[Epidemiology of severe visual impairment and blindness of old people in Germany]. / Epidemiologie hochgradiger Sehbehinderungen und Blindheit älterer Menschen in Deutschland.

Approximately 500,000 blind and 1 million visually impaired persons live in Germany, which lacks a national blind registry. Therefore data from social welfare agencies and population-based studies are used to estimate prevalence and incidence. Main causes for severe visual impairment and blindness are age-related macular degeneration, glaucoma and diabetic eye diseases. We observed a relative decline of the incidence of severe visual impairment and blindness over the last decades, which is primarily due to improved ophthalmic care and better treatment options. However, the absolute number of subjects with severe visual impairment and blindness increases due to population ageing. This will cause significant social and economic challenges in the future.

Follow-up of loci from the International Genomics of Alzheimer's Disease Project identifies TRIP4 as a novel susceptibility gene.

To follow-up loci discovered by the International Genomics of Alzheimer's Disease Project, we attempted independent replication of 19 single nucleotide polymorphisms (SNPs) in a large Spanish sample (Fundació ACE data set; 1808 patients and 2564 controls). Our results corroborate association with four SNPs located in the genes INPP5D, MEF2C, ZCWPW1 and FERMT2, respectively. Of these, ZCWPW1 was the only SNP to withstand correction for multiple testing (P=0.000655). Furthermore, we identify TRIP4 (rs74615166) as a novel genome-wide significant locus for Alzheimer's disease risk (odds ratio=1.31; confidence interval 95% (1.19-1.44); P=9.74 × 10(-)(9)).

Changing prediction of mortality by systolic blood pressure with increasing age: the Rotterdam study.

There are indications that in persons of older age, systolic blood pressure (SBP) is no longer associated with mortality. This raises the question whether the predictive value of SBP changes from younger to older age groups. Analysis in the Rotterdam Study, a population-based prospective cohort study among 4,612 participants aged ≥55 years without previous cardiovascular disease and with a median follow-up of 14.9 (interquartile range, 11.1-15.8) years. Within four age groups (55-64, 65-74, 75-84, ≥85 years), the predictive value of baseline SBP for mortality was studied. From age 55 to ≥85 years, risk of all-cause mortality associated with SBP ≥160 mmHg decreased from HR 1.7 (95%CI 1.2-2.2) to HR 0.7 (95%CI 0.4-1.1), p for trend <0.001. For participants with SBP 140-159 mmHg, the risk decreased from HR 1.2 (95%CI 0.9-1.5) to HR 0.7 (95%CI 0.5-1.1), p for trend <0.001. Analyses in the 5-year age groups showed an increased risk with higher SBPs up to age 75 years. After 75 years, a trend towards SBP no longer being associated with an increased mortality risk was seen in our study. These findings need to be considered with recently reported beneficial effects of antihypertensive treatment in this age group.

Gait patterns in a community-dwelling population aged 50 years and older.

Poor gait is an important risk factor for falls and associated with higher morbidity and mortality. It is well established that older age is associated with worse gait, but it remains unclear at what age this association is first seen. Moreover, previous studies focused mainly on normal walking, but gait also encompasses turning and tandem walking. In a large study of community-dwelling middle-aged and elderly persons we investigated the association of age with gait, focusing on normal walking, turning and tandem walking. In 1500 persons aged 50 years and over, we measured gait using an electronic walkway. Participants performed normal walks, turning and a tandem walk. With principal components analysis of 30 variables we summarized gait into five known gait factors: Rhythm, Variability, Phases, Pace and Base of Support; and uncovered two novel gait factors: Tandem and Turning. The strongest associations with age were found for Variability (difference in Z-score -0.29 per 10 years increase (95% confidence interval: -0.34; -0.24)), Phases (-0.31 per 10 years (-0.36; -0.27)) and Tandem (-0.25 per 10 years (-0.30; -0.20)). Additionally, these factors already showed association with the youngest age groups, from 55 to 60 years of age and older. Our study shows that Variability, Phases and Tandem have the strongest association with age and are the earliest to demonstrate a poorer gait pattern with higher age. Future research should further investigate how these gait factors relate with gait-related diseases in their earliest stages.

Structural and diffusion MRI measures of the hippocampus and memory performance.

