Alzheimer Disease: Breteler MM

Hachinski V, Iadecola C, Petersen RC, Breteler MM, Nyenhuis DL, Black SE, Powers WJ, DeCarli C, Merino JG, Kalaria RN, Vinters HV, Holtzman DM, Rosenberg GA, Wallin A, Dichgans M, Marler JR, Leblanc GG. · London Health Sciences Centre, University Campus, London, Ontario, Canada. · Stroke. · Pubmed #16917086 links to  free full text

Abstract: BACKGROUND AND PURPOSE: One in 3 individuals will experience a stroke, dementia or both. Moreover, twice as many individuals will have cognitive impairment short of dementia as either stroke or dementia. The commonly used stroke scales do not measure cognition, while dementia criteria focus on the late stages of cognitive impairment, and are heavily biased toward the diagnosis of Alzheimer disease. No commonly agreed standards exist for identifying and describing individuals with cognitive impairment, particularly in the early stages, and especially with cognitive impairment related to vascular factors, or vascular cognitive impairment. METHODS: The National Institute for Neurological Disorders and Stroke (NINDS) and the Canadian Stroke Network (CSN) convened researchers in clinical diagnosis, epidemiology, neuropsychology, brain imaging, neuropathology, experimental models, biomarkers, genetics, and clinical trials to recommend minimum, common, clinical and research standards for the description and study of vascular cognitive impairment. RESULTS: The results of these discussions are reported herein. CONCLUSIONS: The development of common standards represents a first step in a process of use, validation and refinement. Using the same standards will help identify individuals in the early stages of cognitive impairment, will make studies comparable, and by integrating knowledge, will accelerate the pace of progress.

in 't Veld BA, Launer LJ, Breteler MM, Hofman A, Stricker BH. · Department of Epidemiology and Biostatistics, Erasmus Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. · Epidemiol Rev. · Pubmed #12762096 links to  free full text

This publication has no abstract.

Breteler MM. · Department of Epidemiology and Biostatistics, Erasmus Medical Center Rotterdam, PO Box 1738, 3000 DR, Rotterdam, The Netherlands. · Neurobiol Aging. · Pubmed #10867200 No free full text.

Abstract: Vascular disease and Alzheimer's disease are both common disorders, in particular among elderly subjects. Therefore, it can be expected that the joint occurrence of these two disorders is not a rare phenomenon. In recent years, evidence is increasing that the two may be more closely linked than just by chance. Epidemiological studies have suggested that risk factors for vascular disease and stroke are associated with cognitive impairment and Alzheimer's disease, and that the presence of cerebrovascular disease intensifies the presence and severity of the clinical symptoms of Alzheimer's disease. In this paper, current knowledge on the relation between vascular risk factors and risk indicators and Alzheimer's disease will be reviewed.

Skoog I, Kalaria RN, Breteler MM. · Institute of Clinical Neuroscience, Section of Psychiatry, Sahlgrenska University Hospital, Göteborg, Sweden. · Alzheimer Dis Assoc Disord. · Pubmed #10609689 No free full text.

Abstract: Vascular risk factors are normally associated with cerebrovascular disease, which may lead to vascular dementia (VaD). Several recent studies suggest that there is increased risk of developing Alzheimer disease when exposed to these same vascular risk factors. In addition to old age, hypertension, peripheral arterial disease, certain types of cardiovascular disorders, diabetes mellitus, and smoking are now considered risk factors for late-onset Alzheimer disease. In this review, we examine several vascular factors and peripheral vascular pathophysiology implicated in Alzheimer disease and suggest certain mechanisms that might promote the association of vascular factors and late-onset Alzheimer disease. We support the implication that prevention or management of peripheral vascular disease may prevent or delay the onset of Alzheimer disease or mixed dementia.

den Heijer T, Schuit SC, Pols HA, van Meurs JB, Hofman A, Koudstaal PJ, van Duijn CM, Uitterlinden AG, Breteler MM. · Department of Epidemiology & Biostatistics, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands. · Mol Psychiatry. · Pubmed #15263903 No free full text.

