Nanoscale flow cytometry-based quantification of blood-based extracellular vesicle biomarkers distinguishes MCI and Alzheimer's disease.

INTRODUCTION: Accurate testing for Alzheimer's disease (AD) represents a crucial step for therapeutic advancement. Currently, tests are expensive and require invasive sampling or radiation exposure. METHODS: We developed a nanoscale flow cytometry (nFC)-based assay of extracellular vesicles (EVs) to screen biomarkers in plasma from mild cognitive impairment (MCI), AD, or controls. RESULTS: Circulating amyloid beta (Aß), tau, phosphorylated tau (p-tau)181, p-tau231, p-tau217, p-tauS235, ubiquitin, and lysosomal-associated membrane protein 1-positive EVs distinguished AD samples. p-tau181, p-tau217, p-tauS235, and ubiquitin-positive EVs distinguished MCI samples. The most sensitive marker for AD distinction was p-tau231, with an area under the receiver operating characteristic curve (AUC) of 0.96 (sensitivity 0.95/specificity 1.0) improving to an AUC of 0.989 when combined with p-tauS235. DISCUSSION: This nFC-based assay accurately distinguishes MCI and AD plasma without EV isolation, offering a rapid approach requiring minute sample volumes. Incorporating nFC-based measurements in larger populations and comparison to "gold standard" biomarkers is an exciting next step for developing AD diagnostic tools. HIGHLIGHTS: Extracellular vesicles represent promising biomarkers of Alzheimer's disease (AD) that can be measured in the peripheral circulation. This study demonstrates the utility of nanoscale flow cytometry for the measurement of circulating extracellular vesicles (EVs) in AD blood samples. Multiple markers including amyloid beta, tau, phosphorylated tau (p-tau)181, p-tau231, p-tau217, and p-tauS235 accurately distinguished AD samples from healthy controls. Future studies should expand blood and cerebrospinal fluid-based EV biomarker development using nanoflow cytometry approaches.

Dual decline in gait speed and cognition is associated with future dementia: evidence for a phenotype.

BACKGROUND: concurrent declines in gait speed and cognition have been associated with future dementia. However, the clinical profile of 'dual decliners', those with concomitant decline in both gait speed and cognition, has not been yet described. We aimed to describe the phenotype and the risk for incident dementia of those who present with dual decline in comparison with non-dual decliners. METHODS: prospective cohort of community-dwelling older adults free of dementia at baseline. We evaluated participants' gait speed, cognition, medical status, functionality, incidence of adverse events and dementia, biannually over 7 years. Gait speed was assessed with a 6-m electronic walkway and global cognition using the MoCA test. We compared characteristics between dual decliners and non-dual decliners using t-test, chi-square and hierarchical regression models. We estimated incident dementia using Cox models. RESULTS: among 144 participants (mean age 74.23 ± 6.72 years, 54% women), 17% progressed to dementia. Dual decliners had a 3-fold risk (HR: 3.12, 95%CI: 1.23-7.93, P = 0.017) of progression to dementia compared with non-dual decliners. Dual decliners were significantly older with a higher prevalence of hypertension and dyslipidemia (P = 0.002). Hierarchical regression models show that age and sex alone explained 3% of the variation in the dual decliners group. Adding hypertension and dyslipidemia increased the explained variation by 8 and 10%, respectively. The risk of becoming a dual decliner was 4-fold higher if hypertension was present. CONCLUSION: older adults with a concurrent decline in gait speed and cognition represent a group at the highest risk of progression to dementia. Older adults with dual decline have a distinct phenotype with a higher prevalence of hypertension, a treatable condition.

Subjective rating of executive functions in mild Alzheimer's disease.

OBJECTIVES: Subjective cognitive decline is considered to be a core feature of pre-Alzheimer's disease (AD) conditions, the vast majority of literature having focused on memory concerns. Neuropsychological studies have implicated executive dysfunction on objective performance measures in AD, but no research has evaluated whether individuals with AD have concerns about their executive functions and whether it differs from their caregiver's concerns. In the present study, we sought to evaluate self- and informant ratings of executive functioning in patients with mild AD. METHOD: Participants were 23 patients with mild AD and 32 healthy elderly controls (HC) and their informants who completed the Behavior Rating Inventory of Executive Function - Adult version. RESULTS: Patients with AD and their informants reported greater executive dysfunction than the HC group and their informants, respectively, and patients reported greater difficulty than their informants. The largest effect size for both self- and informant ratings was obtained for the Working Memory scale. CONCLUSIONS: These findings indicate that subjective cognitive concerns in mild AD extend beyond the memory domain to executive functions. That greater difficulty was endorsed by patients than their informants suggests that at least in the mild stage of AD some awareness of executive dysfunction may be maintained in some patients. Implications for clinical care are discussed.

