IMPORTANCE There are currently no proven treatments to reduce the risk of mild cognitive impairment and dementia. OBJECTIVE To evaluate the effect of intensive blood pressure control on risk of dementia. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial conducted at 102 sites in the United States and Puerto Rico among adults aged 50 years or older with hypertension but without diabetes or history of stroke. Randomization began on November 8, 2010. The trial was stopped early for benefit on its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20,2015. The final date for follow-up of cognitive outcomes was July 22, 2018. INTERVENTIONS Participants were randomized to a systolic blood pressure goal of either less than 120 mm Hg (intensive treatment group; n = 4678) or less than 140 mm Hg (standard treatment group; n = 4683). MAIN OUTCOMES AND MEASURES The primary cognitive outcome was occurrence of adjudicated probable dementia. Secondary cognitive outcomes included adjudicated mild cognitive impairment and a composite outcome of mild cognitive impairment or probable dementia. RESULTS Among 9361 randomized participants (mean age, 67.9 years; 3332 women [35.6%]), 8563 (91.5%) completed at least 1 follow-up cognitive assessment. The median intervention period was 3.34 years. During a total median follow-up of 5.11 years, adjudicated probable dementia occurred in 149 participants in the intensive treatment group vs 176 in the standard treatment group (7.2 vs 8.6 cases per 1000 person-years; hazard ratio [HR], 0.83; 95% CI, 0.67–1.04). Intensive BP control significantly reduced the risk of mild cognitive impairment (14.6 vs 18.3 cases per 1000 person-years; HR, 0.81; 95% CI, 0.69–0.95) and the combined rate of mild cognitive impairment or probable dementia (20.2 vs 24.1 cases per 1000 person-years; HR, 0.85; 95% CI, 0.74–0.97). CONCLUSIONS AND RELEVANCE Among ambulatory adults with hypertension, treating to a systolic blood pressure goal of less than 120 mm Hg compared with a goal of less than 140 mm Hg did not result in a significant reduction in the risk of probable dementia. Because of early study termination and fewer than expected cases of dementia, the study may have been underpowered for this end point.

The effect of intensive blood pressure lowering on brain health remains uncertain. OBJECTIVE To evaluate the association of intensive blood pressure treatment with cerebral white matter lesion and brain volumes. DESIGN, SETTING, AND PARTICIPANTS A substudy of a multicenter randomized clinical trial of hypertensive adults 50 years or older without a history of diabetes or stroke at 27 sites in the United States. Randomization began on November 8, 2010. The overall trial was stopped early because of benefit for its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. Brain magnetic resonance imaging (MRI) was performed on a subset of participants at baseline (n = 670) and at 4 years of follow-up (n = 449); final follow-up date was July 1, 2016. INTERVENTIONS Participants were randomized to a systolic blood pressure (SBP) goal of either less than 120 mm Hg (intensive treatment, n = 355) or less than 140 mm Hg (standard treatment, n = 315). MAIN OUTCOMES AND MEASURES The primary outcome was change in total white matter lesion volume from baseline. Change in total brain volume was a secondary outcome. RESULTS Among 670 recruited patients who had baseline MRI (mean age, 67.3 [SD, 8.2] years; 40.4% women), 449 (67.0%) completed the follow-up MRI at a median of 3.97 years after randomization, after a median intervention period of 3.40 years. In the intensive treatment group, based on a robust linear mixed model, mean white matter lesion volume increased from 4.57 to 5.49 cm 3 (difference, 0.92 cm 3 [95% CI, 0.69 to 1.14]) vs an increase from 4.40 to 5.85 cm 3 (difference, 1.45 cm 3 [95% CI, 1.21 to 1.70]) in the standard treatment group (between-group difference in change, −0.54 cm 3 [95% CI, −0.87 to −0.20]). Mean total brain volume decreased from 1134.5 to 1104.0 cm 3 (difference, −30.6 cm 3 [95% CI, −32.3 to −28.8]) in the intensive treatment group vs a decrease from 1134.0 to 1107.1 cm 3 (difference, −26.9 cm 3 [95% CI, 24.8 to 28.8]) in the standard treatment group (between-group difference in change, −3.7 cm 3 [95% CI, −6.3 to −1.1]). CONCLUSIONS AND RELEVANCE Among hypertensive adults, targeting an SBP of less than 120 mm Hg, compared with less than 140 mm Hg, was significantly associated with a smaller increase in cerebral white matter lesion volume and a greater decrease in total brain volume, although the differences were small.

