Depressive Symptoms and Plasma Markers of Alzheimer's Disease and Neurodegeneration: A Coordinated Meta-Analysis of 8 Cohort Studies.

BACKGROUND: Depressive symptoms are associated with an increased risk of Alzheimer's disease (AD). There has been a recent emergence in plasma biomarkers for AD pathophysiology, such as amyloid-beta (Aß) and phosphorylated tau (p-tau), as well as for axonal damage (neurofilament light, NfL) and astrocytic activation (glial fibrillary acidic protein, GFAP). Hypothesizing that depressive symptoms may occur along the AD process, we investigated associations between plasma biomarkers of AD with depressive symptoms in individuals without dementia. METHODS: A two-stage meta-analysis was performed on 2 clinic-based and 6 population-based cohorts (N = 7210) as part of the Netherlands Consortium of Dementia Cohorts. Plasma markers (Aß42/40, p-tau181, NfL, and GFAP) were measured using Single Molecular Array (Simoa; Quanterix) assays. Depressive symptoms were measured with validated questionnaires. We estimated the cross-sectional association of each standardized plasma marker (determinants) with standardized depressive symptoms (outcome) using linear regressions, correcting for age, sex, education, and APOE ε4 allele presence, as well as subgrouping by sex and APOE ε4 allele. Effect estimates were entered into a random-effects meta-analysis. RESULTS: Mean age of participants was 71 years. The prevalence of clinically relevant depressive symptoms ranged from 1% to 22%. None of the plasma markers were associated with depressive symptoms in the meta-analyses. However, NfL was associated with depressive symptoms only in APOE ε4 carriers (ß 0.11; 95% CI: 0.05-0.17). CONCLUSIONS: Late-life depressive symptoms did not show an association to plasma biomarkers of AD pathology. However, in APOE ε4 allele carriers, a more profound role of neurodegeneration was suggested with depressive symptoms.

Lower cerebral blood flow predicts cognitive decline in patients with vascular cognitive impairment.

INTRODUCTION: Chronic cerebral hypoperfusion is one of the assumed pathophysiological mechanisms underlying vascular cognitive impairment (VCI). We investigated the association between baseline cerebral blood flow (CBF) and cognitive decline after 2 years in patients with VCI and reference participants. METHODS: One hundred eighty-one participants (mean age 66.3 ± 7.4 years, 43.6% women) underwent arterial spin labeling (ASL) magnetic resonance imaging (MRI) and neuropsychological assessment at baseline and at 2-year follow-up. We determined the association between baseline global and lobar CBF and cognitive decline with multivariable regression analysis. RESULTS: Lower global CBF at baseline was associated with more global cognitive decline in VCI and reference participants. This association was most profound in the domain of attention/psychomotor speed. Lower temporal and frontal CBF at baseline were associated with more cognitive decline in memory. DISCUSSION: Our study supports the role of hypoperfusion in the pathophysiological and clinical progression of VCI. HIGHLIGHTS: Impaired cerebral blood flow (CBF) at baseline is associated with faster cognitive decline in VCI and normal aging. Our results suggest that low CBF precedes and contributes to the development of vascular cognitive impairment. CBF determined by ASL might be used as a biomarker to monitor disease progression or treatment responses in VCI.

Contributions of amyloid beta and cerebral small vessel disease in clinical decline.

