rs3851179 Polymorphism at 5′ to the <Emphasis Type="Italic">PICALM</Emphasis> Gene is Associated with Alzheimer and Parkinson Diseases in Brazilian Population

Alzheimer’s (AD) and Parkinson’s diseases (PD) share clinical and pathological features, suggesting that they could have common pathogenic mechanisms, as well as overlapping genetic modifiers. Here, we performed a case–control study in a Brazilian population to clarify whether the risk of AD and PD might be influenced by shared polymorphisms at PICALM (rs3851179), CR1 (rs6656401) and CLU (rs11136000) genes, which were previously identified as AD risk factors by genome-wide association studies. For this purpose, 174 late-onset AD patients, 166 PD patients and 176 matched controls were genotyped using TaqMan^® assays. The results revealed that there were significant differences in genotype and allele frequencies for the SNP PICALM rs3851179 between AD/PD cases and controls, but none for CR1 rs6656401 and CLU rs11136000 intronic polymorphisms. After stratification by APOE ε4 status, the protective effect of the PICALM rs3851179 A allele in AD cases remains evident only in APOE ε4 (?) carriers, suggesting that the APOE ε4 risky allele weakens its protective effect in the APOE ε4 (+) subgroup. More genetic studies using large-sized and well-defined matched samples of AD and PD patients from mixed populations as well as functional correlation analysis are urgently needed to clarify the role of rs3851179 in the AD/PD risk. An understanding of the contribution of rs3851179 to the development of AD and PD could provide new targets for the development of novel therapies.     

<Emphasis Type="Italic">ABCC8</Emphasis> Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI

Objective

Cerebral edema (CE) in traumatic brain injury (TBI) is the consequence of multiple underlying mechanisms and is associated with unfavorable outcomes. Genetic variability in these pathways likely explains some of the clinical heterogeneity observed in edema development. A role for sulfonylurea receptor-1 (Sur1) in CE is supported. However, there are no prior studies examining the effect of genetic variability in the Sur1 gene (ABCC8) on the development of CE. We hypothesize that ABCC8 single nucleotide polymorphisms (SNPs) are predictive of CE.

Methods

DNA was extracted from 385 patients. SNPs in ABCC8 were genotyped using the Human Core Exome v1.2 (Illumina). CE measurements included acute CT edema, mean and peak intracranial pressure (ICP), and need for decompressive craniotomy.

Results

Fourteen SNPs with minor allele frequency >0.2 were identified. Four SNPS rs2283261, rs3819521, rs2283258, and rs1799857 were associated with CE measures. In multiple regression models, homozygote-variant genotypes in rs2283261, rs3819521, and rs2283258 had increased odds of CT edema (OR 2.45, p = 0.007; OR 2.95, p = 0.025; OR 3.00, p = 0.013), had higher mean (β = 3.13, p = 0.000; β = 2.95, p = 0.005; β = 3.20, p = 0.008), and peak ICP (β = 8.00, p = 0.001; β = 7.64, p = 0.007; β = 6.89, p = 0.034). The homozygote wild-type genotype of rs1799857 had decreased odds of decompressive craniotomy (OR 0.47, p = 0.004).

Conclusions

This is the first report assessing the impact of ABCC8 genetic variability on CE development in TBI. Minor allele ABCC8 SNP genotypes had increased risk of CE, while major SNP alleles were protective—potentially suggesting an evolutionary advantage. These findings could guide risk stratification, treatment responders, and the development of novel targeted or gene-based therapies against CE in TBI and other neurological disorders.

     

Influence of four polymorphisms in <Emphasis Type="Italic">ABCA1</Emphasis> and <Emphasis Type="Italic">PTGS2</Emphasis> genes on risk of Alzheimer’s disease: a meta-analysis

