Systemic therapy in children and adolescents with mental disorders: a systematic review and meta-analysis.

BACKGROUND: Systemic therapy (ST) is a psychotherapeutic intervention in complex human systems (both psychological and interpersonal). Cognitive behavioural therapy (CBT) is an established treatment for children and adolescents with mental disorders. As methodologically rigorous systematic reviews on ST in this population are lacking, we conducted a systematic review and meta-analysis to compare the benefit and harm of ST (and ST as an add-on to CBT) with CBT in children and adolescents with mental disorders. METHODS: We searched MEDLINE, Embase, PsycINFO and other sources for randomised controlled trials in 14 mental disorder classes for the above comparisons in respect of effects on patient-relevant outcomes (search date: 7/2022). Where possible, meta-analyses were performed and results were graded into 3 different evidence categories: "proof", "indication", or "hint" (or none of these categories). PRISMA standards were followed. RESULTS: Fifteen studies in 5 mental disorder classes with usable data were identified. 2079 patients (mean age: 10 to 19 years) were analysed. 12/15 studies and 29/30 outcomes showed a high risk of bias. In 2 classes, statistically significant and clinically relevant effects in favour of ST were found, supporting the conclusion of a hint of greater benefit of ST for mental and behavioural disorders due to psychoactive substance use and of ST as an add-on to CBT for obsessive-compulsive disorders. In 2 other classes (eating disorders; hyperkinetic disorders), there was no evidence of greater benefit or harm of ST. For affective disorders, a statistically significant effect to the disadvantage of ST was found for 1 outcome, supporting the conclusion of a hint of lesser benefit of ST. CONCLUSIONS: Our results show a hint of greater benefit of ST (or ST as an add-on to CBT) compared with CBT for 2 mental disorder classes in children and adolescents (mental and behavioural disorders due to psychoactive substance use, obsessive compulsive disorders). Given the importance of CBT as a control intervention, ST can therefore be considered a beneficial treatment option for children and adolescents with certain mental disorders. Limitations include an overall high risk of bias of studies and outcomes and a lack of data for several disorders.

SUCLG2 identified as both a determinator of CSF Aß1-42 levels and an attenuator of cognitive decline in Alzheimer's disease.

Cerebrospinal fluid amyloid-beta 1-42 (Aß1-42) and phosphorylated Tau at position 181 (pTau181) are biomarkers of Alzheimer's disease (AD). We performed an analysis and meta-analysis of genome-wide association study data on Aß1-42 and pTau181 in AD dementia patients followed by independent replication. An association was found between Aß1-42 level and a single-nucleotide polymorphism in SUCLG2 (rs62256378) (P = 2.5×10(-12)). An interaction between APOE genotype and rs62256378 was detected (P = 9.5 × 10(-5)), with the strongest effect being observed in APOE-ε4 noncarriers. Clinically, rs62256378 was associated with rate of cognitive decline in AD dementia patients (P = 3.1 × 10(-3)). Functional microglia experiments showed that SUCLG2 was involved in clearance of Aß1-42.

Genetic interaction of PICALM and APOE is associated with brain atrophy and cognitive impairment in Alzheimer's disease.

BACKGROUND: Evidence has emerged indicating that the ε4 allele of APOE and PICALM interact in conferring risk of Alzheimer's disease (AD). The biologic basis of this interaction is unclear, but it is likely to have phenotypic relevance and contribute to the structural and clinical heterogeneity of AD. METHODS: The aim of this study was to investigate interaction effects of the APOE ε4 allele and the alleles at the single-nucleotide polymorphism rs3851179 located in the PICALM locus. We analyzed brain volumes and cognitive phenotypes of 165 patients with early AD dementia. RESULTS: There was a synergistic adverse effect of homozygosity for the PICALM risk allele G in rs3851179 and APOE ε4 on volume in prefrontal and performance on the Trail Making Test A, which is sensitive to processing speed and working memory function. CONCLUSIONS: The data suggest a neural mechanism for APOE-PICALM interactions in patients with manifest AD and indicate that the PICALM genotype modulates both brain atrophy and cognitive performance in APOE ε4 carriers.

