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 ... Show moreOBJECTIVE 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. Show less
Palm, W.M.; Ferrarini, L.; Flier, W.M. van der; Westendorp, R.G.J.; Bollen, E.L.E.M.; Middelkoop, H.A.M.; ... ; Buchem, M.A. van 2013
BACKGROUND AND PURPOSE On MRI, cerebral white matter lesions, lacunar infarcts, and cerebral microbleeds are common imaging correlates of cerebral small vessel damage in apparently healthy elderly... Show moreBACKGROUND AND PURPOSE On MRI, cerebral white matter lesions, lacunar infarcts, and cerebral microbleeds are common imaging correlates of cerebral small vessel damage in apparently healthy elderly individuals. We investigated whether middle-aged to elderly offspring of nonagenarian siblings, who are predisposed to become long-lived as well, have a lower prevalence of white matter lesions, lacunar infarcts, and cerebral microbleeds than control subjects. METHODS All subjects were from the Leiden Longevity Study. In this study, middle-aged to elderly offspring of nonagenarian siblings, who are predisposed to become long-lived as well, were contrasted to their spouses. Cerebral small vessel disease was assessed using 3-T MRI. RESULTS Offspring were less likely to have severe periventricular frontal caps (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.1-1.1; P trend=0.01) and severe periventricular bands (OR, 0.4; 95% CI, 0.2-0.8; P trend=0.02). Moreover, offspring were less likely to have frontal (OR, 0.4; 95% CI, 0.2-0.9; P trend=0.05), parietal (OR, 0.4; 95% CI, 0.1-0.9; P trend=0.001), temporal (OR, 0.3; 95% CI, 0.1-0.8]; P trend=0.004), and occipital subcortical white matter lesions (OR, 0.3; 95% CI, 0.1-0.6; P trend=0.001). Prevalence of lacunar infarcts also was lower in offspring (OR, 0.3; 95% CI, 0.1-1.1; P=0.07). Prevalence of microbleeds was not significantly different in offspring and control subjects. CONCLUSIONS Exceptional familial longevity is associated with a lower susceptibility to white matter lesions and lacunar infarcts, but not cerebral microbleeds. Show less
Altmann-Schneider, I.; Craen, A.J.M. de; Slagboom, P.E.; Westendorp, R.G.J.; Buchem, M.A. van; Maier, A.B.; Grond, J. van der 2012
BACKGROUND: Reported findings are inconsistent whether hypothalamic-pituitary-adrenal (HPA) signaling becomes hyperactive with increasing age, resulting in increasing levels of cortisol. Our... Show moreBACKGROUND: Reported findings are inconsistent whether hypothalamic-pituitary-adrenal (HPA) signaling becomes hyperactive with increasing age, resulting in increasing levels of cortisol. Our previous research strongly suggests that offspring from long-lived families are biologically younger. In this study we assessed whether these offspring have a lower HPA axis activity, as measured by lower levels of cortisol and higher cortisol feedback sensitivity. METHODS: Salivary cortisol levels were measured at four time points within the first hour upon awakening and at two time points in the evening in a cohort comprising 149 offspring and 154 partners from the Leiden Longevity Study. A dexamethasone suppression test was performed as a measure of cortisol feedback sensitivity. Age, gender and body mass index, smoking and disease history (type 2 diabetes and hypertension) were considered as possible confounding factors. RESULTS: Salivary cortisol secretion was lower in offspring compared to partners in the morning (Area Under the Curve = 15.6 versus 17.1 nmol/L, respectively; p = 0.048) and in the evening (Area Under the Curve = 3.32 versus 3.82 nmol/L, respectively; p = 0.024). Salivary cortisol levels were not different after dexamethasone (0.5 mg) suppression between offspring and partners (4.82 versus 5.26 nmol/L, respectively; p = 0.28). CONCLUSION: Offspring of nonagenarian siblings are marked by a lower HPA axis activity (reflected by lower diurnal salivary cortisol levels), but not by a difference in cortisol feedback sensitivity. Further in-depth studies aimed at characterizing the HPA axis in offspring and partners are needed. Show less
Palm, W.M.; Ferrarini, L.; Flier, W.M. van der; Westendorp, R.G.J.; Bollen, E.L.E.M.; Middelkoop, H.A.M.; ... ; Buchem, M.A. van 2012