We preformed this meta-analysis to investigate the influence of ABCA1 (ATP-binding cassette sub-family A member 1) rs2422493 (C-477T), rs1800977 (C-14T), rs2066718 (V771M), and PTGS2 (Prostaglandin-endoperoxide synthase 2) rs20417 (G-765C) polymorphisms on the risk of Alzheimer’s disease (AD). Seventeen eligible case–control studies were acquired from PubMed, Embase, Alzgene, Chinese National Knowledge Infrastructure and Wanfang databases. The pooled odds ratios (ORs) with 95 % confidence intervals (95 % CI) were calculated to evaluate the association under five genetic models. Combined data indicated that ABCA1 rs2422493 polymorphism was statistically significant associated with increasing AD risk in three genetic models (allelic T vs C: OR = 1.12, 95 % CI: 1.01–1.24; homozygous TT vs CC: OR = 1.26, 95 % CI: 1.03–1.55; and recessive TT vs TC + CC: OR = 1.33, 95 % CI: 1.12–1.58) while no association was found between two other ABCA1 polymorphisms and AD susceptibility. Nevertheless, a further risk-stratification analysis showed that ApoE-ε4 carriers with any ABCA1 polymorphism suffered a much higher probability to be AD patients. Meanwhile, PTGS2 rs20417 polymorphism was linked to decreasing AD risk with a P < 0.0001 in five genetic models (e.g., allelic C vs G: OR = 0.59, 95 % CI: 0.50–0.70; homozygous CC vs GG: OR = 0.31, 95 % CI: 0.18–0.52; and heterozygous CG vs GG: OR = 0.64, 95 % CI: 0.52–0.78). In summary, our meta-analysis results showed that ABCA1 rs2422493 polymorphism was a risk factor for AD while PTGS2 rs20417 variant showed a protective effect on AD risk. In addition, ABCA1 rs2066718 and rs1800977 polymorphisms might not contribute to AD susceptibility in general population, but they should play a role on AD development when interacted with ApoE-ε4.     

Association study on the mitochondrial gene <Emphasis Type="Italic">NDUFV2</Emphasis> and bipolar disorder in the Chinese Han population

Bipolar disorder is known to be subject to maternal transmission. Mitochondrial DNA has been suggested as playing a role in the illness. NDUFV2, located on 18p11.31-p11.2, encodes an important subunit of mitochondrial NADH (complex I). Previous studies have reported the association of NDUFV2 with bipolar disorder in the Japanese and Caucasian populations. Whether it is also a susceptible gene in the Chinese population is unknown. To study the role of NDUFV2 in bipolar disorder in the Chinese population, 506 unrelated bipolar patients and 507 unrelated controls of Chinese Han origin were recruited. Six SNPs (rs11661859, rs6506640, rs1156044, rs4148965, rs906807, rs977581) were genotyped using either TaqMan^® technology or direct sequencing. The haplotype consisting of rs6506640 (?342G > A) and rs906807 (86C > T) was found to be associated with bipolar disorder (global p = 0.012 before corrected, p = 0.030 after 10,000 permutations; individual p (A–T of rs6506640–rs906807) = 0.014 after 100,000 permutations (p = 0.0065 before corrected). The genotype frequency of rs906807 differed between bipolar female patients and female controls (p = 0.012, uncorrected). No other individual associations of SNPs with bipolar were detected. Our study indicated that the regions spanning from the promoter to the exon 2 may contain susceptible polymorphisms which predispose to bipolar disorder.     

<Emphasis Type="Italic">DAT1</Emphasis> and <Emphasis Type="Italic">DRD4</Emphasis> genes involved in key dimensions of adult ADHD

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder often persisting in adulthood. Genetic studies of ADHD mainly focused on the Dopamine Transporter (DAT1) and the Dopamine Receptor 4 (DRD4) genes. Nevertheless, polymorphisms of these genes explain only a small fraction of the assigned risk, suggesting that intermediate dimensions and environmental factors should also be considered. We investigated in 77 adult ADHD subjects compared to 474 controls, how polymorphisms within the genes coding for DAT1 (40-bp VNTR in 3′UTR), the Dopamine Receptor 2 (DRD2) (rs1799732) and DRD4 (48-bp VNTR in exon 3), may modulate the expression of the disorder. By genotyping DAT1, we detected a new 9.5R allele showing a deletion of 40 bp and also an insertion of 19 bp compared to the 10R allele. This novel allele was found to be significantly protective for ADHD (p < 0.0001). Another significant difference was found in the distribution of DRD4 48-bp VNTR 6R allele when comparing patients and controls (p = 0.0007). In addition significant results were also found for DAT1 9.5R allele, which was associated with impulsiveness (p = 1.98 × 10^?4) and trait anger scores (p = 7.66 × 10^?4). Moreover, impulsiveness scores were partly modulated by an interaction between the DRD4 48-bp VNTR 6R allele and childhood maltreatment (p = 0.01), however, this result did not resist correction for multiple comparisons. Altogether, our results show the putative involvement of DAT1 and DRD4 genes in the aetiology of ADHD with a main role in modulation of key dimensions of the disorder.     