A polymorphic microsatellite repeat within the ECE-1c promoter is involved in transcriptional start site determination, human evolution, and Alzheimer's disease.

Genetic factors strongly contribute to the pathogenesis of sporadic Alzheimer's disease (AD). Nevertheless, genome-wide association studies only yielded single nucleotide polymorphism loci of moderate importance. In contrast, microsatellite repeats are functionally less characterized structures within our genomes. Previous work has shown that endothelin-converting enzyme-1 (ECE-1) is able to reduce amyloid ß content. Here we demonstrate that a CpG-CA repeat within the human ECE-1c promoter is highly polymorphic, harbors transcriptional start sites, is able to recruit the transcription factors poly(ADP-ribose) polymerase-1 and splicing factor proline and glutamine-rich, and is functional regarding haplotype-specific promoter activity. Furthermore, genotyping of 403 AD patients and 444 controls for CpG-CA repeat length indicated shifted allelic frequency distributions. Sequencing of 245 haplotype clones demonstrated that the overall CpG-CA repeat composition of AD patients and controls is distinct. Finally, we show that human and chimpanzee [CpG](m)-[CA](n) ECE-1c promoter repeats are genetically and functionally distinct. Our data indicate that a short genomic repeat structure constitutes a novel core promoter element, coincides with human evolution, and contributes to the pathogenesis of AD.

VKORC1-dependent pharmacokinetics of intravenous and oral phylloquinone (vitamin K1) mixed micelles formulation.

OBJECTIVE: The pharmacokinetics of phylloquinone (vitamin K1) were evaluated in healthy human adult volunteers (15 male and 15 female) following oral and intravenous administration of a mixed micelles formulation (Konakion MM 2 mg) in an open label study design. The subjects were allocated to one of three genotype-specific groups (n = 10 in each group) in terms of VKORC1 promoter polymorphism c.-1639 G > A to explore the relationship between genotype and pharmacokinetic parameters. METHODS: Blood samples were collected for up to 24 h after administration. Phylloquinone serum levels were determined by reversed phase HPLC with fluorometric detection after post-column zinc reduction. Pharmacokinetic evaluation was performed using non-compartmental analysis. RESULTS: Pharmacokinetic analysis of serum phylloquinone concentration versus time profiles revealed significant differences in the main pharmacokinetic parameters between groups. Upon oral administration, VKORC1 AG carriers showed 41 % higher mean bioavailability (p = 0.01) compared with homozygous AA individuals. Furthermore, AG subjects exhibited 30 % (p = 0.042) and 36 % (p = 0.021) higher mean AUC compared with GG and AA respectively. Terminal half-life was 32 % and 27 % longer for AG carriers in comparison to GG (p = 0.004) and AA (p = 0.015) genotypes respectively. CONCLUSION: Pharmacokinetic differences indicated significant inter-individual variance of vitamin K fate in the human body. The influence of the VKORC1 promoter polymorphism c.-1639 G > A on the pharmacokinetic properties of phylloquinone could be demonstrated in humans. To gain deeper insight in other potential genetic determinants of systemic vitamin K exposure, further correlation of the phenotype-genotype relationship of different players in vitamin K turnover has to be gained.

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.

Cholesterol metabolism is associated with soluble amyloid precursor protein production in Alzheimer's disease.

Disturbances of the cholesterol metabolism are associated with Alzheimer's disease (AD) risk and related cerebral pathology. Experimental studies found changing levels of cholesterol and its metabolites 24S-hydroxycholesterol (24S-OHC) and 27-hydroxycholesterol (27-OHC) to contribute to amyloidogenesis by increasing the production of soluble amyloid precursor protein (sAPP). The aim of this study was to evaluate the relationship between the CSF and circulating cholesterol 24S-OHC and 27-OHC, and the sAPP production as measured by CSF concentrations of sAPP forms in humans. The plasma and the CSF concentrations of cholesterol, 24S-OHC and 27-OHC, and the CSF concentrations of sAPPα, sAPPß, and Aß1-42 were assessed in subjects with AD and controls with normal cognition. In multivariate regression tests including age, gender, albumin ratio, and apolipoprotein E (APOE)ε4 status CSF cholesterol, 24S-OHC, and 27-OHC independently predicted the concentrations of sAPPα and sAPPß. The associations remained significant when analyses were separately performed in the AD group. Furthermore, plasma 27-OHC concentrations were associated with the CSF sAPP levels. The results suggest that high CSF concentrations of cholesterol, 24S-OHC, and 27-OHC are associated with increased production of both sAPP forms in AD.

