Clinical characterization of a presenilin 1 mutation (F177S) in a family with very early-onset Alzheimer's disease in the third decade of life.

BACKGROUND: Early-onset familial Alzheimer disease (AD) is an autosomal dominant disorder caused by mutations in the amyloid precursor protein, presenilin 1 (PSEN1), or presenilin 2 gene. The objective of this study was to characterize the phenotype in a large family with a PSEN1 F177S mutation by performing detailed clinical assessments, neuroimaging, and neuropathological analysis. METHODS: In two subjects, clinical and neuropsychological assessments, structural magnetic resonance imaging, F-18-2-fluoro-2-deoxy-D-glucose positron emission tomographic imaging, AD biomarkers in cerebrospinal fluid and genetic analysis were available. In three deceased affected subjects, medical records were reviewed. In one subject, a complete neuropathological examination was available. RESULTS: Cognitive impairment and neurological symptoms developed homogeneously around 30 years of age and worsened rapidly. All subjects died about 7 years (range, 6-8 years) after disease onset before 40 years of age. All technical diagnostic information (neuroimaging, cerebrospinal fluid) were typically for AD. Neuropathology showed abundant neuritic plaques and neurofibrillary tangles, typical of severe AD. Antidementia treatment in one subject did not alter the length of survival. CONCLUSIONS: The PSEN1 F177S mutation leads to typical AD starting at age 30 and a homogeneous phenotype with rapid cognitive decline and prominent neurological symptoms. Excessive amyloid beta 42 production in the brain cortex corresponds well with other PSEN1 mutations.

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.

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 Alzheimer's 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.

Impaired sleep quality and restless legs syndrome in idiopathic focal dystonia: a controlled study.

While sleep disorders are common in Parkinson's disease and other basal ganglia disorders, information on sleep disturbances in dystonia is limited to generalized forms or Segawa disease. Although many patients with idiopathic cervical dystonia (CD) and blepharospasm (BL) report poor sleep, there are no data on frequency or interactions with well known symptoms like depression and pain. Standardized interviews and assessment instruments, clinical examinations, and self rating forms were applied in 221 patients with CD and BL, and in 93 neurologically healthy controls. Impaired sleep quality was found in 44% of CD patients, 46% of BL patients, and 20% of controls. In dystonia, it was associated with symptoms of depression (frequency of 26%; p < 0.001) and restless legs syndrome (RLS) (frequency of 19%; p < 0.01). Bruxism (in CD; p < 0.05), and female sex (in BL; p < 0.001) were identified as further risk factors, but not severity of dystonic symptoms. Excessive daytime sleepiness was rare in CD and BL (6%). With a frequency of 45%, impairment of sleep quality is common in focal dystonia and associated with symptoms of depression, bruxism, and RLS. Results in CD and BL patients are similar, pointing to an intrinsic mechanism of sleep disturbances rather than a direct effect of dystonic muscle activity. Further studies on sleep in focal dystonia, including polysomnographic recordings, are warranted.

Visceral and subcutaneous fat in patients treated with olanzapine: a case series.

OBJECTIVES: We hypothesized that olanzapine may contribute to visceral adiposity, a core symptom of metabolic syndrome. METHODS: Using computed tomography, we examined the effect of olanzapine on visceral and subcutaneous fat distribution, body mass index, fasting glucose, and lipids in an unselected population of 14 schizophrenic patients. RESULTS: We found a 6-week olanzapine treatment to be related to increased body mass index and proportion of total fat at the level of the fourth vertebral body. CONCLUSIONS: On the basis of these findings, we conclude that weight gain after a 6-week olanzapine treatment is partly attributable to increased visceral fat and may thus contribute to metabolic syndrome.

Alterations of cholesterol precursor levels in Alzheimer's disease.

Cerebral and extracerebral cholesterol metabolism are altered in Alzheimer's 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.

RXRA gene variations influence Alzheimer's disease risk and cholesterol metabolism.

