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A major obstacle in Alzheimer’s disease (AD) research is the lack of predictive and translatable animal models that reflect disease progression and drug efficacy. Transgenic mice overexpressing amyloid precursor protein (App) gene manifest non-physiological and ectopic expression of APP and its fragments in the brain, which is not observed in AD patients. The App knock-in mice circumvented some of these problems, but they do not exhibit tau pathology and neuronal death. We have generated a rat model, with three familiar App mutations and humanized Aβ sequence knocked into the rat App gene. Without altering the levels of full-length APP and other APP fragments, this model exhibits pathologies and disease progression resembling those in human patients: deposit of Aβ plaques in relevant brain regions, microglia activation and gliosis, progressive synaptic degeneration and AD-relevant cognitive deficits. Interestingly, we have observed tau pathology, neuronal apoptosis and necroptosis and brain atrophy, phenotypes rarely seen in other APP models. This App knock-in rat model may serve as a useful tool for AD research, identifying new drug targets and biomarkers, and testing therapeutics.

Cognitive impairment is an essential feature of schizophrenia; however, the relationship between clinical psychiatric symptoms with cognitive impairment is still unclear. Therefore, we aimed to assess cognitive deficits and the relationship between clinical symptoms and cognitive function in patients with chronic schizophrenia, which provide a reference guide for psychiatrists.We compared the cognitive function in 312 schizophrenia inpatients and 397 healthy controls by using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The positive and negative symptom scale (PANSS) was used to assess the clinical symptoms of the patients.Analysis of covariance showed that the RBANS total and four index scores (allOur findings suggest that patients with chronic schizophrenia exhibit cognitive deficits compared with healthy people. Negative symptoms and some clinical variables are associated with cognitive impairment in patients with schizophrenia.KEYPOINTSThis study indicates that patients with chronic schizophrenia have extensive cognitive impairment shown on RBANS except for the visuospatial/constructional domain.Cognitive impairment in patients is associated with age, negative symptoms, age of onset, and antipsychotic dose.There is a significant negative association between cognitive deficits and negative symptoms in patients with chronic schizophrenia.The results of this study need to be confirmed in future studies with longitudinal designs with a large and sex-balanced sample in first-episode drug naïve patients with schizophrenia.

Previous studies have shown that patients with schizophrenia have higher smoking rates and worse cognitive function than healthy controls. However, there is no consistent conclusion about the relationship between smoking and cognitive impairment. The main purpose of this study was to explore the effects of smoking on cognitive function by using MATRICS Cognitive Consensus Battery (MCCB) in Chinese male patients with schizophrenia. There were 164 patients with chronic schizophrenia and 82 healthy controls. All subjects were interviewed about smoking status. The cognitive function was assessed by MCCB and Stroop tests. The Positive and Negative Syndrome Scale (PANSS) was used to assess the clinical symptoms of the patients. Compared with healthy controls, patients had lower MCCB scores in all of its domain scores (all p < 0.05). In the patients, the scores of spatial span test (42.3 ± 11.6), digital sequence test (42.9 ± 10.6), and Hopkins Verbal Learning Test (42.2 ± 10.1) were lower in smokers than those in nonsmokers (all p < 0.05, effect size: 0.28–0.45). Logistic regression analysis showed that the smoking status of the patients was correlated with digital sequence score (p < 0.05, OR = 1.072, 95%CI: 1.013–1.134). Multivariate regression analysis showed that the spatial span total score (β = − 0.26, t = − 2.74, p < 0.001) was associated with the duration of smoking in patients with schizophrenia. Our findings show that smoking patients with chronic schizophrenia exhibit more severe cognitive impairment than nonsmoking patients, especially in working memory and executive function.

The circadian rhythm plays a central role in immune function, and its disruption has been closely linked to the etiology of depression. However, the mechanisms underlying the association between depression and circadian rhythm remain unclear. We found that mice deficient of Per2, a central clock component of circadian output, were resilient to neuroinflammation-induced depressive behavior. After repeated central lipopolysaccharide (LPS) injections, MCP-1, MIP-1β, and RANTES increased in wild type (WT) but not in Per2-deficient mice. In addition, intracerebroventricular injection of RANTES resulted in depression-like behavior, and Met-RANTES, a CCR5 antagonist, could reverse depression-like behavior induced by LPS treatments. These results indicated that the Per2 gene contributes to depression via chemokines, especially RANTES. Furthermore, BMAL1 expression decreased in LPS-treated Per2-deficient mice and BMAL1 could bind to the promoter of Rantes, indicating clock gene can act as a regulator for neuroinflammation. In conclusion, Rantes, a clock-controlled gene (CCG), is involved in clock-immunological mechanisms underlying the effects of Per2 on neuroinflammation-induced depression-like behavior.

