The plant sterol brassicasterol as additional CSF biomarker in Alzheimer's disease.

OBJECTIVE: Plant sterols (sitosterol, campesterol, stigmasterol and brassicasterol) are solely dietary-derivable sterols that are structurally very similar to cholesterol. In contrast to peripheral cholesterol, plant sterols can cross the blood-brain barrier and accumulate within mammalian brain. As an impaired function of the cerebrospinal fluid (CSF)-blood barrier is linked to neurodegenerative disorders, i.e. Alzheimer's disease (AD), we investigated whether this results in altered plant sterol concentrations in CSF. METHOD: Applying gas chromatography/mass spectrometry analysis, plant sterol concentrations were measured in plasma and CSF of patients with AD (n = 67) and controls (n = 29). Age, gender, plasma-to-CSF albumin ratio, CSF Aß(42) , CSF pTau, APOE4 genotype, and serum creatinine were applied as covariates in the statistical analysis for individual plant sterols in order to compare plasma and CSF plant sterol concentrations between patients with AD and controls. RESULTS: Albumin quotient was a consistent predictor in CSF for cholesterol and methyl plant sterols campesterol and brassicasterol. Comparison of lipid parameters per diagnosis based on relevant predictors revealed significantly lower concentrations of brassicasterol (P < 0.001) in CSF of patients with AD. Binary logistic regression analysis revealed that brassicasterol improved the predictive value when added to pTau and Aß42 in a biomarker model. CONCLUSION: Brassicasterol might be a relevant additional biomarker in AD.

Interaction effects of subjective memory impairment and ApoE4 genotype on episodic memory and hippocampal volume.

BACKGROUND: The apolipoprotein E4 allele (ApoE4) is an established genetic risk factor for Alzheimer's disease (AD). However, its effects on cognitive performance and brain structure in healthy individuals are complex. We investigated the effect of ApoE4 on cognitive performance and medial temporal lobe volumetric measures in cognitively unimpaired young elderly with and without subjective memory impairment (SMI), which is an at-risk condition for dementia.MethodAltogether, 40 individuals with SMI and 62 without were tested on episodic memory and on tasks of speed and executive function. All participants were ApoE genotyped. 21 subjects with SMI and 47 without received additional structural magnetic resonance imaging. Volumetric measures of the hippocampus, the entorhinal cortex and the amygdala were obtained manually. RESULTS: In the SMI group, ApoE4 carriers performed worse on the episodic memory (p=0.049) and showed smaller left hippocampal volumes (p=0.030). In the individuals without SMI, the ApoE4 carriers performed better on episodic memory (p=0.018) and had larger right hippocampal volumes (p=0.039). The interaction of group (SMI/no SMI) and ApoE genotype was significant for episodic memory (p=0.005) and right and left hippocampal volumes (p=0.042; p=0.035). There were no within-group differences or interaction effects on speed and executive function composite measures or other volumetric measures. CONCLUSIONS: The negative effect of ApoE4 on episodic memory and hippocampal volume in SMI supports SMI as a prodromal condition of AD. The positive effects of ApoE4 in subjects without SMI adds to a number of reports on positive ApoE4 effects in young and very old individuals.

The variant methylenetetrahydrofolate reductase c.1298A>C (p.E429A) is associated with multiple sclerosis in a German case-control study.

Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disease of the central nervous system. We investigated the association of two missense variants of the MTHFR gene, i.e. MTHFR c.677C>T (p.A222V) and c.1298A>C (p.E429A), in 138 patients with clinically definite multiple sclerosis of relapsing-remitting course and 138 age- and gender-matched healthy controls. No significant differences were found in the frequency of the MTHFR c.677C>T polymorphism between MS patients and healthy controls. However, the genotype frequencies of the missense variant MTHFR c.1298A>C were significantly different between patients (AA/AC/CC: 0.34/0.55/0.11) and controls (0.52/0.36/0.12; Pearson's chi(2)=11.1; p=0.004). These results suggest that homozygosity for the A allele of MTHFR c.1298A>C may be protective against the incidence of MS. If confirmed in an independent study sample, the underlying mechanisms should be investigated, which may lead to novel insights in biochemical factors influencing the aetiology and pathophysiology of MS.

Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer's disease: a multicenter study.

