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Background: Intracranial atherosclerotic stenosis (ICAS) is the most common cause of stroke, but the relationship of ICAS with fasting blood glucose (FBG) and glycated hemoglobin A1c (HbA 1c ) is unclear. This study aimed to investigate the effects of increased FBG and HbA 1c concentration on ICAS., Methods: A total of 4,012 patients aged over 40 years who underwent cerebral magnetic resonance angiography (MRA) were enrolled in this study, including 1,434 non-stroke controls and 2,578 patients with ischemic stroke. Participants were classified into four groups according to stroke and ICAS status. ICAS was defined as the presence of ≥50% stenosis in any intracranial artery. Multivariate regression analysis was used to evaluate the associations of FBG and HbA 1c with ICAS., Results: Levels of fasting glucose and HbA 1c in patients with ICAS were significantly higher than those in patients without ICAS among both stroke and non-stroke groups. Multivariate regression analysis showed that elevated levels of fasting glucose (OR 1.14, 95% CI, 1.11-1.18, P<0.001) and HbA 1c (OR 1.22, 95% CI, 1.16-1.28, P<0.001) were independent risk factors for ICAS. In addition, patients with the DM (FBG ≥7.0 mmol/L) were at the high risk of ICAS in both non-stroke (OR 2.90, 95% CI, 2.11-3.99, P<0.001) and stroke (OR 1.99, 95% CI, 1.67-2.39, P<0.001) groups. Besides, subjects with the high risk of ICAS were found in the fourth HbA 1c quartile in both non-stroke (OR 3.50, 95% CI, 2.23-5.61, P<0.001) and stroke (OR 1.98, 95% CI, 1.50-2.63, P<0.001) groups., Conclusions: The results suggest that elevated fasting glucose and HbA 1c levels are associated with high risk for ICAS., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Annals of Translational Medicine. All rights reserved.)

Background: Cerebrospinal fluid (CSF) neurofilament light (NFL) is a general biomarker for axonal damage., Methods: This genome-wide association study (GWAS) consisted of 169 mild cognitive impairment (MCI) subjects and 94 cognitively normal (CN) subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Analyses of associations between CSF NFL and genetic polymorphisms were performed using an additive genetic model. The novel single nucleotide polymorphisms (SNPs) identified by GWAS were further examined for their correlation with other AD-related phenotypes at baseline and during follow-up using multiple linear regression model and mixed effects model respectively. Survival analysis was performed to evaluate the respective risks of progression from CN to prodromal AD and from MCI to AD among populations with different genotypes., Results: Two novel SNPs (rs465401 and rs460420), both near the ADAMTS1 gene on chromosome 21, showed genome-wide significant associations with CSF NFL. The minor allele (A) of rs465401 was also associated with higher CSF total tau (t-tau) levels, lower amyloid-β (Aβ) levels as well as greater longitudinal change in both Aβ and t-tau among the CN group. Furthermore, the Cox proportional hazards models showed increased risks for prodromal AD among the cognitive normal AA homozygotes., Conclusions: We found that two SNPs (rs465401 and rs460420) were associated with CSF NFL in non-demented elders. The associations identified in this study may make the SNPs and ADAMTS1 ideal candidates for future genetic studies on aging and neurodegenerative disorders., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Annals of Translational Medicine. All rights reserved.)