Cognitive deficits are core symptoms of schizophrenia; however, their pathophysiological mechanisms are still unclear. A sensory gating deficit, as reflected by P50 suppression, has been repeatedly shown in schizophrenia patients, which may be associated with cognitive deficits in this disorder. The present study was to examine the relationship between the P50 suppression and cognitive deficits in patients with schizophrenia, which is still under-investigated.We recruited 38 chronic schizophrenia patients and 32 matched healthy controls, and assessed their cognition with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and P50 suppression with the electroencephalography system.The total and its 4 index scores (all p 0.05) except for the visuospatial/ constructional index of RBANS were significantly lower in patients compared with healthy controls. However, only the language and attention passed Bonferroni corrections. Patients displayed a significantly higher P50 ratio, higher S2 amplitude, and lower S1 amplitude (all p 0.05) than healthy controls. Interestingly, only in the patients, the S1 amplitude was associated with both language and attention, and the S2 amplitude with both visuospatial/ constructional and language (all p 0.05), although all of these significances did not pass the Bonferroni corrections. The P50 ratio was not associated with any of the RBANS scores (all p 0.05).Our results suggest the P50 suppression deficits in Chinese patients with schizophrenia, which may be associated with cognitive impairments of this illness. Moreover, the amplitude of S1 and the amplitude of S2 may be involved in the different cognitive domain deficits in schizophrenia patients.This study suggests that the P50 components may possibly be effective biomarkers for cognitive deficits in patients with schizophrenia.

The prevalence of obesity in schizophrenia patients is high, especially in chronic and medicated patients. Few studies have explored the relationships between obesity, cognition and clinical correlates in patients with schizophrenia. This study was designed to assess the prevalence and clinical correlates of obesity and its relationship to cognitive impairment in Chinese patients with schizophrenia. We recruited 633 inpatients and collected clinical, demographic data and lipid parameters. The Positive and Negative Syndrome Scale (PANSS) and its five-factor model were adopted for psychopathological symptoms. The prevalence of comorbid obesity in schizophrenia patients was 16.4%. The plasma levels of glucose, triglyceride, low density lipoprotein (LDL), apolipoprotein B, and cholesterol were higher, but high density lipoprotein (HDL) levels were lower in obese patients than those in non-obese patients (all p 0.05). Furthermore, obese patients had lower PANSS negative symptom, cognitive factor and total scores than non-obese patients (all p 0.05). Correlation analysis showed a significant correlation between BMI and the following variables: age, marriage, gender, negative symptoms, general psychopathological symptoms, cognitive factor, PANSS total score, glucose, triglycerides, HDL, LDL, cholesterol and apolipoprotein B (all p 0.05). Further multiple regression showed that PANSS cognitive factor, PANSS total score, and triglyceride were important independent predictors of obesity. Our results indicate a high prevalence of obesity in Chinese patients with chronic schizophrenia. Multiple demographics, clinical variables, and lipid parameters are associated with obesity in schizophrenia. Moreover, obesity appears to be a protective factor for psychological symptoms. However, not having objective assessments for cognition in this study is a limitation.

Catechol-O-methyltransferase (COMT) Val158Met (rs4680) polymorphism is thought to be involved in the pathogenesis of schizophrenia, which is related to the regulation of dopamine transmission in the prefrontal cortex. Recent studies have shown that the influence of COMT Val158Met variation is sexually dimorphic. This study aims to explore the possible effect of the interaction between COMT Val158Met polymorphism and sex on patients’ clinical characteristics and cognitive function. 367 inpatients with chronic schizophrenia (246 males and 121 females) and 419 healthy controls (172 males and 247 females) are recruited. The cognitive performances are assessed by Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and the COMT Val158Met polymorphism is genotyped. The psychopathological symptoms of the patients are assessed by the Positive and Negative Syndrome Scale (PANSS). We find that: 1) sex difference in the allele frequency and genotype distribution of COMT Val158Met are found only in schizophrenia patients; 2) there is sex × COMT genotype interaction in positive symptoms, immediate memory, attention, and RBANS total score indexes in patients with schizophrenia; 3) mainly in the male patients’ sample, Val/Val carriers exhibit more positive symptoms and more severe cognitive impairment than Met carriers. These findings suggest that COMT Val158Met polymorphism is associated with the risk and severity of schizophrenia in a sexually dimorphic way, which is helpful to understand the factors that may lead to different manifestations of male and female patients with schizophrenia.