<Emphasis Type="Italic">TLR4</Emphasis> polymorphisms affect stroke risk and inflammatory response in Chinese ischemic stroke patients

This study aimed to evaluate the association of the toll-like receptor 4 (TLR4) polymorphisms rs1927914, rs10759932, and rs11536889 with susceptibility to ischemic stroke (IS) and the serum levels of inflammatory cytokines. A total of 816 IS patients and 816 control subjects were genotyped using Sequenom MassARRAY technology. The serum levels of interleukin 1 beta (IL-1β), interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor alpha (TNFα) were measured by enzyme-linked immunosorbent assay. rs1927914 was significantly associated with male IS patients in the additive model [odds ratio (OR) = 0.81; 95% confidence interval (CI) = 0.67–0.99; P = 0.039] and in the allele model (OR = 0.81; 95% CI = 0.66–0.99; P = 0.037). In the dominant model, rs10759932 was significantly associated with the serum TNFα level of the male IS patients [regression coefficient (β) = 0.15; 95% CI = 0.01–0.29; P _adj = 0.042]. This polymorphism was also correlated with the serum IL-8 level of female IS patients in the additive model (β = 0.24; 95% CI = 0.25–0.43; P _adj = 0.021) and in the recessive model (β = 0.65; 95% CI = 0.11–1.11; P _adj = 0.026). The TLR4 gene rs1927914 polymorphism was associated with susceptibility to IS in males. Moreover, the rs10759932 polymorphism may affect inflammatory response in IS patients.     

Novel CD137 Gene Polymorphisms and Susceptibility to Ischemic Stroke in the Northern Chinese Han Population

Ischemic stroke is a leading cause of mortality and morbidity worldwide, and atherosclerosis is one of the major risk factors for this neurologic deficit. Recent studies have revealed the important role of CD137 in human atherosclerosis. Here, we analyzed the association of CD137 single nucleotide polymorphisms (SNPs) with ischemic stroke. We assessed three SNPs (rs161827, rs161818, and rs161810) of the CD137 gene and their association with ischemic stroke in a northern Chinese Han population. A total of 496 ischemic stroke patients and 486 gender-matched control subjects were genotyped. We classified these patients according to complications with diabetes and hypertension and also by ischemic stroke subtypes. Allele, genotype, and haplotype association studies were tested in all patients and subgroups. We used multivariable logistic regression analysis combined with 10,000 permutations to analyze the association of CD137 polymorphisms with ischemic stroke. After adjusting for relevant factors, rs161827 was significantly different between patients with and without diabetes and the control group (p = 0.0001, p = 0.014, and p = 0.0001, respectively). In addition, rs161818 and rs161810 differed significantly between patients without diabetes and the control subjects (p = 0.0001 and p = 0.004, respectively). rs161827, rs161818, and rs161810 were all statistically significant among the combination stroke subgroup compared with the controls. These results indicate that the CD137 gene is associated with risk of ischemic stroke in the northern Han Chinese. Moreover, CD137 gene polymorphism may be one mediating factor between diabetes and ischemic stroke.     

Association between cerebral dopamine neurotrophic factor (<Emphasis Type="Italic">CDNF</Emphasis>) 2 polymorphisms and schizophrenia susceptibility and symptoms in the Han Chinese population

Background

Schizophrenia (SZ) is a complex polygenic psychiatric disorder caused in part by abnormal dopamine levels. Cerebral dopamine neurotrophic factor (CDNF) 2 is known to protect and repair the dopaminergic system. Dopamine dysfunction is one of the pathogenesis of SZ. However, the relationship between CDNF2 and SZ has not been previously investigated. We speculated that CDNF2 may be a susceptibility factor for SZ.

Methods

To address this issue, we carried out a study to investigate the association between CDNF2 and SZ in the total sample 1371 (670 SZ patients and 701 healthy controls) Han Chinese population. Stage 1 included 528 SZ patients and 528 healthy controls; and stage 2 included 142 SZ patients and 173 healthy controls. The allele and genotype frequencies of five single nucleotide polymorphisms (rs2577074, rs2577075, rs2249810, rs6506891, and rs2118343) of CDNF2 were compared between patients and controls.