Interaction of insulin and PPAR-α genes in Alzheimer's disease: the Epistasis Project.

Altered glucose metabolism has been described in Alzheimer's disease (AD). We re-investigated the interaction of the insulin (INS) and the peroxisome proliferator-activated receptor alpha (PPARA) genes in AD risk in the Epistasis Project, including 1,757 AD cases and 6,294 controls. Allele frequencies of both SNPs (PPARA L162V, INS intron 0 A/T) differed between Northern Europeans and Northern Spanish. The PPARA 162LL genotype increased AD risk in Northern Europeans (p = 0.04), but not in Northern Spanish (p = 0.2). There was no association of the INS intron 0 TT genotype with AD. We observed an interaction on AD risk between PPARA 162LL and INS intron 0 TT genotypes in Northern Europeans (Synergy factor 2.5, p = 0.016), but not in Northern Spanish. We suggest that dysregulation of glucose metabolism contributes to the development of AD and might be due in part to genetic variations in INS and PPARA and their interaction especially in Northern Europeans.

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.

The dopamine ß-hydroxylase -1021C/T polymorphism is associated with the risk of Alzheimer's disease in the Epistasis Project.

BACKGROUND: The loss of noradrenergic neurones of the locus coeruleus is a major feature of Alzheimer's disease (AD). Dopamine ß-hydroxylase (DBH) catalyses the conversion of dopamine to noradrenaline. Interactions have been reported between the low-activity -1021T allele (rs1611115) of DBH and polymorphisms of the pro-inflammatory cytokine genes, IL1A and IL6, contributing to the risk of AD. We therefore examined the associations with AD of the DBH -1021T allele and of the above interactions in the Epistasis Project, with 1757 cases of AD and 6294 elderly controls. METHODS: We genotyped eight single nucleotide polymorphisms (SNPs) in the three genes, DBH, IL1A and IL6. We used logistic regression models and synergy factor analysis to examine potential interactions and associations with AD. RESULTS: We found that the presence of the -1021T allele was associated with AD: odds ratio = 1.2 (95% confidence interval: 1.06-1.4, p = 0.005). This association was nearly restricted to men < 75 years old: odds ratio = 2.2 (1.4-3.3, 0.0004). We also found an interaction between the presence of DBH -1021T and the -889TT genotype (rs1800587) of IL1A: synergy factor = 1.9 (1.2-3.1, 0.005). All these results were consistent between North Europe and North Spain. CONCLUSIONS: Extensive, previous evidence (reviewed here) indicates an important role for noradrenaline in the control of inflammation in the brain. Thus, the -1021T allele with presumed low activity may be associated with misregulation of inflammation, which could contribute to the onset of AD. We suggest that such misregulation is the predominant mechanism of the association we report here.

Capillary cerebral amyloid angiopathy identifies a distinct APOE epsilon4-associated subtype of sporadic Alzheimer's disease.