Taoist Tai Chi® and Memory Intervention for Individuals with Mild Cognitive Impairment.

OBJECTIVE: It was hypothesized that a combined Taoist Tai Chi (TTC) and a memory intervention program (MIP) would be superior to a MIP alone in improving everyday memory behaviors in individuals with amnestic mild cognitive impairment (aMCI). A secondary hypothesis was that TTC would improve cognition, self-reported health status, gait, and balance. METHOD: A total of 48 individuals were randomly assigned to take part in MIP + TTC or MIP alone. The TTC intervention consisted of twenty 90 min sessions. Outcome measures were given at baseline, and after 10 and 22 weeks. RESULTS: Both groups significantly increased their memory strategy knowledge and use, ratings of physical health, processing speed, everyday memory, and visual attention. No preferential benefit was found for individuals in the MIP + TTC group on cognition, gait, or balance measures. CONCLUSIONS: Contrary to expectations, TTC exercise did not specifically improve cognition or physical mobility. Explanations for null findings are explored.

Reduced N-acetylaspartate to creatine ratio in the posterior cingulate correlates with cognition in Alzheimer's disease following four months of rivastigmine treatment.

AIM: To determine whether 4 months of rivastigmine treatment would result in metabolic changes and whether metabolic changes correlate with changes in cognition in people with Alzheimer's disease (AD). METHODS: Magnetic resonance spectra were acquired from the posterior cingulate cortex of subjects with AD at 3 T. Magnetic resonance imaging scans and cognitive tests were performed before and 4 months after the beginning of the treatment. Metabolite concentrations were quantified and used to calculate the metabolite ratios. RESULTS: On average, the N-acetylaspartate/creatine (NAA/Cr) ratio decreased by 12.7% following 4 months of rivastigmine treatment, but changes in the NAA/Cr ratio correlated positively with changes in Mini-Mental State Examination scores. CONCLUSION: This positive correlation between changes in NAA/Cr and changes in cognitive performance suggests that the NAA/Cr ratio could be an objective indicator of a response to rivastigmine treatment.

Motor cortex and gait in mild cognitive impairment: a magnetic resonance spectroscopy and volumetric imaging study.

Gait disorders are common in the course of dementia, even at the stage of mild cognitive impairment, owing to probable changes in higher levels of motor control. Since motor control message is ultimately supported in the brain by the primary motor cortex and since cortical lesions are frequent in the dementia process, we hypothesized that impairments of the primary motor cortex may explain the early gait disorders observed in mild cognitive impairment. Our purpose was to determine whether the neurochemistry of the primary motor cortex measured with proton magnetic resonance spectroscopy, and its volume, were associated with gait performance while single and dual-tasking in mild cognitive impairment. Twenty community dwellers with mild cognitive impairment, aged 76 years (11) [median (interquartile range)] (30% female) from the 'Gait and Brain Study' were included in this analysis. Gait velocity and stride time variability were measured while single (i.e. walking alone) and dual tasking (i.e. walking while counting backwards by seven) using an electronic walkway (GAITRite System). Ratios of N-acetyl aspartate to creatine and choline to creatine and cortical volume were calculated in the primary motor cortex. Participants were categorized according to median N-acetyl aspartate to creatine and choline to creatine ratios. Age, gender, body mass index, cognition, education level and subcortical vascular burden were used as potential confounders. Participants with low N-acetyl aspartate to creatine (n = 10) had higher (worse) stride time variability while dual tasking than those with high N-acetyl aspartate to creatine (P = 0.007). Those with high choline to creatine had slower (worse) gait velocity while single (P = 0.015) and dual tasking (P = 0.002). Low N-acetyl aspartate to creatine was associated with increased stride time variability while dual tasking (adjusted ß = 5.51, P = 0.031). High choline to creatine was associated with slower gait velocity while single (adjusted ß = -26.56, P = 0.009) and dual tasking (adjusted ß = -41.92, P = 0.022). Cortical volume correlated with faster gait velocity while single (P = 0.029) and dual tasking (P = 0.037), and with decreased stride time variability while single tasking (P = 0.034). Finally, the probability of exhibiting abnormal metabolite ratios in the primary motor cortex was 63% higher among participants with major gait disturbances in dual task. Those with compromised gait velocity in dual task had a 2.05-fold greater risk of having a smaller cortical volume. In conclusion, the neurochemistry and volume of the primary motor cortex were associated with gait performance while single and dual tasking. Stride time variability was mainly sensitive to neuronal function (N-acetyl aspartate to creatine), whereas gait velocity was more affected by inflammatory damage (choline to creatine) and volumetric changes. These findings may contribute to a better understanding of the higher risks of mobility decline and falls in subjects with mild cognitive impairment.

