Effect of preoperative patient education and simulated mouth breathing training on opioid requirements in the post-anesthesia care unit after nasal surgery: a randomized controlled study.

BACKGROUND: A simulated education, prior to surgery about postoperative nasal stuffiness and ease of breathing through the mouth may help patients tolerate discomfort after nasal surgery. This study aimed to investigate the effect of preoperative simulated education on immediate postoperative opioid requirements in patients undergoing elective nasal surgery. METHODS: This randomized controlled trial of 110 patients undergoing nasal surgery randomly allocated patients into either a control (group C) or an education group (group E). One day before surgery, patients in group E were intensively trained to breathe through the mouth by using a nasal clip, with informative explanations about inevitable nasal obstruction and discomfort following surgery. Patients in group C were provided with routine preoperative information. Total intravenous anesthesia (TIVA) with propofol and remifentanil was used for anesthesia. No further opioid was used for analgesia intraoperatively. The primary outcome was index opioid (fentanyl) requirements at the post-anesthesia recovery unit (PACU). Secondary outcomes were emergence agitation, pain scores at the PACU, and postoperative recovery using the Quality of Recovery-15 (QoR15-K). RESULTS: The rate of opioid use in the PACU was 51.0% in the group E and 39.6% in the group C (p = 0.242). Additional request for analgesics other than index opioid was not different between the groups. Emergence agitation, postoperative pain severity, and QoR15-K scores were comparable between the groups. CONCLUSION: Preoperative education with simulated mouth breathing in patients undergoing nasal surgery did not reduce opioid requirements. TRIAL REGISTRATION: KCT0006264; 16/09/2021; Clinical Research Information Services ( https://cris.nih.go.kr ).

Upregulation of PGC-1α Attenuates Oxygen-Glucose Deprivation-Induced Hippocampal Neuronal Injury.

Hippocampal neuronal damage likely underlies cognitive impairment in vascular dementia (VaD). PPARγ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis. However, the role and the precise mechanism of how PGC-1α alleviates hippocampal neuronal injury remain unknown. To address this question, HT-22 cells, an immortalized hippocampal neuron cell line, with or without PGC-1α overexpression were subjected to oxygen-glucose deprivation (OGD), which mimics the circumstance of chronic cerebral hypoperfusion in VaD. After OGD, cell viability was assessed using the MTS assay. The mitochondrial function and reactive oxygen species (ROS) were both detected. ChIP-Seq analysis was employed to discover the underlying molecular mechanism of PGC-1α-mediated neuroprotective effects. Our results showed that mitochondrial membrane potentials were increased and ROS production was decreased in PGC-1α overexpressing cells, which increased cell viability. The further bioinformatics analysis from ChIP-Seq data indicated that PGC-1α may participate in the regulation of apoptosis, autophagy, and mitophagy pathways in HT-22 cells. We found that PGC-1α promoted the LC3-II formation and reduced the neuronal apoptosis determined by TUNEL staining. In addition, PGC-1α upregulated the expressions of mitochondrial antioxidants, including SOD2, Trx2, and Prx3. In summary, our findings indicate that PGC-1α may attenuate OGD-induced hippocampal neuronal damage by regulating multiple mechanisms, like autophagy and mitochondrial function. Thus, PGC-1α may be a potential therapeutic target for hippocampal damage associated with cognitive impairment.

Proteomic regulation during Legionella pneumophila biofilm development: decrease of virulence factors and enhancement of response to oxidative stress.

Legionella pneumophila (L. pneumophila) is a Gram-negative bacterium, which can be found worldwide in aquatic environments. It tends to persist because it is often protected within biofilms or amoebae. L. pneumophila biofilms have a major impact on water systems, making the understanding of the bacterial physiological adaptation in biofilms a fundamental step towards their eradication. In this study, we report for the first time the influence of the biofilm mode of growth on the proteome of L. pneumophila. We compared the protein patterns of microorganisms grown as suspensions, cultured as colonies on agar plates or recovered with biofilms formed on stainless steel coupons. Statistical analyses of the protein expression data set confirmed the biofilm phenotype specificity which had been previously observed. It also identified dozens of proteins whose abundance was modified in biofilms. Proteins corresponding to virulence factors (macrophage infectivity potentiator protein, secreted proteases) were largely repressed in adherent cells. In contrast, a peptidoglycan-associated lipoprotein (Lpg2043) and a peroxynitrite reductase (Lpg2965) were accumulated by biofilm cells. Remarkably, hypothetical proteins, that appear to be unique to the Legionella genus (Lpg0563, Lpg1111 and Lpg1809), were over-expressed by sessile bacteria.