INTRODUCTION: We assessed whether co-morbid small vessel disease (SVD) has clinical predictive value in preclinical or prodromal Alzheimer's disease. METHODS: In 1090 non-demented participants (65.4 ± 10.7 years) SVD was assessed with magnetic resonance imaging and amyloid beta (Aß) with lumbar puncture and/or positron emission tomography scan (mean follow-up for cognitive function 3.1 ± 2.4 years). RESULTS: Thirty-nine percent had neither Aß nor SVD (A-V-), 21% had SVD only (A-V+), 23% Aß only (A+V-), and 17% had both (A+V+). Pooled cohort linear mixed model analyses demonstrated that compared to A-V- (reference), A+V- had a faster rate of cognitive decline. Co-morbid SVD (A+V+) did not further increase rate of decline. Cox regression showed that dementia risk was modestly increased in A-V+ (hazard ratio [95% confidence interval: 1.8 [1.0-3.2]) and most strongly in A+ groups. Also, mortality risk was increased in A+ groups. DISCUSSION: In non-demented persons Aß was predictive of cognitive decline, dementia, and mortality. SVD modestly predicts dementia in A-, but did not increase deleterious effects in A+. HIGHLIGHTS: Amyloid beta (Aß; A) was predictive for cognitive decline, dementia, and mortality. Small vessel disease (SVD) had no additional deleterious effects in A+. SVD modestly predicted dementia in A-. Aß should be assessed even when magnetic resonance imaging indicates vascular cognitive impairment.

Biomarkers of endothelial dysfunction and cognition: A two-step IPD meta-analysis.

INTRODUCTION: This study assessed the association of plasma biomarkers of endothelial dysfunction with cognitive performance and decline. METHODS: Data from 9414 individuals from eight Dutch cohorts were included (Ø  age-range: 57-93 years). Plasma biomarkers of endothelial dysfunction (soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin) were combined into a standardized composite score. Cognitive outcomes included executive function, processing speed, immediate and delayed memory, attention, and language. Linear regressions and linear mixed models were run in the individual cohorts and standardized coefficients were subsequently pooled using random-effects meta-analyses. RESULTS: A higher endothelial dysfunction composite score was cross-sectionally associated with worse performance on executive function, processing speed, delayed memory, and attention, but not immediate memory or language (pooled ß-range: -0.04, -0.02). We found no association with change in cognition over time. DISCUSSION: This comprehensive two-step, individual participant data (IPD) meta-analysis showed a small, consistent cross-sectional association between endothelial dysfunction and worse cognitive performance across multiple domains but no support for a longitudinal association. HIGHLIGHTS: Prior evidence on endothelial dysfunction (ED) biomarkers and cognition is conflicting. This two-step, individual participant data (IPD) meta-analysis used data from eight Dutch cohorts. ED was consistently associated with concurrent cognition. ED was not associated with a change in cognition over time. The association of ED with current cognition may be generic.

Is the association between blood pressure and cognition in the oldest-old modified by physical, vascular or brain pathology markers? The EMIF-AD 90 + Study.

BACKGROUND: Prior studies suggest a changing association between blood pressure (BP) and cognition with aging, however work in the oldest-old has yielded ambiguous results. Potentially, these mixed results can be explained by modifying factors. The aim of this study was to establish whether physical, vascular or brain pathology markers that describe a state of increased vulnerability, affect the association between BP and cognition in the oldest-old. Results may influence clinicians' decisions regarding the use of antihypertensives in this age group. METHODS: We included 122 individuals (84 without cognitive impairment and 38 with cognitive impairment) from the EMIF-AD 90 + Study (mean age 92.4 years). First, we tested cross-sectional associations of systolic and diastolic BP with a cognitive composite score. Second, we tested whether these associations were modified by physical markers (waist circumference, muscle mass, gait speed and handgrip strength), vascular markers (history of cardiac disease, carotid intima media thickness as a proxy for atherosclerosis and carotid distensibility coefficient as a proxy for arterial stiffness) or brain pathology markers (white matter hyperintensities and cortical thickness). RESULTS: In the total sample, there was no association between BP and cognition, however, waist circumference modified this association (p-value for interaction with systolic BP: 0.03, with diastolic BP: 0.01). In individuals with a high waist circumference, higher systolic and diastolic BP tended to be associated with worse cognition, while in individuals with a low waist circumference, higher systolic BP was associated with better cognition. The others physical, vascular and brain pathology markers did not modify the association between BP and cognition. CONCLUSIONS: When examining various markers for physical, vascular and brain vulnerability, only waist circumference affected the association between BP and cognition. This warrants further research to evaluate whether waist circumference may be a marker in clinical practice influencing the use of antihypertensives in the oldest-old.