The crucial roles played by microglia and their release of cytokines in the regulation of brain maturation are increasingly being recognized. Adolescence is a unique period characterized by continued brain maturation, especially in the area of the prefrontal cortex. Our previous studies showed that adolescent social stress induced impairment in extradimensional set-shifting (EDS), a core component of cognitive flexibility mediated by the medial prefrontal cortex (mPFC) in adult mice. The present study further determined the role of microglia and the inflammatory cytokine tumor necrosis factor alpha (TNFα) in cognitive dysfunction. Accompanied by a deficit in EDS in adulthood, previously stressed mice showed significant reductions in the expression of the microglial molecular biomarker Iba1, cell numbers, and the levels of TNFα mRNA and protein in the mPFC. Pharmacological inhibition of TNFα signaling by direct injection of a neutralizer into the mPFC also specifically impaired EDS performance. Moreover, the cognitive and immune alterations in previously stressed adult mice were ameliorated by both acute LPS and chronic antidepressant treatment. Together, our data suggest that microglia and TNFα play important roles in cognitive flexibility and can provide attractive therapeutic targets for the treatment of cognitive deficits in psychiatric disorders.

In patients with schizophrenia, clinical symptoms and cognitive impairment are its core features, both of which have a significant impact on the prognosis and functional outcome. Empathy, as an important social cognition, has been found to be associated with the clinical symptoms in schizophrenia, but the conclusions on this issue are inconsistent. Therefore, this study will continue to explore it through a large sample of inpatients with chronic schizophrenia in the Chinese Han population.We obtained the sociodemographic characteristics of 987 inpatients, measured their clinical symptoms using the Positive and Negative Syndrome Scale (PANSS), and assessed their self-reported empathy using the Interpersonal Reactivity Index (IRI). The factor score for negative symptoms (FSNS) of PANSS was additionally calculated.Correlation and linear regression analysis showed that patients' PANSS scores were widely correlated with their IRI scores. In particular, the negative symptoms of patients were significantly correlated to IRI total score (r = -0.131, p .001) and subscales such as Perspective Taking (PT) (r = -0.233, p .001). FSNS had close relationships with empathy as well. There are also many significant associations between other dimensions, such as general psychopathology and Perspective Taking (PT) or Fantasy (FS) (all p .05).Our results indicated that clinical symptoms, especially negative symptoms, were closely related to their current empathy in patients with schizophrenia, suggesting that the severity of clinical symptoms may be a powerful factor in predicting social cognition such as empathy of schizophrenia.

Hydroxychloroquine (HCQ), which has been proposed as a therapeutic or prophylactic drug for COVID-19, has been administered to thousands of individuals with varying efficacy; however, our understanding of its adverse effects is insufficient. It was reported that HCQ induced psychiatric symptoms in a few patients with autoimmune diseases, but it is still uncertain whether HCQ poses a risk to mental health. Therefore, in this study, we treated healthy mice with two different doses of HCQ that are comparable to clinically administered doses for 7 days. Psychiatric-like behaviors and the expression of related molecules in the brain were evaluated at two time points, i.e., 24 h and 10 days after drug administration. We found that HCQ increased anxiety behavior at both 24 h and 10 days. Furthermore, HCQ decreased the mRNA expression of interleukin-1beta, corticotropin-releasing hormone (Crh), a serotonin transporter (Slc6a4), and a microglia maker (Aif1) in the hippocampus and decreased the mRNA expression of brain-derived neurotrophic factor (Bdnf) in both the hippocampus and amygdala. Lots of these behavioral and molecular changes were sustained beyond 10 days after drug administration, and some of them were dose-dependent. Although this animal study does not prove that HCQ has a similar effect in humans, it indicates that HCQ poses a significant risk to mental health and suggests that further clinical investigation is essential. According to our data, we recommend that HCQ be carefully used as a prophylactic drug in people who are susceptible to mental disorders.

The age of onset of schizophrenia is related to variability in cognitive function and clinical characters, and negative symptoms and cognitive function share similar features that could be closely connected. Alterations in brain-derived neurotrophic factor (BDNF) expression and the Val66Met (rs6562) polymorphism are involved in the pathogenesis of the disease, but few studies have explored its influence on the associations of age of onset, cognitive function and clinical symptoms in schizophrenia. The clinical symptoms of a total of 573 patients with chronic schizophrenia were assessed by using the Positive and Negative Syndrome Scale (PANSS). Cognitive performance was assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The serum BDNF level and Val66Met polymorphism were measured after the assessment. Our results showed the following: (1) patients with an earlier age of onset exhibited more negative symptoms and cognitive deficits, as well as lower levels of serum BDNF; (2) negative symptoms and cognitive function showed negative and positive correlations with age of onset, respectively, and worse cognitive function was associated with a high level of negative symptoms and a low level of serum BDNF; and (3) the moderated mediation analyses indicated that negative symptoms partially mediated the relationship between age of onset and cognitive deficits, which was moderated by serum BDNF. The mediating effect of negative symptoms exhibited a Met allele dose-dependent tendency. These results indicate that age of onset, cognitive function, and clinical symptoms of schizophrenia exhibit different relationships under different serum BDNF levels and BDNF Val66met polymorphisms.

