M.M.B. Breteler

Hippocampal, amygdalar, and global brain atrophy in different apolipoprotein E genotypes

The &egr;4 allele of the APOE gene increases the risk for AD, whereas the &egr;2 allele may be protective. The authors assessed the impact of APOE genotype on hippocampal, amygdalar, and global brain atrophy as putative markers of preclinical AD in a nondemented population. Carriers of &egr;4 had significantly more hippocampal and amygdalar atrophy than &egr;3&egr;3 subjects, but not more global brain atrophy. Carriers of &egr;2 did not have less brain atrophy than &egr;3&egr;3 subjects.

The α2-macroglobulin gene in AD A population-based study and meta-analysis

Background: Whereas several authors recently reported a positive association between the α2-macroglobulin gene (A2M) and late-onset AD (LOAD), others were unable to replicate these findings. Early-onset AD (EOAD) is defined as onset age <65 years. Virtually all patients with LOAD are >65 years of age. Objective: To evaluate the role of A2M in AD, the authors conducted a population-based study of EOAD and LOAD as well as a meta-analysis of all studies conducted to date. Methods: Patients with EOAD (n = 100) were derived from a population-based study in four northern provinces of the Netherlands and the area of metropolitan Rotterdam. Patients with LOAD (n = 344) were drawn from the Rotterdam Study, a population-based prospective study on residents aged 55 years and over of a Rotterdam suburb in the Netherlands. Two polymorphisms were studied, A2M-I/D and A2M-Ile1000Val, in relation to the APOE ε4 allele (APOE*4). Results: No genotypic or allelic association was found for either polymorphism in the population-based series of patients with LOAD. In patients with EOAD without APOE*4, a significant increase of carriers of A2M-1000Val was found. The meta-analysis of available published case–control data on these polymorphisms in white and mixed ethnic populations yielded no significant differences between cases and controls. Pooling the Asian studies conducted to date showed a significant decrease in the frequency of A2M-D among patients. Conclusions: These results suggest that A2M is not genetically associated with LOAD in white patients or mixed populations as found in the United States. In these populations A2M does not have clinical relevance. From a scientific perspective, the findings on EOAD and Asian patients require replication and further research in the A2M region.

Apolipoprotein E genotype, atherosclerosis, and cognitive decline: the Rotterdam study

The apolipoprotein E4 allele (APOE epsilon 4) and atherosclerosis are risk factors for cognitive decline. We investigated whether the effects of APOE epsilon 4 and atherosclerosis on cognitive decline are independent. A population-based follow-up study was performed on 838 subjects who were non-demented at baseline. The Mini Mental State Examination (MMSE) score at follow-up was studied as a function of APOE epsilon 4 and atherosclerosis. Mild, non-significant effects on the MMSE score were found for atherosclerosis in the absence of APOE epsilon 4 and for APOE epsilon 4 in the absence of atherosclerosis. APOE epsilon 4 carriers with two or more indicators of atherosclerosis positive, had a significantly lower MMSE score at follow-up (mean difference -0.7 points; 95% confidence interval -1.1 to -0.2) relative to non-APOE epsilon 4 carriers with no evidence of atherosclerosis. Our findings suggest that the consequences of APOE epsilon 4 and atherosclerosis are not independent, and that particularly APOE epsilon 4 carriers with atherosclerosis are at increased risk of cognitive decline.

MR spectroscopy of brain white matter in the prediction of dementia

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.

Variations in estrogen receptor ? gene and risk of dementia, and brain volumes on MRI.

The role of estrogens in Alzheimers disease (AD) is controversial. We investigated the association between well-recognized, and potentially functional, polymorphisms in the estrogen receptor (ER) α 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 ERα, 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.