Expression of insulin-like growth factor system genes in liver tissue during embryonic and early post-hatch development in duck (Anas platyrhynchos Domestica).

The IGF system is one of the most important endocrine and paracrine growth factor systems that regulate fetal and placental growth, whereas the liver is the principal source of circulation IGF-I. In the present study, expression of IGF-I, IGF type-I receptor (IGF-IR), and IGF binding protein (IGFBP)-3 genes was quantified by RT-PCR in the liver tissue on days 13, 17, 21, 25, and 27 of embryonic development, as well as at 7 days post-hatching (PH) in meat-type Gaoyou ducks and egg-type Jinding ducks. The results showed that IGF-I mRNA could be detected as early as on E 13d, but the expression level was low throughout embryonic development before increasing dramatically by E 27d and 7 days PH in both duck breeds. However, Gaoyou ducks exhibited higher IGF-I mRNA level than Jinding ducks, and the differences were significant on E 13d, E 21d, and at 7 days PH. Expression of IGF-IR in liver increased gradually in the former stages of the embryonic development, reaching its highest point on E 21d, and then declined up until 7 days PH. The expression pattern of IGFBP-3 gene was similar to that of IGF-IR gene, increasing significantly from E 17d. The expression peak appeared on E 25d, then declined significantly just prior to hatching (day 27) and was followed by an increase at 7 days PH. In general, the expression level of IGF-IR and IGFBP-3 genes in Jinding ducks was higher than that in Gaoyou ducks. Inverse relationships were observed for the expression of IGF-I and IGF-IR, and IGF-I and IGFBP-3, whereas a positive relationship was observed for the expression of IGF-IR and IGFBP-3. Our data indicate a differential expression of selected genes that comprise the IGF system in the duck liver tissue during embryonic and early PH growth and development.

Mitochondria-targeting peptide SS-31 attenuates ferroptosis via inhibition of the p38 MAPK signaling pathway in the hippocampus of epileptic rats.

Ferroptosis is a newly identified form of non-apoptotic regulated cell death (RCD) andplaysanimportantrole in epileptogenesis. The p38 mitogen-activated protein kinase (p38 MAPK) pathway has been confirmed to be involved in ferroptosis. The mitochondria-targeting antioxidant Elamipretide (SS-31) can reduce the generation of lipid peroxidation and the buildup of reactive oxygen species (ROS). Collectively, our present study was to decipher whether SS-31 inhibits ferroptosis via the p38 MAPK signaling pathway in the rat epilepsy model induced by pilocarpine (PILO).Adult male Wistar rats were randomly divided into four groups: control group (CON group), epilepsy group (EP group), SS-31 treatment group (SS group), and p38 MAPK inhibitor (SB203580) treatment group (SB group). Our results demonstrated that the rat hippocampal neurons after epilepsy were followed by accumulated iron and malondialdehyde (MDA) content, upregulated phosphorylated p38 MAPK protein (P-p38) and nuclear factor erythroid 2-related factor 2 (Nrf2) levels, reduced glutathione peroxidase 4 (Gpx4) content, and depleted glutathione (GSH) activity. Morphologically, mitochondrial ultrastructural damage under electron microscopy was manifested by a partial increase in outer membrane density, disappearance of mitochondrial cristae, and mitochondrial shrinkage. SS-31 and SB203580 treatment blocked the initiation and progression of ferroptosis in the hippocampus of epileptic rats via reducing the severity of epileptic seizures, reversing the expression of Gpx4, P-p38 , decreasing the levels of iron and MDA, as well as increasing the activity of GSH and Nrf2. To summarize, our findings proved that ferroptosis was coupled with the pathology of epilepsy, and SS-31 can inhibit PILO-induced seizures by preventing ferroptosis, which may be connected to the inhibition of p38 MAPK phosphorylation, highlighting the potential therapeutic value for targeting ferroptosis process in individuals with seizure-related diseases.

Human marrow stromal cells reduce microglial activation to protect motor neurons in a transgenic mouse model of amyotrophic lateral sclerosis.