People with schizophrenia exhibit a high obesity rate. However, little is known about the prevalence of obesity and its relationship with clinical symptoms and metabolic indicators in first-episode drug-naive (FEDN) schizophrenia. Demographic and lipid parameters were gathered from 297 FEDN schizophrenia and 325 healthy controls. The patients’ symptomatology was evaluated by the Positive and Negative Syndrome Scale (PANSS). The obesity rate of FEDN patients was 10.77%, similar to that of controls (10.5%). The prevalence of overweight plus obesity of patients was 44.8%, significantly higher than that of controls (36.6%). Compared with non-obese patients, obese patients had higher levels of cholesterol (4.81 ± 0.93 vs 4.22 ± 1.00 mmol/L), triglyceride (0.27 ± 0.21 vs 0.14 ± 0.24 mg/dL), low-density lipoprotein (0.48 ± 0.12 vs 0.40 ± 0.12 mg/dL), greater ratio of triglyceride/high-density lipoprotein (2.01 ± 1.23 vs 1.44 ± 1.26), and higher PANSS positive symptom subscale score (29.81 ± 6.29 vs 27.05 ± 6.15), general psychopathology subscale score (70.75 ± 11.74 vs 66.87 ± 11.37), and total score (149.81 ± 21.08 vs 140.64 ± 21.58), but lower high-density lipoprotein level (1.09 ± 0.21 vs 1.27 ± 0.34 mg/dL) (all p < 0.05). Correlation analysis revealed that body mass index (BMI) was positively correlated with triglyceride, cholesterol, high-density lipoprotein, low-density lipoprotein, triglyceride/high-density lipoprotein ratio, PANSS positive symptoms, general psychopathology, and total scores (all p < 0.05, r = 0.124 ~ 0.335). Multiple regression analysis confirmed that PANSS positive symptoms, total score, and cholesterol level were significantly associated with BMI (all p < 0.05, β: 0.126–0.162). There was no significant difference in the prevalence of obesity between FEDN patients and the control group. Moreover, BMI was positively associated with positive symptom severity in FEDN patients.

Objective: The purpose of this study was to investigate the lifetime suicide attempt rate, clinical characteristics and cognitive function of Chinese patients with chronic schizophrenia who had attempted suicide. Methods: We collected data from 908 schizophrenia inpatients about suicide attempts through interviews with the patients and their families, as well as through medical records. All patients were assessed with the Positive and Negative Syndrome Scale, the Rating Scale for Extrapyramidal Side Effects, the Abnormal Involuntary Movement Scale, and the Repeated Battery for the Assessment of Neuropsychological Status. Results: Of this sample, 97 (10.68%) had attempted suicide. Patients who had attempted suicide were younger, had longer illness duration, and more severe general psychopathology and depressive symptoms than those who had not. Logistic regression analysis confirmed that suicide attempts were correlated with age, smoking, and depression. No cognitive performance differences were observed between patients who had and had not attempted suicide. Conclusions: In China, patients with chronic schizophrenia may have a higher prevalence of lifetime suicide attempts than the general population. Some demographic and clinical variables were related to suicide attempts in patients with chronic schizophrenia.

Dopaminergic and inflammatory systems have been proven to play an important role in the cognitive deficits of schizophrenia. Although increasing evidence indicates two systems have strong interaction, the relevant research on this interaction is still limited. Catechol-o-methyltransferase (COMT) and Interleukin-10 (IL-10) play critical functions in dopaminergic and inflammatory systems respectively, and their genetic polymorphisms are both associated with cognitive function. However, the interactive effect of their genetic polymorphisms has not been investigated. In this study, COMT Val158Met (rs4680) and IL-10 -592A/C (rs1800872) polymorphisms were measured in patients with chronic schizophrenia (n = 244) and healthy controls (n = 396), and their cognitive functions were assessed using the “Repeatable Battery for the Assessment of Neuropsychological Status” (RBANS). We found that IL-10 alone had no effect on cognitive function, while COMT affected language ability and interacted with the schizophrenia (case vs control) or sex in multiple RBANS indexes. Additionally, we found there was a significant interactive effect between IL-10 and COMT polymorphisms on multiple cognitive indexes of RBANS. In detail, the analysis showed that the IL-10 polymorphism had opposite effects on cognitive function in different COMT genotype carriers; meanwhile, the polymorphism of COMT only had a significant effect on cognitive function in IL-10 C carriers. And this interaction was more significant in schizophrenia than in controls. Our study discovered for the first time, there is an interactive effect between IL-10 and COMT genetic polymorphisms on cognitive function, which is valuable for further investigations and drug administrations associated with both systems.

