Frank Hentschel

Polymorphisms in glutathione S-transferase omega-1 and AD, vascular dementia, and stroke.

Background: Glutathione S-transferase omega-1 (GSTO1) protects from oxidative stress, a risk factor for Alzheimer disease (AD), vascular dementia (VaD), and stroke. Polymorphisms in GSTO1 might influence the function of the protein and thus the risk of AD, VaD, and stroke. Methods: The GSTO1 gene was screened for variations. The effect of the detected polymorphisms on the risk of AD, VaD, and stroke was evaluated. CSF levels of cholesterol and plasma homocysteine levels were compared according to the GSTO1 genotype. Results: Two missense polymorphisms in exon 4 of GSTO1 (Ala140Asp and Glu155ΔGlu) were detected and tested for their association with AD, VaD, and stroke. The Asp/Asp and Ala/Asp genotypes increased the risk of stroke (p = 0.003, OR = 2.1), and the Asp/Asp genotype increased the risk of VaD (p = 0.02, OR = 2.2). GSTO1 polymorphisms did not influence the risk of AD, but the Asp allele influenced the age at onset (p = 0.05). In nondemented probands CSF levels of cholesterol were increased in carriers of the Asp/Asp genotype (p = 0.004); however, in patients with manifest dementia the authors found decreased CSF levels of cholesterol in carriers of the Asp/Asp genotype (p = 0.028). Serum homocysteine levels in stroke patients were higher in carriers of at least one Asp allele (p = 0.011). Conclusion: The GSTO1 Asp allele may be a genetic risk factor for cerebrovascular diseases, and might influence the course of Alzheimer disease, even though effects vary in different studies.

Multicenter stability of diffusion tensor imaging measures: A European clinical and physical phantom study

Diffusion tensor imaging (DTI) detects white matter damage in neuro-psychiatric disorders, but data on reliability of DTI measures across more than two scanners are still missing. In this study we assessed multicenter reproducibility of DTI acquisitions based on a physical phantom as well as brain scans across 16 scanners. In addition, we performed DTI scans in a group of 26 patients with clinically probable Alzheimers disease (AD) and 12 healthy elderly controls at one single center. We determined the variability of fractional anisotropy (FA) measures using manually placed regions of interest as well as automated tract based spatial statistics and deformation based analysis. The coefficient of variation (CV) of FA was 6.9% for the physical phantom data. The mean CV across the multicenter brain scans was 14% for tract based statistics, and 29% for deformation based analysis. The degree of variation was higher in less organized fiber tracts. Our findings suggest that a clinical and physical phantom study involving more than two scanners is indispensable to detect potential sources of bias and to reliably estimate effect size in multicenter diagnostic trials using DTI.

ACE I/D polymorphism is a risk factor of Alzheimer's disease but not of vascular dementia.

Different studies have investigated the effect of the angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism on the risk of Alzheimer dementia (AD). However, results on the association of the ACE-I allele with AD have been inconclusive. A recent meta-analysis reported an association of the I-allele with the risk of AD. A few small studies also investigated the effect of ACE polymorphism on the risk of vascular dementia (VD). We have investigated the effect of ACE I/D polymorphism in 351 AD and 155 VD patients and 348 healthy controls. We found the I/I genotype to be associated with an increased risk of AD, but not with the risk of VD. Cell-specific effects of ACE polymorphism are suggested, additional studies on neuronal cells might help to understand the role of this polymorphism in AD.

Frontal Lobe Degeneration and Alzheimers Disease: A Controlled Study on Clinical Findings, Volumetric Brain Changes and Quantitative Electroencephalography Data

Ten patients with a clinical diagnosis of frontal lobe degeneration (FLD) were compared with a group of patients with probable Alzheimers disease (AD) and with nondemented controls matched for gender and age. In comparison with AD, the duration of illness was slightly shorter and cognitive performance was better in patients with FLD. The greatest enlargement of cerebrospinal fluid volumes was found in FLD and this effect was most pronounced in the anterior fissure and lateral ventricles. Estimates of EEG band-power and EEG coherence in FLD were not remarkably different from nondemented controls, whereas delta- and theta-power were significantly increased in AD. These observations may indicate different disease processes with a dissociation of volumetric computed tomography and quantitative EEG changes, which may be of differential diagnostic value.

Alterations of cholesterol precursor levels in Alzheimer's disease

Cerebral and extracerebral cholesterol metabolism are altered in Alzheimers disease (AD) as indicated by reduced plasma levels of the cholesterol elimination products 24S-hydroxycholesterol, which is of cerebral origin, and of 27-hydroxycholesterol, which is formed extracerebrally. However, it has to be evaluated, if changes of cholesterol metabolism in the whole body or in the CNS are exclusively due to the altered elimination of cholesterol or are also due to altered de novo synthesis in AD. We investigated CSF and plasma levels of cholesterol and of its precursors lanosterol, lathosterol and desmosterol in AD patients and non-demented controls. We found CSF levels of cholesterol (p=0.011), absolute levels of all investigated cholesterol precursors (each p<0.001) and ratios of cholesterol precursors/cholesterol (each <0.01) to be lower in AD patients as compared to controls. In plasma, the absolute levels of lanosterol (p=0.026) and lathosterol (p<0.001) and the ratio of lathosterol/cholesterol (p=0.002) but none of the other investigated parameters were reduced in AD patients (p>0.1). Furthermore, ratios of desmosterol/lathosterol in CSF (p=0.023) and plasma (p=0.009) were higher in AD patients as compared to controls. Our data support the hypothesis that cholesterol metabolism is altered in AD and further suggest that especially cholesterol de novo synthesis within the CNS of AD patients might be reduced. These findings raise doubt on a beneficial effect of cholesterol lowering treatment in manifest AD.