Background: Fluorodeoxyglucose f18 positron emission tomography (18F-FDG PET) is regarded as the only functional neuroimaging biomarker for degeneration which can be used to increase the certainty of Alzheimer's disease (AD) pathophysiological process in research settings or as an optional clinical tool where available. Although a decline in FDG metabolism was confirmed in some regions known to be associated with AD, there was little known about the genetic association of FDG metabolism in AD cohorts. In this study, we present the first genome-wide association study (GWAS) analysis of brain FDG metabolism., Methods: A total of 222 individuals were included from the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI-1) cohort. All subjects were restricted to non-Hispanic Caucasians and met all quality control (QC) criteria. Associations of 18F-FDG with the genetic variants were assessed using PLINK 1.07 under the additive genetic model. Genome-wide associations were visualized using a software program R 3.2.3., Results: One significant SNP rs12444565 in RNA-binding Fox1 ( RBFOX1 ) was found to have a strong association with 18F-FDG (P=6.06×10 -8 ). Rs235141, rs79037, rs12526331 and rs12529764 were identified as four suggestive loci associated with 18F-FDG., Conclusions: Our study results suggest that a genome-wide significant SNP (rs12444565) in the RBFOX1 , and four suggestive loci (rs235141, rs79037, rs12526331 and rs12529764) are associated with 18F-FDG., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: ATP-binding cassette transporter A7 (ABCA7) rs3764650 has been identified to be a susceptibility locus for Alzheimer's disease (AD), but its role in cerebrospinal fluid (CSF) proteins was still unclear., Methods: The associations of rs3764650 with CSF Aβ 1-42 , t-tau and p-tau were analyzed in non-dementia AD, including preclinical and prodromal AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort., Results: Finally, GG + GT genotypes significantly decreased CSF Aβ 1-42 level, but did not alter CSF t-tau and p-tau levels in non-dementia AD at baseline, which was further confirmed in longitudinal studies., Conclusions: Our findings supported that ABCA7 modified AD risk by altering Aβ deposition rather than tau pathology., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: Growth factor receptor-bound protein-associated binding protein 2 gene ( GAB2 ) has been regarded as one of the susceptibility gene associated with Alzheimer's disease (AD). However, the role of GAB2 polymorphisms on cerebrospinal fluid (CSF) proteins in AD continuum remains unclear., Methods: We evaluated the connection between four single nucleotide polymorphisms (SNPs) of GAB2 and AD-related CSF biomarkers including amyloid β (Aβ), total tau (T-tau) and phosphorylated tau (P-tau) level in 627 Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects., Results: rs1385600 and rs1007837 were significantly associated with all the three biomarkers in CSF (rs1385600: Aβ Pc =0.0112, T-tau Pc =0.0356, P-tau Pc =0.0116; rs1007837: Aβ Pc =0.0058, T-tau Pc =0.0278, P-tau Pc =0.0231). rs2373115 only showed significant association with Aβ and P-tau (Aβ, Pc=0.0398, P-tau, Pc=0.0329). rs10793294 showed no significant association with all the three biomarkers., Conclusions: Our study suggested that GAB2 variants were significantly associated with the level of the three CSF biomarkers, which further supported that GAB2 genetic variation modulates AD risk via the alteration of both Aβ and tau pathology., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the brain, which is characterized by the formation of extracellular amyloid plaques (or senile plaques) and intracellular neurofibrillary tangles. However, increasing evidences demonstrated that neuroinflammatory changes, including chronic microgliosis are key pathological components of AD. Microglia, the resident immune cells of the brain, is constantly survey the microenvironment under physiological conditions. In AD, deposition of β-amyliod (Aβ) peptide initiates a spectrum of cerebral neuroinflammation mediated by activating microglia. Activated microglia may play a potentially detrimental role by eliciting the expression of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) influencing the surrounding brain tissue. Emerging studies have demonstrated that up-regulation of pro-inflammatory cytokines play multiple roles in both neurodegeneration and neuroprotection. Understanding the pro-inflammatory cytokines signaling pathways involved in the regulation of AD is crucial to the development of strategies for therapy. This review will discuss the mechanisms and important role of pro-inflammatory cytokines in the pathogenesis of AD, and the ongoing drug targeting pro-inflammatory cytokine for therapeutic modulation.

Background: Mitochondrial impairment and elevated oxidative stress have been implicated in the pathogenesis of Kennedy's disease. However, there is still no study describing the mitochondrial nutrient management in patients with Kennedy's disease., Methods: We assessed the clinical and electrophysiological features in a patient with Kennedy's disease. This patient was diagnosed by genetic analysis. We also measured the plasma 8-hydroxydeoxyguanosine (8-OHdG) levels of the patient and his family members using commercial enzyme-linked immunosorbent assay (ELISA). Treatment with intravenous L-carnitine (2 g/day) for the patient was started on admission, followed by two weeks., Results: Routine laboratory tests revealed a severe elevation of creatine kinase (CK) (606.5 U/L; normal value: 15-170 U/L). Sequencing of the first exon of androgen receptor (AR) revealed an increased number of CAG repeat (50; the normal range from 10-36) in the patient. Plasma 8-OHdG level in the patient was relatively elevated (34.68±1.01 ng/mL) compared with the female carriers and non-carriers. Two weeks after L-carnitine treatment, we observed a reduction of approximately 40% in CK level (391 U/L) in the patient., Conclusions: Oxidative stress resulting from mitochondrial dysfunction could be involved in Kennedy's disease. Targeting the mitochondrial dysfunction in Kennedy's disease may have significant therapeutic potential.