The core features of schizophrenia (SCZ) include cognitive deficits and impaired sensory gating represented by P50 inhibition deficits, which appear to be related to the α7 nicotinic acetylcholine receptor (nAChR). An agonist of nAChR receptor may improve these defects. This study aimed to investigate how administering multiple doses of tropisetron, a partial agonist of nAChR, for 1 day would affect cognitive deficits and P50 inhibition deficits in SCZ patients. We randomized 40 SCZ non-smokers into a double-blind clinical trial with four groups: placebo, 5 mg/d, 10 mg/d, and 20 mg/d of oral tropisetron. Their P50 ratios were all more than 0.5 and they took risperidone at 3–6 mg/day for at least a month before participating in the experiment. We measured the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and P50 inhibition before and one day after treatment. After one day of treatment, the total RBANS scores of the 20 mg and 5 mg tropisetron groups, and the immediate memory of the 10 mg group were significantly higher than placebo group. The P50 ratio was smaller in the 5 mg and 10 mg groups than in the placebo group (both p

Adolescent social stress (ASS) can increase susceptibility to depression in adulthood. However, the underlying psychological and neural mechanisms remain unclear. Cortically mediated cognitive dysfunctions are increasingly recognized as an independent and important risk factor of depression. Using social defeat stress, a classical animal model of depression, our previous studies found that mice subjected to this form of stress during early adolescence displayed cognitive inflexibility (CI) in adulthood. This change was accompanied by a down-regulation of Bdnf gene expression in the medial prefrontal cortex (mPFC); this gene encodes a key molecule involved in depression and antidepressant action. In the present paper, we identified epigenetic modification of Bdnf as a possible mechanism underlying the behavioral and molecular changes. ASS induced a set of depressive phenotypes, including increased social avoidance and CI, as well as reduced levels of total Bdnf and isoform IV but not isoform I or VI transcripts in the mPFC. In parallel with changes in Bdnf gene expression, previously stressed adult mice showed increased levels of dimethylation of histone H3 at lysine K9 (H3K9me2) immediately downstream of the Bdnf IV promoter. On the other hand, no differences were found in trimethylation of histone H3 at lysine K4 (H3K4me3) or in acetylation of histone H3 at lysine K9 (H3K9ac) or at K4 (H3K4ac) in the Bdnf IV promoter. Likewise, no alterations were found in DNA methylation of the Bdnf IV promoter. Additionally, treatment with the chronic antidepressant tranylcypromine reversed Bdnf epigenetic changes and related gene transcription while also reversing CI, but not social avoidance, in previously stressed adult mice. These results suggest that epigenetic changes to the Bdnf gene in the mPFC after adolescent social adversity may be involved in the regulation of cognitive dysfunction in depression and antidepressant action in adulthood.

Altered brain gyrification in diverse cortical regions has been reported in patients with schizophrenia, which possibly reflects deviations in early neurodevelopment. The main purpose of this study was to examine the relationship between clinical symptoms and abnormal cortical gyrification in drug-naïve patients with schizophrenia in a Chinese Han population. We calculated the whole-brain cortical gyrification of 41 patients with first-episode drug-naïve schizophrenia and 30 age- and sex-matched healthy controls. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate the psychopathology of patients with schizophrenia. Our results showed that compared to healthy controls, patients had higher cortical gyrification in the left lateral occipital cortex, but lower cortical gyrification in the left transverse temporal cortex. Moreover, the cortical gyrification in the left entorhinal cortex and left fusiform were both positively correlated with the general psychopathology of PANSS. Our findings indicate that abnormal cortical gyrification has occurred in the early stage of schizophrenia, suggesting that abnormal cortical gyrification may play an important role in the pathogenesis and symptomatology of schizophrenia.

Some studies have shown that long-term exposure to job stress could result in burnout, and BDNF polymorphism may play an important role in its psychopathological mechanism. However, the inter-relationships between the job-related stress, serum BDNF level, BDNF genotype and job burnout have not been examined. This study was to explore the job stress × BDNF rs2049046 interaction and the role of serum BDNF level in job burnout in a Chinese Han population.Using a cross-sectional design, 205 healthy subjects were recruited from a public institution in Beijing and assessed for job stress using the House and Rizzo's Work Stress Scale, and job burnout using the Maslach Burnout Inventory (MBI). The BDNF rs2049046 polymorphism was genotyped and serum BDNF (sBDNF) levels were assayed in all of subjects.The correlations between the job stress score and two burnout subscale scores (emotional exhaustion and cynicism) were significant (both p 0.001), but not with professional efficacy. There were no significant main effects of the BDNF rs2049046 genotype on burnout, and no significant correlation was observed between sBDNF levels and job burnout. However, the interaction between the job stress and the BDNF rs2049046 genotype (F = 2.709, df = 2, 183, p = 0.032) or between the job stress and sBDNF levels on burnout was significant (t = -2.132, p = 0.035). To be specific, the individuals with the BDNF rs2049046 AT genotype showed a greater susceptibility to the burnout cynicism compared to AA homozygote only in medium-stress group (F = 4.327, df = 1,117, p = 0.015). The individuals who had lower sBDNF showed higher burnout level than those who had higher sBDNF in low-stress group.Our findings suggest that the BDNF system may interact with job stress to affect burnout, showing that interaction between BDNF rs2049046 and job stress or the interaction between BDNF levels with work stress on certain burnout dimensions.