Hippocampal atrophy on MRI and changes in diffusion tensor imaging (DTI) measures of the hippocampus have been reported in patients with Alzheimer's disease. We examined the association between hippocampal volumes, DTI measures of the hippocampus and memory performance in 892 non-demented persons (age ≥ 55 years) across different age groups. Hippocampal volume was segmented on 3D volumetric MRI scans. The segmentations were co-registered to mean diffusivity (MD) and fractional anisotropy (FA) maps to yield mean hippocampal MD and FA measurements. Higher MD of the hippocampus was associated with impaired verbal memory performance. In all persons ≥ 55 years, a higher MD of the hippocampus was associated with a worse memory performance. Hippocampal volumes were very weakly positively associated with delayed recall and only in persons > 65 years. FA of the hippocampus was not associated with memory performance. Follow-up studies will be needed to determine whether higher MD of hippocampus at younger ages could be an earlier marker of incident Alzheimer's disease than hippocampal volume.

Is dementia incidence declining?: Trends in dementia incidence since 1990 in the Rotterdam Study.

OBJECTIVE: To investigate whether dementia incidence has changed over the last 2 decades. METHODS: We compared dementia incidence in 2 independent subcohorts of persons aged 60-90 years from the Rotterdam Study, a population-based cohort study. The first subcohort started in 1990 (n = 5,727), the second in 2000 (n = 1,769). Participants were dementia-free at baseline and followed for at maximum 5 years. We calculated age-adjusted dementia incidence rates for the 2 subcohorts in total, in 10-year age strata, and for men and women separately. We also compared mortality rates, differences in prevalence of vascular risk factors, and medication use. Finally, we compared brain volumes and the extent of cerebral small vessel disease in participants who underwent brain imaging 5 years after the baseline examinations. RESULTS: In the 1990 subcohort (25,696 person-years), 286 persons developed dementia, and in the 2000 subcohort (8,384 person-years), 49 persons. Age-adjusted dementia incidence rates were consistently, yet nonsignificantly, lower in the 2000 subcohort in all strata, reaching borderline significance in the overall analysis (incidence rate ratio 0.75, 95% confidence interval [CI] 0.56-1.02). Mortality rates were also lower in the 2000 subcohort (rate ratio 0.63, 95% CI 0.52-0.77). The prevalence of hypertension and obesity significantly increased between 1990 and 2000. This was paralleled by a strong increase in use of antithrombotics and lipid-lowering drugs. Participants in 2005-2006 had larger total brain volumes (p < 0.001) and less cerebral small vessel disease (although nonsignificant in men) than participants in 1995-1996. CONCLUSIONS: Although the differences in dementia incidence were nonsignificant, our study suggests that dementia incidence has decreased between 1990 and 2005.

Cerebral microbleeds are associated with worse cognitive function: the Rotterdam Scan Study.

OBJECTIVE: Cerebral microbleeds are frequently found in the general elderly population and may reflect underlying vascular disease, but their role in cognitive function is unknown. METHODS: We investigated the association between cerebral microbleeds and performance in multiple cognitive domains in 3,979 persons without dementia (mean age, 60.3 years). Mini-Mental State Examination (MMSE) score and neuropsychological tests were used to assess global cognition and the following cognitive domains: memory, information processing speed, executive function, and motor speed. We used number of microbleeds as continuous variable, and additionally distinguished between persons with no microbleeds, 1 microbleed, 2-4 microbleeds, and ≥5 microbleeds. The association of microbleeds with different cognitive domains was estimated using linear regression models. Additional adjustments were made for vascular risk factors, brain atrophy, and other imaging markers of cerebral small vessel disease. We stratified analyses by location of microbleeds. RESULTS: A higher number of microbleeds was associated with lower MMSE score and worse performance on tests of information processing speed and motor speed. When analyzed per category, presence of 5 or more microbleeds was associated with worse performance in all cognitive domains, except memory. These associations were most robust in participants with strictly lobar microbleeds, whereas after additional adjustments associations disappeared for deep or infratentorial microbleeds. CONCLUSIONS: Presence of numerous microbleeds, especially in a strictly lobar location, is associated with worse performance on tests measuring cognitive function, even after adjustments for vascular risk factors and other imaging markers of small vessel disease. These results suggest an independent role for microbleed-associated vasculopathy in cognitive impairment.