BACKGROUND: Human marrow stromal cells (hMSCs) injected intrathecally can effectively increase the lifespan and protect motor neurons in a transgenic mouse model of amyotrophic lateral sclerosis. However, how the transplanted cells exert a neuroprotective effect is still unclear. More recently, the anti-inflammation effect of marrow stromal cells has generated a great deal of interest. In the present study, we sought to investigate whether intrathecally injected hMSCs protect motor neurons through attenuating microglial activation and the secretion of inflammatory factors in Cu/Zn superoxide dismutase 1 (SOD1) transgenic mice. In addition, we also focused on the mode of hMSCs inhibiting microglial activation. METHODS: We transplanted hMSCs into the cisterna magna of SOD1 mice at the age of 8, 10 and 12 weeks. At sacrifice, tissues were harvested for analysis of neuron counts, microglial activation, TNFα secretion and inducible nitric oxide synthase (iNOS) protein expression. In vitro, microglial cells were treated with hMSC co-culture, hMSC transwell culture or hMSC conditioned medium to investigate the mode of hMSCs exerting an anti-inflammation effect. RESULTS: Intrathecally transplanted hMSCs inhibited inflammatory response in SOD1 transgenic mice, which was evidenced by the decreases in microglial activation, TNFα secretion and iNOS protein expression. In addition, the inhibitory effect on microglial activation of hMSCs was through secretion of diffusible molecules adjusted to environmental cues. CONCLUSION: Intrathecally injected hMSCs can attenuate microglial activation through secretion of diffusible molecules to exert a therapeutic effect in SOD1 transgenic mice. Further studies are needed to explore the exact mechanisms by which hMSCs inhibit inflammation for facilitating the therapeutic effect.

Associations Between TREML2 Gene Variants and Alzheimer's Disease: Biomarkers, Neuroimage, and Cognition.

BACKGROUND: Recent genetic research identified a protective factor against late-onset Alzheimer's disease (AD) in Caucasians, a variant called rs3747742-C in the TREML2 gene. However, the roles of other TREML2 variants in AD have not been fully explored. OBJECTIVE: We conducted a focused analysis of 16 TREML2 variants, examining their connection to AD by studying their correlation with cerebrospinal fluid (CSF) proteins, neuroimage, and cognition in the Alzheimer's Disease Neuroimaging Initiative database (ADNI). METHODS: A multiple linear regression model was utilized to estimate potential associations between TREML2 genotypes and various endophenotypes in the entire ADNI sample at baseline, with age, gender, years of education, and APOE ɛ4 status included as covariates. To examine changes in clinical outcomes over time, linear mixed-effects models were employed. RESULTS: We found that the SNP rs17328707-A was associated with higher ADNI-VS scores, smaller ventricles, and larger middle temporal volume at baseline. The SNP rs6915083-G was linked to lower CSF t-tau and p-tau levels, and higher CSF Aß levels. The SNP rs9394766-G was associated with a smaller hippocampus and larger ventricles at baseline. In longitudinal cohorts, the rs6915083-G SNP was associated with changes in ADNI-MEM and ADNI-EF scores, as well as the rate of hippocampal and middle temporal atrophy. CONCLUSION: Our findings reveal that TREML2 gene variants have different effects on AD. Two variants are protective, while one may be a risk factor. This enhances our understanding of AD genetics and could guide future research and personalized treatments.

The CCL2 rs4586 SNP Is Associated with Slower Amyloid-ß Deposition and Faster Tau Accumulation of Alzheimer's Disease.

BACKGROUND: CC-chemokine ligand 2 (CCL2), the key immunomodulatory chemokine for microglial activation, has been implicated in the pathogenesis of Alzheimer's disease (AD). Whether the association of CCL2 single nucleotide polymorphisms (SNPs) and the risk of AD is still controversial. OBJECTIVE: We aimed to investigate whether CCL2 rs4586 SNP is associated with the pathological changes and cognitive decline of AD. METHODS: A total of 486 participants with longitudinal cerebrospinal fluid (CSF) amyloid-ß (Aß) and phospho-tau (P-tau) biomarkers, 18F-Florbetapir and 18F-flortaucipir-positron emission tomography (PET), and cognitive assessments from the Alzheimer's disease Neuroimaging Initiative were included in the study. The effects of CCL2 rs4586 SNP on the pathological changes and cognitive decline of AD were assessed with linear mixed-effects models and evaluated according to the Aß-status so as to identify whether the effects were independent of Aß status. RESULTS: CCL2 rs4586-CC carriers exhibited a slower global Aß-PET accumulation, particularly within stage I and stage II. However, they exhibited a faster accumulation of CSF P-tau and global tau-PET standard uptake value ratios, especially in Braak I and Braak III/IV and the inferior temporal gyrus. The congruent effects of CCL2 rs4586 on tau accumulation existed only in the Aß-group, as is shown in global tau-PET and Braak I. However, CCL2 rs4586 was not associated with the cognitive decline. CONCLUSION: Our findings showed that the CCL2 rs4586-CC (versus TT/TC) genotype was associated with slower Aß deposition and faster tau accumulation, and the latter of which was independent of Aß status.