There is evidence that obesity or higher body mass index is correlated with cognitive impairment in schizophrenia. Recent studies have demonstrated that genetic risk factors, such as the NRG3, are correlated with both elevated BMI and reduced cognitive function. In present study, we aimed to determine whether possession of the NRG3 rs10748842 influences the correlation between elevated BMI and reduced cognitive ability in schizophrenia. To our knowledge, this has never been examined before. A total of 625 inpatients with schizophrenia and 400 controls were recruited. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was performed to assess cognitive function. We used multiple analysis of covariance (MANCOVA), analyses of covariance (ANCOVA), Pearson correlations, partial correlations, and multivariate regression analysis to test the influence of NRG3 rs10748842 on the aforementioned variables. All RBANS five sub-scores and total score were lower in patients than those in controls (all p NRG3 rs10748842 TC + CC heterozygous genotype had lower attention score compared to TT homozygous genotype (adjusted F = 4.77, p = 0.029). BMI was positively associated with language score in patients (β = 0.387, t = 2.59, p = 0.01). Interestingly, we further found positive association between BMI and language score in TT carriers (partial correlations: r = 0.13, adjusted p = 0.004; multivariate regression: β = 0.42, t = 2.66, p = 0.008), but not in CT + CC carrier (p > 0.05). Our study demonstrated that NRG3 rs10748842 was associated with cognitive impairments, especially attention performance in schizophrenia. Moreover, NRG3 rs10748842 altered the effect of BMI on cognitive impairments as measured by the RBANS language score in chronic patients with schizophrenia.

Cognitive impairment is a core symptom of schizophrenia (SCZ); however, its pathophysiological mechanisms remain unclear. The sensory gating (SG) deficits reflected by P50 inhibition are recurring in SCZ, and this inhibition may be related to the cognitive deficits seen in these individuals. This study aimed to investigate the relationship between P50 inhibition and cognitive dysfunction in SCZ, which has not been fully investigated up to this point.A total of 270 individuals with chronic SCZ and 116 healthy controls were enrolled in the study. Psychopathology of SCZ was rated by the positive and negative syndrome scale (PANSS), while cognitive function and P50 inhibition of subjects were assessed by the MATRICS Consensus Cognitive Battery (MCCB) and the electroencephalography system.The MCCB total and its 10 index scores were significantly lower in patients than those in healthy controls (all p 0.001). SCZ patients had a lower amplitude of S1, and higher P50 ratio than healthy controls (both p 0.01). However, there were no significant correlations between the P50 ratio and any of the PANSS total and its subscale scores in SCZ patients (all p 0.05). Moreover, no correlation was found between the P50 components and the MCCB scores (all p 0.05).Our findings suggest that the P50 inhibition deficits occur in Chinese individuals with SCZ, which may not be associated with their clinical symptoms and cognitive impairment.

Pathogenic variants in the argininosuccinate lyase (ASL) gene have been shown to cause argininosuccinate lyase deficiency (ASLD); therefore, sequencing analysis offers advantages for prenatal testing and counseling in families afflicted with this condition. Here, we performed a genetic analysis of an ASLD patient and his family with an aim to offer available information for clinical diagnosis. The research subjects were a 23-month-old patient with a high plasma level of citrulline and his unaffected parents. Whole-exome sequencing identified potential related ASL gene mutations in this trio. Enzymatic activity was detected spectrophotometrically by a coupled assay using arginase and measuring urea production. We identified a novel nonsynonymous mutation (c.206A>G, p.Lys69Arg) and a stop mutation (c.637C>T, p.Arg213∗) in ASL in a Chinese Han patient with ASLD. The enzymatic activity of a p.Lys69Arg ASL construct in human embryonic kidney 293T cells was significantly reduced compared to that of the wild-type construct, and no significant activity was observed for the p.Arg213∗ construct. Compound heterozygous p.Lys69Arg and p.Arg213∗ mutations that resulted in reduced ASL enzyme activity were found in a patient with ASLD. This finding expands the clinical spectrum of ASL pathogenic variants.