Abstract: The role of estrogens in Alzheimer's disease (AD) is controversial. We investigated the association between well-recognized, and potentially functional, polymorphisms in the estrogen receptor (ER) alpha gene and the risk of AD in a prospective study of 6056 Caucasian older men and women aged 55 years and over. In a subset of 468 participants, we assessed volumes of the hippocampus and amygdala, which have a high density of ER alpha, with brain magnetic resonance imaging (MRI) (1.5 T MR unit). During a total of 35 405 person-years of follow-up (mean per persons 5.8 years), 312 new cases of dementia were detected, of whom 230 were diagnosed with AD. Neither the PvuII nor the XbaI polymorphism or haplotypes thereof were associated with the risk of all-cause dementia or AD. In contrast, we found that nondemented women who carried the PvuII p allele or haplotype 'px' had smaller amygdalar volumes on MRI in an allele-dose-dependent fashion. Total amygdalar volume was 4.50 (SE 0.10) in PP genotype, 4.45 (SE 0.06) in Pp genotype, and 4.18 ml (SE 0.08) in pp genotype (P trend=0.008). Further studies are required to investigate whether this smaller amygdalar volume has functional significance.

Vernooij MW, Ikram MA, Hofman A, Krestin GP, Breteler MM, van der Lugt A. · Department of Epidemiology, Erasmus MC UniversityMedical Center, 3015 CE Rotterdam, The Netherlands. · Neurology. · Pubmed #19620607 No free full text.

Abstract: 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.

Devore EE, Grodstein F, van Rooij FJ, Hofman A, Rosner B, Stampfer MJ, Witteman JC, Breteler MM. · Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands. · Am J Clin Nutr. · Pubmed #19474131 No free full text.

Abstract: BACKGROUND: Greater fish and omega-3 (n-3) polyunsaturated fatty acid (PUFA) intake may reduce dementia risk; however, previous studies have reported conflicting results, which were largely based on short-term follow-up. OBJECTIVE: The objective was to study the dietary consumption of fish and omega-3 PUFAs in relation to long-term dementia risk. DESIGN: We studied 5395 participants aged > or =55 y in the Rotterdam Study who were free of dementia and reported dietary information at baseline. We used age- and sex-adjusted Cox proportional hazard and multivariate-adjusted models to evaluate the relative risk of dementia and Alzheimer disease (AD) across categories of typical fish intake (none, low, and high) and fish type consumed (none, lean, and fatty). We also evaluated dementia and AD risk across tertiles of omega-3 PUFA intake, specifically, total long-chain omega-3 fatty acids: eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), alpha-linolenic acid, and EPA and DHA individually. RESULTS: During an average follow-up of 9.6 y, dementia developed in 465 participants (365 with a diagnosis of AD). In multivariate-adjusted models, total fish intake was unrelated to dementia risk (P for trend = 0.7). Compared with participants who typically ate no fish, those with a high fish intake had a similar dementia risk (hazard ratio: 0.95; 95% CI: 0.76, 1.19), as did those who typically ate fatty fish (hazard ratio: 0.98; 95% CI: 0.77, 1.24). Dietary intakes of omega-3 PUFAs were also not associated with dementia risk, and the results were similar when we considered AD specifically. CONCLUSION: In this Dutch cohort, who had a moderate consumption of fish and omega-3 PUFAs, these dietary factors do not appear to be associated with long-term dementia risk.

Haag MD, Hofman A, Koudstaal PJ, Breteler MM, Stricker BH. · Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. · Neurology. · Pubmed #19228584 No free full text.

Abstract: 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.

Haag MD, Hofman A, Koudstaal PJ, Stricker BH, Breteler MM. · Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands. · J Neurol Neurosurg Psychiatry. · Pubmed #18931004 No free full text.