Results

We found a significant association in allele and genotype frequencies between the two groups at rs2249810 (χ² = 4.38 and 6.45, respectively; P = 0.03 and 0.04, respectively). An association was also observed in males at rs2249810 (χ² = 8.76; P = 0.03). Haplotype TGATC differed between SZ and controls in stage 2 samples (χ² = 6.38; P = 0.01), and rs2118343 genotypes were associated with negative factor scores (F = 4.396; P = 0.01).

Conclusions

These results suggest that rs2249810 and haplotype TGATC of CDNF2 are an SZ susceptibility locus and factor, respectively, and that rs2118343 genotypes are associated with negative symptoms of SZ in the Han Chinese population.

     

Interaction between cytochrome P450 2A6 and Catechol-<Emphasis Type="Italic">O</Emphasis>-Methyltransferase genes and their association with smoking risk in young men

Background

Although some effects of gene–gene interactions on nicotine–dopamine metabolism for smoking behavior have been reported, polymorphisms of cytochrome P450 (CYP) 2A6 and catechol-O-methyltransferase (COMT) have not been studied together to determine their effects on smokers. The aim of this study was to investigate the effects of the interaction between the CYP 2A6 and COMT genes on smoking behavior in young Taiwanese men.

Results

A self-report questionnaire regarding smoking status was administered to 500 young men. Polymorphisms of the CYP 2A6 and COMT genes as well as urinary nicotine and urinary cotinine levels were determined. The odds ratio for starting smoking was significantly lower in subjects carrying a CYP2A6 low activity/variant COMT rs4680 genotype than in those possessing a CYP2A6 wild-type/variant COMT rs4680 genotype (0.44, 95% confidence interval = 0.19–0.98, P = 0.043). Comparisons of Fagerstrom Test for Nicotine Dependence (FTND), Physiological Cigarette Dependence Scale (PCDS), and Cigarette Withdrawal symptoms (CWS-21) among the smokers with different CYP2A6/COMT polymorphisms were not significantly different. The adjusted urinary nicotine concentrations were not significantly different between the two groups carrying different genotypes. The adjusted urinary cotinine level was significantly different between the COMT rs4680 wild-type group and COMT rs4680 variant group [92.46 ng/μL vs. 118.24 ng/μL (median value), P = 0.041] and between the COMT rs4680 wild-type/COMT rs165599 variant group and COMT rs4680 variant/COMT rs165599 variant group (97.10 ng/μL vs. 122.18 ng/μL, P = 0.022).

Conclusions

These findings suggest that a single nucleotide polymorphism (rs4680) of the COMT gene and the interaction between the CYP 2A6 and COMT genes affect smoking status in young Taiwanese men.

     

<Emphasis Type="Italic">DRD2 C957T</Emphasis> polymorphism is associated with improved 6-month verbal learning following traumatic brain injury

Traumatic brain injury (TBI) often leads to heterogeneous clinical outcomes, which may be influenced by genetic variation. A single-nucleotide polymorphism (SNP) in the dopamine D2 receptor (DRD2) may influence cognitive deficits following TBI. However, part of the association with DRD2 has been attributed to genetic variability within the adjacent ankyrin repeat and kinase domain containing 1 protein (ANKK1). Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether a novel DRD2 C957T polymorphism (rs6277) influences outcome on a cognitive battery at 6 months following TBI—California Verbal Learning Test (CVLT-II), Wechsler Adult Intelligence Test Processing Speed Index Composite Score (WAIS-PSI), and Trail Making Test (TMT). Results in 128 Caucasian subjects show that the rs6277 T-allele associates with better verbal learning and recall on CVLT-II Trials 1–5 (T-allele carrier 52.8 ± 1.3 points, C/C 47.9 ± 1.7 points; mean increase 4.9 points, 95% confidence interval [0.9 to 8.8]; p = 0.018), Short-Delay Free Recall (T-carrier 10.9 ± 0.4 points, C/C 9.7 ± 0.5 points; mean increase 1.2 points [0.1 to 2.5]; p = 0.046), and Long-Delay Free Recall (T-carrier 11.5 ± 0.4 points, C/C 10.2 ± 0.5 points; mean increase 1.3 points [0.1 to 2.5]; p = 0.041) after adjusting for age, education years, Glasgow Coma Scale, presence of acute intracranial pathology on head computed tomography scan, and genotype of the ANKK1 SNP rs1800497 using multivariable regression. No association was found between DRD2 C947T and non-verbal processing speed (WAIS-PSI) or mental flexibility (TMT) at 6 months. Hence, DRD2 C947T (rs6277) may be associated with better performance on select cognitive domains independent of ANKK1 following TBI.     