Increasing evidence shows that the developmental perturbation of immune activity can lead to long-lasting neurodevelopmental and behavioral abnormalities. In our previous study, we found that deficiencies of microglia and TNFα in the medial prefrontal cortex (mPFC) were involved in the impairment of cognitive flexibility induced by adolescent social stress in adult mice. It remains unclear how and when immune changes occur following adolescent stress exposure and whether it is possible to prevent the delayed occurrence of cognitive impairment through early immune intervention. Firstly, the present study investigated the time courses of microglia and TNFα changes in the mPFC following adolescent social stress. The results showed that compared to the controls, stress-exposed animals showed parallel variations in the protein expression of ionized calcium-binding adaptor molecule 1 (Iba1), a biomarker specific to microglia, and TNFα in the mPFC, with a transient increase during stress exposure, then a gradual decrease after the end of stress, leading to a significantly decreased level in adulthood. We further investigated the preventive effect of chronic treatment with the immune inhibitor minocycline during stress exposure on the cognitive and molecular alterations induced by adolescent social stress. The results showed that minocycline prevented the delayed cognitive deficit and the decreased immune changes in the mPFC of previously stressed adult mice. These results suggest that the transient upregulation of microglia and TNFα in the mPFC induced by adolescent social stress may participate in the development of cognitive flexibility deficit and that immunomodulation may act as a potential target for the early prevention of cognitive deficits in psychiatric disorders.

Many studies have announced that P50 inhibition defects represent sensory gating deficits in schizophrenia, but studies seldom have searched the correlation between P50 inhibition defects and the psychopathology or cognitive impairment of patients with first-episode, drug naïve (FEDN) of schizophrenia. In this study, we investigated the auditory sensory gating deficits in a large number of Han patients with FEDN schizophrenia and their correlation with clinical symptoms and cognitive impairment.A total of 130 patients with FEDN schizophrenia and 189 healthy controls were recruited in this study. Positive and Negative Syndrome Scale (PANSS) and its five-factor model were used to score the psychopathology of the patients, and P50 inhibition was recorded using the 64-channel electroencephalography (EEG) system.Patients exhibited significantly longer S1 and S2 latency, lower S1 and S2 amplitudes and lower P50 difference than healthy controls (all p 0.05). Significant correlations existed between S1 latency and PANSS negative symptoms or cognitive factor, P50 ratio and general psychopathology, P50 ratio and PANSS total score, P50 difference and general psychopathology, and P50 difference and PANSS total score (all p 0.05). Multiple regression analysis revealed that S1 latency, sex, age, and education were contributors to negative symptom score (all p 0.05). S1 latency, S2 latency, sex, age, and smoking status were contributors to cognitive factor (all p 0.05).Our results show that patients with FEDN schizophrenia have P50 inhibition defects, which may be related to their psychopathological symptoms and cognitive impairment.

Depression with comorbid anxiety or cognitive symptoms can vary in terms of symptoms, pathophysiology and antidepressant efficacy, but the underlying neurobiological mechanisms remain to be elucidated. Previous studies from our group and others have shown that as a classic animal model of depression, adolescent social stress (ASS) could stably induce a variety of emotional and cognitive alterations in adult animals, and accompanied by transcriptional decrease in brain-derived neurotrophic factor (BDNF) total and promoter IV levels in the medial prefrontal cortex (mPFC). The present study further identified the GABAergic synaptic and molecular changes downstream of BDNF signaling impairment in the mPFC and roles in various behavioral phenotypes induced by ASS. We found that ASS induced a set of emotional and cognitive symptoms, including decreased social interest, impaired cognitive function, and increased anxiety-like behavior, as well as decreased GABAergic transmission in the mPFC. The specific deletion of BDNF promoter IV directly caused impairments in social interest, cognitive function, and inhibition of GABAergic transmission, but no changes in anxiety-like behavior. Acute microinjections of tropomyosin-related kinase B (TrkB) agonists into the mPFC and chronic antidepressant treatment ameliorated the changes in social behavior and cognition, as well as the reduction in GABAergic synaptic transmission in the mPFC, but not anxiety in previously stressed adult mice. These results suggest that the downstream GABAergic transmission of BDNF signaling in the mPFC involved in depression with comorbid cognitive dysfunction induced by ASS and can be used as a therapeutic target for the treatment of cognitive dysfunction in depression. This article is part of the special issue on Stress, Addiction and Plasticity.

Previous studies have shown that cognitive impairment plays a key role in suicide, an important factor leading to premature death in schizophrenia (SCZ) patients. Empathy has received extensive attention recently; however, the relationship of empathy with suicide in schizophrenia is still unknown. The main aim of this study was to investigate the prevalence of suicide attempts and its association with empathy and other characteristics in Chinese chronic SCZ patients.The suicide attempt data, together with demographic characteristics and clinical variables were collected from 627 chronic inpatients with schizophrenia. We utilized the Positive and Negative Syndrome Scale (PANSS) for the psychopathological symptoms, and the Interpersonal Reactivity Index (IRI) for affective and cognitive empathy in this study.We found a suicide attempt rate of 11.3% in chronic SCZ patients. Compared to non-attempters, suicide attempters were more likely to be women, had younger age and higher education levels, as well as higher positive symptoms and depressive factor score, but lower negative symptoms of PANSS (all p .05). Moreover, after controlling the confounding factors, suicide attempters scored higher in Personal Distress subscale of IRI (FThe prevalence of suicide attempt is high in chronic SCZ patients. Its risk factors include some demographic and clinical variables. Moreover, suicide attempters experienced stronger personal distress, suggesting that stronger empathy may be a risk factor of suicide.

