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Abstract: Background: Decline of hippocampal volume on magnetic resonance imaging (MRI) may be considered as a surrogate biomarker of accumulating Alzheimer disease (AD) pathology. Previously, we showed in the prospective population-based Rotterdam Scan Study that a higher rate of decline of hippocampal volume on MRI precedes clinical AD or memory decline. We studied potential risk factors for decline of hippocampal volume. Methods: At baseline (1995–1996), 518 nondemented elderly subjects were included, and the cohort was re-examined in 1999 and in 2006. At each examination, hippocampal volume was determined using an automated segmentation procedure. In all, 301 persons had at least two three-dimensional MRI scans to assess decline in hippocampal volume. Results: Persons carrying the apolipoprotein E (APOE) ɛ4 allele had lower hippocampal volumes than persons with the ɛ3/ɛ3 genotype, but the rate of decline was not influenced by APOE genotype. In persons who did not use antihypertensive treatment, both a high (>90 mm Hg) and a low (<70 mm Hg) diastolic blood pressure were associated with a faster decline in hippocampal volume. Also, white matter lesions on baseline MRI were associated with a higher rate of decline in hippocampal volume. Conclusions: In a nondemented elderly population, persons with the APOE ɛ4 allele have a smaller hippocampal volume but not a higher rate of decline. Rate of decline of hippocampal volume was influenced by white matter lesions and diastolic blood pressure, supporting their hypothesized role in the pathogenesis of AD. [Copyright &y& Elsevier]

Background: Cross-sectional studies have demonstrated that increased levels of interleukin-6 (IL6) are present in the airways and blood samples of patients with chronic obstructive pulmonary disease (COPD). Objectives: To investigate the association between IL6 and the risk of COPD using a Mendelian randomization approach. Methods: Eight common single-nucleotide polymorphisms (SNPs) in the region of the IL6 gene were genotyped using both TaqMan and Illumina in the Rotterdam Study, a prospective population-based cohort study consisting of 7,983 participants aged 55 years or older, including 928 COPD patients. At baseline, blood was drawn in a random sample of 714 subjects to measure the IL6 plasma level. Analysis of variance, logistic regression, and Cox proportional hazard models - adjusted for age, gender, pack years, and BMI - were used for analyses. Results: High levels of IL6 (>2.4 pg/ml, the highest tertile) were associated with a three-fold increased risk of developing COPD, in comparison to low levels (<1.4 pg/ml, the lowest tertile). The rs2056576 SNP was associated with a 10% increase in the risk of COPD per additional T allele. However, the association was no longer significant after adjustment. No association was found with other common SNPs in the IL6 gene and COPD. Conclusions: Although increased IL6 plasma levels at baseline are associated with the risk of developing COPD during follow-up, there was no strong evidence for an association between common variation in the IL6 gene and the risk of COPD. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Dementia is a common neurodegenerative disorder that affects about 10% of the population over 65 years of age. A distinction can be made between primary degenerative dementias and dementia secondary to other diseases. This review focuses on the primary non-Alzheimer''s disease (AD) dementias: vascular dementia (VaD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). VaD is after AD most frequent subtype of dementia with a prevalence of about 1%, ranging from 0 to 10% mainly depending on the age group investigated and the criteria used. Its incidence rate is between 1.5 and 4.1 per 1000 person-years, with no clear difference between men and women and with possibly a higher incidence in East Asia compared to Canada and Europe. Most of the VaD cases are sporadic although there are some rare familial forms of VaD as cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy and familial cerebral amyloid angiopathy. Important risk factors for sporadic VaD are cerebrovascular pathology (brain infarction, white matter lesions and brain atrophy), midlife hypertension, and diabetes leading to increasing risk ratios. A protective effect is often found for education and moderate use of alcohol. The association between VaD and amyloid β, cholesterol, and statin use remains unclear yet. DLB and FTD are less frequent forms of dementia with prevalence rates of, respectively, 0.1–0.6 and 0.002–0.015%. FTD affects people in their middle age, accounting for up to 10–20% of the presenile dementia cases. About 14% of the FTD cases are caused by an autosomal dominant tau-mutation. However, since the prevalence of sporadic FTD is relatively low, population-based epidemiological studies are hard to perform and no non-genetic risk factors are known yet. DLB is a relative common form of dementia in old age accounting for 15–20% of cases in hospital autopsy case-series. The only known possible risk factor for DLB is the presence of an apolipoprotein E #x03B5;4 allele. [Copyright &y& Elsevier]