In this report, we present the results of a multicenter study to test analytic and diagnostic performance of soluble forms of amyloid precursor proteins alpha and beta (sAPP alpha and sAPP beta) in the cerebrospinal fluid (CSF) of patients with different forms of dementing conditions. CSF samples were collected from 188 patients with early dementia (mini-mental state examination >or=20 in majority of cases) and mild cognitive impairment (MCI) in 12 gerontopsychiatric centers, and the clinical diagnoses were supported by neurochemical dementia diagnostic (NDD) tools: CSF amyloid beta peptides, Tau and phospho-Tau. sAPP alpha and sAPP beta were measured with multiplexing method based on electrochemiluminescence. sAPP alpha and sAPP beta CSF concentrations correlated with each other with very high correlation ratio (R=0.96, P<0.001). We observed highly significantly increased sAPP alpha and sAPP beta CSF concentrations in patients with NDD characteristic for Alzheimer's disease (AD) compared to those with NDD negative results. sAPP alpha and sAPP beta highly significantly separated patients with AD, whose diagnosis was supported by NDD findings (sAPP alpha: cutoff, 117.4 ng ml(-1), sensitivity, 68%, specificity, 85%, P<0.001; sAPP beta: cutoff, 181.8 ng ml(-1), sensitivity, 75%, specificity, 85%, P<0.001), from the patients clinically assessed as having other dementias and supported by NDD untypical for AD. We conclude sAPP alpha and sAPP beta might be regarded as novel promising biomarkers supporting the clinical diagnosis of AD.

A multicenter (1)H-MRS study of the medial temporal lobe in AD and MCI.

OBJECTIVE: The need for biological markers of Alzheimer disease (AD) is constantly increasing. Proton magnetic resonance spectroscopy ((1)H-MRS) studies have provided consistent evidence for a reduction of the neuronal marker N-acetylaspartate (NAA) in patients with AD. Within the German Competence Network on Dementia, we conducted a (1)H-MRS study in patients with mild dementia and mild cognitive impairment (MCI) at four sites to investigate the multicenter feasibility of (1)H-MRS. METHODS: In total, 130 patients with dementia (98 AD, 32 non-AD), 136 subjects with MCI (70 of AD type, 66 of non-AD type), and 45 unimpaired control subjects were included. Single-volume (1)H-MRS of the left medial temporal lobe was performed at long and short echo times. Metabolites were quantified and metabolic ratios were determined. RESULTS: We found a significant reduction of NAA concentration in patients with AD as compared to healthy volunteers and compared to patients with MCI of AD type. NAA/Cr (creatine/phosphocreatine) was also lower in patients with AD compared to control subjects. NAA, choline compounds, and Cr were lower in patients with AD compared to patients with non-AD dementia. CONCLUSIONS: We demonstrated the multicenter feasibility of proton magnetic resonance spectroscopy ((1)H-MRS) of the medial temporal lobe in mild dementia and mild cognitive impairment, which is a prerequisite for the application of (1)H-MRS in large-scale clinical trials. Since the concentration measures of the metabolites are adjusted for brain tissue volume, these findings are indicators of biochemical pathology beyond brain atrophy.

Association of CETP polymorphisms with the risk of vascular dementia and white matter lesions.

Cholesteryl ester transfer protein (CETP), a component of the high density lipoprotein (HDL), plays a central role in reverse cholesterol transport. We investigated the association of two putative functional CETP polymorphisms (C-629A and I405V) with the risk of vascular dementia (VD) and tested if this association is influenced by the presence of APOE4 allele. Our study included 163 VD patients (mean age: 74.25 +/- 7.9 years) and 452 cognitively healthy probands (mean age: 70.81 +/- 7.9 years). As a biological correlate, the association of CETP gene variants with white matter lesion (WML) load was investigated. Neither the C-629A (P = 0.169) nor the I405V (P = 0.840) polymorphism was associated with VD risk in the whole sample. However, in non-carriers of the APOE4 allele, homozygote carriers of the CETP C-629A A allele presented with an increased risk of VD (P = 0.01). Whereas in APOE4 carriers, no association of CETP polymorphisms with VD risk was detected. In addition, carriers of the CETP C-629A AA genotype presented with decreased WML load in the frontal brain (P = 0.009). Our results suggest that CETP gene polymorphisms might influence WML load and the risk of VD, the latter in non-carriers of the APOE4 allele.

Gene variations in GSTM3 are a risk factor for Alzheimer's disease.