Abstract: BACKGROUND: Cross-sectional reports suggest that statin users are less likely to have Alzheimer disease (AD). Prospective studies have provided inconsistent evidence. Moreover, it is unclear whether the association differs for lipophilic statins, those that could more easily pass the blood-brain barrier and hydrophilic statins. OBJECTIVES: To prospectively evaluate whether use of statins is associated with the risk of AD, and to determine whether associations differ for lipophilic and hydrophilic statins. METHOD: 6992 participants of the prospective, population-based Rotterdam Study were followed, from baseline (1990-1993) until January 2005 for incident AD. Data on all filled prescriptions came from pharmacy records. For each date on which each event occurred, cholesterol-lowering drug use for the person who experienced the event and all remaining persons in the cohort was categorised as "any" or "never" use. A distinction was made between statin, lipophilic and hydrophilic statins, and non-statin cholesterol-lowering drugs. Data were analysed with the Cox regression analysis, adjusting for sex, age and potential confounders. RESULTS: During follow-up (mean 9 years), 582 persons developed AD. Compared with never use of cholesterol-lowering drugs, statin use was associated with a decreased risk of AD (HR 0.57; 95% CI 0.37 to 0.90), but non-statin cholesterol-lowering drug use was not (HR 1.05; 95% CI 0.45 to 2.44). HRs were equal for lipophilic (HR 0.54; 95% CI 0.32 to 0.89) and hydrophilic statins (HR 0.54; 95% CI 0.26 to 1.11). CONCLUSION: In the general population, the use of statins, but not of non-statin cholesterol-lowering drugs, was associated with a lower risk of AD compared with never use of cholesterol-lowering drugs. The protective effect was independent of the lipophilicity of statins.

Geerlings MI, den Heijer T, Koudstaal PJ, Hofman A, Breteler MM. · Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands. · Neurology. · Pubmed #18391157 No free full text.

Abstract: BACKGROUND: Depression may increase risk for Alzheimer disease (AD), but it is not clear whether this risk is mediated by structural brain changes. We determined whether history of depressive episodes and presence of depressive symptoms were associated with smaller hippocampal and amygdalar volumes and with increased risk for incident AD. METHODS: Within the Rotterdam Scan Study 503 persons, aged 60-90 years at baseline and without dementia, reported their history of depressive episodes. Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression Scale. Volumetric assessment of the hippocampus and amygdala was performed using three-dimensional MRI. All subjects were followed for an average of 6 years for development of AD, diagnosed according to National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria. RESULTS: A total of 134 subjects (26.6%) reported a history of depression (88 reported an onset <60 years and 46 a late onset). Multiple linear regression analyses did not reveal a significant association with hippocampal or amygdalar volume for any of the depression parameters. During follow-up, 33 persons developed AD. Cox regression analyses showed that subjects with early onset depression had an increased risk for AD (HR 3.76; 95% CI 1.41 to 10.06), independent of hippocampal and amygdalar volume, whereas this risk was 2.34 (95% CI 0.82 to 6.69) in subjects with a late-onset depression. Depressive symptoms at baseline were not associated with increased risk for AD. CONCLUSION: History of depression, and particularly an early onset, but not presence of depressive symptoms increased the risk for Alzheimer disease. This risk was not mediated by smaller hippocampal or amygdalar volumes.

Reitz C, Bos MJ, Hofman A, Koudstaal PJ, Breteler MM. · Department of Epidemiology and Biostatistics, Erasmus Medical Center, PO Box 2040, 3000CA Rotterdam, The Netherlands. · Stroke. · Pubmed #18006863 links to  free full text

Abstract: BACKGROUND AND PURPOSE: Several studies indicate that stroke increases the risk of dementia. Most of these studies lacked the ability to take accurately assessed prestroke cognitive function into account. Whether the effects of stroke merely unravel an ongoing underlying dementing process or in fact cause the dementia has implications for the prevention of dementia in persons with cerebrovascular disease. We explored in a prospective cohort study whether stroke occurrence was related to a higher risk of subsequent dementia and whether this association was dependent on prestroke slope of cognitive function. METHODS: Cox proportional hazard models were used to relate incident stroke as a time-varying exposure with the risk of dementia in 6724 participants of the Rotterdam Study without dementia or stroke at baseline (49,361 person years of follow-up). Subsequently Cox proportional hazard models were performed to assess whether this association was dependent on slope of prestroke cognitive performance and other risk factors for cognitive decline. RESULTS: Independent of both level and the rate of change of prestroke cognitive performance and other risk factors for cognitive decline, incident stroke was associated with a more than doubled risk of subsequent dementia (hazard ratio, 2.1; 95% CI, 1.55 to 2.81). CONCLUSIONS: Prestroke cognitive function is not a major determinant of the effect of stroke on the risk of poststroke dementia.

de Jong FJ, Masaki K, Chen H, Remaley AT, Breteler MM, Petrovitch H, White LR, Launer LJ. · Department of Epidemiology & Biostatistics, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. · Neurobiol Aging. · Pubmed #17870208 No free full text.