Assessing physiological changes that occur with healthy ageing is prerequisite for understanding pathophysiological age-related changes. Eye movements are studied as biomarkers for pathological changes because they are altered in patients with neurodegenerative disorders. However, there is a lack of data from large samples assessing age-related physiological changes and sex differences in oculomotor performance. Thus, we assessed and quantified cross-sectional relations of age and sex with oculomotor performance in the general population. We report results from the first 4,000 participants (aged 30-95 years) of the Rhineland Study, a community-based prospective cohort study in Bonn, Germany. Participants completed fixation, smooth pursuit, prosaccade and antisaccade tasks. We quantified associations of age and sex with oculomotor outcomes using multivariable linear regression models. Performance in 12 out of 18 oculomotor measures declined with increasing age. No differences between age groups were observed in five antisaccade outcomes (amplitude-adjusted and unadjusted peak velocity, amplitude gain, spatial error and percentage of corrected errors) and for blink rate during fixation. Small sex differences occurred in smooth pursuit velocity gain (men have higher gain) and blink rate during fixation (men blink less). We conclude that performance declines with age in two thirds of oculomotor outcomes but that there was no evidence of sex differences in eye movement performance except for two outcomes. Since the percentage of corrected antisaccade errors was not associated with age but is known to be affected by pathological cognitive decline, it represents a promising candidate preclinical biomarker of neurodegeneration. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Incidental brain findings defined as previously undetected abnormalities of potential clinical relevance that are unexpectedly discovered at brain imaging and are unrelated to the purpose of the examination are common in the general population. Because it is unclear whether the prevalence of incidental findings in breast cancer patients treated with chemotherapy is different to that in the general population, we compared the prevalence in breast cancer survivors treated with chemotherapy to that in a population-based sample of women without a history of any cancer. Patients and methods: Structural brain MRI (1.5T) was performed in 191 female CMF (Cyclophosphamide, Methotrexate, 5-Fluorouracil) chemotherapy-exposed breast cancer survivors. A reference group of 1590 women without a history of cancer was sampled from a population-based cohort study. All participants were aged 50 to 80years. Five trained reviewers recorded the brain abnormalities. Two experienced neuro-radiologists reviewed the incidental findings. Results: The cancer survivors had completed chemotherapy on average 21years before. Of the 191 subjects, 2.6% had an aneurysm and 3.7% had a meningioma. The prevalence of meningiomas and aneurysms was not different between the groups. The prevalence of pituitary macro adenomas in the breast cancer survivors (1.6%) was higher than that in the reference group (0.1%) (OR=23.7; 95% CI 2.3–245.8). Conclusion: Contrary to commonly held opinions, we did not observe an increased prevalence of meningiomas in cancer survivors. Breast cancer survivors previously treated with chemotherapy are more likely to develop pituitary adenomas than persons without a history of cancer and chemotherapy treatment. [Copyright &y& Elsevier]

Background: Hippocampal volume loss on magnetic resonance imaging (MRI) has been reported in patients with depression. It is uncertain whether a small hippocampus renders a person vulnerable to develop depression or whether it is a consequence of depression. In this study, we addressed whether smaller baseline MRI hippocampal volumes increase the risk of incident depression. We also examined whether depressive symptoms at baseline were associated with decline in hippocampal volume during follow-up. Methods: Data were obtained in a prospective population-based study over a 10-year period. A sample of 514 nondemented persons aged 60 to 90 years underwent baseline measurements in 1995–1996 including three-dimensional MRI scans for assessment of hippocampal volumes and depressive symptoms (measured with Center for Epidemiologic Studies Depression Scale). Follow-up MRIs were made in 1999–2000 and in 2006. Incident depression was identified through standardized psychiatric examinations and continuous monitoring of medical and pharmaceutical records. Results: During a mean follow-up of 6.8 years per person (range .07–10.01 years), 135 of the 514 persons developed a clinically relevant episode of incident depressive symptoms. There was no association between baseline hippocampal volumes and incident depression (hazard ratio per SD decrease of average hippocampal volume .98 [.81–1.19], p = .84). A baseline Center for Epidemiologic Studies Depression Scale score of 16 or higher predicted a faster rate of decline in hippocampal volume. Also, incident depression was accompanied by a faster decline in left hippocampal volume. Conclusions: This study provides no evidence that a small hippocampal volume precedes the development of late-life depression. Depression, however, may lead to a faster rate of hippocampal volume decline. [ABSTRACT FROM AUTHOR]

