Jessica C. Foster-Dingley

Association of visit-to-visit variability in blood pressure with cognitive function in old age: prospective cohort study

Objective To investigate the association between visit-to-visit variability in blood pressure and cognitive function in old age (>70 years). Design Prospective cohort study. Setting PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) study, a collaboration between centres in Ireland, Scotland, and the Netherlands. Participants 5461 participants, mean age 75.3 years, who were at risk of cardiovascular disease. Blood pressure was measured every three months during an average of 3.2 years. Visit-to-visit variability in blood pressure was defined as the standard deviation of blood pressure measurements between visits. Main outcome measures Four domains of cognitive function, testing selective attention, processing speed, and immediate and delayed memory. In a magnetic resonance imaging substudy of 553 participants, structural brain volumes, cerebral microbleeds, infarcts, and white matter hyperintensities were measured. Results Participants with higher visit-to-visit variability in systolic blood pressure had worse performance on all cognitive tests: attention (mean difference high versus low thirds) 3.08 seconds (95% confidence interval 0.85 to 5.31), processing speed −1.16 digits coded (95% confidence interval −1.69 to −0.63), immediate memory −0.27 pictures remembered (95% confidence interval −0.41 to −0.13), and delayed memory −0.30 pictures remembered (95% confidence interval −0.49 to −0.11). Furthermore, higher variability in both systolic and diastolic blood pressure was associated with lower hippocampal volume and cortical infarcts, and higher variability in diastolic blood pressure was associated with cerebral microbleeds (all P<0.05). All associations were adjusted for average blood pressure and cardiovascular risk factors. Conclusion Higher visit-to-visit variability in blood pressure independent of average blood pressure was associated with impaired cognitive function in old age.

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.

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.

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 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.

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.

Lower Blood Pressure and Apathy Coincide in Older Persons with Poorer Functional Ability: The Discontinuation of Antihypertensive Treatment in Elderly People (DANTE) Study Leiden

To examine the association between blood pressure (BP) measures and symptoms of apathy and depression in older adults with various levels of functional ability.

Influence of Small Vessel Disease and Microstructural Integrity on Neurocognitive Functioning in Older Individuals: The DANTE Study Leiden

BACKGROUND AND PURPOSE: Small vessel disease is a major cause of neurocognitive dysfunction in the elderly. Small vessel disease may manifest as white matter hyperintensities, lacunar infarcts, cerebral microbleeds, and atrophy, all of which are visible on conventional MR imaging or as microstructural changes determined by diffusion tensor imaging. This study investigated whether microstructural integrity is associated with neurocognitive dysfunction in older individuals, irrespective of the conventional features of small vessel disease. MATERIALS AND METHODS: The study included 195 participants (75 years of age or older) who underwent conventional 3T MR imaging with DTI to assess fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. Cognitive tests were administered to assess cognitive domains, and the Geriatric Depression Scale-15 and Apathy Scale of Starkstein were used to assess symptoms of depression and apathy, respectively. The association between DTI measures and neurocognitive function was analyzed by using linear regression models. RESULTS: In gray matter, a lower fractional anisotropy and higher mean diffusivity, axial diffusivity, and radial diffusivity were associated with worse executive function, psychomotor speed, and overall cognition and, in white matter, also with memory. Findings were independent of white matter hyperintensities, lacunar infarcts, and cerebral microbleeds. However, after additional adjustment for normalized brain volume, only lower fractional anisotropy in white and gray matter and higher gray matter radial diffusivity remained associated with executive functioning. DTI measures were not associated with scores on the Geriatric Depression Scale-15 or the Apathy Scale of Starkstein. CONCLUSIONS: Microstructural integrity was associated with cognitive but not psychological dysfunction. Associations were independent of the conventional features of small vessel disease but attenuated after adjusting for brain volume.

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.