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.

Reitz C, den Heijer T, van Duijn C, Hofman A, Breteler MM. · Department of Epidemiology & Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands. · Neurology. · Pubmed #17785668 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: Previous studies relating smoking with the risk of dementia have been inconsistent and limited in their validity by short follow-up times, large intervals between baseline and follow-up assessments, and unspecific determination of dementia diagnosis. We re-assessed after longer follow-up time in the large population-based cohort of the Rotterdam Study whether smoking habits and pack-years of smoking are associated with the risk of dementia, Alzheimer disease (AD), and vascular dementia (VaD). METHODS: Prospective population-based cohort study in 6,868 participants, 55 years or older and free of dementia at baseline. First, Cox proportional hazard models were used to relate smoking status at baseline with the risks of incident dementia, VaD, and AD, using never smokers as the reference category in all analyses. Then Cox proportional hazard models were used to relate pack-years of smoking with the risks of incident dementia, VaD, and AD. To explore the impact of the APOEepsilon4 allele, sex, and age on the association between smoking status and dementia, we repeated all analyses stratifying, in separate models, by APOEepsilon4 genotype, sex, and median of age. RESULTS: After a mean follow-up time of 7.1 years, current smoking at baseline was associated with an increased risk of dementia (HR 1.47, 95% CI 1.18 to 1.86) and AD (HR 1.56, 95% CI 1.21 to 2.02). This increase in disease risk was restricted to persons without the APOEepsilon4 allele. There was no association between current smoking and risk of VaD, and there was no association between past smoking and risk of dementia, AD, or VaD. CONCLUSION: Current smoking increases the risk of dementia. This effect is more pronounced in persons without the APOEepsilon4 allele than APOEepsilon4 carriers.

Alizadeh BZ, Njajou OT, Millán MR, Hofman A, Breteler MM, van Duijn CM. · Department of Epidemiology & Biostatistics, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands. · Neurobiol Aging. · Pubmed #17628213 No free full text.

Abstract: 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.

Reitz C, van Rooij FJ, de Maat MP, den Heijer T, Hofman A, Witteman JC, Breteler MM. · Department of Epidemiology and Biostatistics, Erasmus Medical Center, P.O. Box 1738, 3000DR Rotterdam, The Netherlands. · Neurobiol Aging. · Pubmed #17316907 No free full text.

Abstract: Evidence by post-mortem and animal studies suggests that matrix metalloproteinases (MMPs) may play an important role in the pathophysiology of Alzheimer's disease (AD) through degradation of amyloid beta. We investigated in 5999 elderly whether MMP3-haplotypes are associated with cognitive performance over time, dementia and AD. We also explored the association of MMP-3 haplotypes with changes in hippocampal volume and severity of periventricular and subcortical white matter lesions (WML). There was no association between any individual polymorphism or MMP-3 haplotypes and performance in MMSE over time, dementia or AD, and there was no association between MMP-3 genotypes or haplotypes with hippocampal volume or severity of periventricular or subcortical WML. These associations did not differ between strata of APOEepsilon4 genotype. Our observations do not suggest that variation in the MMP3 gene is causally involved in dementia or AD.

de Jong FJ, Peeters RP, den Heijer T, van der Deure WM, Hofman A, Uitterlinden AG, Visser TJ, Breteler MM. · Department of Epidemiology, Biostatistics, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands. · J Clin Endocrinol Metab. · Pubmed #17105838 links to  free full text

