Michael Borrie

Diagnosis and treatment of dementia: 2. Diagnosis

Background: Dementia can now be accurately diagnosed through clinical evaluation, cognitive screening, basic laboratory evaluation and structural imaging. A large number of ancillary techniques are also available to aid in diagnosis, but their role in the armamentarium of family physicians remains controversial. In this article, we provide physicians with practical guidance on the diagnosis of dementia based on recommendations from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, held in March 2006. Methods: We developed evidence-based guidelines using systematic literature searches, with specific criteria for study selection and quality assessment, and a clear and transparent decision-making process. We selected studies published from January 1996 to December 2005 that pertained to key diagnostic issues in dementia. We graded the strength of evidence using the criteria of the Canadian Task Force on Preventive Health Care. Results: Of the 1591 articles we identified on all aspects of dementia diagnosis, 1095 met our inclusion criteria; 620 were deemed to be of good or fair quality. From a synthesis of the evidence in these studies, we made 32 recommendations related to the diagnosis of dementia. There are clinical criteria for diagnosing most forms of dementia. A standard diagnostic evaluation can be performd by family physicians over multiple visits. It involves a clinical history (from patient and caregiver), a physical examination and brief cognitive testing. A list of core laboratory tests is recommended. Structural imaging with computed tomography or magnetic resonance imaging is recommended in selected cases to rule out treatable causes of dementia or to rule in cerebrovascular disease. There is insufficient evidence to recommend routine functional imaging, measurement of biomarkers or neuropsychologic testing. Interpretation: The diagnosis of dementia remains clinically integrative based on history, physical examination and brief cognitive testing. A number of core laboratory tests are also recommended. Structural neuroimaging is advised in selected cases. Other diagnostic approaches, including functional neuroimaging, neuropsychological testing and measurement of biomarkers, have shown promise but are not yet recommended for routine use by family physicians.

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.

Acute Effects of Exercise on Neuropsychological Function in Elderly Subjects

Fit elderly score higher on tests of fluid intelligence than aged‐matched sedentary controls. Elderly patients who have taken part in exercise programs have shown improvement in mental function. We compared the effects of 45 minutes of exercise on memory, mood, and cognitive function in elderly subjects to a control intervention using a randomized control study design. Neuropsychological tests employed where the color slide test, digit symbol test, digit span test, logical memory test, word fluency test, and the Mini‐Mental State Examination. We measured mood using a mood test and geriatric depression scale. Each subject was tested before, and immediately after, control and exercise sessions. Fifteen elderly subjects [ten men and five women; mean age, 66 years, (range, 60 to 85 years)] completed the study. There was a greater improvement in six of the eight scores of cognitive function following exercise, compared to control. These differences were significantly greater following exercise for the logical memory test score (P ≤ 0.02) and Mini‐Mental State Examination (P ≤ 0.025) compared with the control intervention.

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.

Anatomically-distinct genetic associations of APOE epsilon4 allele load with regional cortical atrophy in Alzheimer's disease.

APOE epsilon4 is the best-established genetic risk factor for sporadic Alzheimers disease (AD). However, while homozygotes show greater disease susceptibility and earlier age of onset than heterozygotes, they may not show faster rates of clinical progression. We hypothesize that there are differential APOE epsilon4 allele-load dependent influences on neuropathology across the brain. Our aim was to define the relationship between APOE epsilon4 allele load and regionally-specific brain cortical atrophy in Alzheimers Disease (AD). For this reason voxel-based morphometry (VBM) was performed using T1-weighted MR images from 83 AD patients, contrasting regional cortical grey matter by APOE epsilon4 load according to either dominant or genotypic models. Patients fulfilled NINCDS-ADRDA criteria and were genotyped for APOE epsilon4 (15 epsilon4/epsilon4, 39 epsilon4/- and 29-/-). We observed that grey matter volume (GMV) decreased additively with increasing allele load in the medial (MTL) and anterior temporal lobes bilaterally. By contrast, a 2 degree-of-freedom genotypic model suggested a dominant effect of the APOE epsilon4 allele in the left temporal lobe. Brain regions showing a significant APOE epsilon4 allele load effect on GMV in AD included only some of those typically described as having greatest amyloid plaque deposition and atrophy. Temporal regions appeared to show a dominant effect of APOE epsilon4 allele load instead of the additive effect previously strongly associated with age of onset. Regional variations with allele load may be related to different mechanisms for effects of APOE epsilon4 load on susceptibility and disease progression.

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.

Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease

BACKGROUND Alzheimers disease is characterized by amyloid‐beta (Aβ) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aβ, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid. METHODS We conducted a double‐blind, placebo‐controlled, phase 3 trial involving patients with mild dementia due to Alzheimers disease, defined as a Mini–Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron‐emission tomography or Aβ1‐42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14‐item cognitive subscale of the Alzheimers Disease Assessment Scale (ADAS‐cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment). RESULTS A total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab and 1072 to receive placebo. The mean change from baseline in the ADAS‐cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between‐group difference at week 80 (difference, ‐0.80; 95% confidence interval, ‐1.73 to 0.14; P=0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was ‐3.17 in the solanezumab group and ‐3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group. CONCLUSIONS Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimers disease did not significantly affect cognitive decline. (Funded by Eli Lilly; EXPEDITION3 ClinicalTrials.gov number, NCT01900665.)