Genetic determinants of von Willebrand factor plasma levels and the risk of stroke: the Rotterdam Study.

BACKGROUND: High von Willebrand factor (VWF) plasma levels are associated with an increased risk of stroke. VWF levels are strongly heritable. A previous meta-analysis of five large genome-wide association studies identified single-nucleotide polymorphisms (SNPs) within eight genetic loci as determinants of VWF levels. Whether these SNPs are associated with stroke risk is not known. The aim of our study was to investigate the association between genetic determinants of VWF levels and stroke risk. METHODS: The study was part of the Rotterdam Study, a large population-based cohort study among subjects aged ≥ 55 years. A total of 5763 participants for whom DNA was available, and who were free of stroke at baseline, were eligible for analysis. VWF antigen (VWF:Ag) levels were measured in 3379 eligible participants. Within each of the eight loci, one top SNP was defined. The association between the eight SNPs and the risk of stroke was analyzed. Then, a genetic score, based on these eight SNPs, was constructed, and its total contribution to VWF plasma levels and stroke risk was investigated. RESULTS: None of the eight SNPs was individually associated with stroke risk. A higher genetic score was significantly associated with a higher VWF:Ag level, but was not associated with an increased risk of stroke. CONCLUSION: Eight SNPs that strongly determine VWF levels are not associated with stroke risk, either individually, or combined in a genetic score.

Retinal vascular caliber and risk of dementia: the Rotterdam study.

BACKGROUND: Retinal vessels provide a unique opportunity to study both systemic and cerebrovascular disease. Smaller retinal arteriolar calibers are strongly related to hypertension, whereas larger retinal venular calibers are more related to inflammation, cerebral hypoperfusion, and cerebrovascular disease. Whether retinal vessel calibers are related to dementia remains unclear. METHODS: We investigated whether retinal arteriolar and venular calibers are associated with risk of dementia, and its subtypes Alzheimer disease (AD) and vascular dementia, in the prospective population-based Rotterdam Study. Digitized retinal images were available in 5,553 participants aged 55 years or over and dementia-free at baseline (1990-1993). Participants were re-examined in 1993-1994, 1997-1999, and 2002-2004 and were continuously monitored for development of dementia. RESULTS: During a mean follow-up of 11.6 years, 655 participants developed dementia. AD was diagnosed in 519 and vascular dementia in 73 participants. Larger venular calibers were associated with an increased risk of dementia, in particular vascular dementia (age- and sex-adjusted hazard ratio per SD increase: 1.31; 95% confidence interval 1.06-1.64), but not AD. The association remained significant after adjustment for stroke and cardiovascular risk factors. Smaller arteriolar calibers were also associated with an increased risk of vascular dementia, yet only when adjusted for venular calibers. CONCLUSIONS: Retinal venular widening is associated with an increased risk of vascular dementia. Our findings are in line with previous observations in stroke and cerebral small-vessel disease and suggest that the association between larger retinal venular calibers and dementia may reflect cerebral hypoperfusion and subsequent ischemia.

Cathepsin D gene and the risk of Alzheimer's disease: a population-based study and meta-analysis.

Cathepsin D (CTSD) is a gene involved in amyloid precursor protein processing and is considered a candidate for Alzheimer's disease (AD). The aim of the current study was to examine if variation in CTSD increases the risk of AD. We performed a candidate-gene analysis in a population-based cohort study (N=7983), and estimated the effect of CTSD on the risk of AD. Additionally, a large meta-analysis was performed incorporating our data and previously published data. The T-allele of CTSD rs17571 was associated with an increased risk of AD (p-value 0.007) in the Rotterdam Study. This association was predominantly found in APOE ε4 noncarriers. A meta-analysis of previously published data showed a significantly increased risk of AD in carriers of the T-allele of rs17571 (OR 1.22, 95% CI 1.03-1.44), irrespective of APOE ε4 carrier status. This study adds to the evidence that CTSD increases the risk of AD, although the effect size is moderate.

Genetic risk factors for cerebral small-vessel disease in hypertensive patients from a genetically isolated population.

