Assessing the Relationship between Vitamin D Status and Impairments in Cognitive and Physical Performance in Older Adults Using a Dual Task Physical Performance Test.

BACKGROUND: Vitamin D deficiency has been associated with an increased risk of falls in older adults. Several studies have demonstrated an association between vitamin D deficiency and gait and cognitive impairments, which are two risk factors for falls in the elderly. There is lack of research about the role of vitamin D in cognitive function in the context of mobility. OBJECTIVE: The purpose of this study was to evaluate the association between vitamin D status with the age-related changes in mobility through higher order cognitive function using a dual task physical performance test. DESIGN: Cross-sectional. SETTING: Community-dwelling older adult population located in Miami, Fl. PARTICIPANTS: Healthy participants over the age of 55 (n=97) who participated in the parent interventional study. MEASUREMENTS: Participants completed assessments that included serum levels of vitamin D, surveys, and dual task physical performance tests. Spearman's correlations, independent t-tests, repeated measures ANOVAs and multiple logistic regressions were used to examine the relationship between vitamin D insufficiency (25-hydroxyvitamin D <30 ng/ml) and sufficiency (≥30 ng/ml) and dual task physical performance variables. The significance level was set at α=0.05. RESULTS: There were no significant associations between vitamin D insufficiency and gait velocity during either task. Using Spearman correlations, slower single (P=0.011) and dual task counting rates (P=0.006) were significantly associated with vitamin D insufficiency. Independent t-tests showed dual and single task counting rates were significantly lower in the vitamin D insufficient group compared to the sufficient group (P=0.018 and P=0.028, respectively). The results for the ANOVAs indicated that velocities and counting rates were not significantly different by vitamin D status (Wilk's Lambda =0.999; F (1, 95) =.11, P=.740) (Wilk's Lambda =.999, F(1,95)=.13, P=.718). Vitamin D status was not significantly associated with dual task physical performance (defined as the difference in dual and single task) in gait velocity (OR=1.00, 95% CI: 0.98; 1.02, P=0.772) and counting rate (OR=1.684, 95% CI: 0.15; 19.57, P=0.677), when controlling for confounders. CONCLUSIONS: Since counting backward is a mental tracking task, which is a component of executive function, our results suggest a relationship between vitamin D insufficiency and executive dysfunction. Executive dysfunction has been previously associated with fall risks in the elderly, and it could be a possible mediator between vitamin D and falls. Our data suggest that cognition may play a significant role in vitamin D's influence on falls, while motor function may play a lesser role.

Reliability of functioning free muscle transfer and vascularized ulnar nerve grafting for elbow flexion in complete brachial plexus palsy.

We compared outcomes of primary vascularized ulnar nerve grafts from the C5 root neurotizing biceps and brachialis muscles, and gracilis functioning free muscle transfer neurotized by the distal spinal accessory nerve, as a primary or salvage procedure after complete brachial plexus injury. At 45 months, three of eight primary vascularized ulnar nerve graft patients regained grade 4 elbow flexion, while one regained grade 3. All 13 primary gracilis transfer patients regained grade 4 elbow flexion. Four patients with vascularized ulnar nerve grafts failed and subsequently had salvage functioning free muscle transfer procedures resulting in delayed recovery. Although vascularized ulnar nerve graft-based primary reconstructions can provide useful elbow flexion, this was achieved in less than half the cases. We consider primary gracilis functioning free muscle transfer neurotized by the distal spinal accessory nerve as the most reliable reconstruction for the restoration of elbow flexion in complete brachial plexus injury. LEVEL OF EVIDENCE: IV.

Evaluation of an 8-item Severe Impairment Battery (SIB-8) vs. the full SIB in moderate to severe Alzheimer's disease patients participating in a donepezil study.