The deposition of amyloid beta-protein (Abeta) in the vessel wall, i.e., cerebral amyloid angiopathy (CAA), is associated with Alzheimer's disease (AD). Two types of CAA can be differentiated by the presence or absence of capillary Abeta-deposits. In addition, as in Alzheimer's disease, risk for capillary CAA is associated with the apolipoprotein E (APOE) epsilon4-allele. Because these morphological and genetic differences between the two types of AD-related CAA exist, the question arises as to whether there exist further differences between AD cases with and without capillary CAA and, if so, whether capillary CAA can be employed to distinguish and define specific subtypes of AD. To address this question, we studied AD and control cases both with and without capillary CAA to identify the following: (1) distinguishing neuropathological features; (2) alterations in perivascular protein expression; and (3) genotype-specific associations. More widespread Abeta-plaque pathology was observed in AD cases with capillary CAA than in those without. Expression of perivascular excitatory amino acid transporter 2 (EAAT-2/GLT-1) was reduced in cortical astrocytes of AD cases with capillary CAA in contrast to those lacking capillary Abeta-deposition and controls. Genetically, AD cases with capillary CAA were strongly associated with the APOE epsilon4 allele compared to those lacking capillary CAA and to controls. To further validate the existence of distinct types of AD we analyzed polymorphisms in additional apoE- and cholesterol-related candidate genes. Our results revealed an association between AD cases without capillary CAA (i.e., AD cases with CAA but lacking capillary CAA and AD cases without CAA) and the T-allele of the alpha(2)macroglobulin receptor/low-density lipoprotein receptor-related protein-1 (LRP-1) C766T polymorphism as opposed to AD cases with capillary CAA and non-AD controls. Taken together, these results indicate that AD cases with capillary CAA differ significantly from other AD cases both genetically and morphologically, thereby pointing to a specific capillary CAA-related and APOE epsilon4-associated subtype of AD.

Multicentre variability of MRI-based medial temporal lobe volumetry in Alzheimer's disease.

Magnetic resonance imaging (MRI)-based volumetry of medial temporal lobe regions is among the best established biomarker candidates of Alzheimer's disease (AD) to date. This study assessed the effect of multicentre variability of MRI-based hippocampus and amygdala volumetry on the discrimination between patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) and on the association of morphological changes with ApoE4 genotype and cognition. We studied 113 patients with clinically probable AD and 150 patients with amnestic MCI using high-resolution MRI scans obtained at 12 clinical sites. We determined effect sizes of group discrimination and random effects linear models, considering multicentre variability. Hippocampus and amygdala volumes were significantly reduced in AD compared with MCI patients using data pooled across centres. Multicentre variability did not significantly affect the power to detect a volume difference between AD and MCI patients. Among cognitive measures, delayed recall of verbal and non-verbal material was significantly correlated with hippocampus and amygdala volumes. Amygdala and hippocampus volumes were not associated with ApoE4 genotype in AD or MCI. Our data indicate that multicentre acquisition of MRI data using manual volumetry is reliable and feasible for cross-sectional diagnostic studies, and they replicate essential findings from smaller scale monocentre studies.

S-adenosylmethionine is decreased in the cerebrospinal fluid of patients with Alzheimer's disease.

BACKGROUND: Increased plasma homocysteine levels have been described as an independent risk factor for Alzheimer's disease (AD), but the underlying pathophysiology is unclear. OBJECTIVE: This single-center, cross-sectional, correlational study analyzed homocysteine metabolism in 60 AD patients and 60 control subjects. METHODS: Fasting plasma levels of vitamin B12, folate and homocysteine as well as cerebrospinal fluid (CSF) levels of folate derivates, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and homocysteine were measured. In addition, the apolipoprotein E (APOE) genotype was determined. RESULTS: As expected, the APOE4 allele was significantly overrepresented in AD patients compared with controls (p < 0.001). Homocysteine plasma levels in the highest quartile were more frequent in the AD patients than in the controls (p = 0.008). In addition, AD patients had significantly lower CSF levels of the methyl group donor SAM (193 ± 31 vs. 207 ± 37 nmol/l; p = 0.032). Accordingly, the SAM/SAH ratio, which represents the methylation capacity, was significantly lower in the CSF of the AD patients (7.6 ± 2.4 vs. 9.1 ± 2.8; p = 0.003). Further, explorative analysis of all subjects showed that CSF SAM levels were lower in carriers of the APOE4 allele compared with noncarriers (189 ± 30 vs. 207 ± 36 nmol/l; p = 0.010). Of the individuals with CSF SAM levels in the lowest quartile, 63% carried the APOE4 allele compared with 17% of the individuals with CSF SAM levels in the highest quartile (Pearson: χ² = 9.9; p = 0.002; odds ratio 0.126, 95% confidence interval 0.32-0.49). CONCLUSION: These data suggest that AD is associated with lower CSF SAM levels and that this is at least partly due to an association of the APOE4 allele with reduced SAM levels in the CSF.

