Cerebral autoregulation and baroreflex sensitivity are key mechanisms that maintain cerebral blood flow. This study assessed whether these control mechanisms are affected in patients with dementia and mild cognitive impairment due to Alzheimer disease, as this would increase the risks of antihypertensive treatment. We studied 53 patients with dementia (73.1 years [95% confidence interval (CI), 71.4-74.8]), 37 patients with mild cognitive impairment (69.2 years [95% CI, 66.4-72.0]), and 47 controls (69.4 years [95% CI, 68.3-70.5]). Beat-to-beat blood pressure (photoplethysmography), heart rate, and cerebral blood flow velocity (transcranial Doppler) were measured during 5-minute rest (sitting) and 5 minutes of orthostatic challenges, using repeated sit-to-stand maneuvers. Cerebral autoregulation was assessed using transfer function analysis and the autoregulatory index. Baroreflex sensitivity was estimated with transfer function analysis and by calculating the heart rate response to blood pressure changes during the orthostatic challenges. Dementia patients had the lowest cerebral blood flow velocity (=0.004). During rest, neither transfer function analysis nor the autoregulatory index indicated impairments in cerebral autoregulation. During the orthostatic challenges, higher autoregulatory index (=0.011) and lower transfer function gain (=0.017), indicating better cerebral autoregulation, were found in dementia (4.56 arb. unit [95% CI, 4.14-4.97]; 0.59 cm/s per mm Hg [95% CI, 0.51-0.66]) and mild cognitive impairment (4.59 arb. unit [95% CI, 4.04-5.13]; 0.51 cm/s per mm Hg [95% CI, 0.44-0.59]) compared with controls (3.71 arb. unit [95% CI, 3.35-4.07]; 0.67 cm/s per mm Hg [95% CI, 0.59-0.74]). Baroreflex sensitivity measures did not differ between groups. In conclusion, the key mechanisms to control blood pressure and cerebral blood flow are not reduced in 2 stages of Alzheimer disease compared with controls, both in rest and during orthostatic changes that reflect daily life challenges.

Background Research links blood pressure variability ( BPV ) with stroke; however, the association with cerebral small‐vessel disease ( CSVD ) remains unclear. As BPV and mean blood pressure are interrelated, it remains uncertain whether BPV adds additional information to understanding cerebrovascular morphological characteristics. Methods and Results A systematic review was performed from inception until March 3, 2019. Eligibility criteria included population, adults without stroke (<4 weeks); exposure, BPV quantified by any metric over any duration; comparison, (1) low versus high or mean BPV and (2) people with versus without CSVD ; and outcomes, (1) CSVD as subcortical infarct, lacunae, white matter hyperintensities, cerebral microbleeds, or enlarged perivascular spaces; and (2) standardized mean difference in BPV . A total of 27 articles were meta‐analyzed, comprising 12 309 unique brain scans. A total of 31 odds ratios ( OR s) were pooled, indicating that higher systolic BPV was associated with higher odds for CSVD ( OR, 1.27; 95% CI, 1.14–1.42; I 2 =85%) independent of mean systolic pressure. Likewise, higher diastolic BPV was associated with higher odds for CSVD ( OR, 1.30; 95% CI, 1.14–1.48; I 2 =53%) independent of mean diastolic pressure. There was no evidence of a pairwise interaction between systolic/diastolic and BPV /mean OR s ( P =0.47), nor a difference between BPV versus mean pressure OR s ( P =0.58). Fifty‐four standardized mean differences were pooled and provided similar results for pairwise interaction ( P =0.38) and difference between standardized mean differences ( P =0.70). Conclusions On the basis of the available studies, BPV was associated with CSVD independent of mean blood pressure. However, more high‐quality longitudinal data are required to elucidate whether BPV contributes unique variance to CSVD morphological characteristics.

Research links high blood pressure variability (BPV) with stroke and cerebrovascular disease, however, its association with cognition remains unclear. Moreover, it remains uncertain which BP-derived parameter (ie, variability or mean) holds more significance in understanding vascular contributions to cognitive impairment. We searched PubMed, Embase, PsycINFO, and Scopus and performed a meta-analysis of studies that quantified the association between resting BPV with dementia or cognitive impairment in adults. Two authors independently reviewed all titles, abstracts, and full-texts and extracted data, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analysis of Observational Studies in Epidemiology guidelines. Study quality was assessed using the (modified) Newcastle-Ottawa Scale. A multilevel meta-analysis was used, which included effect sizes for both BPV and mean BP, with a combined end point of dementia or cognitive impairment as primary outcome. In the primary analysis, 54 effect sizes were extracted from 20 studies, with a total analytical sample of n=7 899 697. Higher systolic BPV (odds ratio [OR], 1.25 [95% CI, 1.16–1.35]), mean systolic pressure (OR, 1.12 [95% CI, 1.02–1.29]), diastolic BPV (OR, 1.20 [95% CI, 1.12–1.29]), and mean diastolic pressure (OR, 1.16 [95% CI, 1.04–1.29]) were associated with dementia and cognitive impairment. A direct comparison showed that mean BP effect sizes were less strong than BPV effect sizes (OR, 0.92 [95% CI, 0.87–0.97], P <0.01), indicating that the relative contribution of BPV exceeded that of mean BP. Methodological and statistical heterogeneity was high. Secondary analyses were less consistent as to whether BPV and mean BP were differentially associated with dementia subtypes and cognitive domains. Future studies are required to investigate BPV as a target for dementia prevention.