Association of <Emphasis Type="Italic">TNFSF4</Emphasis> Polymorphisms with Neuromyelitis Optica Spectrum Disorders in a Chinese Population

The tumor necrosis factor ligand superfamily member 4 (TNFSF4) gene encodes a vital co-stimulatory molecule of the immune system and has been identified as a susceptibility locus for systemic lupus erythematosus, systemic sclerosis, and primary Sjögren’s syndrome. However, the association of TNFSF4 polymorphisms with neuromyelitis optica spectrum disorders (NMOSD), an inflammatory, demyelinating autoimmune disease of the central nervous system, has not yet been investigated. To evaluate whether TNFSF4 polymorphisms contribute to risk of NMOSD, four single-nucleotide polymorphisms (SNPs) (rs1234315, rs2205960, rs704840, and rs844648) were selected and genotyped in a cohort of 312 patients with NMOSD and 487 healthy controls. Our study showed that rs844648 was associated with an increased risk of NMOSD, according to the allelic model (OR = 1.30, 95% CI 1.06–1.59, P = 0.011, Pcorr = 0.044). Significant associations of rs844648 (OR = 1.67, 95% CI 1.17–2.38, P = 0.005, Pcorr = 0.02) and rs704840 (OR = 1.75, 95% CI 1.17–2.63, P = 0.007, Pcorr = 0.027) with NMOSD occurrence were also observed under the recessive model. Moreover, linkage disequilibrium analysis revealed two blocks within TNFSF4; in one block, the haplotype A_rs844648G_rs704840 significantly increased the risk of NMOSD, whereas G_rs844648T_rs704840 reduced the risk. This study demonstrates an association between TNFSF4 polymorphisms and susceptibility for the development of NMOSD in the Chinese population.     

The BRAIN test: a keyboard-tapping test to assess disability and clinical features of multiple sclerosis

Background

The BRadykinesia Akinesia INcordination (BRAIN) test is an online keyboard-tapping test previously validated as a sensitive tool for detecting signs of Parkinson’s disease.

Objectives

To determine whether the BRAIN test can measure disability in MS and identify the presence of pyramidal or cerebellar dysfunction.

Methods

Kinesia scores (KS, number of key taps in 30 s), akinesia times (AT, mean dwell time on each key) and incoordination scores (IS, variance of travelling time between keys) were calculated in 39 MS patients. These were correlated against the Expanded Disability Status Scale (EDSS) scores, pyramidal and cerebellar functional system scores and 9-hole peg test scores.

Results

EDSS correlated with KS (r = ? 0.594, p < 0.001), AT (r = 0.464, p = 0.003) and IS (r = 0.423, p = 0.007). 9-HPT scores strongly correlated with KS (r = 0.926, p < 0.001). Pyramidal scores correlated with KS (r = ? 0.517, p < 0.001). Cerebellar scores correlated with KS (r = ? 0.665, p < 0.001), AT (r = 0.567, p < 0.001) and IS (r = 0.546, p = 0.007). Receiver operating characteristic curves demonstrate that KS can distinguish between the presence or absence of pyramidal and cerebellar dysfunction with area under curve 0.840 (p < 0.001) and 0.829 (p < 0.001), respectively.

Conclusions

The BRAIN test can remotely measure disability in MS. Specific scores differ according to the presence and severity of pyramidal or extrapyramidal dysfunction. It demonstrates huge potential in monitoring disease progression in clinical trials.

