BACKGROUND The most appropriate targets for systolic blood pressure to reduce cardiovascular morbidity and mortality among persons without diabetes remain uncertain. METHODS We randomly assigned 9361 persons with a systolic blood pressure of 130 mm Hg or higher and an increased cardiovascular risk, but without diabetes, to a systolic blood-pressure target of less than 120 mm Hg (intensive treatment) or a target of less than 140 mm Hg (standard treatment). The primary composite outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. RESULTS At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard-treatment group. The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the standard-treatment group (1.65% per year vs. 2.19% per year; hazard ratio with intensive treatment, 0.75; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). All-cause mortality was also significantly lower in the intensive-treatment group (hazard ratio, 0.73; 95% CI, 0.60 to 0.90; P = 0.003). Rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensive-treatment group than in the standard-treatment group. CONCLUSIONS Among patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01206062.)

SUMMARY Importance In older adults reduced mobility is common and is an independent risk factor for morbidity, hospitalization, disability, and mortality. Limited evidence suggests that physical activity may help prevent mobility disability; however, there are no definitive clinical trials examining if physical activity prevents or delays mobility disability. Objective To test the hypothesis that a long-term structured physical activity program is more effective than a health education program (also referred to as a successful aging program) in reducing the risk of major mobility disability. Design, Setting, and Participants The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicenter, randomized trial that enrolled participants between February 2010 and December 2011, who participated for an average of 2.6 years. Follow-up ended in December 2013. Outcome assessors were blinded to the intervention assignment. Participants were recruited from urban, suburban and rural communities at 8 field centers throughout the US. We randomized a volunteer sample of 1,635 sedentary men and women aged 70–89 years who had physical limitations, defined as a score on the Short Physical Performance Battery of 9 or below, but were able to walk 400 m. Interventions Participants were randomized to a structured moderate intensity physical activity program (n=818) done in a center and at home that included including aerobic, resistance and flexibility training activities or to a health education program (n=817) consisting of workshops on topics relevant to older adults and upper extremity stretching exercises. Main Outcomes and Measures The primary outcome was major mobility disability objectively defined by loss of ability to walk 400 m. Results Incident major mobility disability occurred in 30.1% (n=246/818) of physical activity and 35.5% (n=290/817) of health education participants (HR=0.82, 95%CI=0.69–0.98, p=0.03). Persistent mobility disability was experienced by 120/818 (14.7%) physical activity and 162/817 (19.8%) health education participants (HR=0.72; 95%CI=0.57–0.91; p=0.006). Serious adverse events were reported by 404/818 (49.4%) of the physical activity and 373/817 (45.7%) of the health education participants (Risk Ratio=1.08; 95%CI=0.98–1.20). Conclusions and Relevance A structured moderate intensity physical activity program, compared with a health education program, reduced major mobility disability over 2.6 years among older adults at risk of disability. These findings suggest mobility benefit from such a program in vulnerable older adults. Registration ClinicalsTrials.gov identifier NCT01072500.

No abstract

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.

P TO 50% OF COMMUNITYdwelling elderly individuals older than 85 years have dementia, with Alzheimer disease (AD), vascular dementia, and dementia with Lewy bodies accounting for most cases. 1,2 Although cognitive deficits are the clinical hallmark of dementing illnesses, noncognitive symptoms are common and can dominate disease presentation. These include an array of neuropsychiatric symptoms, such as agitation, aggression, delusions, hallucinations, repetitive vocalizations, and wandering, among other symptoms. Neuropsychiatric symptoms have been observed in 60% to 98% of patients with dementia, [3][4][5][6][7] especially in later stages, and are associated with caregiver stress and depression, as well as reduced caregiver employment and income. [8][9][10][11][12][13] Neuropsychiatric symptoms are also associated with increased hospital lengths of stay 14 and commonly lead to nursing home placement. [15][16][17] Federal expenditures for dementia are expected to triple in the next 10 years 18 and 30% of the cost of caring for patients with AD is attributed directly to the management of neuropsychiatric CME available online at www.jama.com Context Neuropsychiatric symptoms of dementia are common and associated with poor outcomes for patients and caregivers. Although nonpharmacological interventions should be the first line of treatment, a wide variety of pharmacological agents are used in the management of neuropsychiatric symptoms; therefore, concise, current, evidence-based recommendations are needed.Objective To evaluate the efficacy of pharmacological agents used in the treatment of neuropsychiatric symptoms of dementia.Evidence Acquisition A systematic review of English-language articles published from 1966 to July 2004 using MEDLINE, the Cochrane Database of Systematic Reviews, and a manual search of bibliographies was conducted. Inclusion criteria were double-blind, placebo-controlled, randomized controlled trials (RCTs) or metaanalyses of any drug therapy for patients with dementia that included neuropsychiatric outcomes. Trials reporting only depression outcomes were excluded. Data on the inclusion criteria, patients, methods, results, and quality of each study were independently abstracted. Twenty-nine articles met inclusion criteria.Evidence Synthesis For typical antipsychotics, 2 meta-analyses and 2 RCTs were included. Generally, no difference among specific agents was found, efficacy was small at best, and adverse effects were common. Six RCTs with atypical antipsychotics were included; results showed modest, statistically significant efficacy of olanzapine and risperidone, with minimal adverse effects at lower doses. Atypical antipsychotics are associated with an increased risk of stroke. There have been no RCTs designed to directly compare the efficacy of typical and atypical antipsychotics. Five trials of antidepressants were included; results showed no efficacy for treating neuropsychiatric symptoms other than depression, with the exception of 1 study of citalopram. For mood stabilizers, 3 RCTs in...