A heterogeneous and slowly progressive disease with extracellular amyloid-β (Aβ) deposits and intracellular hyperphosphorylated tau protein aggregates, Alzheimer's disease (AD) is already a hard nut to crack, featured with cognitive decline and memory lapse. Body fluid biomarkers are proved to be useful in exploring further study of AD, might benefit for a full comprehension of the etiopathogenesis, an improved precision of the prognosis and diagnosis, and a positive response of treatments. The cerebrospinal fluid biomarkers Aβ, total tau, and hyperphosphorylated tau reflect the main pathologic changes of AD. We also review data from several novel biomarkers, such as, β-site APP cleaving enzyme 1, soluble amyloid precursor proteins α and β, soluble Aβ oligomers and so on, which are associated with the occurrence and deterioration of this disease and couldn't be ignored. The rationale for the clinical use of those biomarkers, the challenges faced with and the properties of the most appropriate biomarkers are also summarized in the paper. We aim to find several ideal biomarkers to improve the diagnosis and optimize the treatment respectively.

It is generally accepted that the population rate of early onset Alzheimer's disease (EOAD) in Alzheimer's disease (AD) is 1-2%. However, the true population based rate of EOAD has never been verified by a systematic review and meta-analysis. We used electronic searches of Cochrane Library, Embase, Medline and PubMed databases to identify published related studies. The systematic review and meta-analysis was then to be conducted to calculate a pooled rate of EOAD and make comparisons between studies and geographic distribution. A total of 13 papers were included in our systematic review and meta-analysis. The rate of EOAD, 5.5% [95% confidence interval (CI): 0.039-0.079, P<0.001], was generated after pooled analysis of all studies in random effect model. The pooled analysis of the rate in developed country was 5.9% (95% CI: 0.040-0.085, P<0.001). The pooled analysis of the rate in developing countries was 4.4% (95% CI: 0.028-0.066, P<0.001). Our study showed that the rate of EOAD in AD is 5.5%, not 1-2% as usually demonstrated. And our results indicated that the rate in developed countries was relative higher than in developing countries. Further trials with larger samples across more countries and more careful designed of experiments are required to confirm whether our findings are truly significant.

Genome-wide association studies (GWAS) are a powerful tool for understanding the genetic underpinnings of human disease. In this article, we briefly review the role and findings of GWAS in common neurological diseases, including Stroke, Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, migraine, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, restless legs syndrome, intracranial aneurysm, human prion diseases and moyamoya disease. We then discuss the present and future implications of these findings with regards to disease prediction, uncovering basic biology, and the development of potential therapeutic agents.

Genetic risk factors that underlie many rare and common neurological diseases remain poorly understood because of the multi-factorial and heterogeneous nature of these disorders. Although genome-wide association studies (GWAS) have successfully uncovered numerous susceptibility genes for these diseases, odds ratios associated with risk alleles are generally low and account for only a small proportion of estimated heritability. These results implicated that there are rare (present in <5% of the population) but not causative variants exist in the pathogenesis of these diseases, which usually have large effect size and cannot be captured by GWAS. With the decreasing cost of next-generation sequencing (NGS) technologies, whole-genome sequencing (WGS) and whole-exome sequencing (WES) have enabled the rapid identification of rare variants with large effect size, which made huge progress in understanding the basis of many Mendelian neurological conditions as well as complex neurological diseases. In this article, recent NGS-based studies that aimed to investigate genetic causes for neurological diseases, including Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, stroke, amyotrophic lateral sclerosis and spinocerebellar ataxias, have been reviewed. In addition, we also discuss the future directions of NGS applications in this article.

Post-stroke cognitive impairment occurs frequently in the patients with stroke. The prevalence of post-stroke cognitive impairment ranges from 20% to 80%, which varies for the difference between the countries, the races, and the diagnostic criteria. The risk of post-stroke cognitive impairment is related to both the demographic factors like age, education and occupation and vascular factors. The underlying mechanisms of post-stroke cognitive impairment are not known in detail. However, the neuroanatomical lesions caused by the stroke on strategic areas such as the hippocampus and the white matter lesions (WMLs), the cerebral microbleeds (CMBs) due to the small cerebrovascular diseases and the mixed AD with stroke, alone or in combination, contribute to the pathogenesis of post-stroke cognitive impairment. The treatment of post-stroke cognitive impairment may benefit not only from the anti-dementia drugs, but also the manage measures on cerebrovascular diseases. In this review, we will describe the epidemiological features and the mechanisms of post-stroke cognitive impairment, and discuss the promising management strategies for these patients.