Abstract: We investigated in a population-based cohort study the association of global and lobar brain tissue volumes with specific cognitive domains and risk of dementia. Participants (n =490; 60–90 years) were non-demented at baseline (1995–1996). From baseline brain MRI-scans we obtained global and lobar volumes of CSF, GM, normal WM, white matter lesions and hippocampus. We performed neuropsychological testing at baseline to assess information processing speed, executive function, memory function and global cognitive function. Participants were followed for incident dementia until January 1, 2005. Larger volumes of CSF and WML were associated with worse performance on all neuropsychological tests, and an increased risk of dementia. Smaller WM volume was related to poorer information processing speed and executive function. In contrast, smaller GM volume was associated with worse memory function and increased risk of dementia. When investigating lobar GM volumes, we found that hippocampal volume and temporal GM volume were most strongly associated with risk of dementia, even in persons without objective and subjective cognitive deficits at baseline, followed by frontal and parietal GM volumes. [Copyright &y& Elsevier]

Abstract: Thyroid dysfunction is associated with cognitive impairment and dementia, including Alzheimer''s disease (AD). It remains unclear whether thyroid dysfunction results from, or contributes to, Alzheimer pathology. We determined whether thyroid function is associated with dementia, specifically AD, and Alzheimer-type neuropathology in a prospective population-based cohort of Japanese-American men. Thyrotropin, total and free thyroxine were available in 665 men aged 71–93 years and dementia-free at baseline (1991), including 143 men who participated in an autopsy sub-study. During a mean follow-up of 4.7 (S.D.: 1.8) years, 106 men developed dementia of whom 74 had AD. Higher total and free thyroxine levels were associated with an increased risk of dementia and AD (age and sex adjusted hazard ratio (95% confidence interval) per S.D. increase in free thyroxine: 1.21 (1.04; 1.40) and 1.31 (1.14; 1.51), respectively). In the autopsied sub-sample, higher total thyroxine was associated with higher number of neocortical neuritic plaques and neurofibrillary tangles. No associations were found for thyrotropin. Our findings suggest that higher thyroxine levels are present with Alzheimer clinical disease and neuropathology. [Copyright &y& Elsevier]

Abstract: Brain atrophy and small vessel disease increase the risk of dementia and stroke. In a population-based cohort study (n =490; 60–90 years) we investigated how volumetric measures of atrophy and small vessel disease were related to mortality and whether this was independent of incident dementia or stroke. Brain volume and hippocampal volume were considered as measures of atrophy, whereas white matter lesions (WML) and lacunar infarcts reflected small vessel disease. We first investigated all-cause mortality in the whole cohort. In subsequent analyses we censored persons at incident dementia or incident stroke. Finally, we separately investigated cardiovascular mortality. The average follow-up was 8.4 years, during which 191 persons died. Brain atrophy and hippocampal atrophy, as well as WML increased the risk of death. The risks associated with hippocampal atrophy attenuated when censoring persons at incident dementia, but not at incident stroke. Censoring at either incident dementia or stroke did not change the risk associated with brain atrophy and WML. Moreover, WML were particularly associated with cardiovascular mortality. [Copyright &y& Elsevier]

