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Purpose of Review: To review the pathophysiology of hypertension in Alzheimer's disease and related dementias and explore the current landscape of clinical trials involving treatment of hypertension to improve cognition., Recent Findings: Hypertension is increasingly recognized as a contributor to cognitive impairment. Clinical trials that explore blood pressure reductions with cognitive outcomes have been promising. Various antihypertensives have been evaluated in clinical trials, with growing interest in those agents that impact the renin-angiotensin-aldosterone system due to its own association with cognitive impairment. No antihypertensive agent has been found to be superior to others in reducing cognitive impairment risk or conferring neuroprotective benefits. In this review, the pathophysiology of and clinical trial data involving hypertension and dementia will be explored. Hypertension is a significant risk factor for the development of neurodegenerative dementias, and clinical trials have been overall favorable in improving cognition by reductions in blood pressure using antihypertensive agents., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: To examine the effect of intensive blood pressure control on the occurrence of subtypes of mild cognitive impairment (MCI) and determine the risk of progression to dementia or death., Methods: Secondary analysis of a randomized trial of community-dwelling adults (≥50 years) with hypertension. Participants were randomized to a systolic blood pressure (SBP) goal of <120 mm Hg (intensive treatment; n = 4678) or <140 mm Hg (Standard treatment; n = 4683). Outcomes included adjudicated MCI, MCI subtype (amnestic, non-amnestic, multi-domain, single domain), and probable dementia. Multistate survival models were used to examine transitions in cognitive status accounting for the competing risk of death., Results: Among 9361 randomized participants (mean age, 67.9 years; 3332 women [35.6%]), 640 participants met the protocol definition for MCI, with intensive treatment reducing the risk of MCI overall (hazard ratio [HR], 0.81 [95% confidence interval {CI}, 0.69-0.94]), as previously reported. This effect was largely reflected in amnestic subtypes (HR, 0.78 [95% CI, 0.66-0.92]) and multi-domain subtypes (HR, 0.78 [95% CI, 0.65-0.93]). An adjudication of MCI, as compared with normal cognitive function, substantially increased the probability of progressing to probable dementia (5.9% [95% CI: 4.5%-7.7%] vs. 0.6% [95% CI: 0.3%-0.9%]) and to death (10.0% [95% CI: 8.3%-11.9%] vs. 2.3% [95% CI: 2.0%-2.7%]) within 2 years., Conclusions: Intensive treatment reduced the risk for amnestic and multi-domain subtypes of MCI. An adjudication of MCI was associated with increased risk of progression to dementia and death, highlighting the relevance of MCI as a primary outcome in clinical and research settings., (© 2021 The American Geriatrics Society.)

Purpose: Hypertension is a risk factor for cognitive impairment; however, the mechanisms leading to cognitive changes remain unclear. In this cross-sectional study, we evaluate the impact of white matter lesion (WML) burden on brain functional connectivity (FC) and cognition in a large cohort of hypertensive patients from the Systolic Blood Pressure Intervention Trial (SPRINT) at baseline., Methods: Functional networks were identified from baseline resting state functional MRI scans of 660 SPRINT participants using independent component analysis. WML volumes were calculated from structural MRI. Correlation analyses were carried out between mean FC of each functional network and global WML as well as WML within atlas-defined white matter regions. For networks of interest, voxel-wise-adjusted correlation analyses between FC and regional WML volume were performed. Multiple variable linear regression models were built for cognitive test performance as a function of network FC, followed by mediation analysis., Results: Mean FC of the default mode network (DMN) was negatively correlated with global WML volume, and regional WML volume within the precuneus. Voxel-wise correlation analyses revealed that regional WML was negatively correlated with FC of the DMN's left lateral temporal region. FC in this region of the DMN was positively correlated to performance on the Montreal Cognitive Assessment and demonstrated significant mediation effects. Additional networks also demonstrated global and regional WML correlations; however, they did not demonstrate an association with cognition., Conclusion: In hypertensive patients, greater WML volume is associated with lower FC of the DMN, which in turn is related to poorer cognitive test performance., Trial Registration: NCT01206062.

