Blood Pressure Variability and Progression of Clinical Alzheimer Disease.

Blood pressure variability (BPV) has been shown to have predictive value over blood pressure (BP) levels alone in stroke patients. We assessed whether BPV predicts cognitive and functional decline in Alzheimer disease, using data from a randomized trial (NILVAD [A European Multicentre Double-blind Placebo-controlled Phase III Trial of Nilvadipine in Mild to Moderate Alzheimer's Disease]). Patients with mild-to-moderate Alzheimer disease were included if they had ≥3 office BP measurements available to determine visit-to-visit BPV. Day-to-day BPV was assessed using home BP measurements in a subsample. The variation independent of mean was used to calculate BPV. Outcomes were change in Alzheimer's Disease Assessment Scale-cognitive subscale-12 and Disability Assessment for Dementia after 1 and 1.5 years. A total of 460 patients aged 72.1 (SD=8.1) years, with mean BP of 134.0/75.1 (10.9/6.3) mm Hg were included. After 1 year, patients in the highest quartile of BPV had deteriorated more on Alzheimer's Disease Assessment Scale-cognitive subscale compared with patients in the lowest quartile (systolic: ß, 2.24 [95% CI, 0.11-4.38], P=0.040; diastolic: ß, 2.54 [95% CI, 0.33-4.75] P=0.024). This association was still present after 1.5 years (systolic: ß, 2.86 [95% CI, 0.35-5.36], P=0.026; diastolic: ß, 3.30 [95% CI, 0.67-5.93], P=0.014). There was no effect of visit-to-visit BPV on Disability Assessment for Dementia. Day-to-day BPV was available for 46 patients. Significant associations were observed between day-to-day BPV and deterioration on Alzheimer's Disease Assessment Scale-cognitive subscale (systolic: P=0.036) and Disability Assessment for Dementia (systolic: P=0.020; diastolic: P=0.007) after 1 year, but not after 1.5 years. All associations were adjusted for potential confounders, including intervention group. In conclusion, this post hoc analysis indicates that higher visit-to-visit and day-to-day BPV might be associated with progression of Alzheimer disease. Targeting BPV may be a future target to slow decline in patients with Alzheimer disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02017340.

Effects of Nilvadipine on Cerebral Blood Flow in Patients With Alzheimer Disease.

Cerebrovascular changes, including reduced cerebral blood flow (CBF), occur early in the development of Alzheimer disease and may accelerate disease progression. This randomized, double-blind, placebo-controlled study investigated how 6 months of treatment with the calcium antagonist nilvadipine would affect CBF in patients with mild-to-moderate Alzheimer disease. CBF was measured with magnetic resonance arterial spin labeling in whole-brain gray matter and in a priori defined regions of interest including the hippocampus. Fifty-eight patients were randomly assigned (29 in each group), of whom 22 in both groups had no magnetic resonance exclusion criteria and were medication compliant over 6 months. Mean age was 72.8±6.2 years, mean mini-mental state examination was 20.4±3.4. Nilvadipine treatment lowered systolic blood pressure (Δ=-11.5 [95% CI, -19.7 to -3.2] mm Hg; P<0.01), while whole-brain gray-matter CBF remained stable (Δ=5.4 [95% CI, -6.4 to 17.2] mL/100 g per minute; P=0.36). CBF in the hippocampus increased (left: Δ=24.4 [95% CI, 4.3-44.5] mL/100 g per minute; P=0.02; right: Δ=20.1 [95% CI, -0.6 to 40.8] mL/100 g per minute; P=0.06). There was no significant change in CBF in the posterior cingulate cortex (Δ=5.2 [95% CI, -16.5 to 27.0] mL/100 g per minute; P=0.63) or other regions of interest. In conclusion, nilvadipine reduced blood pressure and increased CBF in the hippocampus, whereas other regions showed stable or small nonsignificant increases in CBF. These findings not only indicate preserved cerebral autoregulation in Alzheimer disease but also point toward beneficial cerebrovascular effects of antihypertensive treatment. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT02017340.

Blood Pressure Lowering With Nilvadipine in Patients With Mild-to-Moderate Alzheimer Disease Does Not Increase the Prevalence of Orthostatic Hypotension.