AIM: The Severe Impairment Battery (SIB), a reliable cognitive measure for evaluating treatment response in advanced Alzheimer's disease (AD), takes approximately 20 min to administer. A recently derived 8-item version of the SIB - the SIB-8 - which takes about 3 min to administer, may represent a more convenient tool for use in clinical practice. The current analyses further explored the SIB-8 scale with respect to its validity and sensitivity. METHODS: A post hoc analysis was performed using data from a 24-week trial of donepezil 23 mg/day and 10 mg/day in > 1400 patients with moderate to severe AD [baseline Mini-Mental State Examination (MMSE) score 0-20]. Treatment effects on cognition (patterns of score change) were assessed using the full SIB and SIB-8 in the total study population and subgroups based on concomitant memantine use and baseline MMSE. Internal consistency/agreement and correlations between the SIB and SIB-8 and other clinical end points were evaluated. RESULTS: Assessment of score changes from baseline to week 24 with donepezil (23 or 10 mg/day) demonstrated comparable patterns of change when using the SIB-8 and the full SIB, despite inherent differences in the total score ranges for the two scales. Internal consistency/agreement between the full SIB and SIB-8 was good (Cronbach's alphas: 0.77-0.95). SIB-8 scores reliably correlated with SIB total scores (r = 0.859, baseline; r = 0.900, week 24; p < 0.0001), as well as MMSE scores (r = 0.7163, baseline; r = 0.7963, week 24; p < 0.0001). Scores on both SIB scales were moderately associated with functional measures at baseline and week 24. CONCLUSIONS: In this post hoc analysis, similar treatment effects were measured by the full SIB and the SIB-8. Very good internal consistency/agreement and strong correlations between the SIB and the more rapid and convenient SIB-8 indicate that the SIB-8 may be a useful and efficient clinical proxy for the full SIB in evaluating treatment response in patients with advanced AD.

Novel white matter tract integrity metrics sensitive to Alzheimer disease progression.

BACKGROUND AND PURPOSE: Along with cortical abnormalities, white matter microstructural changes such as axonal loss and myelin breakdown are implicated in the pathogenesis of Alzheimer disease. Recently, a white matter model was introduced that relates non-Gaussian diffusional kurtosis imaging metrics to characteristics of white matter tract integrity, including the axonal water fraction, the intra-axonal diffusivity, and the extra-axonal axial and radial diffusivities. MATERIALS AND METHODS: This study reports these white matter tract integrity metrics in subjects with amnestic mild cognitive impairment (n = 12), Alzheimer disease (n = 14), and age-matched healthy controls (n = 15) in an effort to investigate their sensitivity, diagnostic accuracy, and associations with white matter changes through the course of Alzheimer disease. RESULTS: With tract-based spatial statistics and region-of-interest analyses, increased diffusivity in the extra-axonal space (extra-axonal axial and radial diffusivities) in several white matter tracts sensitively and accurately discriminated healthy controls from those with amnestic mild cognitive impairment (area under the receiver operating characteristic curve = 0.82-0.95), while widespread decreased axonal water fraction discriminated amnestic mild cognitive impairment from Alzheimer disease (area under the receiver operating characteristic curve = 0.84). Additionally, these white matter tract integrity metrics in the body of the corpus callosum were strongly correlated with processing speed in amnestic mild cognitive impairment (r = |0.80-0.82|, P < .001). CONCLUSIONS: These findings have implications for the course and spatial progression of white matter degeneration in Alzheimer disease, suggest the mechanisms by which these changes occur, and demonstrate the viability of these white matter tract integrity metrics as potential neuroimaging biomarkers of the earliest stages of Alzheimer disease and disease progression.

Structural variation of the mouse natural killer gene complex.