Background: Results from the Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive control of systolic blood pressure significantly reduced the occurrence of mild cognitive impairment, but not probable dementia. We investigated the effects of intensive lowering of systolic blood pressure on specific cognitive functions in a preplanned substudy of participants from SPRINT., Methods: SPRINT was an open-label, multicentre, randomised controlled trial undertaken at 102 sites, including academic medical centres, Veterans Affairs medical centres, hospitals, and independent clinics, in the USA and Puerto Rico. Participants were adults aged 50 years or older with systolic blood pressure higher than 130 mm Hg, but without diabetes, history of stroke, or dementia. Participants were randomly assigned (1:1) to a systolic blood pressure goal of less than 120 mm Hg (intensive treatment) versus less than 140 mm Hg (standard treatment). All major classes of antihypertensive agents were included. A subgroup of randomly assigned participants including, but not limited to, participants enrolled in an MRI substudy was then selected for a concurrent substudy of cognitive function (target 2800 participants). Each individual was assessed with a screening cognitive test battery and an extended cognitive test battery at baseline and biennially during the planned 4-year follow-up. The primary outcomes for this substudy were standardised composite scores for memory (Logical Memory I and II, Modified Rey-Osterrieth Complex Figure [immediate recall], and Hopkins Verbal Learning Test-Revised [delayed recall]) and processing speed (Trail Making Test and Digit Symbol Coding). SPRINT was registered with ClinicalTrials.gov, NCT01206062., Findings: From Nov 23, 2010, to Dec 28, 2012, 2921 participants (mean age 68·4 years [SD 8·6], 1080 [37%] women) who had been randomly assigned in SPRINT were enrolled in the substudy (1448 received intensive treatment and 1473 received standard treatment). SPRINT was terminated early due to benefit observed in the primary outcome (composite of cardiovascular events). After a median follow-up of 4·1 years (IQR 3·7-5·8), there was no between-group difference in memory, with an annual decline in mean standardised domain score of -0·005 (95% CI -0·010 to 0·001) in the intensive treatment group and -0·001 (-0·006 to 0·005) in the standard treatment group (between-group difference -0·004, 95% CI -0·012 to 0·004; p=0·33). Mean standardised processing speed domain scores declined more in the intensive treatment group (between-group difference -0·010, 95% CI -0·017 to -0·002; p=0·02), with an annual decline of -0·025 (-0·030 to -0·019) for the intensive treatment group and -0·015 (-0·021 to 0·009) for the standard treatment group., Interpretation: Intensive treatment to lower systolic blood pressure did not result in a clinically relevant difference compared with standard treatment in memory or processing speed in a subgroup of participants from SPRINT. The effect of blood pressure lowering might not be evident in specific domains of cognitive function, but instead distributed across multiple domains., Funding: National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Alzheimer's Association., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: To evaluate the effect of intensive systolic blood pressure (SBP) control in older adults with hypertension, considering cognitive and physical function., Design: Secondary analysis., Setting: Systolic Blood Pressure Intervention Trial (SPRINT) PARTICIPANTS: Adults 80 years or older., Intervention: Participants with hypertension but without diabetes (N = 1167) were randomized to an SBP target below 120 mm Hg (intensive treatment) vs a target below 140 mm Hg (standard treatment)., Measurements: We measured the incidence of cardiovascular disease (CVD), mortality, changes in renal function, mild cognitive impairment (MCI), probable dementia, and serious adverse events. Gait speed was assessed via a 4-m walk test, and the Montreal Cognitive Assessment (MoCA) was used to quantify baseline cognitive function., Results: Intensive treatment led to significant reductions in cardiovascular events (hazard ratio [HR] = .66; 95% confidence interval [CI] = .49-.90), mortality (HR = .67; 95% CI = .48-.93), and MCI (HR = .70; 95% CI = .51-.96). There was a significant interaction (P < .001) whereby participants with higher baseline scores on the MoCA derived strong benefit from intensive treatment for a composite of CVD and mortality (HR = .40; 95% CI = .28-.57), with no appreciable benefit in participants with lower scores on the MoCA (HR = 1.33 = 95% CI = .87-2.03). There was no evidence of heterogeneity of treatment effects with respect to gait speed. Rates of acute kidney injury and declines of at least 30% in estimated glomerular filtration rate were increased in the intensive treatment group with no between-group differences in the rate of injurious falls., Conclusion: In adults aged 80 years or older, intensive SBP control lowers the risk of major cardiovascular events, MCI, and death, with increased risk of changes to kidney function. The cardiovascular and mortality benefits of intensive SBP control may not extend to older adults with lower baseline cognitive function., Trial Registration: Clinicaltrials.gov identifier: NCT01206062. J Am Geriatr Soc 68:496-504, 2020., (© 2019 The American Geriatrics Society.)