Abstract: CONTEXT: Thyroid function has been related to Alzheimer disease (AD) and neuroimaging markers thereof. Whether thyroid dysfunction contributes to or results from developing AD remains unclear. Variations in the deiodinase type 1 (DIO1) and type 2 (DIO2) genes that potentially alter thyroid hormone bioactivity may help in elucidating the role of thyroid function in AD. OBJECTIVE: We investigated the association of recently identified polymorphisms in the DIO1 (D1a-C/T, D1b-A/G) and DIO2 (D2-ORFa-Gly3Asp, D2-Thr92Ala) genes with circulating thyroid parameters and early neuroimaging markers of AD. DESIGN AND PARTICIPANTS: The Rotterdam Scan Study is a population-based cohort study among 1,077 elderly individuals aged 60-90 yr. MAIN OUTCOME MEASURES: DIO1 and DIO2 polymorphisms and serum TSH, free T4, T3, and reverse T3 (rT3) levels were determined in 995 nondemented elderly, including 473 persons with assessments of hippocampal and amygdalar volume on brain magnetic resonance imaging. RESULTS: Carriers of the D1a-T allele had higher serum free T4 and rT3, lower T3, and lower T3/rT3. The D1b-G allele was associated with higher serum T3 and T3/rT3. The DIO2 variants were not associated with serum thyroid parameters. No associations were found with hippocampal or amygdalar volume. CONCLUSION: This is the first study to report an association of D1a-C/T and D1b-A/G polymorphisms with iodothyronine levels in the elderly. Polymorphisms in the DIO1 and DIO2 genes are not associated with early magnetic resonance imaging markers of AD. This suggests that the previously reported association between iodothyronine levels and brain atrophy reflects comorbidity or nonthyroidal illness rather than thyroid hormones being involved in developing AD.

de Jong FJ, den Heijer T, Visser TJ, de Rijke YB, Drexhage HA, Hofman A, Breteler MM. · Department of Epidemiology and Biostatistics, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands. · J Clin Endocrinol Metab. · Pubmed #16636121 links to  free full text

Abstract: CONTEXT: Thyroid function has been related to Alzheimer disease (AD), but it remains unclear whether thyroid dysfunction results from or contributes to developing AD. OBJECTIVE: The objective of the study was to determine the association between thyroid function and both medial temporal lobe atrophy on brain magnetic resonance imaging (MRI) as putative early sign of AD and risk of dementia. DESIGN AND PARTICIPANTS: This was a population-based cohort study among 1077 elderly subjects aged 60-90 yr and dementia free at baseline (1995-1996). MAIN OUTCOME MEASURES: Nonfasting serum levels of TSH, free T(4) (fT(4)), T(3), and rT(3) were available in 1025 subjects followed up for incident dementia until 2005. In a subset of 489 nondemented elderly, we assessed volumes of the hippocampus and amygdala on brain MRI. Subjects using thyroid medication were excluded. RESULTS: During 5657 person-years of follow-up (mean 5.5 yr), 63 subjects were diagnosed with dementia (46 with AD). TSH and thyroid hormones were not associated with risk of dementia or AD. TSH and T(3) were also not related to brain atrophy, whereas nondemented subjects with higher fT(4) levels had more hippocampal and amygdalar atrophy on MRI. Similar associations were found for rT(3). Excluding subjects with thyroid disorders or incipient AD did not change the results. CONCLUSION: In our study, TSH was related neither to risk of AD nor with early MRI markers thereof, arguing against an important role of thyroid function in the development of AD. Whether the association of higher fT(4) and rT(3) levels with brain atrophy on MRI has functional significance remains to be elucidated.

van Oijen M, Arp PP, de Jong FJ, Hofman A, Koudstaal PJ, Uitterlinden AG, Breteler MM. · Department of Epidemiology & Biostatistics, Erasmus Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. · Neurosci Lett. · Pubmed #16635548 No free full text.