Negative pressure wound therapy in patients with wounds healing by secondary intention: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Negative pressure wound therapy (NPWT) is a widely used method of wound treatment. We performed a systematic review of randomised controlled trials (RCTs) comparing the patient-relevant benefits and harms of NPWT with standard wound therapy (SWT) in patients with wounds healing by secondary intention. METHODS: We searched for RCTs in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and study registries (last search: July 2018) and screened reference lists of relevant systematic reviews and health technology assessments. Manufacturers and investigators were asked to provide unpublished data. Eligible studies investigated at least one patient-relevant outcome (e.g. wound closure). We assessed publication bias and, if feasible, performed meta-analyses, grading the results into different categories (hint, indication or proof of a greater benefit or harm). RESULTS: We identified 48 eligible studies of generally low quality with evaluable data for 4315 patients and 30 eligible studies with missing data for at least 1386 patients. Due to potential publication bias (proportion of inaccessible data, 24%), we downgraded our conclusions. A meta-analysis of all wound healing data showed a significant effect in favour of NPWT (OR 1.56, 95% CI 1.15 to 2.13, p = 0.008). As further analyses of different definitions of wound closure did not contradict that analysis, we inferred an indication of a greater benefit of NPWT. A meta-analysis of hospital stay (in days) showed a significant difference in favour of NPWT (MD - 4.78, 95% CI - 7.79 to - 1.76, p = 0.005). As further analyses of different definitions of hospital stay/readmission did not contradict that analysis, we inferred an indication of a greater benefit of NPWT. There was neither proof (nor indication nor hint) of greater benefit or harm of NPWT for other patient-relevant outcomes such as mortality and adverse events. CONCLUSIONS: In summary, low-quality data indicate a greater benefit of NPWT versus SWT for wound closure in patients with wounds healing by secondary intention. The length of hospital stay is also shortened. The data show no advantages or disadvantages of NPWT for other patient-relevant outcomes. Publication bias is an important problem in studies on NPWT, underlining that all clinical studies need to be fully reported.

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.

Replication by the Epistasis Project of the interaction between the genes for IL-6 and IL-10 in the risk of Alzheimer's disease.

BACKGROUND: Chronic inflammation is a characteristic of Alzheimer's disease (AD). An interaction associated with the risk of AD has been reported between polymorphisms in the regulatory regions of the genes for the pro-inflammatory cytokine, interleukin-6 (IL-6, gene: IL6), and the anti-inflammatory cytokine, interleukin-10 (IL-10, gene: IL10). METHODS: We examined this interaction in the Epistasis Project, a collaboration of 7 AD research groups, contributing DNA samples from 1,757 cases of AD and 6,295 controls. RESULTS: We replicated the interaction. For IL6 rs2069837 AA x IL10 rs1800871 CC, the synergy factor (SF) was 1.63 (95% confidence interval: 1.10-2.41, p = 0.01), controlling for centre, age, gender and apolipoprotein E epsilon4 (APOEepsilon4) genotype. Our results are consistent between North Europe (SF = 1.7, p = 0.03) and North Spain (SF = 2.0, p = 0.09). Further replication may require a meta-analysis. However, association due to linkage disequilibrium with other polymorphisms in the regulatory regions of these genes cannot be excluded. CONCLUSION: We suggest that dysregulation of both IL-6 and IL-10 in some elderly people, due in part to genetic variations in the two genes, contributes to the development of AD. Thus, inflammation facilitates the onset of sporadic AD.

Gene polymorphisms in prodynorphin (PDYN) are associated with episodic memory in the elderly.