Objective: To examine the association of global cognitive function assessed via the Montreal Cognitive Assessment (MoCA) and deficiencies in instrumental activities of daily living (IADL) on the Functional Activity Questionnaire (FAQ) in hypertensive older adults in the Systolic Blood Pressure Intervention Trial (SPRINT)., Methods: In cross-sectional analysis, 9,296 SPRINT participants completed the MoCA at baseline. The FAQ was obtained from 2,705 informants for SPRINT participants scoring <21 or <22 on the MoCA, depending on education. FAQ severity ranged from no dysfunction (Score = 0) to moderate/severe dysfunction (Score = 5+)., Results: Participants who triggered FAQ administration were older, less educated, and more likely to be Black or Hispanic (p < 0.001). Sixty-one percent (n = 1,661) of participants' informants reported no functional difficulties in IADLs. An informant report, however, of any difficulty on the FAQ was associated with lower MoCA scores after controlling for age, sex, race/ethnicity, and education (p < 0.05). Partial proportional odds regression indicates that participants scoring lower on the MoCA (in the 10th to <25th, fifth to <10th, and

Importance: 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 cm3 (difference, 0.92 cm3 [95% CI, 0.69 to 1.14]) vs an increase from 4.40 to 5.85 cm3 (difference, 1.45 cm3 [95% CI, 1.21 to 1.70]) in the standard treatment group (between-group difference in change, -0.54 cm3 [95% CI, -0.87 to -0.20]). Mean total brain volume decreased from 1134.5 to 1104.0 cm3 (difference, -30.6 cm3 [95% CI, -32.3 to -28.8]) in the intensive treatment group vs a decrease from 1134.0 to 1107.1 cm3 (difference, -26.9 cm3 [95% CI, 24.8 to 28.8]) in the standard treatment group (between-group difference in change, -3.7 cm3 [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., Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.

Hypertension and dementia are both common disorders whose prevalence increases with age. There are multiple mechanisms by which hypertension affects the brain and alters cognition. These include blood flow dynamics, development of large and small vessel pathology and diverse molecular mechanisms including formation of reactive oxygen species and transcriptional cascades. Blood pressure interacts with Alzheimer disease pathology in numerous and unpredictable ways, affecting both β-amyloid and tau deposition, while also interacting with AD genetic risk factors and other metabolic processes. Treatment of hypertension may prevent cognitive decline and dementia, but methodological issues have limited the ability of randomized clinical trials to show this conclusively. Recent studies have raised hope that hypertension treatment may protect the function and structure of the aging brain from advancing to mild cognitive impairment and dementia.

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., Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.