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 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: β, 2.24 [95% CI, 0.11–4.38], P =0.040; diastolic: β, 2.54 [95% CI, 0.33–4.75] P =0.024). This association was still present after 1.5 years (systolic: β, 2.86 [95% CI, 0.35–5.36], P =0.026; diastolic: β, 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.

Background: In older age, the benefits of antihypertensive treatment (AHT) become less evident, with greater associated risk. Of particular concern is compromising cerebral blood flow (CBF), especially in those with cognitive impairment. Methods: We created a synthesis of the published evidence by searching multiple electronic databases from 1970 to May 2021. Included studies had participants with mean age ≥50 years, hypertension and cognitive impairment, and assessed CBF before and after initiating AHT. Two authors independently determined eligibility and extracted data. Study quality was assessed using The Risk of Bias in Nonrandomized Studies of Interventions tool. We summarized study characteristics (qualitative synthesis) and performed random-effects meta-analyses (quantitative synthesis). Results: Thirty-two studies (total n=1306) were included, of which 23 were eligible for meta-analysis. In line with the qualitative synthesis, the meta-analysis indicated no effect of AHT initiation on CBF (standardized mean difference, 0.08 [95% CI, −0.07 to 0.22]; P =0.31, I 2 =42%). This was consistent across subgroups of acute versus chronic AHT, drug class, study design, and CBF measurement. Subgroups by age demonstrated an increase in CBF after AHT in those aged >70 years (standardized mean difference, 4.15 [95% CI, 0.16–8.15]; P =0.04, I 2 =42%), but not in those aged 50 to 65 and 65 to 70 years (standardized mean difference, 0.18 [95% CI,−2.02 to 2.38]; P =0.87, I 2 =49%; standardized mean difference, 1.22 [95% CI, −0.45 to 2.88]; P =0.15, I 2 =68%). Overall, risk of bias was moderate-to-high and quality of evidence (Grading of Recommendations Assessment, Development and Evaluation) was very low, reflecting the observational nature of the data. Conclusions: Accepting the observed limitations, current evidence does not suggest a harmful effect of AHT on CBF. Concerns over CBF should not preclude treatment of hypertension.

Background: High visit-to-visit blood pressure variability (BPV) has been associated with cognitive decline and cerebral small vessel disease (cSVD), in particular cerebrovascular lesions. Whether day-today BPV also relates to cSVD has not been investigated. Objective: To investigate the cross-sectional association between day-today BPV and total cSVD MRI burden in older memory clinic patients. Methods: We included outpatients referred to our memory clinic, who underwent cerebral MRI as part of their diagnostic assessment. We determined the validated total cSVD score (ranging from 0-4) by combining four markers of cSVD that were visually rated. Home blood pressure (BP) measurements were performed for one week, twice a day, according to international guidelines. BPV was defined as the within-subject coefficient of variation (CV; standard deviation/mean BP*100). We used multivariable ordinal logistic regression analyses adjusted for age, sex, smoking, diabetes, antihypertensive medication, history of cardiovascular disease, and mean BP. Results: For 82 patients (aged 71.2 ± 7.9 years), mean home BP was 140/79 ± 15/9 mmHg. Dementia and mild cognitive impairment were diagnosed in 46% and 34%, respectively. 78% had one or more markers of cSVD. Systolic CV was associated with cSVD burden (adjusted odds ratio per point increase in CV = 1.29, 95% confidence interval = 1.04-1.60, p = 0.022). There were no differences in diastolic CV and mean BP between the cSVD groups. When we differentiated between morning and evening BP, only evening BPV remained significantly associated with total cSVD burden. Conclusion: Day-today systolic BPV is associated with cSVD burden in memory clinic patients. Future research should indicate whether lowering BPV should be included in BP management in older people with memory complaints.

Background Impaired recovery of blood pressure (BP) after standing has been shown to be related to cognitive function and mortality in people without dementia, but its role in people with Alzheimer’s disease (AD) is unknown. The aim of this study was to investigate the association of the orthostatic BP response with cognitive decline and mortality in AD. Methods In this post hoc analysis of a randomized controlled trial (Nilvad), we measured the beat-to-beat response of BP upon active standing in mild-to-moderate AD. This included the initial drop (nadir within 40 seconds) and recovery after 1 minute, both expressed relative to resting values. We examined the relationship between a small or large initial drop (median split) and unimpaired (≥100%) or impaired recovery (&lt;100%) with 1.5-year change in Alzheimer’s Disease Assessment—cognitive subscale (ADAS-cog) scores and all-cause mortality. Results We included 55 participants (age 73.1 ± 6.2 years). Impaired BP recovery was associated with higher increases in ADAS-cog scores (systolic: β [95% confidence interval] = 5.6 [0.4–10.8], p = .035; diastolic: 7.6 [2.3–13.0], p = .006). During a median follow-up time of 49 months, 20 participants died. Impaired BP recovery was associated with increased mortality (systolic: HR [95% confidence interval] = 2.9 [1.1–7.8], p = .039; diastolic: HR [95% confidence interval] = 5.5 [1.9–16.1], p = .002). The initial BP drop was not associated with any outcome. Results were adjusted for age, sex, and intervention group. Conclusions Failure to fully recover BP after 1 minute of standing is associated with cognitive decline and mortality in AD. As such, BP recovery can be regarded as an easily obtained marker of progression rate of AD.