Postmortem studies show pathological changes in the striatum in Alzheimer's disease (AD). Here, we examine the surface of the striatum in AD and assess whether changes of the surface are associated... Show morePostmortem studies show pathological changes in the striatum in Alzheimer's disease (AD). Here, we examine the surface of the striatum in AD and assess whether changes of the surface are associated with impaired cognitive functioning. The shape of the striatum (n. accumbens, caudate nucleus, and putamen) was compared between 35 AD patients and 35 individuals without cognitive impairment. The striatum was automatically segmented from 3D T1 magnetic resonance images and automatic shape modeling tools (Growing Adaptive Meshes) were applied for morphometrical analysis. Repeated permutation tests were used to identify locations of consistent shape deformities of the striatal surface in AD. Linear regression models, corrected for age, gender, educational level, head size, and total brain parenchymal volume were used to assess the relation between cognitive performance and local surface deformities. In AD patients, differences of shape were observed on the medial head of the caudate nucleus and on the ventral lateral putamen, but not on the accumbens. The head of the caudate nucleus and ventral lateral putamen are characterized by extensive connections with the orbitofrontal and medial temporal cortices. Severity of cognitive impairment was associated with the degree of deformity of the surfaces of the accumbens, rostral medial caudate nucleus, and ventral lateral putamen. These findings provide evidence for the hypothesis that in AD primarily associative and limbic cerebral networks are affected. Show less
Es, A.C.G.M. van; Grond, J. van der; Craen, A.J.M. de; Westendorp, R.G.J.; Bollen, E.L.E.M.; Blauw, G.J.; ... ; PROSPER Study Grp 2011
OBJECTIVES Cerebral microbleeds (MBs) are an important indicator of cerebral small-vessel disease, and their prevalence increases with increasing age. Little is known about the functional... Show moreOBJECTIVES Cerebral microbleeds (MBs) are an important indicator of cerebral small-vessel disease, and their prevalence increases with increasing age. Little is known about the functional consequences of MBs in the aging population. In this study we investigated whether the presence and location of MBs are associated with cognition in the PROSPER study. METHODS For 439 subjects the number and location (cortico-subcortical, deep white matter, basal ganglia, and infratentorial) of the MBs was recorded. Difference in cognitive performance between subjects with and without MBs was calculated by entering the variables sex, age, white matter hyperintensity volume, infarction, and MBs in a linear mixed model. Differences in cognition between subjects with and without one or more MBs at different anatomic locations were assessed using the same model. RESULTS We found that after correction for sex, age, white matter hyperintensity volume, and infarction, subjects with infratentorial MBs had a significantly lower score on the Immediate Picture-Word Learning test, Delayed Picture-Word Learning, and Instrumental Activities of Daily Living. CONCLUSIONS Our data demonstrate that in elderly individuals at increased vascular risk, infratentorial MBs are associated with loss in cognitive functioning. Show less
Widya, R.L.; Roos, A. de; Trompet, S.; Craen, A.J.M. de; Westendorp, R.G.J.; Smit, J.W.A.; ... ; PROSPER Study Grp 2011
Background: The basal ganglia, hippocampus, and thalamus are involved in the regulation of human feeding behavior. Recent studies have shown that obesity [body mass index (BMI; in kg/m(2)) > 30]... Show moreBackground: The basal ganglia, hippocampus, and thalamus are involved in the regulation of human feeding behavior. Recent studies have shown that obesity [body mass index (BMI; in kg/m(2)) > 30] is associated with loss of gray and white matter. Objective: It is unknown whether the subcortical brain structures that are actually involved in feeding behavior also show volume changes in obesity. Therefore, the purpose of this study was to evaluate the volumes of the basal ganglia, hippocampus, and thalamus in obesity. Design: Three-dimensional T1-weighted magnetic resonance imaging scans of the brain were analyzed by using automatic segmentation to measure volumes of the nucleus accumbens, globus pallidus, amygdala, putamen, caudate nucleus, thalamus, and hippocampus in 471 subjects (mean age: 74.4 y; 56% men). Results: Obese subjects had larger left (P = 0.013) and right (P = 0.003) amygdalar volumes and a larger left hippocampal volume (P = 0.040) than did normal-weight subjects (BMI, 25). None of the other subcortical structures differed in size between these groups. After correction for age, sex, smoking, hypertension, and pravastatin use, BMI was associated with left (beta = 0.175, P = 0.001) and right (beta = 0.157, P = 0.001) amygdalar volumes and with left hippocampal volume (beta = 0.121, P = 0.016). Conclusions: This study showed that the amygdala and hippocampus are enlarged in obesity. In consideration of the function of these structures, this finding may indicate that hedonic memories could be of major importance in the regulation of feeding. Because of the cross-sectional design, cause and effect could not be discriminated in this study. Am J Clin Nutr 2011;93:1190-5. Show less