Introduction: Erectile function, an important aspect of quality of life, is gaining increased research and clinical attention in older men with hypertension., Aim: To assess the cross-sectional association between blood pressure measures (systolic blood pressure [SBP]; diastolic blood pressure [DBP]; and pulse pressure [PP]) and (i) sexual activity and (ii) erectile function in hypertensive men., Methods: We performed analyses of 1,255 male participants in a larger randomized clinical trial of 9,361 men and women with hypertension aged ≥50 years., Main Outcome Measures: The main outcome measures were self-reported sexual activity (yes/no) and erectile function using the 5-item International Index of Erectile Function (IIEF-5)., Results: 857 participants (68.3%) reported being sexually active during the previous 4 weeks. The mean (SD) IIEF-5 score for sexually active participants was 18.0 (5.8), and 59.9% of the sample reported an IIEF-5 score <21, suggesting erectile dysfunction (ED). In adjusted logistic regression models, neither SBP (adjusted odds ratio = 0.998; P = .707) nor DBP (adjusted odds ratio = 1.001; P = .929) was significantly associated with sexual activity. In multivariable linear regression analyses in sexually active participants, lower SBP (β = -0.04; P = .025) and higher DBP (β = 0.05; P = .029) were associated with better erectile function. In additional multivariable analyses, lower PP pressure was associated with better erectile function (β = -0.04; P = .02)., Clinical Implications: Blood pressure is an important consideration in the assessment of erectile function in men with hypertension., Strengths & Limitations: Assessments of blood pressure and clinical and psychosocial variables were performed using rigorous methods in this multi-ethnic and geographically diverse sample. However, these cross-sectional analyses did not include assessment of androgen or testosterone levels., Conclusions: Erectile dysfunction was highly prevalent in this sample of men with hypertension, and SBP, DBP, and PP were associated with erectile function in this sample. Foy CG, Newman JC, Berlowitz DR, et al. Blood Pressure, Sexual Activity, and Erectile Function in Hypertensive Men: Baseline Findings from the Systolic Blood Pressure Intervention Trial (SPRINT). J Sex Med 2019;16:235-247., (Copyright © 2019 International Society for Sexual Medicine. All rights reserved.)

Background and Objectives: Cognitive function worsens as kidney function declines, but mechanisms contributing to this association are not completely understood. Metabolic acidosis, a common complication of CKD, leads to neural networks overexcitation and is involved in cerebral autoregulation. We aimed to evaluate the association between serum bicarbonate concentration as a measure of metabolic acidosis, and cognitive function in hypertensive adults with and without CKD., Design, Setting, Participants, & Measurements: Five cognitive summary scores were measured (global cognitive function, executive function, memory, attention/concentration, and language) in 2853 participants in the Systolic BP Intervention Trial (SPRINT). Multivariable linear regression models adjusted for demographics, comorbidities, systolic BP, medications, eGFR and albuminuria evaluated the cross-sectional association between bicarbonate and cognition at SPRINT baseline. In a subset ( n =681) who underwent brain magnetic resonance imaging, the models were adjusted for white matter hyperintensity volume, vascular reactivity, and cerebral blood flow., Results: The mean age (SD) was 68 (8.5) years. Global cognitive and executive functions were positively associated with serum bicarbonate (estimate [SEM]: 0.014 [0.006]; P =0.01, and 0.018 [0.006]; P =0.003, respectively). Each 1 mEq/L lower bicarbonate level had a similar association with global cognitive and executive function as being 4.3 and 5.4 months older, respectively. The association with global cognition persisted after magnetic resonance imaging findings adjustment (estimate [SEM]: 0.03 [0.01]; P =0.01). There was no association between serum bicarbonate level and memory, attention/concentration, and language., Conclusions: In a large cohort of hypertensive adults, higher serum bicarbonate levels were independently associated with better global cognitive and executive performance. (ClinicalTrials.gov: NCT01206062)., (Copyright © 2018 by the American Society of Nephrology.)

Objectives: To determine the extent of concern about falling in older adults with hypertension, whether lower blood pressure (BP) and greater use of antihypertensive medications are associated with greater concern about falling, and whether lower BP has a greater effect on concern about falling in older and more functionally impaired individuals., Design: Secondary analysis involving cross-sectional study of baseline characteristics of participants enrolled in the Systolic Blood Pressure Intervention Trial (SPRINT)., Setting: Approximately 100 outpatient sites., Participants: SPRINT enrollees aged 50 and older (mean age 69) diagnosed with hypertension (N = 2,299)., Measurements: Concern about falling was determined using the shortened version of the Falls Efficacy Scale International as measured at the baseline examination., Results: Mild concern about falling was present in 29.3% of participants and moderate to severe concern in 17.9%. Neither low BP (systolic BP<120 mmHg, diastolic BP <70 mmHg) nor orthostatic hypotension was associated with concern about falling (P > .10). Participants with moderate to severe concern about falling were taking significantly more antihypertensive medications than those with mild or no concern. After adjusting for baseline characteristics, no associations were evident between BP, medications, and concern about falling. Results were similar in older and younger participants; interactions between BP and age and functional status were not significantly associated with concern about falling., Conclusion: Although concern about falling is common in older adults with hypertension, it was not found to be associated with low BP or use of more antihypertensive medications in baseline data from SPRINT., (© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.)