     

The Reciprocal Influence of Callous-Unemotional Traits,Oppositional Defiant Disorder and Parenting Practices in Preschoolers

The present study investigates reciprocal associations between positive parenting, parental monitoring, CU traits, and ODD in children assessed at age 3 and again at age 6. Data were collected from a sample of preschoolers (N = 419; 51.58 % female) through diagnostic interviews and questionnaires answered by parents and teachers. Structural equation modeling revealed a bidirectional relationship between poor monitoring and ODD, with poor monitoring at age 3 predicting ODD at age 6 (β = 0.11, p < 0.05), and ODD at age 3 predicting poor monitoring at age 6 (β = 0.10, p < 0.05). While poor monitoring at age 3 predicted CU traits at age 6 (β = 0.11, p < 0.05), CU traits at age 3 predicted positive parenting (β = 0.09, p < 0.05) and ODD (β = 0.13, p < 0.05) at age 6. Results have important implications for early targeted parenting interventions for CU traits and ODD.     

Role of <Emphasis Type="Italic">TLR4</Emphasis> (C1196T) and <Emphasis Type="Italic">CD14</Emphasis> (C-260T) Polymorphisms in Development of Ischemic Stroke,Its Subtypes and Hemorrhagic Stroke

In the present study, we evaluated the association of TLR4 and CD14 polymorphisms, i.e. C1196T and C-260T, respectively, with ischemic stroke (n = 700), its subtypes and hemorrhagic stroke (n = 300) in a South Indian population from Telangana. The genotypes were determined using PCR–RFLP, and the strength of association between genotypes and stroke was determined by odds ratio with 95% confidence interval (CI) and chi-square analysis. The results revealed a lack of association for TLR4 variant with ischemic stroke and hemorrhagic stroke, although a significant association was observed with the subtypes extracranial large artery (p = 0.008), other determined aetiology (p = 0.03) and undetermined aetiology (p = 0.01). Investigations on the variant of CD14 gene revealed negative association among ischemic stroke patients; however, a significant association was observed for hemorrhagic stroke following dominant and recessive genotypic model (p = 0.05, p = 0.02). Among ischemic stroke subtype, a significant association was observed with intracranial large artery, extracranial large artery, other determined aetiology and undetermined aetiology form of stroke (p < 0.01). Further, analysis of the CD14 variant between the two major stroke types revealed a significant difference in genotype distribution following the co-dominant genotypic model (p = 0.01).     

Clinical Value of Neutrophil to Lymphocyte and Platelet to Lymphocyte Ratio After Aneurysmal Subarachnoid Hemorrhage

Background

Inflammation and thrombosis are associated with the pathogenesis of aneurysmal subarachnoid hemorrhage (aSAH) and neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are emerging as novel inflammatory markers in stroke. We aimed to identify the association of NLR and PLR with delayed cerebral ischemia (DCI) and 3-month outcome after aSAH.

Methods

Two hundred and forty-seven patients diagnosed with aSAH within 24 h of symptoms onset were enrolled. Clinical, neuroradiological, laboratory, and follow-up data were collected from electronic database. Functional outcome was assessed by modified Rankin Scale. Admission NLR, PLR, and combined NLR-PLR associated with outcomes were evaluated by logistic regression analysis, and we used receiver operating characteristic curves to detect the overall predictive accuracy of these markers.

Results

Fifty-five (22.3 %) patients had unfavorable outcome and 47 (19 %) developed DCI. Both NLR and PLR were correlated with WFNS grade (ρ = 0.35[p < 0.001], ρ = 0.28[p < 0.001]) and modified Fisher grade (ρ = 0.25[p = 0.001], ρ = 0.28[p = 0.003]) and independently related to DCI (OR 2.18, 95 %CI 1.51–3.15, p = 0.016; OR 2.21, 95 %CI 1.61–3.32, p = 0.008) and functional outcome (OR 1.89, 95 %CI 1.52–3.17, p = 0.015; OR 1.77, 95 %CI 1.48–3.21, p = 0.018) at 3 months after aneurysm repair. They had comparable predictive ability in DCI occurrence (area under the curve [AUC] 0.65, 95 %CI 0.55–0.74, p = 0.002; AUC 0.68, 95 %CI 0.60–0.76, p < 0.001) and poor outcome (AUC 0.70, 95 %CI 0.63–0.77, p < 0.001; AUC 0.65, 95 %CI 0.58–0.72, p = 0.001). However, combination of the two indexes showed a better predictive value than each alone (AUC 0.73, 95 %CI 0.66–0.81, p < 0.001 for DCI; AUC 0.76, 95 %CI 0.70–0.83, p < 0.001 for poor outcome).

