Jennie Wells

Ventricular enlargement as a possible measure of Alzheimer's disease progression validated using the Alzheimer's disease neuroimaging initiative database

Ventricular enlargement may be an objective and sensitive measure of neuropathological change associated with mild cognitive impairment (MCI) and Alzheimers disease (AD), suitable to assess disease progression for multi-centre studies. This study compared (i) ventricular enlargement after six months in subjects with MCI, AD and normal elderly controls (NEC) in a multi-centre study, (ii) volumetric and cognitive changes between Apolipoprotein E genotypes, (iii) ventricular enlargement in subjects who progressed from MCI to AD, and (iv) sample sizes for multi-centre MCI and AD studies based on measures of ventricular enlargement. Three dimensional T(1)-weighted MRI and cognitive measures were acquired from 504 subjects (NEC n = 152, MCI n = 247 and AD n = 105) participating in the multi-centre Alzheimers Disease Neuroimaging Initiative. Cerebral ventricular volume was quantified at baseline and after six months using semi-automated software. For the primary analysis of ventricle and neurocognitive measures, between group differences were evaluated using an analysis of covariance, and repeated measures t-tests were used for within group comparisons. For secondary analyses, all groups were dichotomized for Apolipoprotein E genotype based on the presence of an epsilon 4 polymorphism. In addition, the MCI group was dichotomized into those individuals who progressed to a clinical diagnosis of AD, and those subjects that remained stable with MCI after six months. Group differences on neurocognitive and ventricle measures were evaluated by independent t-tests. General sample size calculations were computed for all groups derived from ventricle measurements and neurocognitive scores. The AD group had greater ventricular enlargement compared to both subjects with MCI (P = 0.0004) and NEC (P < 0.0001), and subjects with MCI had a greater rate of ventricular enlargement compared to NEC (P = 0.0001). MCI subjects that progressed to clinical AD after six months had greater ventricular enlargement than stable MCI subjects (P = 0.0270). Ventricular enlargement was different between Apolipoprotein E genotypes within the AD group (P = 0.010). The number of subjects required to demonstrate a 20% change in ventricular enlargement was substantially lower than that required to demonstrate a 20% change in cognitive scores. Ventricular enlargement represents a feasible short-term marker of disease progression in subjects with MCI and subjects with AD for multi-centre studies.

State of the Art in Geriatric Rehabilitation. Part I: Review of Frailty and Comprehensive Geriatric Assessment

OBJECTIVES To increase recognition of geriatric rehabilitation and to provide recommendations for practice and future research. DATA SOURCES A CINAHL and 2 MEDLINE searches were conducted for 1980 to 2001. A fourth search used the Cochrane database. STUDY SELECTION One author reviewed the reference for relevance and another for quality. A total of 336 articles were selected. Excluded articles were unrelated to geriatric rehabilitation or were anecdotal or descriptive reports. DATA EXTRACTION The following major geriatric rehabilitation subtopics were identified: frailty, comprehensive geriatric assessment, admission screening, assessment tools, interdisciplinary teams, hip fracture, stroke, nutrition, dementia, and depression. Part I describes the first 5 subtopics on concepts and processes in geriatric rehabilitation. Part II focuses on the latter 5 subtopics of common clinical problems in frail older persons. A level-of-evidence framework was used to review the literature. Level 1 evidence was a randomized controlled trial (RCT) or a meta-analysis or systematic review of RCTs. Level 2 evidence included controlled trials without randomization, cohort, or case-control studies. Level 3 evidence involved consensus statements from experts or descriptive studies. DATA SYNTHESIS Of the 336 articles evaluated, 108 were level 1, 39 were level 2, and 189 were level 3. Recommendations were made for each subtopic. In cases in which several articles were written on the same topic and drew similar conclusions, the authors chose those articles with the strongest level of evidence, reducing the total number of references. CONCLUSIONS Frail elderly patients should be screened for rehabilitation potential. Standardized tools are recommended to aid diagnosis, assessment, and outcome measurement. The team approach to geriatric rehabilitation should be interdisciplinary and use a comprehensive geriatric assessment. Medication reviews and self-medication programs may be beneficial. Future research should address cost effectiveness, consensus on outcome measures, which components of geriatric rehabilitation are most effective, screening, and what outcomes are sustainable.