Abstract: Inflammatory mechanisms are involved in the pathogenesis of dementia. Inflammatory cytokines, including interleukin-6 (IL-6) and transforming growth factor beta1 (TGFbeta1), have been found in association with Alzheimer pathology and there is evidence for direct involvement of these cytokines in formation of amyloid plaques. Polymorphisms in genes encoding for IL-6 and TGFbeta1 are associated with plasma levels of IL-6 and TGFbeta1. Studies examining the association between polymorphisms in these genes and dementia yielded conflicting results. The purpose of this study was to examine the association between genetic variance in IL-6 and TGFbeta1 and risk of dementia. We examined this association in the Rotterdam Study, a prospective population-based cohort study in the elderly. Polymorphisms in the IL-6 (-174G>C) and TGFbeta1 gene (-800G>A, -509C>T, +10T>C, +25G>C and 263C>T) were genotyped and haplotypes of the TGFbeta1 gene were constructed. In a random subset IL-6 plasma levels were measured. During follow-up (mean 9.2 years), 743 dementia cases were identified. We estimated the association between individual polymorphisms and haplotypes with dementia with Cox' proportional hazard models. No association was found between the -174G>C polymorphism in the IL-6 gene and risk of dementia. No association was found between polymorphisms and constructed haplotypes in the TGFbeta1 gene and risk of dementia or Alzheimer's disease. No association was found between IL-6 genotype and IL-6 plasma levels in the random subset. Associations did not differ across APOE genotypes. Our findings do not suggest involvement of genetic variance in IL-6 and TGFbeta1 in the development of dementia.

den Heijer T, Sijens PE, Prins ND, Hofman A, Koudstaal PJ, Oudkerk M, Breteler MM. · Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, The Netherlands. · Neurology. · Pubmed #16505309 No free full text.

Abstract: BACKGROUND: Previous 1H-MR spectroscopy (MRS) studies compared biochemical spectra of persons with dementia with those of healthy control subjects. Given the long prodromal period of Alzheimer disease (AD), the authors sought to investigate whether biochemical changes can be observed also in the preclinical period. METHODS: The authors prospectively followed 509 elderly persons (ages 60 to 90), who were free of clinical dementia at baseline, for on average 5.9 years. At baseline, 1H-MRS of the brain (1.5 T) was performed in a plane above the lateral ventricles that comprised mainly white matter voxels. Standard ratios of N-acetyl aspartate (NAA), choline (Cho), and creatine (Cr) were calculated. Structural MRI was administered to assess white matter lesions and hippocampal atrophy. All persons were followed for incident dementia through repeated neuropsychological testing and linkage with medical records. RESULTS: During follow-up, 37 persons developed dementia, of whom 27 fulfilled criteria for AD. Overall, biochemical ratios on 1H-MRS at baseline were not associated with the risk of incident dementia. However, people with higher Cho/Cr ratios had a higher risk to develop dementia or AD within 4 years (hazard ratio for dementia per SD increase 1.55 [95% CI 1.05 to 2.28]). This association attenuated and became nonsignificant after adjustment for white matter lesions on MRI. CONCLUSION: These data suggest that there are biochemical changes on 1H-MR spectroscopy of brains of persons with presymptomatic dementia.

den Heijer T, Geerlings MI, Hoebeek FE, Hofman A, Koudstaal PJ, Breteler MM. · Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, the Netherlands. · Arch Gen Psychiatry. · Pubmed #16389197 links to  free full text

Abstract: CONTEXT: The recent focus on the development of preventive interventions for Alzheimer disease has fueled the search for biomarkers of presymptomatic disease. Patients with Alzheimer disease and mild cognitive impairment have marked atrophy of the hippocampus and amygdala compared with healthy elderly people. Whether atrophy of these structures is also present in persons without cognitive impairment who later develop dementia is unknown. OBJECTIVE: To assess whether volumetric assessment of the hippocampus and amygdala using magnetic resonance imaging (MRI) predicts dementia in elderly people without cognitive impairment. DESIGN: Longitudinal cohort study. SETTING: A general community in the Netherlands. PARTICIPANTS: Five hundred eleven persons, aged 60 to 90 years, free of dementia at baseline were followed up during 3043 person-years (mean per person, 6.0 years). We performed volumetric assessment of the hippocampus and amygdala, obtained information about daily memory problems, and performed extensive neuropsychological testing in all study participants. MAIN OUTCOME MEASURE: Dementia, as assessed by repeated neuropsychological screening and monitoring of medical records. RESULTS: Thirty-five persons developed dementia (26 with Alzheimer disease). Hippocampal and amygdalar volumes were strongly associated with the risk of dementia; the age-, sex-, and education-adjusted hazard ratio per 1-SD decrease in volume was 3.0 (95% confidence interval, 2.0-4.6) for the hippocampus and 2.1 (95% confidence interval, 1.5-2.9) for the amygdala. The hazard ratios associated with atrophy were similar in persons without memory complaints or low cognitive function at baseline. Compared with those remaining free of dementia, baseline brain volumes were 17% smaller in persons who received a clinical diagnosis of dementia within 2 to 3 years after MRI and still 5% smaller in those whose conditions were diagnosed 6 years after MRI. CONCLUSION: Atrophy of the hippocampus and amygdala on MRI in cognitively intact elderly people predicts dementia during a 6-year follow-up.