Cardiac output, cerebral blood flow and cognition in patients with severe aortic valve stenosis undergoing transcatheter aortic valve implantation: design and rationale of the CAPITA study.

BACKGROUND: Approximately one-third of patients with symptomatic severe aortic valve stenosis who are scheduled for transcatheter aortic valve implantation (TAVI) have some degree of cognitive impairment. TAVI may have negative cognitive effects due to periprocedural micro-emboli inducing cerebral infarction. On the contrary, TAVI may also have positive cognitive effects due to increases in cardiac output and cerebral blood flow (CBF). However, studies that systematically assess these effects are scarce. Therefore, the main aim of this study is to assess cerebral and cognitive outcomes in patients with severe aortic valve stenosis undergoing TAVI. STUDY DESIGN: In the prospective CAPITA (CArdiac OutPut, Cerebral Blood Flow and Cognition In Patients With Severe Aortic Valve Stenosis Undergoing Transcatheter Aortic Valve Implantation) study, cerebral and cognitive outcomes are assessed in patients undergoing TAVI. One day before and 3 months after TAVI, patients will undergo echocardiography (cardiac output, valve function), brain magnetic resonance imaging (CBF, structural lesions) and extensive neuropsychological assessment. To assess longer-term effects of TAVI, patients will again undergo echocardiography and neuropsychological assessment 1 year after the procedure. The co-primary outcome measures are change in CBF (in ml/100 g per min) and change in global cognitive functioning (Z-score) between baseline and 3­month follow-up. Secondary objectives include change in cardiac output, white matter hyperintensities and other structural brain lesions. (ClinicalTrials.gov identifier NCT05481008) CONCLUSION : The CAPITA study is the first study designed to systematically assess positive and negative cerebral and cognitive outcomes after TAVI. We hypothesise that TAVI improves cardiac output, CBF and cognitive functioning.

Race, sex, and mid-life changes in brain health: Cardia MRI substudy.

OBJECTIVE: To examine longitudinal race and sex differences in mid-life brain health and to evaluate whether cardiovascular health (CVH) or apolipoprotein E (APOE) ε4 explain differences. METHODS: The study included 478 Black and White participants (mean age: 50 years). Total (TBV), gray (GMV), white (WMV), and white matter hyperintensity (WMH) volumes and GM-cerebral blood flow (CBF) were acquired with 3T-magnetic resonance imaging at baseline and 5-year follow-up. Analyses were based on general linear models. RESULTS: There were race x sex interactions for GMV (P-interaction = .004) and CBF (P-interaction = .01) such that men showed more decline than women, and this was most evident in Blacks. Blacks compared to Whites had a significantly greater increase in WMH (P = .002). All sex-race differences in change were marginally attenuated by CVH and APOE ε4. CONCLUSION: Race-sex differences in brain health emerge by mid-life. Identifying new environmental factors beyond CVH is needed to develop early interventions to maintain brain health.

Validity of the three apathy items of the Geriatric Depression Scale (GDS-3A) in measuring apathy in older persons.

OBJECTIVE: The Geriatric Depression Scale (GDS)-3A, a three-item subset of the GDS-15, is increasingly used as a measure for apathy in research settings to assess factors associating with this neuropsychiatric syndrome. We aimed to assess how accurately the GDS-3A discriminates between presence and absence of apathy in two populations of community-dwelling older persons, using the Apathy Scale as reference standard. METHODS: Baseline data were used from 427 participants of the Discontinuation of Antihypertensive Treatment in Elderly people (DANTE) Study Leiden and 1118 participants of the PROactive Management Of Depression in the Elderly (PROMODE) Study, all ≥75 years and with available GDS-3A and Apathy Scale measurements. A cut-off score of ≥14 was used for presence of apathy according to the Apathy Scale. Areas under the receiver operating characteristic curve (AUC) were calculated. Based on the likelihood ratios for GDS-3A scores, a cut-off of ≥2 was used for presence of apathy according to the GDS-3A to calculate test characteristics. RESULTS: The AUC was 0.68 (95% confidence interval 0.62-0.73) in the DANTE Study and 0.72 (0.67-0.77) in the PROMODE Study. In the DANTE Study sensitivity was 29.3% (21.4-38.1) and specificity was 88.5% (84.4-91.8), whereas in the PROMODE Study sensitivity was 32.8% (24.5-41.1) and specificity 92.6% (90.9-94.2). Stratification on population characteristics did not yield more favourable test characteristics. CONCLUSION: The GDS-3A has low sensitivity and high specificity as a measure of apathy in two populations of older persons. Using the GDS-3A in research might yield estimates biassed towards the null in case of non-differential misclassification. Copyright © 2016 John Wiley & Sons, Ltd.