BACKGROUND: Asymptomatic cerebral lesions on MRI such as white matter lesions (WML), lacunes and microbleeds are commonly seen in older people. We examined the role of a series of candidate genes involved in blood pressure regulation and amyloid metabolism. MATERIALS AND METHODS: The study was embedded in a family-based cohort sampled from a Dutch genetically isolated population. We selected individuals between 55 and 75 years of age with hypertension (N=129). Volumes of WML and presence of lacunes and microbleeds were assessed with MRI. We studied three genes involved in blood pressure regulation (angiotensin, angiotensin II type 1 receptor, α-adducin) and two genes involved in the amyloid pathway (apolipoprotein E (APOE) and sortilin-related receptor gene (SORL1)). RESULTS: All participants had WML (median volume, 3.1 ml; interquartile range, 1.5-6.5 ml); lacunar infarcts were present in 15.5% and microbleeds in 23.3%. Homozygosity for the APOE ε4 allele was associated with lacunes (OR, 4.8; 95% CI, 1.2 to 19.3). Individuals carrying two copies of the variant allele of four single nucleotide polymorphism (SNPs) located at the 3'-end of SORL1 (rs1699102, rs3824968, rs2282649, rs1010159) had significantly more often microbleeds (highest OR, 6.87; 95% CI, 1.78 to 26.44). CONCLUSION: The association of SORL1 with microbleeds suggests that the amyloid cascade is involved in the aetiology of microbleeds in populations with hypertension.

Insulin metabolism and the risk of Alzheimer disease: the Rotterdam Study.

OBJECTIVE: Diabetes mellitus has been associated with an increased risk of Alzheimer disease (AD), but how it exerts its effect remains controversial. Possible pathophysiologic mechanisms are glucose toxicity and a direct effect of insulin on amyloid metabolism. Most studies had short follow-up, and longer-term effects of diabetes on AD risk are unknown. We investigated whether fasting glucose and insulin levels and insulin resistance are associated with the risk of AD and whether this risk is constant over time. METHODS: The study was based on 3,139 participants of the Rotterdam Study, a population-based cohort study. All subjects were free from dementia, did not have a history of diabetes, and had fasting levels of glucose and insulin measured at baseline. Insulin resistance was estimated with the homeostasis model assessment. We investigated how fasting glucose, insulin, and insulin resistance are related to the risk of AD in 3 different strata according to time-to-event, using Cox proportional hazards models. RESULTS: During follow-up, 211 participants developed AD, 71 of them within 3 years of baseline. Levels of insulin and insulin resistance were associated with a higher risk of AD within 3 years of baseline. After 3 years, the risk was no longer increased. Glucose was not associated with a higher risk of AD. There was no interaction of APOE ε4 carriership and insulin metabolism on the risk of AD. CONCLUSIONS: Our findings suggest that insulin metabolism influences the clinical manifestation of AD only within 3 years.

Heart failure and the risk of stroke: the Rotterdam Study.

Patients with heart failure used to have an increased risk of stroke, but this may have changed with current treatment regimens. We assessed the association between heart failure and the risk of stroke in a population-based cohort that was followed since 1990. The study uses the cohort of the Rotterdam Study and is based on 7,546 participants who at baseline (1990­1993) were aged 55 years or over and free from stroke. The associations between heart failure and risk of stroke were assessed using time-dependent Cox proportional hazards models, adjusted for cardiovascular risk factors (smoking, diabetes mellitus, BMI, ankle brachial index, blood pressure, atrial fibrillation, myocardial infarction and relevant medication). At baseline, 233 participants had heart failure. During an average follow-up time of 9.7 years, 1,014 persons developed heart failure, and 827 strokes (470 ischemic, 75 hemorrhagic, 282 unclassified) occurred. The risk of ischemic stroke was more than five-fold increased in the first month after diagnosis of heart failure (age and sex adjusted HR 5.79, 95% CI 2.15­15.62), but attenuated over time (age and sex adjusted HR 3.50 [95% CI 1.96­6.25] after 1­6 months and 0.83 [95% CI 0.53­1.29] after 0.5­6 years). Additional adjustment for cardiovascular risk factors only marginally attenuated these risks. In conclusion, the risk of ischemic stroke is strongly increased shortly after the diagnosis of heart failure but returns to normal within 6 months after onset of heart failure.

Risk factors for coronary, aortic arch and carotid calcification; The Rotterdam Study.