van Oijen M, Witteman JC, Hofman A, Koudstaal PJ, Breteler MM. · Department of Epidemiology and Biostatistics, Erasmus University Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands. · Stroke. · Pubmed #16269641 links to  free full text

Abstract: BACKGROUND AND PURPOSE: Vascular and inflammatory factors may play an important role in the pathogenesis of dementia. Studies reported an association between plasma levels of inflammation markers and the risk of dementia. Both fibrinogen and C-reactive protein are considered inflammatory markers. Fibrinogen also has important hemostatic properties. We investigated the association of fibrinogen and C-reactive protein with dementia. METHODS: The study was based on the prospective population-based Rotterdam Study. Fibrinogen was measured in a random sample of 2835 persons. High-sensitivity C-reactive protein was measured in the total cohort of 6713 persons. We identified 395 incident dementia cases during follow-up (mean, 5.7 years). We estimated the associations of fibrinogen and C-reactive protein with dementia using Cox proportional hazard models. RESULTS: Persons with higher levels of fibrinogen had an increased risk of dementia. The hazard ratio for dementia per SD increase of fibrinogen was 1.26 (95% CI, 1.11 to 1.44), adjusted for age and gender, and 1.30 (95% CI, 1.13 to 1.50) after additional adjustment for cardiovascular factors and stroke. For Alzheimer disease, the adjusted hazard ratio was 1.25 (95% CI, 1.04 to 1.49), and for vascular dementia it was 1.76 (95% CI, 1.34 to 2.30). High levels of C-reactive protein were not associated with an increased risk of dementia. CONCLUSIONS: High fibrinogen levels were associated with an increased risk of both Alzheimer disease and vascular dementia, but levels of C-reactive protein were not. This suggests that the increased risk of dementia associated with fibrinogen is because of the hemostatic rather than the inflammatory properties of fibrinogen.

Ruitenberg A, den Heijer T, Bakker SL, van Swieten JC, Koudstaal PJ, Hofman A, Breteler MM. · Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, the Netherlands. · Ann Neurol. · Pubmed #15929050 No free full text.

Abstract: Cerebral blood flow (CBF) velocity is decreased in patients with Alzheimer's disease. It is being debated whether this reflects diminished demand because of advanced neurodegeneration or that cerebral hypoperfusion contributes to dementia. We examined the relation of CBF velocity as measured with transcranial Doppler with dementia and markers of incipient dementia (ie, cognitive decline and hippocampal and amygdalar atrophy on magnetic resonance imaging) in 1,730 participants of the Rotterdam Study aged 55 years and older. Cognitive decline in the 6.5 years preceding CBF velocity measurement was assessed with repeated Mini-Mental State Examinations in nondemented subjects (n = 1,716). Hippocampal and amygdalar volumes were assessed in a subset of 170 nondemented subjects. Subjects with greater CBF velocity were less likely to have dementia. Furthermore, in nondemented subjects, greater CBF velocity was related to significantly less cognitive decline over the preceding period (odds ratio per standard deviation increase in mean CBF 0.74 [95% confidence interval, 0.58-0.98]) and larger hippocampal and amygdalar volumes. A low CBF is associated with dementia, but also with markers of incipient dementia. Although we cannot exclude that this is caused by preclinical neurodegeneration leading to hypoperfusion, it does suggest that cerebral hypoperfusion precedes and possibly contributes to onset of clinical dementia.