Oxidative stress is a relevant pathomechanism in Alzheimer's disease (AD) and gene variations in the glutathione S-transferase M3 gene (GSTM3), involved in the detoxification of oxygen radicals, might influence the risk of AD. We investigated the effect of three polymorphisms in GSTM3: rs1332018 (C/A); rs1799735 (del/AGG); rs7483 (G/A), on the risk of AD in 363 AD patients and 358 healthy controls. Single marker association analyses revealed that the AGG/AGG genotype of the GSTM3 rs1799735 (del/AGG) polymorphism was associated with an increased risk of AD (p=0.05), especially in the group of APOE4-allele non-carriers (p=0.004; OR=2.07). Examination of the haplotypes identified a two-marker haplotype (C/AGG) consisting of rs1332018 (C/A) and rs1799735 (del/AGG) to increase the risk of AD (p=0.029), this effect was also most prevalent in APOE4-allele non-carriers (p=0.009; OR=1.95). The population attributable risk of this haplotype in APOE4-allele non-carriers was 32.2%. Our results suggest that there is a group of AD patients in which variations in metabolism of oxidative stress play an important role.

KIBRA gene variants are associated with episodic memory in healthy elderly.

The first hypothesis free genome wide association study on cognition recently revealed the thus far unknown association of a single nucleotide polymorphism (SNP) of the KIBRA gene with episodic memory in healthy young and middle aged volunteers. Here, we report the first independent replication of this finding in an in-depth characterized sample of healthy elderly subjects. The effectsizes of the respective KIBRA SNP on memory even exceed those of the initial report. In parallel to the first study, the effect is restricted to hippocampus-related episodic memory without effects on frontal lobe function. The impact of KIBRA on memory is most likely of high relevance in elderly subjects as it is in young.

Influence of lysosomal acid lipase polymorphisms on chromosome 10 on the risk of Alzheimer's disease and cholesterol metabolism.

Linkage analyses have identified a possible hot spot for a late-onset Alzheimer's disease (LOAD) risk gene on chromosome 10q21-22 and 10q25. It was also shown that cholesterol metabolism is involved in the pathogenic mechanisms of AD. The gene of lysosomal acid lipase (LIPA) is located next to the putative hot spot on chromosome 10. Its protein is involved in cholesterol metabolism and responsible for catalysing the hydrolysis of cholesteryl esters and triglycerides inside the lysosome. Previous publications reported controversial results on the role of LIPA polymorphisms on the risk of LOAD. We investigated two LIPA polymorphisms (rs1051338 and rs2297472) for their putative effect on the risk of LOAD in a homogenous sample of German origin. Genotypes of the investigated polymorphisms in AD patients and controls were compared. Also the effect of the LIPA gene polymorphisms on plasma cholesterol levels and 24S-hydroxycholesterol/cholesterol ratios on AD patients were investigated. None of the observed polymorphisms showed a significant influence on the risk of AD. We found that LIPA exon 2 polymorphism (rs1051338) influenced plasma 24S-hydroxycholesterol/cholesterol ratios in AD patients where carriers of the C/C allele presented with higher ratios than heterozygote carriers of the LIPA allele. Even though the biological function and gene location of LIPA on chromosome 10 suggest that LIPA might be a candidate for an AD risk gene, our results revealed that polymorphisms in LIPA did not influence the risk of AD in our study.

Polymorphism in neuropeptide Y influences CSF cholesterol levels but is no major risk factor of Alzheimer's disease.

Neuropeptide Y (NPY) is a neurotransmitter expressed in the central nervous system and involved in learning and memory. The NPY L7P polymorphism has been associated with altered cholesterol levels in obese patients. Since altered cholesterol metabolism is also involved in Alzheimer's disease (AD), the effects of two NPY polymorphisms (L7P and IVS1-100 T/G) on CSF and plasma cholesterol and 24S-hydroxycholesterol were investigated in AD patients and non-demented controls. Furtheremore, the effect of both NPY polymorphisms on the risk of AD was studied. The NPY IVS1-100 T/G polymorphism influenced CSF levels of cholesterol, whereas CSF and plasma levels of 24S-hydroxycholesterol and plasma cholesterol were not altered by genotype. NPY L7P polymorphism did not influence CSF or plasma cholesterol or 24S-hydroxycholesterol. Both NPY polymorphisms did not influence the risk of AD. Our data support the observation, that NPY polymorphisms might influence cholesterol metabolism, but might not act as major risk factor in AD.

Common genetic variants of homocysteine metabolism in ischemic stroke: a case-control study.

Hyperhomocysteinemia is a risk factor for ischemic stroke. We investigated five functional polymorphisms involved in homocysteine metabolism in each 159 stroke patients and controls. The folate-sensitive polymorphism methylenetetrahydrofolate reductase (MTHFR) c. 677 C > T (A222V) referred a non-significant risk of ischemic stroke (odds ratio: 1.20) in all patients, and homozygosity for MTHFR c. 677 C > T was associated with an earlier onset of stroke selectively in patients younger than 60 years (38 +/- 3 years vs. 45 +/- 1 years; P = 0.043). This study suggests that the investigated polymorphisms are no major risk factors for stroke, although MTHFR c. 677 C > T could be a minor factor of vulnerability especially in young patients (TT genotype), which might be helpful for the clinical work-up of stroke cases and for preventive dietary strategies.