Genome-Wide Association Study of Vascular Dementia

Background and Purpose— Most studies investigating the genetics of dementia have focused on Alzheimer disease, but little is known about the genetics of vascular dementia. The aim of our study was to identify new loci associated with vascular dementia. Methods— We performed a genome-wide association study in the Rotterdam Study, a large prospective population-based cohort study in the Netherlands. We sought to replicate genome-wide significant loci in 2 independent replication samples. Results— In the discovery analysis of 5700 dementia-free individuals, 67 patients developed incident vascular dementia over a mean follow-up time of 9.3±3.2 years. We showed genome-wide significance for rs12007229, which is located on the X chromosome near the androgen receptor gene (OR, 3.7; 95% CI, 2.3–5.8, per copy of the minor allele; P=1.3×10−8). This association was further confirmed in 2 independent populations (probability value of combined replication samples=0.024). Conclusions— Our study shows a novel genetic locus for vascular dementia on the X chromosome. Further replication of this finding is required.

CYP46A1 variants influence Alzheimer's disease risk and brain cholesterol metabolism

BACKGROUND Cholesterol 24S-hydroxylase (CYP46) catalyzes the conversion of cholesterol to 24S-hydroxycholesterol, the primary cerebral cholesterol elimination product. Only few gene variations in CYP46 gene (CYP46A1) have been investigated for their relevance as genetic risk factors of Alzheimers disease (AD) and results are contradictory. METHODS We performed a gene variability screening in CYP46A1 and investigated the effect of gene variants on the risk of AD and on CSF levels of cholesterol and 24S-hydroxycholesterol. RESULTS Two of the identified 16 SNPs in CYP46A1 influenced AD risk in our study (rs7157609: p=0.016; rs4900442: p=0.019). The interaction term of both SNPs was also associated with an increased risk of AD (p=0.006). Haplotypes including both SNPs were calculated and haplotype G-C was identified to influence the risk of AD (p=0.005). AD patients and non-demented controls, who were carriers of the G-C haplotype, presented with reduced CSF levels of 24S-hydroxycholesterol (p=0.001) and cholesterol (p<0.001). CONCLUSION Our results suggest that CYP46A1 gene variations might act as risk factor for AD via an influence on brain cholesterol metabolism.

Alzheimer disease versus mixed dementias: An EEG perspective

OBJECTIVE To examine differences between patients with AD (n=54) and mixed (vascular Alzheimer) dementia (n=24), and controls (n=66), with respect to clinic, neuropsychology, neuroradiology and quantitative EEG (QEEG). METHODS We used CAMDEX, CT and QEEG. RESULTS Patients with mixed dementia had more subcortical lesions. Increased slow frequency EEG power was observed in mixed dementia compared to AD, whereas the level of high frequency power was nearly normal in mixed dementia, but decreased in pure AD. Topography of slow band power was unaltered in both groups, but was changed for fast bands. The Hachinski score and neuropsychological tests showed small differences between mixed dementia and pure AD. CONCLUSION Neuroimaging and QEEG made a greater differential diagnostic contribution than clinical symptoms and neuropsychology. An alteration of slow frequency power with nearly normal high frequency power in mixed dementia may reflect subcortical pathology, whereas cortical pathology in pure AD may relate to decreased fast frequency power. With vascular pathology, less AD pathology is needed for a similar severity of dementia. SIGNIFICANCE In dementia of the Alzheimer type a vascular component is often found - especially at an older age. The quantitative EEG can contribute to a better understanding of the interaction of the two components.

Proton magnetic resonance spectroscopy in acute, juvenile anorexia nervosa

Anorexia nervosa is usually associated with a shrinkage of the brain that is at least partially reversible with weight gain. The pathogenesis of this brain abnormality is unclear. The purpose of this study was to investigate potential alterations in localized proton magnetic resonance (1H MR) spectra of anorectic patients immediately after an interval of excessive weight loss. Twelve patients and seventeen control subjects were examined. Water suppressed 1H MR spectra were recorded from two voxels placed in the thalamus and in the parieto-occipital white matter. The spectra of ten patients could be evaluated. Comparing patients and control subjects, significantly higher signal intensity ratios of choline containing compounds (Cho) relative to total creatine (Cr) as well as significantly lower ratios of N-acetyl-aspartate (NAA) relative to Cho were found in the white matter region. We hypothesize that these results indicate an abnormal starvation, associated membrane turnover, which predominantly takes place in the white matter. No evidence for neuronal degeneration was found in the thalamus or in the white matter region.

CETP polymorphisms influence cholesterol metabolism but not Alzheimer's disease risk

Cholesteryl ester transfer protein (CETP) is a component of the high density lipoprotein (HDL). Variations in the CETP gene may cause CETP deficiency, which is characterized by decreased mass and activity of the protein as well as altered HDL and LDL levels. We investigated the effect of three putative functional CETP polymorphisms (-1946 VNTR, C-629A and I405V) on the risk of Alzheimers disease (AD) and on cholesterol, lathosterol and 24S-hydroxycholesterol levels in CSF and plasma of AD patients and controls. None of the investigated CETP polymorphisms or haplotypes had any effect on the risk of AD. However, we found that a three marker CETP haplotype (L/C/V) influenced CSF levels of lathosterol and 24S-hydroxycholesterol as well as plasma levels of total cholesterol in controls but not in AD patients. Our data suggest that CETP gene variations influence cerebral and peripheral cholesterol metabolism, but not AD risk.