Effect of discontinuation of antihypertensive medication on orthostatic hypotension in older persons with mild cognitive impairment: the DANTE Study Leiden.

BACKGROUND: the relationship between antihypertensive medication and orthostatic hypotension in older persons remains ambiguous, due to conflicting observational evidence and lack of data of clinical trials. OBJECTIVE: to assess the effect of discontinuation of antihypertensive medication on orthostatic hypotension in older persons with mild cognitive impairment. METHODS: a total of 162 participants with orthostatic hypotension were selected from the Discontinuation of Antihypertensive Treatment in Elderly people (DANTE) Study. This randomised clinical trial included community-dwelling participants aged ≥75 years, with mild cognitive impairment, using antihypertensive medication and without serious cardiovascular disease. Participants were randomised to discontinuation or continuation of antihypertensive treatment (ratio 1:1). Orthostatic hypotension was defined as a drop of at least 20 mmHg in systolic blood pressure and/or 10 mmHg in diastolic blood pressure on standing from a seated position. Outcome was the absence of orthostatic hypotension at 4-month follow-up. Relative risks (RR) were calculated by intention-to-treat and per-protocol analyses. RESULTS: at follow-up, according to intention-to-treat analyses, of the 86 persons assigned to discontinuation of antihypertensive medication, 43 (50%) were free from orthostatic hypotension, compared with 29 (38%) of the 76 persons assigned to continuation of medication [RR 1.31 (95% confidence interval (CI) 0.92-1.87); P = 0.13]. Per-protocol analysis showed that recovery from orthostatic hypotension was significantly higher in persons who completely discontinued all antihypertensive medication (61%) compared with the continuation group (38%) [RR 1.60 (95% CI 1.10-2.31); P = 0.01]. CONCLUSION: in older persons with mild cognitive impairment and orthostatic hypotension receiving antihypertensive medication, discontinuation of antihypertensive medication may increase the probability of recovery from orthostatic hypotension.

Plasma Markers of Alzheimer's Disease Pathology, Neuronal Injury, and Astrocytic Activation and MRI Load of Vascular Pathology and Neurodegeneration: The SMART-MR Study.

BACKGROUND: Two of the main causes for dementia are Alzheimer's disease (AD) and vascular pathology, with most patients showing mixed pathology. Plasma biomarkers for Alzheimer's disease-related pathology have recently emerged, including Aß (amyloid-beta), p-tau (phosphorylated tau), NfL (neurofilament light), and GFAP (glial fibrillary acidic protein). There is a current gap in the literature regarding whether there is an association between these plasma biomarkers with vascular pathology and neurodegeneration. METHODS AND RESULTS: Cross-sectional data from 594 individuals (mean [SD] age: 64 [8] years; 17% female) were included from the SMART-MR (Second Manifestations of Arterial Disease-Magnetic Resonance) study, a prospective cohort study of individuals with a history of arterial disease. Plasma markers were assessed using single molecular array assays (Quanterix). Magnetic resonance imaging markers included white matter hyperintensity volume, presence of infarcts (yes/no), total brain volume, and hippocampal volume assessed on 1.5T magnetic resonance imaging. Linear regressions were performed for each standardized plasma marker with white matter hyperintensity volume, total brain volume, and hippocampal volume as separate outcomes, correcting for age, sex, education, and intracranial volume. Logistic regressions were performed for the presence of lacunar and cortical infarcts. Higher p-tau181 was associated with larger white matter hyperintensity volume (b per SD increase=0.16 [95% CI, 0.06-0.26], P=0.015). Higher NfL (b=-5.63, [95% CI, -8.95 to -2.31], P=0.015) was associated with lower total brain volume and the presence of infarcts (odds ratio [OR], 1.42 [95% CI, 1.13-1.78], P=0.039). Higher GFAP levels were associated with cortical infarcts (OR, 1.45 [95% CI, 1.09-1.92], P=0.010). CONCLUSIONS: Plasma biomarkers that have been associated with tau pathology, axonal injury, and astrocytic activation are related to magnetic resonance imagingmarkers of vascular pathology and neurodegeneration in patients with manifest arterial disease.