Conclusions

NLR and PLR as novel inflammatory biomarkers are independent predictors of DCI development and functional outcome after acute aSAH. When combined together, they may help to identify high-risk patients more powerfully.

     

Peripheral nerve diffusion tensor imaging as a measure of disease progression in ALS

Clinical trial design in amyotrophic lateral sclerosis (ALS) remains hampered by a lack of reliable and sensitive biomarkers of disease progression. The present study evaluated peripheral nerve diffusion tensor imaging (DTI) as a surrogate marker of axonal degeneration in ALS. Longitudinal studies were undertaken in 21 ALS patients studied at 0 and 3 months, and 19 patients at 0, 3 and 6 months, with results compared to 13 age-matched controls. Imaging metrics were correlated across a range of functional assessments including amyotrophic lateral sclerosis functional rating scale revised (ALSFRS-R), lower limb muscle strength (Medical Research Council sum score, MRCSS-LL), compound muscle action potential amplitudes and motor unit number estimation (MUNE). Fractional anisotropy was reduced at baseline in ALS patients in the tibial (p < 0.05), and peroneal nerve (p < 0.05). Fractional anisotropy and axial diffusivity declined in the tibial nerve between baselines, 3- and 6-month scans (p < 0.01). From a functional perspective, ALSFRS-R correlated with fractional anisotropy values from tibial (R = 0.75, p < 0.001) and peroneal nerves (R = 0.52, p = 0.001). Similarly, peroneal nerve MUNE values correlated with fractional anisotropy values from the tibial (R = 0.48, p = 0.002) and peroneal nerve (R = 0.39, p = 0.01). There were correlations between the change in ALSFRS-R and tibial nerve axial diffusivity (R = 0.38, p = 0.02) and the change in MRCSS-LL and peroneal nerve fractional anisotropy (R = 0.44, p = 0.009). In conclusion, this study has demonstrated that some peripheral nerve DTI metrics are sensitive to axonal degeneration in ALS. Further, that DTI metrics correlated with measures of functional disability, strength and neurophysiological measures of lower motor neuron loss.     

<Emphasis Type="Italic">PLXNA3</Emphasis> Variant rs5945430 is Associated with Severe Clinical Course in Male Multiple Sclerosis Patients

Multiple sclerosis (MS) exhibits sex bias in disease clinical course as male MS patients develop severe, progressive clinical course with accumulating disability. So far, no factors have been found associating with this sex bias in MS severity. We set out to determine the genetic factor contributing to MS male-specific progressive disease. This is an MS cross-sectional study involving 213 Kuwaiti MS patients recruited at Dasman Diabetes Institute. Exome sequencing was performed on 18 females and 8 male MS patients’ genomic DNA. rs5945430 genotyping was performed using Taqman genotyping assay. Estradiol levels were determined by enzyme-linked immunosorbent assay. Exome analysis revealed a missense variant (rs5945430) in Plexin A3 (PLXNA3) gene (Xq28) associated with male-specific MS severity. Genotyping of 187 MS patients for rs5945430 confirmed the association of rs5945430G with increased disease severity in MS males (p = 0.013; OR 3.8; 95% CI 1.24–11.7) and disability (p = 0.024). Estradiol levels shown to effect PLXNA3 expression were lower in MS males compared to MS females, and they were lower than control rs5945430G males (p = 0.057), whereas MS females had similar estradiol levels to healthy females reducing the level of expressed PLXNA3 GG in MS females. PLXNA3 rs5945430G is associated with increased disease severity in MS male patients. Estradiol is a possible protective factor against the expression of rs5945430G in MS females.     

Positive effects of fampridine on cognition,fatigue and depression in patients with multiple sclerosis over 2 years

Objective

To assess the effects of PR-fampridine on cognitive functioning, fatigue and depression in patients with multiple sclerosis (PwMS).

Methods

Thirty-two PwMS were included in this trial. Cognitive performance was assessed in an open-label and randomized double-blind, placebo-controlled study design using a comprehensive neuropsychological test battery as well as questionnaires examining depression and fatigue.