Abstract: Amyloid β (Aβ) may disturb cerebral autoregulation by damaging the wall of small cerebral blood vessels and by direct negative vasoactive properties. We assessed whether previous and concurrent plasma Aβ1–40 and Aβ1–42 levels were associated with an impaired CO2-induced cerebral vasomotor response. In the longitudinal population-based Rotterdam Study we measured plasma Aβ levels and cerebral vasomotor reactivity to hypercapnia with transcranial Doppler ultrasonography (TCD) in 441 people, aged 60–90 years. We performed age and sex adjusted logistic regression analysis. Plasma Aβ levels assessed on average 6.5-year before TCD were linearly associated with an impaired CO2-induced cerebral vasomotor response (odds ratio 1.48 (95%CI 1.19;1.84) per standard deviation increase in Aβ1–40, and 1.36 (95%CI 1.09;1.70) per standard deviation increase in Aβ1–42). Such an association was not present for Aβ assessed concurrently with the TCD measurement. Persons whose plasma Aβ1–40 levels had decreased in the 6.5-year period preceding TCD measurements were more likely to have an impaired CO2-induced vasomotor reactivity. Overall our observations are most compatible with plasma Aβ levels representing vascular Aβ deposits years later resulting in impaired CO2-induced vasomotor reactivity. [Copyright &y& Elsevier]

The relation between blood pressure level and degree of global brain atrophy is equivocal. We evaluated past and present blood pressure levels and change in blood pressure over 20 years in relation to the degree of cortical atrophy on magnetic resonance imaging (MRI). In 1995–1996, we measured blood pressure and performed MRI in 1077 nondemented elderly (age 60–90 years). For 513 of these, we had information on a blood pressure level 20 years before. The degree of cortical atrophy was semi-quantitatively scored (range 0–15). In late life, a high (≥90 mmHg) and low (<65 mmHg) diastolic blood pressure were associated with more cortical atrophy than a diastolic blood pressure level between 65–74 mmHg (adjusted difference 0.60 units (95% confidence interval (CI), 0.18–1.02) and 0.77 units (0.28–1.25), respectively). Persons whose diastolic blood pressure had declined more than 10 mmHg over 20 years had more cortical atrophy than those with stable blood pressure levels (adjusted difference 0.53 units, 0.05–1.02). Both high and declining diastolic blood pressure levels are associated with more global brain atrophy on MRI. [Copyright &y& Elsevier]

• Subjective and physiological measures of chronic stress were unrelated in adults. • Higher perceived stress was associated with worse cognitive performance. • Higher perceived self-efficacy was related to better cognition, particularly in old age. • Men showed stronger associations between perceived stress and executive functioning. • Hair cortisol concentration was not associated with cognitive performance. Chronic stress detrimentally affects cognition but evidence from population-based studies is scarce and largely based on one-dimensional stress assessments. In this study, we aimed to investigate associations of subjective and psychological chronic stress measures with cognition in a population-based sample of adults aged 30–95 years from the Rhineland Study. Participants completed the Perceived Stress Scale (subjective measure) and a cognitive test battery (N = 1766). Hair cortisol concentration (physiological measure) was assessed by liquid chromatography tandem mass spectrometry in 1098 participants. Cross-sectional associations between the two measures of chronic stress and cognition were investigated using multivariable linear regression models. Subjective and physiological measures of chronic stress were not associated with each other (B = 0.005 [95 %CI = -0.005 – 0.015]). Participants with higher perceived stress and specifically lower perceived self-efficacy performed worse in all cognitive domains (effect sizes ranged from β = -0.129 [95 %CI = -0.177 – -0.080] to -0.054 [95 %CI = -0.099 – -0.009]; and from β = 0.052 [95 %CI = 0.005 – 0.098] to 0.120 [95 %CI = 0.072 – 0.167], respectively). Relationships between subjective chronic stress measures and executive functioning were stronger in men compared to women (interaction β = -0.144 [95 %CI = -0.221 – -0.067]). Relationships between perceived stress and working memory, and between perceived self-efficacy and executive functioning, processing speed, verbal episodic and working memory, increased with older age. Hair cortisol concentration was not associated with performance in any cognitive domain. Our results suggest that subjective and physiological measures capture different aspects of chronic stress in the general population. [ABSTRACT FROM AUTHOR]