The role of orexin in Alzheimer disease: From sleep-wake disturbance to therapeutic target.

Accumulating evidence has shown that sleep disturbance is a common symptom in Alzheimer's disease (AD), which is regarded as a modifiable risk factor for AD. Orexin is a key modulator of the sleep-wake cycle and has been found to be dysregulated in AD patients. The increased orexin in cerebrospinal fluid (CSF) is associated with decreased sleep efficiency and REM sleep, as well as cognitive impairment in AD patients. The orexin system has profuse projections to brain regions that are implicated in arousal and cognition and has been found to participate in the progression of AD pathology. Conversely the orexin receptor antagonists are able to consolidate sleep and reduce AD pathology. Therefore, improved understanding of the mechanisms linking orexin system, sleep disturbance and AD could make orexin receptor antagonists a promising target for the prevention or treatment of AD.

The Associations of Cerebrospinal Fluid ApoE and Biomarkers of Alzheimer's Disease: Exploring Interactions With Sex.

BACKGROUND: Sex-related difference in Alzheimer's disease (AD) has been proposed, and apolipoprotein E (ApoE) isoforms have been suggested to be involved in the pathogenesis of AD. OBJECTIVE: We aimed to explore whether cerebrospinal fluid (CSF) ApoE is associated with AD biomarkers and whether the associations are different (between sexes). METHODS: Data of 309 participants [92 with normal cognition, 148 with mild cognitive impairment (MCI), and 69 with AD dementia] from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were cross-sectionally evaluated with the multiple linear regression model and longitudinally with the multivariate linear mixed-effects model for the associations of CSF ApoE with AD biomarkers. Sex-ApoE interaction was used to estimate whether sex moderates the associations of CSF ApoE and AD biomarkers. RESULTS: Significant interactions between CSF ApoE and sex on AD biomarkers were observed [amyloid-ß (Aß): p = 0.0169 and phosphorylated-tau (p-tau): p = 0.0453]. In women, baseline CSF ApoE levels were significantly associated with baseline Aß (p = 0.0135) and total-tau (t-tau) (p < 0.0001) as well as longitudinal changes of the biomarkers (Aß: p = 0.0104; t-tau: p = 0.0110). In men, baseline CSF ApoE levels were only correlated with baseline p-tau (p < 0.0001) and t-tau (p < 0.0001) and did not aggravate AD biomarkers longitudinally. CONCLUSION: The associations between CSF ApoE and AD biomarkers were sex-specific. Elevated CSF ApoE was associated with longitudinal changes of AD biomarkers in women, which indicates that CSF ApoE might be involved in the pathogenesis of AD pathology in a sex-specific way.

Dose-response relationship between blood pressure and intracranial atherosclerotic stenosis.

BACKGROUND AND AIMS: We aimed to explore the association between blood pressure, intracranial atherosclerotic stenosis (ICAS) risks and ICAS burden in the Chinese population. METHODS: A retrospective hospital-based multi-center case-control study with large sample size was conducted. 1055 ICAS patients and 1296 non-ICAS subjects with complete clinical information and intracranial artery evaluation were identified between 2014 and 2019. Cerebral arteries were evaluated by magnetic resonance angiography, and/or computed tomography, and/or digital subtraction angiography. Two or more neurologists were involved in reading and assessment of images. The association between ICAS and burden of ICAS with blood pressure was evaluated with univariate logistic models and multivariate logistic models. RESULTS: With every increase of 10 mmHg in systolic blood pressure, diastolic blood pressure and pulse pressure, the odds of ICAS increased by 32%, 28% and 35% in multivariate analysis, respectively (odds ratio = 1.32, 1.28, and 1.35 respectively, all p < 0.001). Similarly, every increment of 10 mmHg in systolic blood pressure and pulse pressure was associated with an increased risk of ICAS burden (each odds ratio = 1.08, p < 0.05). CONCLUSIONS: Systolic blood pressure, diastolic blood pressure, and pulse pressure were associated with the risk of ICAS in a dose-response manner. Moreover, higher systolic blood pressure and pulse pressure could lead to higher ICAS burdens.