The natural killer gene complex (NKC) on chromosome 6 contains clusters of genes that encode both activation and inhibitory receptors expressed on mouse natural killer (NK) cells. NKC genes, particularly belonging to the Nkrp1 and Ly49 gene families, display haplotype differences between different mouse strains and allelic polymorphisms of individual genes, as previously revealed by conventional analysis in a small number of inbred mouse strains. Herein we used array-based comparative genomic hybridization (aCGH) to efficiently compare the NKC in 21 mouse strains to the reference C57BL/6 strain. By using unsupervised clustering methods, we could sort these variations into the same groups as determined by previous RFLP analyses of Nkrp1 and Ly49 genes. Prospective analyses of aCGH and RFLP data validated these relationships. Moreover, aCGH data predicted monoclonal antibody reactivity with an allospecific determinant on molecules expressed by NK cells. Taken together, these data demonstrate the structural variation in the NKC between mouse strains as well as the usefulness of aCGH in analysis of complex, polymorphic gene clusters.

Effect of tramiprosate in patients with mild-to-moderate Alzheimer's disease: exploratory analyses of the MRI sub-group of the Alphase study.

OBJECTIVES: The efficacy, safety and disease-modification of tramiprosate (homotaurine)were investigated in a recently completed large-scale Phase III clinical study in patients with mild to moderate Alzheimer's disease (AD), the Alphase study. Disease-modification was assessed using longitudinal volumetric MRI (vMRI) measurements of the hippocampus in a subgroup of patients. The present study describes the vMRI, cognitive and clinical results obtained in this subgroup. DESIGN: Multi-center, double-blind, randomized, placebo-controlled study in a subset of the 1052 patients of the Alphase study. SETTING: 51 vMRI investigative sites in the United States and Canada. PARTICIPANTS: A total of 508 patients underwent vMRI scanning. Of these, 312 provided scan pairs for assessing hippocampus volume changes and were included in the analyses. INTERVENTIONS: Patients were randomized to receive Placebo BID (n = 109), tramiprosate 100 mg BID (n = 103), or tramiprosate 150 mg BID (n = 100) for 78 weeks. MEASUREMENTS: Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinical Dementia Rating-Sum-of-boxes CDR-SB assessments were conducted at Baseline and at Weeks 13, 26, 39, 52, 65 and 78. Exploratory analyses were performed using similar First and Final mixed-effects repeated-measures models that were used for the analysis of the entire patient dataset. RESULTS: Psychometric score results showed numerical trends in favour of tramiprosate that did not reach statistical significance. While there were no statistically significant group differences in hippocampus volume using the First modeling approach, a significant dose-response reduction in hippocampus volume change was found in the Final models. Moreover, there was a marginally significant overall treatment main effect and a significant slope difference in favour of tramiprosate according to the Final model analysis of the ADAS-cog scores. ADAS-cog scores analyzed according to this model also revealed differences in favor of the tramiprosate 150 mg group at weeks 26 and 52, with marginally significant differences at Weeks 13 and 39. Slope analyses of ADAS-cog score changes showed significant differences in favor of the 150 mg BID group, and when both active groups were combined, in comparison to the placebo group. No between-group differences with respect to changes to each visit in the CDR-SB were observed with either modeling approach. Although there was a similar dose-response relationship observed in the hippocampus volume and ADAS-cog Final model analyses, the overall changes in psychometric scores and hippocampus volume were not significantly correlated. CONCLUSION: Exploratory analysis of the vMRI subgroup suggests that tramiprosate slows hippocampal atrophy, and reveals some evidence of a beneficial effect on cognition. The clinical validity of the vMRI biomarker is discussed.

Donepezil treatment of patients with MCI: a 48-week randomized, placebo-controlled trial.