Correcting the MoCA for education: effect on sensitivity.

OBJECTIVE: The goal of this study was to quantify the impact of the suggested education correction on the sensitivity and specificity of the Montreal Cognitive Assessment (MoCA). METHOD: Twenty-five outpatients with dementia and 39 with amnestic mild cognitive impairment (aMCI) underwent a diagnostic evaluation, which included the MoCA. Thirty-seven healthy controls also completed the MoCA and psychiatric, medical, neurological, functional, and cognitive difficulties were ruled out. RESULTS: For the total MoCA score, unadjusted for education, a cut-off score of 26 yielded the best balance between sensitivity and specificity (80% and 89% respectively) in identifying cognitive impairment (people with either dementia or aMCI, versus controls). When applying the education correction, sensitivity decreased from 80% to 69% for a small specificity increase (89% to 92%). The cut-off score yielding the best balance between sensitivity and specificity for the education adjusted MoCA score fell to 25 (61% and 97%, respectively). CONCLUSIONS: Adjusting the MoCA total score for education had a detrimental effect on sensitivity with only a slight increase in specificity. Clinically, this loss in sensitivity can lead to an increased number of false negatives, as education level does not always correlate to premorbid intellectual function. Clinical judgment about premorbid status should guide interpretation. However, as this effect may be cohort specific, age and education corrected norms and cut-offs should be developed to help guide MoCA interpretation.

Components of cognitive competence predictive of occupational competence in persons with dementia: a Delphi study.

BACKGROUND: Within the area of dementia care, occupational therapists are asked to predict occupational competence in everyday living and often do so by assessing cognitive competence. Considering the cognitive changes that occur with dementia over time, the construct of cognitive competence is a key consideration. Still, a gap exists in the literature examining the relationship between cognitive competence and occupational competence. PURPOSE: This study developed a consensus among participating Canadian occupational therapists regarding the components of cognitive competence they considered essential to predict occupational competence in people with dementia. METHOD: A three-round Delphi study was completed with English- and French-speaking occupational therapists (n = 127; 116; 125) experienced in dementia care. FINDINGS: Ten cognitive components were identified as essential to predict occupational competence in individuals with dementia. IMPLICATIONS: The 10 identified components provide direction for assessment practices and education in dementia care and for development of measurement tools.

Examining the construct validity of the Cognitive Competency Test for occupational therapy practice.

BACKGROUND: Enhancing occupational therapy practice requires critical examination of assessment tools and the conclusions being drawn from their use. When working with cognitively impaired older individuals, judgments about occupational competence are often informed by an assessment of cognitive competence. PURPOSE: The Cognitive Competency Test (CCT) is a frequently used measure in Canada to inform predictions of occupational competence. However, there is an absence of published evidence that addresses its validity. METHODS: To appraise validity of the CCT, a retrospective chart review (n = 107) of CCT reports for inpatient and outpatient clients with cognitive impairment was conducted. Data were subjected to exploratory factor analyses to examine the factor structure, and the measure was compared with commonly used clinical variables reflecting cognitive and occupational competence. FINDINGS: Results suggest that the CCT measures a unitary construct and provide some support for its predictive capacity. IMPLICATIONS: CCT scores can add incremental validity to cognitive screens, such as the Mini Mental State Exam, when evaluating occupational competence.

Can cognitive enhancers reduce the risk of falls in older people with mild cognitive impairment? A protocol for a randomised controlled double blind trial.

BACKGROUND: Older 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/DESIGN: Double 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. DISCUSSION: By 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 REGISTRATION: The protocol for this study is registered with the Clinical Trials Registry, identifier number: NCT00934531 http://www.clinicaltrials.gov.