Molecular Mechanisms Underlying Reciprocal Interactions Between Sleep Disorders and Parkinson's Disease.

Sleep-wake disruptions are among the most prevalent and burdensome non-motor symptoms of Parkinson's disease (PD). Clinical studies have demonstrated that these disturbances can precede the onset of typical motor symptoms by years, indicating that they may play a primary function in the pathogenesis of PD. Animal studies suggest that sleep facilitates the removal of metabolic wastes through the glymphatic system via convective flow from the periarterial space to the perivenous space, upregulates antioxidative defenses, and promotes the maintenance of neuronal protein homeostasis. Therefore, disruptions to the sleep-wake cycle have been associated with inefficient metabolic clearance and increased oxidative stress in the central nervous system (CNS). This leads to excessive accumulation of alpha-synuclein and the induction of neuronal loss, both of which have been proposed to be contributing factors to the pathogenesis and progression of PD. Additionally, recent studies have suggested that PD-related pathophysiological alterations during the prodromal phase disrupt sleep and circadian rhythms. Taken together, these findings indicate potential mechanistic interactions between sleep-wake disorders and PD progression as proposed in this review. Further research into the hypothetical mechanisms underlying these interactions would be valuable, as positive findings may provide promising insights into novel therapeutic interventions for PD.

Zonisamide for the Treatment of Parkinson Disease: A Current Update.

Zonisamide has been used as an add-on treatment in order to overcome the deficiencies of the general therapies currently used to resolve the motor complications and non-motor symptoms of Parkinson disease. Various trials have been designed to investigate the mechanism of action and treatment effects of zonisamide in this condition. Most clinical trials of zonisamide in Parkinson disease were from Japan. The vast majority of studies used changes in the Unified Parkinson's Disease Rating Scale (UPDRS) scores and daily "OFF" time as primary endpoints. Based on adequate randomized controlled trials, zonisamide is considered a safe and efficacious add-on treatment in Parkinson disease. The most convincing proof is available for a dosage of 25-50 mg, which was shown to lead to a significant reduction in the UPDRS III score and daily "OFF" time, without increasing disabling dyskinesia. Furthermore, zonisamide may play a beneficial role in improving non-motor symptoms in PD, including impulsive-compulsive disorder, rapid eye movement sleep behavior disorder, and dementia. Among the various mechanisms reported, inhibition of monoamine oxidase-B, blocking of T-type calcium channels, modulation of the levodopa-dopamine metabolism, modulation of receptor expression, and neuroprotection are the most often cited. The mechanisms underlying neuroprotection, including modulation of dopamine turnover, induction of neurotrophic factor expression, inhibition of oxidative stress and apoptosis, inhibition of neuroinflammation, modulation of synaptic transmission, and modulation of gene expression, have been most extensively studied. This review focuses on structure, pharmacokinetics, mechanisms, therapeutic effectiveness, and safety and tolerability of zonisamide in patients with Parkinson disease.

Cognitive Effects of Treating Obstructive Sleep Apnea: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with cognitive impairment and increased risks of dementia. However, the effect of continuous positive airway pressure (CPAP) on cognitive function in patients with OSA is still controversial. OBJECTIVE: To evaluate the cognitive effects of CPAP treatment on OSA. METHODS: We systematically searched PubMed, EMBASE, and Cochrane Library for randomized controlled trials (RCT) in the corresponding fields. RESULTS: Totally 14 studies and 1,926 participants were included in our meta-analysis. Standardized mean difference (SMD) or weighted mean difference (WMD) were calculated for subjective sleepiness and cognitive domains including attention and speed of information processing, executive function, and memory. Individual cognitive scale and subgroup analyses according to OSA severity, length of trial, and RCT design type were further conducted. Significant treatment effect on attention and speed of information processing was only observed in severe OSA patients (SMD, 0.17; 95% CI, 0.02 to 0.31; p = 0.025; I2 = 0%). CONCLUSIONS: Therefore, our meta-analysis indicates that CPAP treatment can partially improve cognitive impairment in the population of severe OSA.

Pharmacotherapeutic strategies for managing comorbid depression and diabetes.