This study was performed to examine the association of cardiovascular risk factors with calcification in the coronary arteries, aortic arch and carotid arteries, assessed by multislice computed tomography (MSCT). This study was embedded in the Rotterdam Study, a population-based study in subjects aged 55 years and over. From October 2003 until December 2004, subjects were invited to undergo a MSCT scan. Coronary, aortic arch and carotid calcification were quantified according to the Agatston score. Analyses were performed in the first 1003 subjects. Age and current smoking were the strongest independent risk factors for arterial calcification. The odds ratio (OR) for age in women, irrespective of the vessel bed, was 1.1 (P<0.001) and in men it was 1.2 with aortic arch and 1.1 with carotid calcification (both P<0.001). Current smoking was associated with aortic arch calcification with an OR of 3.5 in women and of 4.7 in men (both P<0.001); and with carotid calcification with an OR of 2.1 in women (P<0.05) and of 4.1 in men (P<0.01). Hypertension, hypercholesterolemia and diabetes were also independently related to calcification, although not consistent across all vessel beds and for men and women. Obesity tended to be inversely related to arterial calcification in women, whereas low high-density lipoprotein-cholesterol showed no relation with arterial calcification. In conclusion, although associations were not completely consistent across the different vessel beds and for men and women, our results indicate that generally the same risk factors are present for atherosclerosis in the coronary, aortic arch and carotid circulation.

Superficial siderosis in the general population.

BACKGROUND: Superficial siderosis is a rare radiologic diagnosis of hemosiderin deposition in subpial brain layers. In case studies, an association between superficial siderosis and cerebral amyloid angiopathy (CAA) has been described. Also, a potential role of superficial siderosis in Alzheimer disease (AD) was hypothesized. All previously reported cases of superficial siderosis were detected because of overt clinical symptoms. We studied the occurrence of superficial siderosis on brain MRI in a general population of nondemented elderly. METHODS: In 1,062 persons (mean age 69.6 years) from the population-based Rotterdam Scan Study, we performed T2*-weighted MRI to assess the presence of superficial siderosis. Furthermore, the presence, number, and location of cerebral microbleeds were rated, as lobar microbleeds are thought to be indicative of CAA. RESULTS: We found that superficial siderosis was present in 7 (0.7%) individuals, all of whom had cerebral microbleeds in lobar locations. Furthermore, in all 7 persons, microbleeds were located in close vicinity to superficial siderosis. CONCLUSIONS: Our results provide further indirect support for the presumed link between superficial siderosis and cerebral amyloid angiopathy (CAA). Whether superficial siderosis may be a marker for severity or worse prognosis of CAA needs to be further evaluated in longitudinal follow-up.

Familial aggregation of parkinsonism in progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder characterized by aggregates of the microtubule-associated protein tau (MAPT). A nonsignificant trend for positive family history has been observed in two case-control studies and several pedigrees with familial clustering of parkinsonism have been described. Occasionally, mutations in MAPT are found in patients with a clinical phenotype similar to PSP. In this case-control study, we compared the occurrence of dementia and parkinsonism among first-degree relatives of patients with PSP with an age- and sex-matched control group. METHODS: Family history of dementia and parkinsonism was collected from all first-degree relatives of patients with PSP who fulfilled the international National Institute of Neurological Disorders and Stroke criteria for PSP. Age- and sex-matched controls were selected from the Rotterdam Study. Genetic testing and pathologic examination was performed in a subset of familial PSP cases. RESULTS: Fifty-seven (33%) of the 172 patients with PSP had at least one first-degree relative who had dementia or parkinsonism compared to 131 (25%) of the control subjects (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.01-2.13). In patients with PSP, more first-degree relatives with parkinsonism were observed compared to controls, with an OR 3.9 (95% CI 1.99-7.61). Twelve patients with PSP (7%) fulfilled the criteria for an autosomal dominant mode of transmission. The intrafamilial phenotype within these pedigrees varied among PSP, dementia, tremor, and parkinsonism. Genetic studies revealed one patient with a P301L mutation in MAPT. Pathologic examination of five familial cases confirmed the clinical diagnosis of PSP, with predominant four repeat tau pathology in affected brain areas. CONCLUSION: This study demonstrates familial aggregation of parkinsonism in progressive supranuclear palsy.