Introduction: Sexual function, an important component of quality of life, is gaining increased research and clinical attention in older women with hypertension., Aim: To assess the association between systolic blood pressure (SBP) and other variables, and sexual activity and sexual dysfunction in hypertensive women., Methods: Baseline analysis of 635 women participants of a larger randomized clinical trial of 9361 men and women., Main Outcome Measures: Self-reported sexual activity (yes/no), and sexual function using the Female Sexual Function Inventory (FSFI)., Results: 452 participants (71.2%) reported having no sexual activity during the previous 4 weeks. The mean (SD) FSFI score for sexually active participants was 25.3 (6.0), and 52.6% of the sample reported a FSFI score ≤26.55 designating sexual dysfunction. In logistic regression models, SBP was not significantly associated with sexual activity (AOR = 1.002; P > .05). Older age (AOR = 0.95, P < .05), and lower education (AOR for < high school vs college degree = 0.29, P < .05) were associated with lower odds of being sexually active, as was living alone versus living with others (AOR = 0.56, P < .05). Higher weekly alcohol consumption was associated with increased odds of being sexually active (AOR = 1.39; P < .05). In logistic regression models among sexually active participants, SBP was not associated with sexual dysfunction (AOR = 1.01; P > .05). Higher depressive symptoms from the Patient Health Questionnaire-9 (PHQ-9) was associated with higher odds of sexual dysfunction (AOR = 1.24, P < .05), as was increased number of physical comorbidities (AOR = 1.25, P < .05). Diuretic use was associated with lower odds of being sexually active in participants with chronic kidney disease (AOR = 0.33, P < .05)., Conclusion: Younger age, higher education, living with others, and higher weekly alcohol consumption were significantly associated with higher odds of being sexually active in a sample of middle-aged and older women with hypertension. Increased depressive symptoms and increased physical comorbidities were significantly associated with increased odds of sexual dysfunction. SBP was not significantly associated with sexual activity or sexual dysfunction., Competing Interests: None, (Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Small vessel disease (SVD) in the brain manifests in the periventricular and deep white matter and radiographically is described as "leukoaraiosis". It is increasingly recognized as a cause of morbidity from middle age onward and this clinical relevance has paralleled advances in the field of neuroradiology. Overall, SVD is a heterogenous group of vascular disorders that may be asymptomatic, or a harbinger of many conditions that jeopardize brain health. Management and prevention focuses on blood pressure control, lifestyle modification, and symptomatic treatment.

Introduction: Lowering blood pressure (BP) reduces the risk for cognitive impairment and the progression of cerebral white matter lesions. It is unclear whether hypertension control also influences plasma biomarkers related to Alzheimer's disease and non‐disease‐specific neurodegeneration. Methods: We examined the effect of intensive (< 120 mm Hg) versus standard (< 140 mm Hg) BP control on longitudinal changes in plasma amyloid beta (Aβ)40 and Aβ42, total tau, and neurofilament light chain (NfL) in a subgroup of participants from the Systolic Blood Pressure Intervention Trial (N = 517). Results: Over 3.8 years, there were no significant between‐group differences for Aβ40, Aβ42, Aβ42/Aβ40, or total tau. Intensive treatment was associated with larger increases in NfL compared to standard treatment. Adjusting for kidney function, but not BP, attenuated the association between intensive treatment and NfL. Discussion: Intensive BP treatment was associated with changes in NfL, which were correlated with changes in kidney function associated with intensive treatment. Trial Registration: clinicaltrials.gov Identifier: NCT01206062 [ABSTRACT FROM AUTHOR]