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.

Influence of peroxisome proliferator-activated receptor gamma gene polymorphism on 24S-hydroxycholesterol levels in Alzheimer's patients.

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear hormone receptor, that is involved in lipid and glucose metabolism, which both seem to influence the risk of Alzheimer's disease (AD). 24S-Hydroxycholesterol is the major cholesterol elimination product of the brain and plasma and CSF 24S-hydroxycholesterol levels are altered in patients with neurodegenerative diseases. We investigated the effect of the common Pro12Ala variant of the PPARgamma gene on plasma cholesterol levels and 24S-hydroxycholesterol/ cholesterol ratios in 124 AD patients and 77 healthy controls. Furthermore, the influence of PPARgamma polymorphism on the risk of AD in 247 AD patients and 324 healthy controls was investigated. We found that PPARgamma Pro12Ala polymorphism influenced plasma 24S-hydroxycholesterol/ cholesterol ratios in AD patients in that carriers of the Ala allele presented with higher ratios than homozygote carriers of the Pro-allele. PPARgamma polymorphism did not influence the risk of AD. These results might point to an influence of PPARgamma Pro12Ala polymorphism on the elimination of 24S-hydroxycholesterol.

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 Glu155DeltaGlu) 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.

Pharmacokinetics of m-chlorophenylpiperazine after intravenous and oral administration in healthy male volunteers: implication for the pharmacodynamic profile.

INTRODUCTION: Serotonin plays an important role in psychiatric diseases, most notably in depression and anxiety. Seven different major serotonin receptor subtypes have been described. Receptor-selective agonists and antagonists have been searched for to find a suitable drug to test the in vivo receptor sensitivity. Different serotonin receptor subtypes take part in the control of neuroendocrine function. m-Chlorophenylpiperazine (mCPP) acts as an agonist to serotonin 2C, 1A, 1B, and 1D receptor subtypes and is applied in challenge tests. The object of this study was to develop a pharmacokinetic-pharmacodynamic model to describe the effects of mCPP on pituitary hormone secretion. METHODS: The hormone and mCPP plasma concentrations were determined after intravenous and oral administration of mCPP to 12 healthy men. The kinetic parameters of mCPP were compared to the drug's effect on hormonal response. RESULTS: After mCPP treatment, ACTH, cortisol, and prolactin levels were significantly increased compared to placebo. There was also a significant increase in clinical response (anxiety, shivering, dizziness, heightened sensitivity toward light and noise, and fear of losing control). Maximum mCPP concentrations varied 2.3-fold after intravenous infusion and 8-fold after oral administration. The absolute bioavailability ranged from 12% to 84%. mCPP's elimination half-life ranged from 2.4 h to 6.8 h after intravenous infusion and from 2.6 h to 6.1 h after oral application. However, the kinetic data as well as the pharmacodynamic response varied to an extent that precluded pharmacokinetic-pharmacodynamic modeling. The wide interindividual variability in mCPP's disposition kinetics could not be fully explained by genetic variation of the mCPP-metabolizing enzyme cytochrome P4502D6, which was determined in all probands. DISCUSSION: Other factors contributing to the variability in disposition kinetics could not be ruled out in this study, suggesting that mCPP is not a suitable model drug to test serotonin 2C receptor activity in vivo.

Altered levels of plasma 24S- and 27-hydroxycholesterol in demented patients.

Alterations in brain cholesterol metabolism and reduced 24S-hydroxycholesterol plasma levels have been described in Alzheimer's disease (AD) and vascular dementia (VD). We hypothesize that changes in peripheral cholesterol metabolism, such as alterations in the plasma levels of 27-hydroxycholesterol, might also be involved. Plasma levels of 24S-hydroxycholesterol and 27-hydroxycholesterol in patients suffering from dementing disorders such as AD, VD, and mild cognitive impairment (MCI) were compared to those in age- and cholesterol matched non-demented and depressed subjects. Cholesterol corrected concentrations of plasma 24S-hydroxycholesterol and 27-hydroxycholesterol were significantly reduced in patients with dementing disorders compared to non-demented subjects and depressed patients. A strong positive correlation between plasma 24S-hydroxycholesterol and 27-hydroxycholesterol levels was observed. The ratios of plasma 24S-hydroxycholesterol to 27-hydroxycholesterol were higher in patients with dementing disorders compared to non-demented subjects. Our results support the observation, that cholesterol metabolism is altered in dementing disorders, indicated by different plasma concentrations of brain specific and peripherally produced oxysterols.