Contributions of Cerebral Blood Flow to Associations Between Blood Pressure Levels and Cognition: The Age, Gene/Environment Susceptibility-Reykjavik Study.

[Figure: see text].

Lower Blood Pressure, Small-Vessel Disease, and Apathy in Older Persons With Mild Cognitive Deficits.

BACKGROUND: In older persons, both high and low blood pressure (BP) levels are associated with symptoms of apathy. Population characteristics, such as burden of cerebral small-vessel disease (CSVD), may underlie these apparently contradictory findings. We aimed to explore, in older persons, whether the burden of CSVD affects the association between BP and apathy. DESIGN: Cross-sectional study. SETTING: Primary care setting, the Netherlands. PARTICIPANTS: Community-dwelling older persons (mean age = 80.7 years; SD = 4.1 years) with mild cognitive deficits and using antihypertensive treatment, participating in the baseline measurement of the magnetic resonance imaging substudy (n = 210) of the Discontinuation of Antihypertensive Treatment in the Elderly Study Leiden. MEASUREMENTS: During home visits, BP was measured in a standardized way and apathy was assessed with the Apathy Scale (range = 0-42). Stratified linear regression analyses were performed according to the burden of CSVD. A higher burden of CSVD was defined as 2 or more points on a compound CSVD score (range = 0-3 points), defined as presence of white matter hyperintensities (greater than median), any lacunar infarct, and/or two or more microbleeds. RESULTS: In the entire population, those with a lower systolic and those with a lower diastolic BP had more symptoms of apathy (ß = -.35 [P = .01] and ß = -.66 [P = .02], respectively). In older persons with a higher burden of CSVD (n = 50 [24%]), both lower systolic BP (ß = -.64, P = .02) and lower diastolic BP (ß = -1.6, P = .01) were associated with more symptoms of apathy, whereas no significant association was found between BP and symptoms of apathy in older persons with a lower burden of CSVD (n = 160). CONCLUSIONS: Particularly in older persons with a higher burden of CSVD, lower BP was associated with more symptoms of apathy. Adequate BP levels for optimal psychological functioning may vary across older populations with a different burden of CSVD. J Am Geriatr Soc 68:1811-1817, 2020.

Orthostatic hypotension in older persons is not associated with cognitive functioning, features of cerebral damage or cerebral blood flow.

OBJECTIVE: Particularly in old age, orthostatic hypotension has been related to worse cognitive functioning, possibly caused by reduced cerebral blood flow (CBF). This study investigates whether orthostatic hypotension in older people is associated with cognitive dysfunction and, if so, whether this association is mediated by cerebral vascular damage and/or decreased CBF. METHODS: Four hundred and twenty participants of the Discontinuation of ANtihypertensive Treatment in Elderly People (DANTE) Study Leiden (mean age 81 years, all using antihypertensive medication and with mild cognitive deficits), and MRI data from 214 participants of the nested DANTE MRI sub-study. Orthostatic hypotension was defined as either a SBP decrease at least 20 mmHg and/or a DBP decrease of at least 10 mmHg within 3 min of standing up. Cognitive functioning was assessed using a battery of six cognitive tests covering global cognition, memory function, executive function and psychomotor speed. Cerebral vascular damage and CBF were assessed using MRI. RESULTS: The prevalence of orthostatic hypotension was 47% (n = 199). Compared with the group without orthostatic hypotension, participants with orthostatic hypotension showed no differences in any of the cognitive functions, features of cerebral small vessel disease, microstructural integrity or CBF. CONCLUSION: In this population of older persons, the presence of orthostatic hypotension was not associated with decreased cognition. In addition, no differences were found in the supposedly underlying cerebral vascular mechanisms.