Cholesterol metabolism is altered in Alzheimer's disease (AD). The nuclear hormone receptor Retinoic X Receptor a (RXRa) is a member of the nuclear ligand-activated transcription factor family. RXRs are key regulators of cholesterol synthesis and thus cholesterol metabolism. We performed a systematic screen for gene variants in the RXRA gene. The effect of these gene variants on the risk of AD was investigated in 405 AD patients (mean age: 74.27 +/- 9.37 years; female 78.6%) and 347 controls (mean age: 73.26 +/- 8.37 years; female 57.2%). Furthermore, the influence of RXRA gene variants on CSF and plasma levels of cholesterol, lathosterol and 24S-hydroxycholesterol were evaluated. One of the identified seven SNPs in RXRA influenced AD risk in our single marker analysis (rs3132293: P= 0.006). Haplotype analysis identified a three-marker haplotype (TGC) consisting of rs3118570, rs1536475 and rs3132293, which decreased the risk of AD (P= 0.009). The single marker rs3132293 (P= 0.026) and the TGC haplotype (P= 0.026) influenced CSF lathosterol levels in non-demented controls, and cholesterol levels in the combined sample comprising AD patients and controls (Rs3132293: P= 0.050; TGC haplotype: P= 0.035). 24S-Hydroxycholesterol CSF and plasma levels were also influenced by rs3132293 (CSF: P= 0.004; plasma: P= 0.001) and the TGC haplotype (CSF: P= 0.004; plasma: P= 0.002); this effect was most pronounced in AD patients (rs3132293: CSF: P= 0.009, plasma: P= 0.002; TGC haplotype: CSF: P= 0.019, plasma: P= 0.005). Our results suggest that RXRA gene variants might act as risk factor for AD via an influence on cerebral cholesterol metabolism.

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 Alzheimer's 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.

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 Alzheimer's 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.

Metabolic changes in elderly patients with major depression: evidence for increased accumulation of visceral fat at follow-up.

The accumulation of visceral fat is promoted by a specific endocrine syndrome, which is similarly found in major depression. The aim of this study was to investigate whether visceral fat depots increase in depressed patients during a follow-up period explaining the increased risk for cardiovascular disorders. Intraabdominal fat was measured in 29 depressed patients and 17 controls by computer tomography at the level of lumbar vertebra 4. In patients fat measurements were done initially during a major depressive episode and again after a follow-up period of 14 months; in controls the mean time interval between measurements was 28 months. In both groups, saliva was taken at 800 h over a period of seven days prior to each CT for the estimation of free cortisol. In patients only, an oral glucose tolerance test was also carried out. Compared to controls hyper- and normocortisolemic depressed patients showed a larger accumulation of visceral fat mass over time (hypercort.:132.0 +/- 45 vs. 144.7 +/- 47 cm(2), p = 0.07; normocort.: 115.5 +/- 53 vs. 135.0 +/- 51 cm(2), p = 0.002; controls: 130.1 +/- 66 vs. 137.3 +/- 76 cm(2), p = 0.4), despite similar weight gain (hypercort.: 2.1 +/- 5 kg, normocort.: 1.7 +/- 5 kg and controls: 2.3 +/- 4 kg). Further, normocortisolemic patients showed a trend for an higher percentile increase in visceral fat accumulation than controls (23.9 +/- 27 vs. 5.8 +/- 28%, p = 0.07). At follow-up, free cortisol concentrations were still above normal in patients who had been hypercortisolemic at first assessment (35.0 +/- 8 vs. 28.8 +/- 18 nmol/l, p = 0.1). Fasting and 2 h glucose concentrations were higher in hypercortisolemic compared to normocortisolemic patients at the index examination (6.2 +/- 1.1 vs. 5.0 +/- 0.05 mmol/l, p = 0.02; 11.5 +/- 2.7 vs. 7.8 +/- 1.9 mmol/l, p = 0.01). The larger proportion of visceral fat accumulation in patients may constitute a link for explaining the increased cardiovascular mortality in patients suffering from major depression.

Optimized neuropsychological procedures at different stages of dementia diagnostics.

OBJECTIVE: To establish a staged procedure in dementia diagnostics and to propose specific, abbreviated test batteries suitable for the three diagnostic stages: Primary medical care, neuro-psychiatry, and memory clinic. METHODS: A total of 159 participants underwent comprehensive clinical, neurological, neuropsychological, and MRI examinations. The neuropsychological examination took approximately 90 min per individual and was based on tests of verbal and visual memory, language, abstract thinking, attention, visuo-constructive and spatial functions. Stepwise discriminant analyses were performed to identify which subset of the 18 variables of the comprehensive test battery was the most appropriate to differentiate between specific diagnostic groups, and which variables could be discarded to abbreviate the test battery without substantial loss in diagnostic accuracy. RESULTS: The abbreviated versions of the test battery retained adequate diagnostic accuracy. The accuracy decreased by maximally 4%, whereas the test administration time dropped substantially from previously 90 min to a maximum of 50 min. CONCLUSION: Depending on the diagnostic question, a specifically abbreviated version of the comprehensive test battery can be used without unacceptably reducing diagnostic accuracy.