The methionine synthase polymorphism D919G alters susceptibility to primary central nervous system lymphoma.

Primary central nervous system lymphomas (PCNSL) frequently reveal genomic instability. We analysed different functional genetic variants affecting the folate and homocysteine metabolism important for DNA integrity in 31 PCNSL patients and 142 controls. We found significantly less carriers of the methionine synthase c.2756A>G (D919G) missense polymorphism among the patients (0.16 vs 0.42; odds ratio 0.26, CI(95%): 0.09-0.74; P=0.005), suggesting a protective function of the G allele. These data stimulate further epidemiological and functional studies focusing on the role of homocysteine and folate metabolism in lymphoma tumorigenesis.

Polymorphism in the peroxisome proliferator-activated receptor alpha gene influences the risk for Alzheimer's disease.

The peroxisome proliferator-activated receptor alpha (PPAR-alpha) is a member of the steroid hormone super family of ligand-inducible transcription factors, involved in glucose and lipid metabolism. We screened for polymorphisms in the PPAR-alpha gene and detected two known polymorphisms located in exon 5 and intron 7. These polymorphisms were investigated for their possible association with Alzheimer's disease (AD) and for their effect in carriers of an insulin gene (INS) polymorphism. The PPAR-alpha C --> G polymorphism in exon 5 (L162V) was associated with AD, in that the V-allele was more frequent in AD patients than in healthy subjects. Further data analysis revealed that carriers of an PPAR-alpha L162V V-allele and an INS-1 allele presented with an increased risk for AD. Cerebrospinal fluid amyloid-beta levels were influenced by PPAR-alpha L162V genotype. These results suggest, that PPAR-alpha polymorphism may be a risk factor for AD.

The role of 24S-hydroxycholesterol in Alzheimer's disease.

Studies on Alzheimer's disease (AD) revealed that cholesterol metabolism might be involved in the pathogenesis of this neurodegenerative disorder. The apolipoprotein E4 genotype is a known risk factor in AD. Elevated serum cholesterol concentrations are detected in patients with AD and two recent epidemiological studies have indicated that treatment with inhibitors of cholesterol synthesis (statins) decrease the incidence of AD. 24R- and 24S-hydroxycholesterol, the major cholesterol elimination product of the brain, possess neurotoxic effects in vitro, and increased concentrations of 24S-hydroxycholesterol have been detected in patients from our department, suggesting a role for this oxysterol in the pathogenesis of AD. This review will give a brief overview on the relevance of 24S-hydroxycholesterol as a possible risk factor and diagnostic state marker for AD.

Effects of estrogen on brain development and neuroprotection--implications for negative symptoms in schizophrenia.

Increasing evidence during the last few years suggests that there are gender-specific differences in schizophrenia, influencing the age of onset, treatment outcome and the prevalence of negative symptoms. With respect to the latter in postmortem brain and cerebrospinal fluid of schizophrenic patients with negative symptoms a reduction of dopaminergic activity became evident. Measures of noradrenergic activity, dopamine beta-hydroxylase and the metabolite MHPG, appear to decrease with brain atrophy seen in patients with negative symptoms. Serotonergic activity tends to be low in patients with impaired cognitive function as is seen in negative schizophrenia. In these patients ventricular enlargement is associated with the severity of negative symptoms, low monoamine activity and low cerebral glucose metabolism. On the other hand atypical antipsychotic drugs that modulate also glutamate receptor activity, suggest an additional alternative mechanism of antipsychotic action beyond aminergic neurotransmitters. These drugs improve glutamatergic transmission and decrease negative symptoms; this suggests a glutamatergic deficiency as an extension of the dopamine model. The glutamate-dopamine interaction illustrates the importance of cross-talk between projections to the cortex, striatum, and lower brainstem for the expression of negative symptomatology. On the other hand, estradiol-17beta the most potent female sex hormone influences not only primary and secondary sexual characteristics but also embryonal and fetal growth as well as development of the brain aminergic networks, which are involved in schizophrenia. Estradiol-l7beta possesses neuroprotective properties, which are relevant for the course of schizophrenia and this may explain the pronounced gender differences with respect to progression and therapeutic response of schizophrenia. The present review attempts an update and synthesis of the information about the hormonal influence on neuronal pathways in negative symptoms of schizophrenia. It shows that estradiol-l7beta influences transporters and receptors as well as the morphological appearance of neuronal systems and that it may be an integral part of the neuroprotective system ameliorating schizophrenia.