Introduction: The increasing prevalence of comorbid depression and diabetes exerts a heavy burden on global health. Co-occurrence of depression and diabetes is common, affecting 14% to 35.8% of patients with diabetes, leading to a higher mortality and morbidity rate, more micro- and macro-vascular diseases and more cognitive decline. Areas covered: In this paper, the authors address various areas from epidemiology, the association between depression and diabetes, treatment strategies and future directions based on the currently available literature to provide novel insight into the pharmacotherapeutic management of comorbid depression and diabetes. Expert opinion: Pharmacotherapy can help patients with comorbid depression and diabetes by relieving depressive symptoms and improving glycemic control. When combined with psychological therapy, as a collaborative care effort, pharmacological therapy based on selective serotonin reuptake inhibitors (SSRIs) is recommended for comorbid depression with diabetes. Furthermore, studies with larger sample sizes that can help to define different subtypes of diabetes and severity of depression are needed so that clinicians can draw up a precise and applicable management guidelines for the personalized therapy of these diseases.

Emerging Role of Sirtuin 2 in Parkinson's Disease.

Parkinson's disease (PD), the main risk factor of which is age, is one of the most common neurodegenerative diseases, thus presenting a substantial burden on the health of affected individuals as well as an economic burden. Sirtuin 2 (SIRT2), a subtype in the family of sirtuins, belongs to class III histone deacetylases (HDACs). It is known that SIRT2 levels increase with aging, and a growing body of evidence has been accumulating, showing that the activity of SIRT2 mediates various processes involved in PD pathogenesis, including aggregation of α-synuclein (α-syn), microtubule function, oxidative stress, inflammation, and autophagy. There have been conflicting reports about the role of SIRT2 in PD, in that some studies indicate its potential to induce the death of dopaminergic (DA) neurons, and that inhibition of SIRT2 may, therefore, have protective effects in PD. Other studies suggest a protective role of SIRT2 in the context of neuronal damage. As current treatments for PD are directed at alleviating symptoms and are very limited, a comprehensive understanding of the enzymology of SIRT2 in PD may be essential for developing novel therapeutic agents for the treatment of this disease. This review article will provide an update on our knowledge of the structure, distribution, and biological characteristics of SIRT2, and highlight its role in the pathogenesis of PD.

Elevated homocysteine as an independent risk for intracranial atherosclerotic stenosis.

To investigate the association of homocysteine concentration with intracranial atherosclerotic stenosis (ICAS), we assessed 933 acute ischemic stroke patients (346 with ICAS, 587 without ICAS) and 798 non-stroke controls (175 with ICAS, 623 without ICAS) with magnetic resonance angiography (MRA). Homocysteine concentration was found to be significantly higher in participants with ICAS than those without ICAS. In logistic regression analyses, homocysteine concentration was significantly associated with ICAS both in patients (OR: 1.04; 95% CI: 1.01-1.08; P=0.008) and controls (OR: 1.10; 95% CI: 1.06-1.15; P<0.001) for 1 µmol/L increment in homocysteine. Compared with the lowest quartile, the second (OR:1.53; 95% CI: 1.01-2.33), third (OR:1.71; 95% CI: 1.14 -2.60) and fourth (OR:2.48; 95%CI: 1.63-3.81) quartiles were independent predictors of ICAS in patients (P for trend<0.001); the third (OR:1.99; 95% CI: 1.18-3.40) and fourth (OR:2.36; 95%CI: 1.38-4.10) quartiles were independent predictors of ICAS in controls (P for trend<0.001). Hence, elevated homocysteine might be an independent risk for ICAS.

Distinct neurological disorders with C9orf72 mutations: genetics, pathogenesis, and therapy.

The G4C2 repeat expansion within C9orf72 has been recently identified as the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. This mutation has also been detected in a variety of other neurological diseases with distinct clinical manifestations. The exact mechanisms of how this mutation leads to the wide spectrum of clinical syndromes remain unknown. A series of molecular changes together with some potential modifiers may play a key role. Nucleolar stress, nucleocytoplasmic transport defect, oxidative damage, inhibited stress granules assembly, activated endoplasmic reticulum stress, and inhibited proteasome activity are mechanisms that contribute to the pathogenesis of these diseases. Additional mutations, epigenetic modifiers, and repeat size are potential modifiers that modulate specific phenotypes on the basis of the molecular changes. Here, we summarize distinct C9orf72-related neurological disorders and their corresponding neuropathological changes. Then, we elucidate the existing molecular knowledge and the potential modifiers. Finally, we detail the main target of treatment aiming at controlling expanded RNA transcripts.