Gait assessment in mild cognitive impairment and Alzheimer's disease: The effect of dual-task challenges across the cognitive spectrum

Gait impairment is a prominent falls risk factor and a prevalent feature among older adults with cognitive impairment. However, there is a lack of comparative studies on gait performance and fall risk covering the continuum from normal cognition through mild cognitive impairment (MCI) to Alzheimers disease (AD). We evaluated gait performance and the response to dual-task challenges in older adults with AD, MCI and normal cognition without a history of falls. We hypothesized that, in older people without history of falls, gait performance will deteriorate across the cognitive spectrum with changes being more evident under dual-tasking. Gait was assessed using an electronic walkway under single and three dual-tasks conditions. Gait velocity and stride time variability were not significantly different between the three groups under the single-task condition. By contrast, significant differences of decreasing velocity (p<0.0001), increasing stride time (p=0.0057) and increasing stride time variability (p=0.0037) were found under dual-task testing for people with MCI and AD. Less automatic and more complex dual-task tests, such as naming animals and serial subtraction by sevens from 100, created the greatest deterioration of gait performance. Gait changes under dual-tasking for the MCI and AD groups were statistically different from the cognitively normal controls. Dual-task assessment exposed gait impairments not obvious under a single-task test condition and may facilitate falls risk identification in cognitively impaired persons without a history of falls.

Quantitative gait analysis under dual-task in older people with mild cognitive impairment: a reliability study

BackgroundReliability of quantitative gait assessment while dual-tasking (walking while doing a secondary task such as talking) in people with cognitive impairment is unknown. Dual-tasking gait assessment is becoming highly important for mobility research with older adults since better reflects their performance in the basic activities of daily living. Our purpose was to establish the test-retest reliability of assessing quantitative gait variables using an electronic walkway in older adults with mild cognitive impairment (MCI) under single and dual-task conditions.MethodsThe gait performance of 11 elderly individuals with MCI was evaluated using an electronic walkway (GAITRite® System) in two sessions, one week apart. Six gait parameters (gait velocity, step length, stride length, step time, stride time, and double support time) were assessed under two conditions: single-task (sG: usual walking) and dual-task (dG: counting backwards from 100 while walking). Test-retest reliability was determined using intra-class correlation coefficient (ICC). Gait variability was measured using coefficient of variation (CoV).ResultsEleven participants (average age = 76.6 years, SD = 7.3) were assessed. They were high functioning (Clinical Dementia Rating Score = 0.5) with a mean Mini-Mental Status Exam (MMSE) score of 28 (SD = 1.56), and a mean Montreal Cognitive Assessment (MoCA) score of 22.8 (SD = 1.23). Under dual-task conditions, mean gait velocity (GV) decreased significantly (sGV = 119.11 ± 20.20 cm/s; dGV = 110.88 ± 19.76 cm/s; p = 0.005). Additionally, under dual-task conditions, higher gait variability was found on stride time, step time, and double support time. Test-retest reliability was high (ICC>0.85) for the six parameters evaluated under both conditions.ConclusionIn older people with MCI, variability of time-related gait parameters increased with dual-tasking suggesting cognitive control of gait performance. Assessment of quantitative gait variables using an electronic walkway is highly reliable under single and dual-task conditions. The presence of cognitive impairment did not preclude performance of dual-tasking in our sample supporting that this methodology can be reliably used in cognitive impaired older individuals.

Reduced hippocampal glutamate in Alzheimer disease.