Unilateral fetal-type circle of Willis anatomy causes right-left asymmetry in cerebral blood flow with pseudo-continuous arterial spin labeling: A limitation of arterial spin labeling-based cerebral blood flow measurements?

The accuracy of cerebral blood flow measurements using pseudo-continuous arterial spin labeling can be affected by vascular factors other than cerebral blood flow, such as flow velocity and arterial transit time. We aimed to elucidate the effects of common variations in vascular anatomy of the circle of Willis on pseudo-continuous arterial spin labeling signal. In addition, we investigated whether possible differences in pseudo-continuous arterial spin labeling signal could be mediated by differences in flow velocities. Two hundred and three elderly participants underwent magnetic resonance angiography of the circle of Willis and pseudo-continuous arterial spin labeling scans. Mean pseudo-continuous arterial spin labeling-cerebral blood flow signal was calculated for the gray matter of the main cerebral flow territories. Mean cerebellar gray matter pseudo-continuous arterial spin labeling-cerebral blood flow was significantly lower in subjects having a posterior fetal circle of Willis variant with an absent P1 segment. The posterior fetal circle of Willis variants also showed a significantly higher pseudo-continuous arterial spin labeling-cerebral blood flow signal in the ipsilateral flow territory of the posterior cerebral artery. Flow velocity in the basilar artery was significantly lower in these posterior fetal circle of Willis variants. This study indicates that pseudo-continuous arterial spin labeling measurements underestimate cerebral blood flow in the posterior flow territories and cerebellum of subjects with a highly prevalent variation in circle of Willis morphology. Additionally, our data suggest that this effect is mediated by concomitant differences in flow velocity between the supplying arteries.

Structural Covariance Networks and Their Association with Age, Features of Cerebral Small-Vessel Disease, and Cognitive Functioning in Older Persons.

Recently, cerebral structural covariance networks (SCNs) have been shown to partially overlap with functional networks. However, although for some of these SCNs a strong association with age is reported, less is known about the association of individual SCNs with separate cognition domains and the potential mediation effect in this of cerebral small vessel disease (SVD). In 219 participants (aged 75-96 years) with mild cognitive deficits, 8 SCNs were defined based on structural covariance of gray matter intensity with independent component analysis on 3DT1-weighted magnetic resonance imaging (MRI). Features of SVD included volume of white matter hyperintensities (WMH), lacunar infarcts, and microbleeds. Associations with SCNs were examined with multiple linear regression analyses, adjusted for age and/or gender. In addition to higher age, which was associated with decreased expression of subcortical, premotor, temporal, and occipital-precuneus networks, the presence of SVD and especially higher WMH volume was associated with a decreased expression in the occipital, cerebellar, subcortical, and anterior cingulate network. The temporal network was associated with memory (p = 0.005), whereas the cerebellar-occipital and occipital-precuneus networks were associated with psychomotor speed (p = 0.002 and p < 0.001). Our data show that a decreased expression of specific networks, including the temporal and occipital lobe and cerebellum, was related to decreased cognitive functioning, independently of age and SVD. This indicates the potential of SCNs in substantiating cognitive functioning in older persons.

Blood Pressure Is Not Associated With Cerebral Blood Flow in Older Persons.

