: 51 controls, 29 with MCI, 60 with 'possible' or 'probable' Alzheimer's disease (AD) (NINCDS/ADRDA) and 12 with cerebrovascular disease (CVD). Mann-Whitney U tests were used to compare performance of controls with other diagnostic groups. The sensitivity and specificity of the tests were determined using Receiver Operating Characteristic curve analyses. The effects of age, gender and years of education on test performance were determined with Spearman's rank correlations. RESULTS: The AD group performed worse than controls on all tests except an attention task. The Hopkins Verbal Learning Test and The Placing Test for episodic memory showed significant discriminative capacity between controls and other groups. Attention and processing speed tests discriminated CVD from controls. Category fluency, episodic memory tests and the CLOX test for executive function distinguished MCI from AD. Spearman's correlations showed negative associations between age and processing speed. Years of education affected performance on all tests, except The Placing Test. CONCLUSIONS: Certain neuropsychological tests have been shown to be sensitive and specific in the differential diagnosis of various types of dementia and may prove to be useful for detection of MCI.

Association of the androgen receptor CAG repeat polymorphism with Alzheimer's disease in men.

We examined the CAG repeat polymorphism in exon 1 of the androgen receptor (AR) in an Oxford cohort of 150 cases (101 men) of definite or probable Alzheimer's disease (AD) and 190 elderly controls (140 men). We found that short alleles (< or = 20 CAG repeats) were associated with AD (adjusted odds ratio = 2.5, 95% confidence intervals: 1.2-5.0) in men, but not in women. This association appeared stronger in early-onset AD (< 65 years). We conclude that this AR polymorphism is of potential relevance to the risk of AD in men.

Serial brain MRI at 3-6 month intervals as a surrogate marker for Alzheimer's disease.

A surrogate marker is needed for Alzheimer's disease (AD) both to aid diagnosis and to assess interventions. Despite widespread use, brain imaging markers have largely been confounded by overlap with "normal" ageing. 39 elderly subjects completed up to four serial volumetric brain MRI scans with intervals from 2.5 months to 7 months. By National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) criteria, five subjects had probable AD, two possible AD and 32 were negative for AD, although this group included memory-impaired subjects. Total brain and ventricular volumes were measured for each scan, and rates of change for each interval calculated. The rate of change in ventricle-to-brain ratio was 15.6% per year (standard deviation (SD) 2.8%) for probable AD compared with 4.3% per year (SD 1.1%) for negative AD (p<0.001). There was no significant difference between these groups' mean ventricle-to-brain ratios measured at a single time point (p=0.25). Rates of change in brain or ventricular volume over time also differed between the two groups (p<0.001). Power calculations reveal that to detect a 20% reduction in the excess rate of atrophy of a probable AD cohort in just 6 months, with 90% power, 135 subjects would be required in each arm of a randomized placebo controlled trial. For a 30% reduction in the excess rate of atrophy, 61 subjects would be required. Rate of change analysis makes serial brain MRI a valuable surrogate marker for Alzheimer's disease. Since only 6 months or less is required between scans, this procedure has both clinical relevance and potential for monitoring interventions.

An inverse relationship of rat liver folate polyglutamate chain length to nutritional folate sufficiency.

The relative concentrations of folylpolyglutamates of differing chain length in rat liver and the uptake of exogenous [3H]folic acid (20 microCi, 20 microgram) into liver folylpolyglutamates were examined in rats maintained on (a) standard and folate-supplemented standard diets and (b) semi-defined folate-sufficient and folate-deficient diets. Folylpolyglutamates extracted from liver were cleaved to p-aminobenzoylpolyglutamates which were separated by ion-exchange chromatography. The relative concentrations and ultimate radiolabeling of longer-chain folylpolyglutamates (six, seven and eight glutamate residues) were greatest in the livers of folate-deficient rats, whereas the intermediate-chain folylpolyglutamates (three, four and five glutamate residues) were the greatest portion of total liver folates of folate-supplemented rats. Thus, the length of the polyglutamate chain added to liver folates is inversely related to the total concentration of liver folates. These data suggest that folylpolyglutamate biosynthesis in the liver may be controlled by the liver folate concentrations. In folate insufficiency such a control mechanism would serve to enhance the affinity of folates for folate-dependent enzymes and to conserve the liver folate concentration.