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 Alzheimer's 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 Alzheimer's 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.

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

BACKGROUND: Reliability 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. METHODS: The 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). RESULTS: Eleven 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. CONCLUSION: In 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.

Uses of the National Rehabilitation Reporting System: perspectives of geriatric rehabilitation clinicians.

BACKGROUND: The National Rehabilitation Reporting System (NRS) is a minimum data set for inpatient rehabilitation units. The system was designed to support administrative decision making from the facility to the national level. PURPOSE: To conduct a pilot study to explore current and potential clinician uses of NRS data, particularly for hip-fractured clients. METHODS: Focus groups with rehabilitation teams from two urban academic geriatric rehabilitation units in Ontario. FINDINGS: Few current uses were identified; barriers to use included timeliness of data reports and perceived lack of sensitivity to clinically significant changes in functional status. Strategies for resolving these barriers were identified, including customization of data reports. IMPLICATIONS: Clinicians will need to work collaboratively with managers, information technology specialists, and software vendors to explore opportunities to maximize potential usefulness of NRS data.

High field (1)H 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.

Motor and Cognitive Trajectories Before Dementia: Results from Gait and Brain Study.

OBJECTIVES: To compare the trajectories of motor and cognitive decline in older adults who progress to dementia with the trajectories of those who do not. To evaluate the added value of measuring motor and cognitive decline longitudinally versus cross-sectionally for predicting dementia. DESIGN: Prospective cohort study with 5 years of follow-up. SETTING: Clinic based at a university hospital in London, Ontario, Canada. PARTICIPANTS: Community-dwelling participants aged 65 and older free of dementia at baseline (N=154). MEASUREMENTS: We evaluated trajectories in participants' motor performance using gait velocity and cognitive performance using the MoCA test twice a year for 5 years. We ascertained incident dementia risk using Cox regression models and attributable risk analyses. Analyses were adjusted using a time-dependent covariate. RESULTS: Overall, 14.3% progressed to dementia. The risk of dementia was almost 7 times as great for those whose gait velocity declined (hazard ratio (HR)=6.89, 95% confidence interval (CI)=2.18-21.75, p=.001), more than 3 times as great for those with cognitive decline (HR=3.61, 95% CI=1.28-10.13, p=.01), and almost 8 times as great in those with combined gait velocity and cognitive decline (HR=7.83, 95% CI=2.10-29.24, p=.002), with an attributable risk of 105 per 1,000 person years. Slow gait at baseline alone failed to predict dementia (HR=1.16, 95% CI=0.39-3.46, p=.79). CONCLUSION: Motor decline, assessed according to serial measures of gait velocity, had a higher attributable risk for incident dementia than did cognitive decline. A decline over time of both gait velocity and cognition had the highest attributable risk. A single time-point assessment was not sufficient to detect individuals at high risk of dementia.

Association of Dual-Task Gait With Incident Dementia in Mild Cognitive Impairment: Results From the Gait and Brain Study.

Importance: Gait performance is affected by neurodegeneration in aging and has the potential to be used as a clinical marker for progression from mild cognitive impairment (MCI) to dementia. A dual-task gait test evaluating the cognitive-motor interface may predict dementia progression in older adults with MCI. Objective: To determine whether a dual-task gait test is associated with incident dementia in MCI. Design, Setting, and Participants: The Gait and Brain Study is an ongoing prospective cohort study of community-dwelling older adults that enrolled 112 older adults with MCI. Participants were followed up for 6 years, with biannual visits including neurologic, cognitive, and gait assessments. Data were collected from July 2007 to March 2016. Main Outcomes and Measures: Incident all-cause dementia was the main outcome measure, and single- and dual-task gait velocity and dual-task gait costs were the independent variables. A neuropsychological test battery was used to assess cognition. Gait velocity was recorded under single-task and 3 separate dual-task conditions using an electronic walkway. Dual-task gait cost was defined as the percentage change between single- and dual-task gait velocities: ([single-task gait velocity - dual-task gait velocity]/ single-task gait velocity) × 100. Cox proportional hazard models were used to estimate the association between risk of progression to dementia and the independent variables, adjusted for age, sex, education, comorbidities, and cognition. Results: Among 112 study participants with MCI, mean (SD) age was 76.6 (6.9) years, 55 were women (49.1%), and 27 progressed to dementia (24.1%), with an incidence rate of 121 per 1000 person-years. Slow single-task gait velocity (<0.8 m/second) was not associated with progression to dementia (hazard ratio [HR], 3.41; 95% CI, 0.99-11.71; P = .05)while high dual-task gait cost while counting backward (HR, 3.79; 95% CI, 1.57-9.15; P = .003) and naming animals (HR, 2.41; 95% CI, 1.04-5.59; P = .04) were associated with dementia progression (incidence rate, 155 per 1000 person-years). The models remained robust after adjusting by baseline cognition except for dual-task gait cost when dichotomized. Conclusions and Relevance: Dual-task gait is associated with progression to dementia in patients with MCI. Dual-task gait testing is easy to administer and may be used by clinicians to decide further biomarker testing, preventive strategies, and follow-up planning in patients with MCI. Trial Registration: clinicaltrials.gov: NCT03020381.