Altmann-Schneider, I.; Trompet, S.; Craen, A.J.M. de; Es, A.C.G.M. van; Jukema, J.W.; Stott, D.J.; ... ; Grond, J. van der 2011
Background and Purpose-To investigate the prognostic value of cerebral microbleeds (CMB) regarding overall, cardiovascular-related, and stroke-related mortality and to investigate possible... Show moreBackground and Purpose-To investigate the prognostic value of cerebral microbleeds (CMB) regarding overall, cardiovascular-related, and stroke-related mortality and to investigate possible differences based on a cerebral amyloid angiopathy-type and nonlobar distribution of microbleeds. Methods-We included 435 subjects who were participants from the nested MRI substudy of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Cox proportional hazard models were applied to estimate the risk of overall, cardiovascular-related, and stroke-related death associated with microbleeds in general and microbleeds with a lobar distribution suggestive of the presence of cerebral amyloid angiopathy. The corresponding Kaplan-Meier survival curves were calculated. Results-Subjects with >1 CMB had a 6-fold risk of stroke-related death compared to subjects without CMB (hazard ratio, 5.97; 95% CI, 1.60-22.26; P=0.01). The diagnosis of nonlobar microbleeds was associated with >2-fold risk of cardiovascular death compared to subjects without microbleeds (hazard ratio, 2.67; 95% CI, 1.23-5.81; P=0.01). Subjects with probable cerebral amyloid angiopathy-type microbleeds had >7-fold risk of stroke-related death compared to subjects without CMB (hazard ratio, 7.20; 95% CI, 1.44-36.10; P=0.02). Conclusions-This is the first study investigating the association between microbleeds and risk of overall, cardiovascular-related, and stroke-related mortality in an elderly population. Our findings indicate that the diagnosis of microbleeds is potentially of clinical relevance. Larger studies are needed to expand our observations and to address potential clinical implications and cost-benefits of such a policy. (Stroke. 2011;42:638-644.) Show less
Altmann-Schneider, I.; Trompet, S.; Craen, A.J.M. de; Es, A.C.G.M. van; Jukema, J.W.; Stott, D.J.; ... ; Grond, J. van der 2011
BACKGROUND AND PURPOSE: To investigate the prognostic value of cerebral microbleeds (CMB) regarding overall, cardiovascular-related, and stroke-related mortality and to investigate possible... Show moreBACKGROUND AND PURPOSE: To investigate the prognostic value of cerebral microbleeds (CMB) regarding overall, cardiovascular-related, and stroke-related mortality and to investigate possible differences based on a cerebral amyloid angiopathy-type and nonlobar distribution of microbleeds. METHODS: We included 435 subjects who were participants from the nested MRI substudy of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Cox proportional hazard models were applied to estimate the risk of overall, cardiovascular-related, and stroke-related death associated with microbleeds in general and microbleeds with a lobar distribution suggestive of the presence of cerebral amyloid angiopathy. The corresponding Kaplan-Meier survival curves were calculated. RESULTS: Subjects with >1 CMB had a 6-fold risk of stroke-related death compared to subjects without CMB (hazard ratio, 5.97; 95% CI, 1.60-22.26; P=0.01). The diagnosis of nonlobar microbleeds was associated with >2-fold risk of cardiovascular death compared to subjects without microbleeds (hazard ratio, 2.67; 95% CI, 1.23-5.81; P=0.01). Subjects with probable cerebral amyloid angiopathy-type microbleeds had >7-fold risk of stroke-related death compared to subjects without CMB (hazard ratio, 7.20; 95% CI, 1.44-36.10; P=0.02). CONCLUSIONS: This is the first study investigating the association between microbleeds and risk of overall, cardiovascular-related, and stroke-related mortality in an elderly population. Our findings indicate that the diagnosis of microbleeds is potentially of clinical relevance. Larger studies are needed to expand our observations and to address potential clinical implications and cost-benefits of such a policy. Show less