Duration of antihypertensive drug use and risk of dementia: A prospective cohort study.

BACKGROUND: The evidence from prospective observational research for a protective effect of antihypertensive drug use on the risk of dementia is far from uniform. Duration of follow-up was limited and relied mainly on baseline drug exposure data without information on duration of use. We investigated the association between the duration of antihypertensive use and risk of dementia. METHODS: We followed 6,249 participants (mean 68.4 years, 60% women) of a prospective, population-based cohort from baseline (1990-1993) until 2005 for incident dementia. Continuous data on filled prescriptions came from pharmacy records. Total cumulative duration of antihypertensive use was expressed in years. We subtracted a latent 4-year period before the date of dementia diagnosis in the quantification of exposure duration to avoid potential bias in antihypertensive prescription due to prodromal changes in blood pressure or cognition. With Cox regression models, we calculated crude and adjusted hazard ratios (HRs) of all dementia and Alzheimer disease (AD) with antihypertensive use vs never used. RESULTS: Compared to never used, antihypertensive use was associated with a reduced risk of all dementia (adjusted HR per year of use 0.95; 95% confidence interval [CI] 0.91-0.99). We observed an 8% (95% CI -15% to -1%) risk reduction per year of use for persons < or =75 years, whereas for persons >75 years this was 4% (95% CI -11% to 4%). Equivalent estimates were observed for AD. No apparent differences were observed among different types of antihypertensive drugs. CONCLUSIONS: Antihypertensive drug use was associated with 8% risk reduction of dementia per year of use for persons < or =75 years.

HFE variants, APOE and Alzheimer's disease: findings from the population-based Rotterdam study.

Iron is a reactive oxygen species and has been implicated in the pathogenesis of Alzheimer's disease (AD). In a population-based cohort study, including 268 incident AD patients and 2079 control individuals, we investigated the influence of the HFE C282Y and H63D variants and the apolipoprotein E4 (APOE epsilon 4) allele on the incidence, and age at onset of AD. There was no significant difference in the frequency of HFE variants in AD patients compared to controls. There was no significant effect modification by the APOE epsilon 4 allele. The mean age at onset was earlier in H63D homozygotes compared to non-carriers of this variant, in men (76.9+/-3.2 compared to 82.2+/-1.7) and women (82.1+/-3.9 compared to 84.5+/-1.7). In addition, in APOE epsilon 4 carriers, the mean age at onset of AD was earlier in men homozygous for the H63D variant (73.2+/-2.1 versus 78.7+/-1.6, p=0.05). Our results suggest that HFE variants are not strong determinants of AD in the general population but may modify the age of onset.

Plasma vitamin B12 status and cerebral white-matter lesions.

BACKGROUND AND OBJECTIVE: Elevated homocysteine has been associated with a higher prevalence of cerebral white-matter lesions and infarcts, and worse cognitive performance. This raises the question whether factors involved in homocysteine metabolism, such as vitamin B(12), are also related to these outcomes. This study examined the association of several markers of vitamin B(12) status with cerebral white-matter lesions, infarcts and cognition. METHODS: The study evaluated the association of plasma concentrations of vitamin B(12), methylmalonic acid, holotranscobalamin and transcobalamin saturation with cerebral white-matter lesions and infarcts at baseline and cognition at baseline and during follow-up among 1019 non-demented elderly participants of the population-based Rotterdam Scan Study. Analyses were adjusted for several potential confounders, including homocysteine and folate concentration. RESULTS: Poorer vitamin B(12) status was significantly associated with greater severity of white-matter lesions, in particular periventricular white-matter lesions, in a concentration-related manner. Adjustment for common vascular risk factors (including blood pressure, smoking, diabetes and intima media thickness) did not alter the associations. Adjustment for homocysteine and folate modestly weakened the associations. No association was observed for any of the studied markers of vitamin B(12) status with presence of brain infarcts and baseline cognition or cognitive decline during follow-up. CONCLUSIONS: These results indicate that vitamin B(12) status in the normal range is associated with severity of white-matter lesions, especially periventricular lesions. Given the absence of an association with cerebral infarcts, it is hypothesised that this association is explained by effects on myelin integrity in the brain rather than through vascular mechanisms.