Altered neurometabolic profiles have been detected in Alzheimer disease (AD) using (1)H magnetic resonance spectroscopy (MRS), but no definitive biomarker of mild cognitive impairment (MCI) or AD has been established. This study used MRS to compare hippocampal metabolite levels between normal elderly controls (NEC) and subjects with MCI and AD. Short echo-time (TE=46 ms) (1)H spectra were acquired at 4T from the right hippocampus of 23 subjects with AD, 12 subjects with MCI and 15 NEC. Absolute metabolite levels and metabolite ratios were compared between groups using a multivariate analysis of covariance (covariates: age, sex) followed by post hoc Tukeys test (p<0.05 significant). Subjects with AD had decreased glutamate (Glu) as well as decreased Glu/creatine (Cr), Glu/myo-inositol (mI), Glu/N-acetylaspartate (NAA), and NAA/Cr ratios compared to NEC. Subjects with AD also had decreased Glu/mI ratio compared to MCI. There were no differences between subjects with MCI and NEC. Therefore, in addition to NAA/Cr, decreased hippocampal Glu may be an indicator of AD.

State of the art in geriatric rehabilitation. Part II: Clinical challenges

OBJECTIVES To examine common clinical problems in geriatric rehabilitation and to make recommendations for current practice based on evidence from the literature. DATA SOURCES A CINAHL database and 2 MEDLINE searches were conducted for 1980 to 2001. A fourth search was completed by using the Cochrane database. STUDY SELECTION One author reviewed the references for relevance and another for quality. A total of 336 articles were considered relevant. Excluded articles were unrelated to geriatric rehabilitation or were anecdotal or descriptive reports on a small number of patients. DATA EXTRACTION The following areas were the major geriatric rehabilitation subtopics identified in the search: frailty, comprehensive geriatric assessment, admission screening, assessment tools, interdisciplinary teams, hip fracture, stroke, nutrition, dementia, and depression. This article focuses on the latter 5 subtopics. The literature was reviewed by using a level-of-evidence framework. Level 1 evidence was a randomized controlled trial (RCT) or meta-analysis or systematic review of RCTs. Level 2 evidence included controlled trials without randomization, cohort, or case-control studies. Level 3 evidence involved consensus statements from experts, descriptive studies, or reports of expert committees. DATA SYNTHESIS Of the 336 articles evaluated, 108 were level 1, 39 were level 2, and 189 were level 3. Recommendations were made for each subtopic according to the level of evidence in the specific area. In cases in which several articles were written on a topic with similar conclusions, we selected the articles with the strongest level of evidence, thereby reducing the total number of references. CONCLUSIONS Frail older patients with hip fracture should receive geriatric rehabilitation. They should also be screened for nutrition, cognition, and depression. Older persons should receive nutritional supplementation when malnourished. If severe dysphagia occurs in stroke patients, gastrostomy tube feeding is superior to nasogastric tube feeding.

Can cognitive enhancers reduce the risk of falls in older people with Mild Cognitive Impairment? A protocol for a randomised controlled double blind trial

BackgroundOlder adults with cognitive problems have a higher risk of falls, at least twice that of cognitively normal older adults. The consequences of falls in this population are very serious: fallers with cognitive problems suffer more injuries due to falls and are approximately five times more likely to be admitted to institutional care. Although the mechanisms of increased fall risk in cognitively impaired people are not completely understood, it is known that impaired cognitive abilities can reduce attentional resource allocation while walking. Since cognitive enhancers, such as cholinesterase inhibitors, improve attention and executive function, we hypothesise that cognitive enhancers may reduce fall risk in elderly people in the early stages of cognitive decline by improving their gait and balance performance due to an enhancement in attention and executive function.Method/DesignDouble blinded randomized controlled trial with 6 months follow-up in 140 older individuals with Mild Cognitive Impairment (MCI). Participants will be randomized to the intervention group, receiving donepezil, and to the control group, receiving placebo. A block randomization by four and stratification based on fall history will be performed. Primary outcomes are improvements in gait velocity and reduction in gait variability. Secondary outcomes are changes in the balance confidence, balance sway, attention, executive function, and number of falls.DiscussionBy characterizing and understanding the effects of cognitive enhancers on fall risk in older adults with cognitive impairments, we will be able to pave the way for a new approach to fall prevention in this population. This RCT study will provide, for the first time, information regarding the effect of a medication designed to augment cognitive functioning have on the risk of falls in older adults with Mild Cognitive Impairment. We expect a significant reduction in the risk of falls in this vulnerable population as a function of the reduced gait variability achieved by treatment with cognitive enhancers. This study may contribute to a new approach to prevent and treat fall risk in seniors in early stages of dementia.Trial RegistrationThe protocol for this study is registered with the Clinical Trials Registry, identifier number: NCT00934531 http://www.clinicaltrials.gov