BACKGROUND: Treatment of mild cognitive impairment (MCI) with cholinesterase inhibitors may improve symptoms. METHODS: In this multicenter, randomized, placebo-controlled trial, subjects with MCI entered a 3-week placebo run-in period followed by 48 weeks of double-blind donepezil (5 mg/day for 6 weeks, then 10 mg/day for 42 weeks) or placebo treatment. Primary efficacy variables included change from baseline in the modified Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-Cog) and Clinical Dementia Rating Scale-sum of boxes (CDR-SB) after 48 weeks of treatment (modified intention-to-treat analysis). Secondary efficacy measures evaluated cognition, behavior, and function. RESULTS: The dual primary efficacy endpoint was not reached. We noted a small, but significant, decrease in modified ADAS-Cog scores in favor of donepezil at study endpoint. Little change from baseline in CDR-SB and secondary variables was observed for either group. Patient Global Assessment scores favored donepezil at all time points except week 12 (p < or = 0.05). Perceived Deficits Questionnaire scores favored donepezil at week 24 (p = 0.05). Clinical Global Impression of Change-MCI scores favored donepezil only at week 6 (p = 0.04). Adverse events were generally mild or moderate. More donepezil-treated subjects (18.4%) discontinued treatment due to adverse events than placebo-treated subjects (8.3%). CONCLUSIONS: Donepezil demonstrated small but significant improvement on the primary measure of cognition but there was no change on the primary measure of global function. Most other measures of global impairment, cognition, and function were not improved, possibly because these measures are insensitive to change in MCI. Responses on subjective measures suggest subjects perceived benefits with donepezil treatment.

Developments in perforator imaging for the anterolateral thigh flap: CT angiography and CT-guided stereotaxy.

INTRODUCTION: The anterolateral thigh flap is an increasingly popular reconstructive option despite uncertainty in its perforator anatomy. Perforators are not always present, vary in size and intramuscular course, and have variable cutaneous courses and supply. As such, preoperative imaging has become favored. METHODS: The current study describes the preliminary use of two new modalities for preoperative imaging: computed tomography (CT) Angiography and CT-guided stereotaxy. These have been utilized in the preoperative imaging of two patients undergoing ALT flap reconstruction. Each patient underwent each of these techniques combined with Doppler ultrasound, the previous standard modality. The size, location, and course of perforators were explored and compared with operative findings. RESULTS: Both techniques are technically feasible, highly accurate, and provide more information to the surgeon than ultrasound. CONCLUSION: CT Angiography and CT-guided stereotaxy are useful adjuncts to Doppler ultrasound for imaging perforators prior to ALT flaps. A larger study is suggested to quantify the accuracy of these techniques.

Analysis of the promoters and 5'-UTR of mouse Cd59 genes, and of their functional activity in erythrocytes.

The complement regulatory protein CD59 inhibits formation of the membrane attack complex (MAC), the terminal effector of the complement system. There are two mouse Cd59 genes in mice but only one in humans. In the work reported here we (a) mapped the promoter regions of both mCd59a and mCd59b genes, (b) identified two different promoters for each mCd59 gene, (c) defined a previously unrecognized additional exon 1 in each mCd59 gene, (d) identified that each mCd59 gene expresses two different tissue-specific transcripts that differ in their 5'-UTR, and (e) confirmed the presence of mCd59b mRNA in multiple tissues. At the functional level, comparison of the sensitivity of mCd59ab(-/-) and mCd59a(-/-) red blood cells to MAC-mediated lysis revealed that mCd59b protects RBC from MAC-mediated lysis, at least in the setting of mCd59a deficiency. Together these findings indicate that the mCd59 genes may have complex and perhaps different regulatory mechanisms in different tissues.

Prediction of longitudinal cognitive decline in normal elderly with subjective complaints using electrophysiological imaging.

An extensive literature reports changes in quantitative electroencephalogram (QEEG) with aging and a relationship between magnitude of changes and degree of clinical deterioration in progressive dementia. Longitudinal studies have demonstrated QEEG differences between mild cognitively impaired (MCI) elderly who go on to decline and those who do not. This study focuses on normal elderly with subjective cognitive complaints to assess the utility of QEEG in predicting future decline within 7 years. Forty-four normal elderly received extensive clinical, neurocognitive and QEEG examinations at baseline. All study subjects (N = 44) had only subjective complaints but no objective evidence of cognitive deficit (evaluated using the Global Deterioration Scale [GDS] score, GDS stage = 2) at baseline and were re-evaluated during 7-9 year follow-up. Baseline QEEGs of Decliners differed significantly (p < 0.0001, by MANOVA) from Non-Decliners, characterized by increases in theta power, slowing of mean frequency, and changes in covariance among regions, especially on the right hemisphere. Using logistic regression, an R2 of 0.93 (p < 0.001) was obtained between baseline QEEG features and probability of future decline, with an overall predictive accuracy of 90%. These data indicate high sensitivity and specificity for baseline QEEG as a differential predictor of future cognitive state in normal, subjectively impaired elderly.

Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of the acetylcholinesterase inhibitor donepezil in a placebo-controlled trial in patients with mild cognitive impairment (MCI). METHODS: A total of 270 patients with MCI were enrolled in a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Patients were randomized to receive donepezil (n = 133; 5 mg/day for 42 days, followed by forced dose escalation to 10 mg/day) or placebo (n = 137). Primary efficacy measures were the New York University (NYU) Paragraph Delayed Recall test and the Alzheimer disease (AD) Cooperative Study Clinician's Global Impression of Change for MCI (ADCS CGIC-MCI). Secondary efficacy measures included the modified AD Assessment Scale-cognitive subscale (ADAS-cog), the Patient Global Assessment (PGA), and additional neuropsychologic measures. Efficacy analyses were performed on intent-to-treat (ITT) and fully evaluable (FE) populations. RESULTS: Primary efficacy measures of the NYU Paragraph Recall test and the ADCS CGIC-MCI did not show significant treatment effects in the ITT population. Some secondary measures showed effects favoring donepezil. More donepezil-treated patients showed improvements in ADAS-cog total scores, in tests of attention and psychomotor speed, and in PGA scores. More donepezil-treated than placebo-treated patients experienced adverse events, most of which were mild to moderate and transient. CONCLUSION: Although significant treatment effects were not seen in the primary efficacy measures, outcomes on secondary measures suggest promising directions for further evaluation of donepezil treatment in patients with MCI.

Behavioral symptoms in mild cognitive impairment.

The authors investigated neuropsychiatric symptoms in mild cognitive impairment (MCI) from baseline data of the Investigation in the Delay to Diagnosis of AD with Exelon (InDDEx) study (n = 1,010). Neuropsychiatric symptoms were reported in 59% of subjects (Neuropsychiatric Inventory [NPI]). NPI+ subjects had significantly greater impairment on global, cognitive, and functional scores than NPI- subjects. The presence of neuropsychiatric symptoms appears to be a marker of MCI severity.

Measuring cognition in advanced Alzheimer's disease for clinical trials.

Measurement of cognitive dysfunction and treatment response in the early stages of Alzheimer's disease (AD) has used such scales as the Mini-Mental State Examination (MMSE) and the AD Assessment Scale (ADAS). With the exception of clinical rating scales, however, there are only a few objective measures of cognition for tracking progression in advanced AD. Given renewed interest in potential therapies for advanced AD, objective measures of cognition are important for the adequate evaluation of change due to AD progression or therapy. Several cognitive measures for advanced AD are reviewed. One measure, the Severe Impairment Battery (SIB) is reviewed in detail. Preliminary analyses from a trial of memantine show significant change on the SIB in memory (p < 0.001) and visuospatial functions (p < 0.02) over six-months with a trend for language and praxis. Data from a donepezil trial also highlight the importance of accurate assessment in advanced AD.

Addition of a frequency-weighted score to the Behavioral Pathology in Alzheimer's Disease Rating Scale: the BEHAVE-AD-FW: methodology and reliability.

The Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) is a well-established instrument, designed to assess potentially remediable behavioral symptoms in Alzheimer's disease (AD) patients as well as to evaluate treatment outcome. It consists of 25 symptoms grouped into seven categories. Each symptom is scored on the basis of severity on a four-point scale. A knowledgeable caregiver is queried and items are scored on the basis of symptoms noted in the preceding two weeks. Reliability, construct validity and criterion validity data for the BEHAVE-AD have previously been published. Because of the significance of psychopathology in dementia, it is necessary to optimally describe and define the nature, magnitude and prevalence of behavioral symptomatology. Accordingly, a frequency component was added to each of the 25 items of the BEHAVE-AD scale. The objective of the present report is to describe this new Behavioral Pathology in Alzheimer's Disease Frequency-Weighted Severity Scale (BEHAVE-AD-FW) and to establish its inter-rater reliability. In this investigation the BEHAVE-AD-FW scale was administered to caregivers of 28 patients with either mildly impaired cognitive function or a dementia diagnosis. Two clinicians separately and independently rated the responses. Analyses determined that the intraclass correlation coefficients (ICCs) for the frequency component varied between 0.86 and 0.97 for each of the seven BEHAVE-AD categories (p(s) < 0.001). ICCs for the frequency-weighted scores (item severity score x item frequency score) ranged from 0.69 to 0.98 for the seven symptom categories (p(s) < 0.001). For the BEHAVE-AD-FW total scores, the ICC was 0.91 (P < 0.001). These results indicate that the frequency-weighted component is a reliable addition to the BEHAVE-AD scale.

Switching previous therapies for Alzheimer's disease to galantamine.

Acetylcholinesterase inhibitors (AChEIs) are the most frequently prescribed drugs for the treatment of Alzheimer's disease (AD). To date, donepezil is prescribed most often, but newer AChEIs have become available. Rivastigmine entered the pharmaceutics market for AD in 2000, and galantamine was approved for use in the United States in February 2001. Some patients with AD may already be taking a cholinesterase inhibitor, but they or their caregivers may want to change therapies for various reasons, such as lack of efficacy or poor tolerability. Therefore, defined protocols for discontinuing one therapy and initiating another therapy (ie, "switching") while maintaining efficacy and minimizing cholinergic toxicity will be essential. A post-hoc analysis of a clinical trial that enrolled patients with and without previous exposure to AChEIs indicated that the efficacy and tolerability of a second and different cholinesterase treatment were similar in both subpopulations of patients. These findings suggest that discontinuation of prior AChEI treatment is not predictive of future poor response to an effective treatment.

Outcome measures for probable vascular dementia and Alzheimer's disease with cerebrovascular disease.

Vascular dementia (VaD) can be defined as dementia associated with cerebrovascular disease (CVD), and accounts for a large proportion of all dementia cases. There is substantial overlap in the clinical symptomatology, pathophysiology and neurochemical mechanisms in VaD compared with Alzheimer's disease, suggesting that an effective treatment for Alzheimer's disease may also offer benefit as a symptomatic treatment in VaD. However, there are currently no explicit guidelines for conducting clinical pharmacotherapy trials in VaD patients. Two important requirements for assessing therapeutic benefits in such trials are 1) the inclusion of appropriate patients and 2) the use of appropriate outcome measures. Debate on the precise definition of VaD in relation to patient selection criteria continues, but many of the recommendations for outcome measures in Alzheimer's disease are already applicable to VaD. There is consensus that cognitive and global function measures, and assessments of abilities to perform activities of daily living (ADL) must be included as part of the optimal assessment battery in VaD trials. A measure of reduced behavioural symptoms with associated reductions in demands on caregivers would also be desirable. However, care must be taken in extrapolating Alzheimer's disease-specific evaluations to VaD, in that important differences in specific domains affected and characteristics of disease course must be taken into account. Between them, measures such as the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog; perhaps with supplemental tests of attention and other frontal lobe functions), evaluations of clinical global impression of change and a functional assessment addressing instrumental as well as basic ADL, e.g. Disability Assessment in Dementia (DAD) scale, should provide a good overall description of VaD-related deficits and sufficient appraisal of treatment effects. The Neuropsychiatric Inventory has also been shown to have good potential utility for measuring behavioural alterations in VaD. These and other assessments are reviewed to provide a balanced and realistic view of the type of treatment outcomes that can be expected in VaD pharmacotherapy trials, and to address the best ways of measuring these outcomes.