Sleegers K, den Heijer T, van Dijk EJ, Hofman A, Bertoli-Avella AM, Koudstaal PJ, Breteler MM, van Duijn CM. · Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands. · Neurobiol Aging. · Pubmed #15917098 No free full text.

Abstract: Despite biological support for a role of angiotensin converting enzyme (ACE) in Alzheimer's disease (AD), studies assessing the ACE I/D polymorphism in AD are conflicting. We re-evaluated this association in the Rotterdam Study, a population-based cohort study. The mechanism of association was further explored by adjusting for vascular factors, and by analysing atrophy, white matter lesions and infarcts on MRI in non-demented individuals. Genotypes were available for 6488 participants. During average follow-up of 6 years 250 subjects developed AD. MRI data were available for 494 non-demented participants. Homozygosity for the I-allele conferred a slightly increased risk of AD compared to carrying a D-allele (RR 1.12 (95% CI 0.99-1.25)). This increase was only significant in women, and independent of vascular factors (RR 1.39 (95% CI 1.14-1.69)). Non-demented women with the II genotype had smaller hippocampal and amygdalar volumes. Vascular pathology was not significantly associated with ACE. This suggests a modest but significant increase in risk of AD and early AD pathology in women homozygous for the ACE I-allele independent of vascular factors.

den Heijer T, Launer LJ, Prins ND, van Dijk EJ, Vermeer SE, Hofman A, Koudstaal PJ, Breteler MM. · Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands. · Neurology. · Pubmed #15668423 No free full text.

Abstract: BACKGROUND: Blood pressure level is associated with the risk of clinical Alzheimer disease (AD), yet the underlying mechanisms are unclear. High blood pressure levels may cause cerebral small-vessel pathology, which contributes to cognitive decline in patients with AD. Alternatively, in persons with high blood pressure, increased numbers of neurofibrillary tangles and amyloid plaques at autopsy have also been observed, suggesting direct links between blood pressure and AD. OBJECTIVE: To investigate the association of blood pressure and markers of small-vessel disease (white matter lesions [WMLs] on MRI) with hippocampal and amygdalar atrophy on MRI-potential in vivo indicators of Alzheimer pathology. METHODS: In 1995 to 1996, 511 nondemented elderly subjects (age 60 to 90) underwent MRI. The extent of WMLs was assessed, and volumes of the hippocampus and amygdala were measured. Blood pressure levels were assessed at the time of MRI and 5 years before the MRI. RESULTS: Higher diastolic blood pressure 5 years before MRI predicted more hippocampal atrophy in persons untreated for hypertension (per SD increase -0.10 mL [95% CI -0.19 to -0.02, p = 0.02]). Conversely, in persons treated for hypertension, a low diastolic blood pressure was associated with more severe atrophy. Persons with more WMLs on MRI more often had severe atrophy of the hippocampus and amygdala. CONCLUSION: Blood pressure and indicators of small-vessel disease in the brain may be associated with atrophy of structures affected by Alzheimer pathology.

Engelhart MJ, Ruitenberg A, Meijer J, Kiliaan A, van Swieten JC, Hofman A, Witteman JC, Breteler MM. · Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands. · Dement Geriatr Cogn Disord. · Pubmed #15627760 No free full text.

Abstract: Antioxidants prevent oxidative stress that possibly causes neuronal loss in Alzheimer's disease (AD). We examined whether high plasma levels of the antioxidant vitamins A and E were associated with lower prevalence of AD or cognitive decline (CD). We performed a cross-sectional study within the Rotterdam Study. In an univariate model, higher levels of vitamins A and E were significantly associated with lower prevalence of AD. However, when additional adjustments were made for important confounders, such as age, gender and total cholesterol, the relation substantially weakened -- odds ratios per standard deviation increase were 0.87 (95% CI 0.64-1.19) for vitamin A and 0.94 (95% CI 0.60-1.48) for vitamin E. Antioxidants were not related to CD in non-demented subjects. Our findings suggest no association between plasma levels of vitamin A and E and AD or CD.