Background Hypertension is common among patients with Alzheimer disease. Because this group has been excluded from hypertension trials, evidence regarding safety of treatment is lacking. This secondary analysis of a randomized controlled trial assessed whether antihypertensive treatment increases the prevalence of orthostatic hypotension (OH) in patients with Alzheimer disease. Methods and Results Four hundred seventy-seven patients with mild-to-moderate Alzheimer disease were randomized to the calcium-channel blocker nilvadipine 8 mg/day or placebo for 78 weeks. Presence of OH (blood pressure drop ≥20/≥10 mm Hg after 1 minute of standing) and OH-related adverse events (dizziness, syncope, falls, and fractures) was determined at 7 follow-up visits. Mean age of the study population was 72.2±8.2 years and mean Mini-Mental State Examination score was 20.4±3.8. Baseline blood pressure was 137.8±14.0/77.0±8.6 mm Hg. Grade I hypertension was present in 53.4% (n=255). After 13 weeks, blood pressure had fallen by -7.8/-3.9 mm Hg for nilvadipine and by -0.4/-0.8 mm Hg for placebo ( P<0.001). Across the 78-week intervention period, there was no difference between groups in the proportion of patients with OH at a study visit (odds ratio [95% CI]=1.1 [0.8-1.5], P=0.62), nor in the proportion of visits where a patient met criteria for OH, corrected for number of visits (7.7±13.8% versus 7.3±11.6%). OH-related adverse events were not more often reported in the intervention group compared with placebo. Results were similar for those with baseline hypertension. Conclusions This study suggests that initiation of a low dose of antihypertensive treatment does not significantly increase the risk of OH in patients with mild-to-moderate Alzheimer disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT02017340.

The impact of exercise on the cognitive functioning of healthy older adults: a systematic review and meta-analysis.

Data from epidemiological, cross-sectional, and neuroimaging research show a relationship between higher levels of exercise and reduced risk of cognitive decline but evidence from randomised controlled trials (RCTs) is less consistent. This review examines the impact of aerobic exercise, resistance training, and Tai Chi on the cognitive function of older adults without known cognitive impairment. We investigate explanations for inconsistent results across trials and discrepancies between evidence from RCTs and other research data. Twenty-five RCTs were included in the review. Meta-analysis results revealed significant improvements for resistance training compared to stretching/toning on measures of reasoning (p<0.005); and for Tai Chi compared to 'no exercise' controls on measures of attention (p<0.001) and processing speed (p<0.00001). There were no significant differences between exercise and controls on any of the remaining 26 comparisons. Results should be interpreted with caution however as differences in participant profiles, study design, exercise programmes, adherence rates, and outcome measures contribute to both discrepancies within the exercise research literature and inconsistent results across trials.

Impaired capacity for autonoetic reliving during autobiographical event recall in mild Alzheimer's disease.

The capacity to mentally travel back in time and relive past events via autonoetic consciousness has been shown to be compromised even in the early stages of Alzheimer's disease (AD). To further understand the unravelling of the recollective experience in pathological ageing, we investigated autobiographical memory (ABM) using the Episodic Autobiographical Memory Interview (EAMI) in thirty middle-aged and thirty healthy elderly controls, and twenty patients with mild AD. Of key interest was the recall of contextual details and the behavioural markers predictive of autonoetic reliving. AD patients exhibited significant difficulties in recalling contextual details across all life epochs on the EAMI manifesting in a negative temporal gradient from the Early Adulthood epoch onwards. Overall there was a low incidence of autonoetic consciousness during ABM recall across all participant groups and life epochs when compared with previous studies. AD patients showed a compromised capacity to mentally relive past memories (AD

Exploring the recollective experience during autobiographical memory retrieval in amnestic mild cognitive impairment.

Autonoetic consciousness refers to the ability to mentally transport oneself back in subjective time to relive elements of, or all, of a past event, and is compromised in the early stages of Alzheimer's disease (AD). Here, we investigate autobiographical memory (ABM) and the recollective experience in amnestic mild cognitive impairment (aMCI). aMCI participants exhibited significant deficits compared with healthy elderly controls for both personal semantic and event detail components of ABM. These decrements were evident across all life epochs for episodic recall. Recall of an event that occurred 1 week previously, was tested in the same spatiotemporal context, and provided the greatest group dissociation, with elderly controls benefitting from a context-dependent memory effect. This reinstantiation of context did not ameliorate the anterograde deficits in the aMCI cohort, nor did it facilitate the mental reliving of these memories for either participant group. Whereas reliving judgments were comparable in both groups, aMCI participants exhibited a compromised capacity to generate vivid, self-referential visual imagery and to re-experience the original emotion of events. These contextual and experiential deficits extended beyond recently encountered events into remote epochs, and suggest a greater level of ABM impairment in aMCI than previously assumed.

Investigating the enhancing effect of music on autobiographical memory in mild Alzheimer's disease.

The enhancing effect of music on autobiographical memory recall in mild Alzheimer's disease individuals (n = 10; Mini-Mental State Examination score >17/30) and healthy elderly matched individuals (n = 10; Mini-Mental State Examination score 25-30) was investigated. Using a repeated-measures design, each participant was seen on two occasions: once in music condition (Vivaldi's 'Spring' movement from 'The Four Seasons') and once in silence condition, with order counterbalanced. Considerable improvement was found for Alzheimer individuals' recall on the Autobiographical Memory Interview in the music condition, with an interaction for condition by group (p < 0.005). There were no differences in terms of overall arousal using galvanic skin response recordings or attentional errors during the Sustained Attention to Response Task. A significant reduction in state anxiety was found on the State Trait Anxiety Inventory in the music condition (p < 0.001), suggesting anxiety reduction as a potential mechanism underlying the enhancing effect of music on autobiographical memory recall.