Early diagnosis of dementia based on intersubject whole-brain dissimilarities

This article studies the possibility of detecting dementia in an early stage, using nonrigid registration of MR brain scans in combination with dissimilarity-based pattern recognition techniques. Instead of focussing on the shape of a single brain structure, we take into account the shape differences within the entire brain. Imaging data was obtained from a longitudinal, population based study of the elderly. A set of 29 subjects was identified, who were asymptomatic at the time of scanning, but were diagnosed as having dementia within 0.7 to 5 years after the scan, and a set of 29 age and gender matched healthy controls were selected. Each subject was registered to all other subjects, using a nonrigid registration algorithm. Based on statistics of the deformation field in the brain, a dissimilarity measure was calculated between each pair of subjects, yielding a 58×58 dissimilarity matrix. A kNN classifier was trained on the dissimilarity matrix and the performance was tested in a leave-one-out experiment. A classification accuracy of 81% was attained (spec. 83%, sens. 79%). This demonstrates the potential of whole-brain intersubject dissimilarities to aid in early diagnosis of dementia.

Variable expression of presenilin 1 is not a major determinant of risk for late-onset Alzheimer's Disease

Abstract We have previously reported a significant association between early-onset Alzheimers disease (EOAD) and an allele in the promoter of presenilin 1 (PSEN1) significantly decreasing PSEN1 expression in vitro. For late-onset Alzheimers disease (LOAD), numerous studies have reported inconsistent associations with a PSEN1 intronic polymorphism. We therefore hypothesized that linkage disequilibrium between the intronic PSEN1 polymorphism and the functional promoter polymorphism might explain the conflicting reports in LOAD. We analysed both variations in 356 LOAD patients and 230 controls in a population-based case-control study. In addition, we re-analysed all published literature on the PSEN1 intronic polymorphism in a meta-analysis. No significant association was found with the PSEN1 intronic or promoter polymorphism in our case-control sample. In the meta-analysis no major differences between patients and controls were found for the PSEN1 intronic variation. Together, our results do not support a major role for variable expression of PSEN1 in LOAD.

Interaction between polymorphisms in the renin–angiotensin–system and angiotensin-converting enzyme inhibitor or β-blocker use and the risk of myocardial infarction and stroke

This study investigates whether the interaction between angiotensin-converting enzyme (ACE) inhibitors or β-blockers and the ACE insertion/deletion (I/D) polymorphism or angiotensin receptor II type 1 (AGTR1) 573C/T polymorphism modifies the risk of myocardial infarction (MI) or stroke. In total, 4097 subjects with hypertension were included in this study. The drug–gene interaction on the risk of MI or stroke was determined with a Cox proportional hazard model. The risk of MI was reduced in current users of ACE inhibitors with the AGTR1 573CT or CC genotype compared to ACE inhibitors with the AGTR1 573TT genotype (synergy index (SI):0.32; 95% confidence interval (CI): 0.14–0.70). No significant drug–gene interaction was found on the risk of stroke (SI:0.82; 95% CI: 0.44–1.52) or in β-blocker users. Also, no significant drug–gene interaction was found with the ACE I/D polymorphism. In conclusion, subjects with at least one copy of the AGTR1 573C allele might have more benefit from ACE inhibitor therapy.

AUTOMATIC SEGMENTATION OF BRAIN TISSUE ANDWHITEMATTER LESIONS IN MRI

A method to automatically segment cerebrospinal fluid, gray matter, white matter and white matter lesions is presented. The method uses magnetic resonance brain images from proton density. T1-weighted and fluid-attenuated inversion recovery sequences. The method is based on an automatically trained k-nearest neighbour classifier extended with an additional step for the segmentation of white matter lesions. On six datasets, segmentations are quantitatively compared with manual segmentations, which have been carried out by two expert observers. For the tissues, similarity indices between method and observers approximate those between manual segmentations. Reasonably good lesion segmentation results are obtained compared to interobserver variability

Vascular Disease and Vascular Risk Factors and Dementia

In recent years evidence has increased that vascular disease is associated with cognitive impairment and dementia (Breteler et al. 1994; Hofman et al. 1997). Moreover, the presence of cerebrovascular disease may intensify the presence and severity of the clinical symptoms of Alzheimer’s disease (Snowdon et al. 1997).