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Background: In addition to cognitive deficits, people with mild cognitive impairment (MCI) can experience motor dysfunction, including deficits in gait and balance. Objective, instrumented motor performance assessment may allow the detection of subtle MCI-related motor deficits, allowing early diagnosis and intervention. Motor assessment under dual-task conditions may increase diagnostic accuracy; however, the sensitivity of different cognitive tasks is unclear. Objective: To systematically review the extant literature focusing on instrumented assessment of gait and balance parameters for discriminating MCI patients from cognitively intact peers. Methods: Database searches were conducted in PubMed, EMBASE, Cochrane Library, PsycINFO and Web of Science. Inclusion criteria were: (1) clinically confirmed MCI; (2) instrumented measurement of gait and/or balance; (3) English language, and (4) reporting gait or balance parameters which could be included in a meta-analysis for discriminating between MCI patients and cognitively intact individuals based on weighted effect size (d). Results: Fourteen studies met the inclusion criteria and reported quantitative gait (n = 11) or postural balance (n = 4) parameters to be included in the meta-analysis. The meta-analysis revealed that several gait parameters including velocity (d = -0.74, p < 0.01), stride length (d = -0.65, p < 0.01), and stride time (mean: d = 0.56, p = 0.02; coefficient of variation: d = 0.50, p < 0.01) discriminated best between MCI and healthy controls under single-task conditions. Importantly, dual-task assessment increased the discriminative power of gait variables wherein gait variables with counting tasks appeared to be more sensitive (range d = 0.84-1.35) compared to verbal fluency tasks such as animal naming (range d = 0.65-0.94). Balance parameters identified as significant discriminators were anterior-posterior (d = 0.49, p < 0.01) and mediolateral (d = -0.34, p = 0.04) sway position in the eyes-open condition but not eyes-closed condition. Conclusion: Existing studies provide evidence that MCI affects specificgait parameters. MCI-related gait changes were most pronounced when subjects are challenged cognitively (i.e., dual task), suggesting that gait assessment with an additional cognitive task is useful for diagnosis and outcome analysis in the target population. Static balance seems to also be affected by MCI, although limited evidence exists. Instrumented motor assessment could provide a critical opportunity for MCI diagnosis and tailored intervention targeting specific deficits and potentially slowing progression to dementia. Further studies are required to confirm our findings.

Background Epidemiologic evidence suggests that non-steroidal anti-inflammatory drugs (NSAIDs) delay onset of Alzheimer’s dementia (AD), but randomized trials show no benefit from NSAIDs in symptomatic AD. ADAPT randomized 2,528 elderly persons to naproxen or celecoxib vs. placebo for two years (s.d. 11 months) before treatments were terminated. During the treatment interval, 32 cases of AD revealed increased rates in both NSAID-assigned groups. Methods We continued the double-masked ADAPT protocol for two additional years to investigate incidence of AD (primary outcome). We then collected cerebrospinal fluid (CSF) from 117 volunteer participants to assess their ratio of CSF tau to Aβ1–42. Results Including 40 new events observed during follow-up of 2,071 randomized individuals (92% of participants at treatment cessation), there were now 72 AD cases. Overall NSAID-related harm was no longer evident, but secondary analyses showed that increased risk remained notable in the first 2.5 years of observations, especially in 54 persons enrolled with Cognitive Impairment – No Dementia (CIND). These same analyses showed later reduction in AD incidence among asymptomatic enrollees given naproxen. CSF biomarker assays suggested that the latter result reflected reduced Alzheimer-type neurodegeneration. Conclusions These data suggest a revision of the original ADAPT hypothesis that NSAIDs reduce AD risk, thus: NSAIDs have an adverse effect in later stages of AD pathogenesis, while asymptomatic individuals treated with conventional NSAIDs like naproxen experience reduced AD incidence, but only after 2 – 3 years. Thus, treatment effects differ at various stages of disease. This hypothesis is consistent with data from both trials and epidemiological studies.

Previous studies have suggested that statin therapy may be of benefit in treating Alzheimer's disease (AD). We initiated a double-blind, placebo-controlled, randomized (1:1) trial with a 1-year exposure to once-daily atorvastatin calcium (80 mg; two 40 mg tablets) or placebo among individuals with mild-to-moderate AD [Mini-Mental State Examination (MMSE) score of 12-28]. Stable dose use of cholinesterase inhibitors, estrogen and vitamin E was allowed, as was the use of most other medications in the treatment of co-morbidities. We demonstrated that atorvastatin treatment produced significantly (P = 0.003) improved performance on cognition and memory after 6 months of treatment (ADAS-cog) among patients with mild-to-moderate AD. This superior effect persisted at 1 year (P = 0.055). This positive effect on the ADAS-cog performance after 6 months of treatment was more prominent among individuals entering the trial with higher MMSE scores (P = 0.054). Benefit on other clinical measures was identified in the atorvastatin-treated population compared with placebo. Accordingly, atorvastatin therapy may be of benefit in the treatment of mild-to-moderately affected AD patients, but the level of benefit produced may be predicated on earlier treatment. Evidence also suggests that atorvastatin may slow the progression of mild-to-moderate AD, thereby prolonging the quality of an afflicted individual's life.

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