[Optimised neuro-psychological tests on different stages of dementia diagnostics]. / Optimierte neuropsychologische Verfahren für unterschiedliche Ebenen der Demenzdiagnostik.

OBJECTIVE: We postulated three level of dementia diagnostics: the general practitioner, the neuro-psychiatrist and the memory clinic. For each level, definite diagnostic questions were defined as the main diagnostic focus. The aim was to establish a staged process in dementia diagnostics, proposing for each diagnostic level a specific test battery suitable for the respective diagnostic focus. On each level, the test battery can be supplemented by other tests proposed on the subsequent diagnostic level. METHOD: 159 patients were examined clinically, neuropsychologically, and neuroradiologically. Discriminant analyses were computed to find out which tests out of a comprehensive test battery are most suitable in differentiating between several diagnostic groups. RESULTS: The diagnostic accuracy of the test batteries proposed for general practitioners and neuro-psychiatrists were maximally 3 % below that of the complete test battery which we suggest for memory clinics. CONCLUSION: Depending on the diagnostic level, a definite short form of a comprehensive test battery can be implemented without unacceptably reducing diagnostic accuracy.

SREBP-1a polymorphism influences the risk of Alzheimer's disease in carriers of the ApoE4 allele.

Sterol regulatory element-binding proteins (SREBPs) are transcription factors involved in cholesterol and fatty acid synthesis. Recently, a polymorphism in the 5'-region of the SREBP-1a gene has been described to be correlated with alterations in the plasma levels of cholesterol. Consequently the relationship between this SREBP-1a gene polymorphism and Alzheimer's disease (AD) alone and in combination with the apolipoprotein E (ApoE) 4 allele was evaluated. No association between SREBP-1a polymorphism alone and AD could be seen. However, in the group of healthy ApoE4 allele carriers, the number of homozygote SREBP-1a DeltaG allele carriers was significantly higher than in AD patients. Cerebrospinal fluid levels of cholesterol were lower in AD patients who were carriers of the SREBP-1a DeltaG allele, and the ratio of 24S-hydroxycholesterol to cholesterol was increased in these probands. Our data suggest a reduced risk of AD in carriers of an ApoE4 allele who are additionally homozygous for the SREBP-1a DeltaG allele, which is possibly due to the influence of SREBP-1a polymorphism on brain cholesterol metabolism. This is the first report on a genetic factor which prevents the deleterious effect of the ApoE4 allele and thus reduces the risk of AD.

Hypercortisolemic depression is associated with increased intra-abdominal fat.

OBJECTIVE: Similar to patients with a metabolic syndrome, patients with major depression are at increased risk of developing cardiovascular disorders. Interestingly, both disorders share a specific endocrine syndrome that promotes the accumulation of visceral fat, which again is considered a marker of increased cardiovascular morbidity and mortality. METHODS: Intra-abdominal fat was measured in 22 postmenopausal depressed women and 23 age-matched healthy women by computer tomography at the level of lumbar vertebrae 1 (L1) and 4 (L4). Saliva was taken in patients and control subjects at 08:00 hours over a period of 7 drug-free days for the measurement of free cortisol. In patients only we performed an oral glucose tolerance test. RESULTS: Compared with control subjects, depressed patients with elevated free cortisol concentrations showed similar visceral fat depots at L1 (113.0 +/- 41.6 vs. 94.3 +/- 53.2 cm(2)). Hypercortisolemic depressed patients also showed greater fat depots in this area (74.5 +/- 55.5 cm(2), p =.04) than the normocortisolemic patients. However, a comparison of all patients with control subjects revealed no difference in fat accumulation at either L1 or L4. Finally, glucose concentrations during the glucose tolerance test were higher in hypercortisolemic than in normocortisolemic patients, whereas their insulin levels showed only a tendency toward being increased. CONCLUSIONS: Hypercortisolemic depressed patients suffer from resistance to insulin and increased visceral fat. The fact that hypercortisolemia reverses depression-related fat loss, particularly in the visceral area, might partially explain why major depression can be considered a risk factor for cardiovascular disorders.