Results

We found significant improvements in cognitive measures assessing alertness (tonic alertness, p = 0.0244 and phasic alertness, p = 0.0428), psychomotor speed (p = 0.0140) as well as verbal fluency (p = 0.0002) during open-label treatment with PR-fampridine. These effects of performance were paralleled by patients’ perception of reduced fatigue (physical, p = 0.0131; cognitive, p = 0.0225; total, p = 0.0126). Fampridine-induced improvements in phasic alertness (p = 0.0010) and measures of fatigue (physical, p = 0.0014; cognitive, p = 0.0003; total, p = 0.0005) were confirmed during randomized, double-blind, placebo-controlled assessment in the second year. In addition, we found positive effects of PR-fampridine on depressive symptoms (p = 0.0049). We demonstrated persisting beneficial effects of PR-fampridine on fatigue in PwMS over a period of more than 2 years. Drug responsiveness regarding cognitive performance and fatigue was not limited to walking responders.

Conclusions

Our data demonstrate significant positive effects of treatment with PR-fampridine over 2 years on different cognitive domains as well as fatigue and depression in a cohort of PwMS. These findings imply that PR-fampridine should be considered as symptomatic treatment improving aspects of cognition, fatigue and depression in PwMS.

     

Integrins AV and B8 Gene Polymorphisms and Risk for Intracerebral Hemorrhage in Greek and Polish Populations

Α limited number of genetic variants have been linked to the development of intracerebral hemorrhage (ICH). Ιntegrin AV and/or B8-deficient mice were found to develop ICH. The present candidate gene association study was designed to investigate possible influence of integrin AV (ITGAV) and integrin B8 (ITGB8) gene region polymorphisms on the risk of ICH. 1015 participants (250 Greek and 193 Polish patients with primary ICH and 250 Greek and 322 Polish controls) were included in the study. Using logistic regression analyses, 11 tag single nucleotide polymorphisms (SNPs) for ITGAV and 11 for ITGB8 gene were tested for associations with ICH risk, lobar ICH risk and non-lobar ICH after adjustment for age, gender, history of hypertension and country of origin. Linear regression models were used to test the effect of tag SNPs on the ICH age of onset. Correction for multiple comparisons was carried out. The rs7565633 tag SNP of the ITGAV gene was independently associated with the risk of lobar ICH in the codominant model of inheritance [odds ratio (95 % confidence interval (CI)) 0.56 (0.36–0.86), p = 0.0013]. Furthermore, heterozygous individuals of the rs10251386 and the rs10239099 of the ITGB8 gene had significantly lower age of ICH onset compared to the wild-type genotypes [regression coefficient (b) ?3.884 (95 % CI ?6.519, ?1.249), p = 0.0039 and b = ?4.502 (95 % CI ?7.159, ?1.845), p = 0.0009, respectively]. The present study provides preliminary indication for an influence of ITGAV gene tag SNP in the development of lobar ICH and of ITGB8 gene variants in the age of ICH onset.     

TREM2 variants and risk of Alzheimer’s disease: a meta-analysis

Recent studies show that heterozygous variant of triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk of Alzheimer’s disease (AD) but with inconclusive results. Here, we conducted a meta-analysis to summarize and clarify the association between TREM2 variants and AD, and examined the relationship between TREM2 genetic variant and the etiology of AD. Relevant case–control studies were retrieved and collected according to established inclusion criteria. Odds ratio (OR) and 95 % confidence interval (95 % CI) were used to estimate the associations between three TREM2 variants (rs75932628, rs104894002, and rs143332484) and AD. In overall meta-analysis, the summary ORs for rs75932628, rs104894002, and rs143332484 were 2.70 [95 % CI: 2.24, 3.24; P < 0.001], 7.21 (95 % CI: 1.28, 40.78; P = 0.025), and 1.65 (95 % CI: 1.24, 2.21; P = 0.001), respectively, indicating that the TREM2 rs75932628, rs104894002, and rs143332484 may contribute to AD risk. However, sensitivity analysis showed that the results of rs104894002 and rs143332484 should be interpreted with caution, and larger sample size, particularly in different ethnicities, are needed to validate the two variants. The current meta-analysis demonstrates that TREM2 is a candidate gene for AD susceptibility, and TREM2 variant rs75932628 may be a risk factor for AD.