Cognitive functions show large variation in elderly people and are substantially heritable. Animal studies revealed that dynorphins influence cognition and memory, especially in aged animals. Thus, we tested the effect of four SNPs (rs7272891, rs1997794, rs2235751 and rs910080) and the VNTR promoter polymorphism in the prodynorphin gene (PDYN) on episodic memory and verbal fluency in a large (n = 1619) sample of elderly people (mean age: 80 +/- 3.39 years; range 75-90 years) recruited through the German study on ageing, cognition and dementia in primary care patients (AgeCoDe). We found that carriers of the minor alleles of rs1997794 (P < 0.002) and rs910080 (P < 0.005) presented with higher episodic memory scores than homozygote carriers of the major allele. Also, a three marker haplotype including these two SNPs and rs2235751 was associated with better episodic memory scores. Verbal fluency scores were non-significantly better in carriers of these respective alleles. Thus, our results suggest a role of PDYN gene variations in determining memory function also in elderly humans.

Association of the PPARgamma gene polymorphism Pro12Ala with delayed onset of multiple sclerosis.

PPARs belong to a receptor family of ligand-activated transcription factors involved in the regulation of inflammation. A crucial role both for PPARgamma and for PPARalpha for the regulation of autoimmunity has been clearly demonstrated, as receptor agonists had beneficial effects on several CD4(+) T cell mediated autoimmune diseases including experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. We investigated the association of two common single nucleotide polymorphisms in the PPARA (Leu162Val) and the PPARG (Pro12Ala) genes in 116 patients with clinically definite multiple sclerosis (MS) and 211 age-matched healthy controls. The Ala allele of the PPARG Pro12Ala polymorphism was strongly associated with delayed disease onset (44.1+/-5.3 years vs 34.5+/-4.2 years; p=0.006). No significant differences were found in genotype distributions and allele frequencies of the PPARA Leu162Val and the PPARG Pro12Ala polymorphisms between MS patients and healthy controls, respectively. Our population-based study demonstrates that the Pro12Ala polymorphism resulting in an amino acid exchange in the N-terminal sequence of PPARgamma may influence the onset of MS.

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.

The Epistasis Project: A Multi-Cohort Study of the Effects of BDNF, DBH, and SORT1 Epistasis on Alzheimer's Disease Risk.

Pre-synaptic secretion of brain-derived neurotrophic factor (BDNF) from noradrenergic neurons may protect the Alzheimer's disease (AD) brain from amyloid pathology. While the BDNF polymorphism (rs6265) is associated with faster cognitive decline and increased hippocampal atrophy, a replicable genetic association of BDNF with AD risk has yet to be demonstrated. This could be due to masking by underlying epistatic interactions between BDNF and other loci that encode proteins involved in moderating BDNF secretion (DBH and Sortilin). We performed a multi-cohort case-control association study of the BDNF, DBH, and SORT1 loci comprising 5,682 controls and 2,454 AD patients from Northern Europe (87% of samples) and Spain (13%). The BDNF locus was associated with increased AD risk (odds ratios; OR = 1.1-1.2, p = 0.005-0.3), an effect size that was consistent in the Northern European (OR = 1.1-1.2, p = 0.002-0.8) but not the smaller Spanish (OR = 0.8-1.6, p = 0.4-1.0) subset. A synergistic interaction between BDNF and sex (synergy factor; SF = 1.3-1.5 p = 0.002-0.02) translated to a greater risk of AD associated with BDNF in women (OR = 1.2-1.3, p = 0.007-0.00008) than men (OR = 0.9-1.0, p = 0.3-0.6). While the DBH polymorphism (rs1611115) was also associated with increased AD risk (OR = 1.1, p = 0.04) the synergistic interaction (SF = 2.2, p = 0.007) between BDNF (rs6265) and DBH (rs1611115) contributed greater AD risk than either gene alone, an effect that was greater in women (SF = 2.4, p = 0.04) than men (SF = 2.0, p = 0.2). These data support a complex genetic interaction at loci encoding proteins implicated in the DBH-BDNF inflammatory pathway that modifies AD risk, particularly in women.