Many studies showing a relation between low blood pressure (BP) and adverse health outcomes in older persons suggest that low BP gives rise to reduced cerebral blood flow (CBF). However, limited evidence is available about this association. Baseline data of 203 participants in the Discontinuation of Antihypertensive Treatment in the Elderly (DANTE) trial were used (mean age, 81 years, using antihypertensive medication and with mild cognitive deficits). BP, BP changes on standing, and CBF derived from pseudo-continuous arterial spin-labeling magnetic resonance imaging were assessed in all participants. In 102 participants who were randomly assigned to 4-month continuation (n=47) or discontinuation of antihypertensive treatment (n=55), BP and CBF change were evaluated at 4-month follow-up. Systolic and diastolic BP were not associated with CBF (B=-0.21, P=0.50 and B=-1.07, P=0.07), neither were mean arterial pressure, pulse pressure, and BP changes on standing. In subgroups of participants with small vessel-related cerebral pathologies, including high white matter hyperintensity volume, microbleeds, and lacunar infarcts, or in participants with lower cognition or diabetes mellitus, no association was found between any BP parameters and CBF. Furthermore, compared to the continuation group, CBF change at 4 months was not different in the discontinuation group (B=-0.12, P=0.23). Contrary to the notion that lower BP in old age is associated with decreased CBF, our data do not show this association in older persons using antihypertensive medication and with mild cognitive deficits. Also, this association was not present in subgroups of more vulnerable persons, reflected by small vessel-related cerebral pathologies, lower cognition, or diabetes mellitus.

Lower blood pressure and apathy coincide in older persons with poorer functional ability: the Discontinuation of Antihypertensive Treatment in Elderly People (DANTE) Study Leiden.

OBJECTIVES: To examine the association between blood pressure (BP) measures and symptoms of apathy and depression in older adults with various levels of functional ability. DESIGN: Cross-sectional study using baseline data from the Discontinuation of Antihypertensive Treatment in Elderly people (DANTE) Study Leiden. SETTING: Primary care setting, the Netherlands. PARTICIPANTS: Community-dwelling individuals aged 75 and older (N = 430). MEASUREMENTS: Systolic BP (SBP), diastolic BP (DBP), and mean arterial pressure (MAP) were measured during home visits. Symptoms of apathy and depression were assessed using the Apathy Scale and the Geriatric Depression Scale (GDS-15), respectively. Stratified linear regression was performed in participants with better and worse functional ability according to the median of the Groningen Activity Restriction Scale. RESULTS: In participants with lower functional ability, each 10-mmHg lower SBP, DBP, and MAP was associated with higher Apathy Scale scores (0.63, 0.92, and 0.94 points, respectively, all P < .005) but not with GDS-15 scores. In participants with higher functional ability, BP measures were not associated with Apathy Scale or GDS-15 scores. CONCLUSION: In older participants with poorer functional ability, lower BP was associated with more symptoms of apathy but not depression.

Lower Blood Pressure and Gray Matter Integrity Loss in Older Persons.

In contrast to middle age, it is unclear whether blood pressure (BP) in older persons is associated with cerebral small vessel disease (cSVD). The authors evaluated the association of BP with signs of cSVD as well as gray and white matter integrity in older persons. In 220 participants aged 75 years and older from the Discontinuation of Antihypertensive Treatment in the Elderly (DANTE) study, cSVD was assessed with conventional magnetic resonance imaging, and microstructural integrity with diffusion tensor and magnetization transfer (MT) imaging. BP measures were not associated with cSVD. However, lower systolic and diastolic BP and mean arterial pressure were associated with decreased gray matter MT ratio peak height and MT ratio in cortical gray matter. Mean arterial pressure was also associated with increased gray matter diffusivity. A lower level of BP was especially associated with worse gray matter integrity. Results suggest that not only upper but preferably lower thresholds of BP values should be observed in older persons.

Effect of Discontinuation of Antihypertensive Treatment in Elderly People on Cognitive Functioning--the DANTE Study Leiden: A Randomized Clinical Trial.