Factors associated with a second hip fracture: a systematic review:

Objective: To provide a systematic review of factors associated with subsequent hip fracture among individuals who have fractured a hip. Data sources: We searched Ageline, CINAHL, EMBASE and MEDLINE, from database inceptions to the week of 5 June 2006. Review methods: Studies were selected if they provided information regarding risk of subsequent hip fracture among individuals who had fractured a hip. Study quality was assessed using the Jadad criteria for randomized controlled trials (RCTs) and a simple scale based on the MOOSE criteria for cohort studies. Results: Four RCTs and seven cohort studies were identified. Older age, cognitive impairment and lower bone mass appear to increase the risk of subsequent fracture, as did impaired depth perception, impaired mobility, previous falls, dizziness and poor or fair self-perceived health. Pharmacologic treatment for osteoporosis decreased the risk of subsequent fracture. Use of hip protectors by community-dwelling seniors did not appear to protect against a second fracture. Conclusion: A number of easily observed risk factors may help identify those individuals at higher risk for subsequent fracture.

High field 1H MRS of the hippocampus after donepezil treatment in Alzheimer disease

The purpose of this study was to measure metabolite level changes in patients with newly diagnosed Alzheimer Disease (AD) following four months of donepezil treatment. A small number of cognitively normal elderly subjects were also scanned longitudinally (twice within one year) to assess the reproducibility. Short echo-time (1)H magnetic resonance spectra were acquired at 4.0 T in the right hippocampus. Subjects were scanned at the time of first diagnosis (prior to receiving donepezil) and then following four months of donepezil treatment (5 mg/day for the first month, 10 mg/day thereafter). Changes in absolute metabolite levels and metabolite ratios were quantified and compared. There was no change in measured cognitive function following four months of donepezil treatment in the AD patients. Decreased levels of N-acetylaspartate, choline, N-acetylaspartate/creatine, choline/creatine, and myo-inositol/creatine were observed in AD patients after four months of treatment. Cognitively normal elderly subjects showed an increase in myo-inositol/choline ratio following one year. The reduced levels of N-acetylaspartate in AD patients indicates continued decline in neuronal function and/or integrity. However decreased levels of choline and myo-inositol/creatine ratio may indicate a positive treatment effect.

Increased glutamate in the hippocampus after galantamine treatment for Alzheimer disease

Galantamine is a cholinesterase inhibitor and allosteric potentiating ligand modulating presynaptic nicotinic acetylcholine receptors that is used in the treatment of Alzheimer disease (AD). The purpose of this study was to determine if galantamine treatment would result in detectable hippocampal metabolite changes that correlated with changes in cognition, as measured by the Mini-Mental State Examination (MMSE) and the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog). Short echo-time proton magnetic resonance (MR) spectra were acquired from within the right hippocampus of ten patients using a 4 Tesla magnetic resonance imaging (MRI) scanner. Spectra were used to quantify absolute metabolite levels for N-acetylaspartate (NAA), glutamate (Glu), choline (Cho), creatine (Cr), and myo-inositol (mI). Patient scans and cognitive tests were performed before and 4 months after beginning galantamine treatment, which consisted of an 8 mg daily dose for the first month and a 16 mg daily dose for the remaining three months. The levels of Glu, Glu/Cr, and Glu/NAA increased after four months of treatment, while there were no changes in MMSE or ADAS-cog scores. Additionally, changes (Delta) in Glu over the four months (DeltaGlu) correlated with DeltaNAA, and Delta(Glu/Cr) correlated with DeltaMMSE scores. Increased Glu and the ratio of Glu to Cr measured by MR spectroscopy after galantamine treatment were associated with increased cognitive performance. The increase in Glu may be related to the action of galantamine as an allosteric potentiating ligand for presynaptic nicotinic acetylcholine receptors, which increases glutamatergic neurotransmission.