Disentangling Cognitive-Frailty: Results From the Gait and Brain Study.

BACKGROUND: Cognitive-frailty, defined as the presence of both frailty and cognitive impairment, is proposed as a distinctive entity that predicts dementia. However, it remains controversial whether frailty alone, cognitive-frailty, or the combination of cognitive impairment and slow gait pose different risks of incident dementia. METHODS: Two hundred and fifty-two older adults free of dementia at baseline (mean age 76.6±8.6 years) were followed up to 5 years with bi-annual visits including medical, cognitive, and gait assessments. Incident all-cause of dementia and cognitive decline were the main outcomes. Frailty was defined using validated phenotypic criteria. Cognition was assessed using the Montreal Cognitive Assessment while gait was assessed using an electronic walkway. Cox Proportional Hazards models were used to estimate the risk of cognitive decline and dementia for frailty, cognitive-frailty, and gait and cognition models. RESULTS: Fifty-three participants experienced cognitive decline and 27 progressed to dementia (incident rate: 73/1,000 person-years). Frailty participants had a higher prevalence of cognitive impairment compared with those without frailty (77% vs. 54%, p = .02) but not significant risk to incident dementia. Cognitive-frailty increased incident rate (80/1,000 person-years) but not risk for progression to dementia. The combination of slow gait and cognitive impairment posed the highest risk for progression to dementia (hazard ratio: 35.9, 95% confidence interval: 4.0-319.2; p = 0.001, incident rate: 130/1,000 person-years). None of the models explored significantly predicted cognitive decline. CONCLUSIONS: Combining a simple motor test, such as gait velocity, with a reliable cognitive test like the Montreal Cognitive Assessment is superior than the cognitive-frailty construct to detect individuals at risk for dementia. Cognitive-frailty may embody two different manifestations, slow gait and low cognition, of a common underlying mechanism.

Donepezil improves gait performance in older adults with mild Alzheimer's disease: a phase II clinical trial.

BACKGROUND: Gait deficits are prevalent in people with dementia and increase their fall risk and future disability. Few treatments exist for gait impairment in Alzheimer's disease (AD) but preliminary studies have shown that cognitive enhancers may improve gait in this population. OBJECTIVE: To determine the efficacy of donepezil, a cognitive enhancer that improves cholinergic activity, on gait in older adults newly diagnosed with AD. METHODS: Phase II clinical trial in 43 seniors with mild AD who received donepezil. Participants had not previously received treatment with cognitive enhancers. Primary outcome variables were gait velocity (GV) and stride time variability (STV) under single and dual-task conditions measured using an electronic walkway. Secondary outcomes included attention and executive function. RESULTS: After four months of treatment, participants with mild AD improved their GV from 108.4 ± 18.6 to 113.3 ± 19.5 cm/s, p = 0.010; dual-task GV from 80.6 ± 23.0 to 85.3 ± 22.3 cm/s, p = 0.028. Changes in STV were in the expected direction although not statistically significant. Participants also showed improvements in Trail Making Tests A (p = 0.030), B (p = 0.001), and B-A (p = 0.042). CONCLUSION: Donepezil improved gait in participants with mild AD. The enhancement of dual-task gait suggests the positive changes achieved in executive function as a possible causal mechanism. This study yielded a clinically significant estimate of effect size; as well, the findings are relevant to the feasibility and ethics considerations for the design of a Phase III clinical trial.