IMPORTANCE: Observational studies indicate that lower blood pressure (BP) increases risk for cognitive decline in elderly individuals. Older persons are at risk for impaired cerebral autoregulation; lowering their BP may compromise cerebral blood flow and cognitive function. OBJECTIVE: To assess whether discontinuation of antihypertensive treatment in older persons with mild cognitive deficits improves cognitive, psychological, and general daily functioning. DESIGN, SETTING, AND PARTICIPANTS: A community-based randomized clinical trial with a blinded outcome assessment at the 16-week follow-up was performed at 128 general practices in the Netherlands. A total of 385 participants 75 years or older with mild cognitive deficits (Mini-Mental State Examination score, 21-27) without serious cardiovascular disease who received antihypertensive treatment were enrolled in the Discontinuation of Antihypertensive Treatment in Elderly People (DANTE) Study Leiden from June 26, 2011, through August 23, 2013 (follow-up, December 16, 2013). Intention-to-treat analyses were performed from January 20 through April 11, 2014. INTERVENTIONS: Discontinuation (n=199) vs continuation (n=186) of antihypertensive treatment (allocation ratio, 1:1). MAIN OUTCOMES AND MEASURES: Change in the overall cognition compound score. Secondary outcomes included changes in scores on cognitive domains, the Geriatric Depression Scale-15, Apathy Scale, Groningen Activity Restriction Scale (functional status), and Cantril Ladder (quality of life). RESULTS: Compared with 176 participants undergoing analysis in the control (continuation) group, 180 in the intervention (discontinuation) group had a greater increase (95% CI) in systolic BP (difference, 7.36 [3.02 to 11.69] mm Hg; P=.001) and diastolic BP (difference, 2.63 [0.34 to 4.93] mm Hg; P=.03). The intervention group did not differ from the control group in change (95% CI) in overall cognition compound score (0.01 [-0.14 to 0.16] vs -0.01 [-0.16 to 0.14]; difference, 0.02 [-0.19 to 0.23]; P=.84). The intervention and control groups did not differ significantly in secondary outcomes, including differences (95% CIs) in change in compound scores of the 3 cognitive domains (executive function, -0.07 [-0.29 to 0.15; P=.52], memory, 0.08 [-0.12 to 0.29; P=.43], and psychomotor speed, -0.85 [-1.72 to 0.02; P=.06]), symptoms of apathy (0.17 [-0.65 to 0.99; P=.68]) and depression (0.14 [-0.20 to 0.48; P=.41]), functional status (-0.72 [-1.52 to 0.09; P=.08]), and quality-of-life score (-0.09 [-0.34 to 0.16; P=.46]). Adverse events were equally distributed. CONCLUSIONS AND RELEVANCE: In older persons with mild cognitive deficits, discontinuation of antihypertensive treatment did not improve cognitive, psychological, or general daily functioning at the 16-week follow-up. TRIAL REGISTRATION: trialregister.nl Identifier: NTR2829.

Lower Blood Pressure Is Associated With Smaller Subcortical Brain Volumes in Older Persons.

BACKGROUND: Both high and low blood pressure (BP) have been positively as well as negatively associated with brain volumes in a variety of populations. The objective of this study was to investigate whether BP is associated with cortical and subcortical brain volumes in older old persons with mild cognitive deficits. METHODS: Within the Discontinuation of Antihypertensive Treatment in the Elderly trial, the cross-sectional relation of BP parameters with both cortical and subcortical brain volumes was investigated in 220 older old persons with mild cognitive deficits (43% men, mean age = 80.7 (SD = 4.1), median Mini-Mental State Examination score = 26 (interquartile range: 25-27)), using linear regression analysis. All analyses were adjusted for age, gender, volume of white matter hyperintensities, and duration of antihypertensive treatment. Brain volumes were determined on 3DT1-weighted brain magnetic resonance imaging scans. RESULTS: Lower systolic BP, diastolic BP, and mean arterial pressure (MAP) were significantly associated with lower volumes of thalamus and putamen (all P ≤ 0.01). In addition, lower MAP was also associated with reduced hippocampal volume (P = 0.035). There were no associations between any of the BP parameters with cortical gray matter or white matter volume. CONCLUSION: In an older population using antihypertensive medication with mild cognitive deficits, a lower BP, rather than a high BP is associated with reduced volumes of thalamus, putamen, and hippocampus.