BackgroundThe efficacy of non-pharmacological intervention approaches such as physical activity, strength, and cognitive training for improving brain health has not been established. Before definitive trials are mounted, important design questions on participation/adherence, training and interventions effects must be answered to more fully inform a full-scale trial.MethodsSHARP-P was a single-blinded randomized controlled pilot trial of a 4-month physical activity training intervention (PA) and/or cognitive training intervention (CT) in a 2 × 2 factorial design with a health education control condition in 73 community-dwelling persons, aged 70-85 years, who were at risk for cognitive decline but did not have mild cognitive impairment.ResultsIntervention attendance rates were higher in the CT and PACT groups: CT: 96%, PA: 76%, PACT: 90% (p=0.004), the interventions produced marked changes in cognitive and physical performance measures (p≤0.05), and retention rates exceeded 90%. There were no statistically significant differences in 4-month changes in composite scores of cognitive, executive, and episodic memory function among arms. Four-month improvements in the composite measure increased with age among participants assigned to physical activity training but decreased with age for other participants (intervention*age interaction p = 0.01). Depending on the choice of outcome, two-armed full-scale trials may require fewer than 1,000 participants (continuous outcome) or 2,000 participants (categorical outcome).ConclusionsGood levels of participation, adherence, and retention appear to be achievable for participants through age 85 years. Care should be taken to ensure that an attention control condition does not attenuate intervention effects. Depending on the choice of outcome measures, the necessary sample sizes to conduct four-year trials appear to be feasible.Trial RegistrationClinicaltrials.gov Identifier: NCT00688155

OBJECTIVEWe examined the effects of an intensive lifestyle intervention (ILI), compared with a diabetes support and education (DSE) control intervention, on long-term changes in depression symptoms, antidepressant medication (ADM) use, and health-related quality of life (HRQoL) in overweight/obese individuals with type 2 diabetes.RESEARCH DESIGN AND METHODSLook AHEAD was a multisite randomized controlled trial of 5,145 overweight/obese participants assigned to ILI (designed to produce weight loss) or DSE and followed for a median of 9.6 years. The Beck Depression Inventory (BDI) was administered at baseline, annually at years 1–4, and again at year 8. Mean BDI scores and incidence of BDI scores ≥10, indicative of likely mild or greater depression, were examined. Annually through year 10, participants reported their ADM use and completed the Medical Outcomes Study Short Form 36 (SF-36) questionnaire, which yields physical component summary (PCS) and mental component summary (MCS) scores.RESULTSILI significantly reduced the incidence of mild or greater depression symptoms (BDI scores ≥10) compared with DSE (hazard ratio [HR] = 0.85; 95% CI 0.75–0.97; P = 0.0145). Although SF-36 PCS scores worsened over time in both groups, ILI participants reported better physical function than DSE throughout the first 8 years (all P values <0.01). There were no significant differences between treatment arms in the proportion of participants who used ADMs or in SF-36 MCS scores.CONCLUSIONSILI for overweight/obese patients with type 2 diabetes may reduce the risk of developing clinically significant symptoms of depression and preserve physical HRQoL. These findings should be considered when evaluating the potential benefits of ILIs.

This review discusses major findings from the Women's Health Initiative Memory Study (WHIMS). WHIMS reported hormone therapy (HT) - conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA) - increased the risk for dementia (HR 1.76 [95% CI, 1.19-2.60]; P=0.005) and global cognitive decline, with a mean decrement relative to placebo of 0.21 points on the Modified Mini Mental State Examination (3MS) (P=0.006) in women age 65 and older. A subset of WHIMS participants joined the ancillary WHI Study of Cognitive Aging (WHISCA) trials, in which domain-specific cognitive tests and mood were measured annually. Compared with placebo, CEE+MPA had a negative impact on verbal memory over time (p=0.01); and CEE-Alone was associated with lower spatial rotational ability (p=<.01) at the initial assessment, but the difference diminished over time. The ancillary WHIMS-MRI study measured subclinical cerebrovascular disease to possibly explain the negative cognitive findings reported by WHIMS and the increased clinical stroke in older women reported by the WHI. WHIMS-MRI reported that while CEE+MPA and CEE-Alone were not associated with increased ischemic brain lesion volume relative to placebo; both CEE+MPA and CEE-Alone were associated with lower mean brain volumes in the hippocampus (p=0.05); frontal lobe (p=0.004);and total brain (p=0.07). HT-associated reductions in hippocampal volumes were greatest in women with baseline 3MS scores ≤ 90.