The roles of D-serine in depression are raised concerned recently as an intrinsic co-agonist for the NMDA receptor. However, the mechanisms underlying its regulation are not fully elucidated. ASCT2 is a Na+-dependent D-serine transporter. We found that decreased D-serine and increased hippocampal ASCT2 levels correlated with chronic social defeat stress (CSDS) in mice. Lentivirus-mediated shRNA-mediated knockdown of ASCT2 and the administration of exogenous D-serine in the hippocampus alleviated CSDS-induced social avoidance and immobility. In vivo and in vitro experiments revealed that upregulation of ASCT2 expression in CSDS was regulated through histone hyper-acetylation, not DNA methylation in its promoter region. Immunohistochemistry demonstrated the co-localization of ASCT2 and D-serine. Uptake of D-serine by ASCT2 was demonstrated by in vivo and in vitro experiments. Our results indicate that CSDS induces ASCT2 expression through epigenetic activation and decreases hippocampal D-serine levels, leading to social avoidance, and immobility. Thus, targeting D-serine transport represents an attractive new strategy for treating depression.

Abnormal BDNF signaling contributes to the structural and behavioral plasticity induced by drugs of abuse. However, the mechanisms regulating expression of Bdnf in drug addiction remain elusive. In the present study, using the conditioned place preference (CPP) model, we showed that expression of Bdnf IV is upregulated in the nucleus accumbens (NAc) of conditioned animals while Bdnf I is upregulated in cocaine-treated mice irrespective of conditioning. The methylation level of a putative c-MYB binding site in the promoter region of Bdnf IV was significantly decreased in the NAc under cocaine CPP conditioning but remained unchanged without conditioning, concurrently with increased binding of c-MYB to this site. Exon IV promoter/luciferase reporter assays revealed that transactivation of Bdnf by c-MYB was blocked by methylation of this c-MYB binding site. Administration of methionine, a precursor of SAM, inhibited cocaine CPP, reversed demethylation of c-MYB binding site and induction of Bdnf IV expression by cocaine CPP. Our results imply that Bdnf IV demethylation at c-MYB binding site is involved in cocaine-triggered seeking behavior, whereas Bdnf I responds to the immediate pharmacological effects of cocaine.

BACKGROUND: The present study was designed to investigate the hypolipidaemic and hypoglycaemic effects of total flavonoids from seed residues of Hippophae rhamnoides L. (FSH) in a high-fat diet fed mouse model. Consumption of a high-fat diet (HFD) for 4 weeks caused a significant rise of serum total cholesterol in mice. These hypercholesterolaemic mice then were orally administrated with different doses of FSH (50, 100 and 150 mg kg−1 body weight) and simvastatin (20 mg kg−1 body weight) for another 12 weeks under continuous HFD feeding. RESULTS: FSH administration markedly reduced total mouse body, liver, and epididymal fat pad weights. Serum total cholesterol and low density of lipoprotein-cholesterol levels were also significantly decreased by FSH treatment. Additionally, FSH significantly lowered total cholesterol and triglyceride concentrations in liver, and the results were corroborated by transmission electron microscope findings. The rise in serum glucose was significantly suppressed by FSH treatment while improving impaired glucose tolerance. CONCLUSION: These results suggest that FSH possesses hypolipidaemic and hypoglycaemic properties in mice fed a high-fat diet and could be developed as a supplement in healthcare foods and drugs. Copyright © 2011 Society of Chemical Industry

During industrial processing of Asparagus (Asparagus officinalis L.), around half of each spear is discarded. However, these discarded asparagus (by-products) might be used as food supplements for their potential therapeutic effects. This study evaluated the hypolipidemic effect of n-butanol extract (BEA) from asparagus by-products in mice fed a high-fat diet (HFD). Continuous HFD feeding caused hyperlipidemia, oxidative stress and liver damage in mice. Interestingly, while BEA significantly decreased the levels of body weight gain, serum total cholesterol and low density lipoprotein cholesterol, it dramatically increased the high density lipoprotein level when administered at three different doses (40, 80 or 160 mg/kg body weight) for 8 weeks in hyperlipidemic mice. In addition, BEA decreased the levels of alanine transaminase, aspartate transaminase and alkaline phosphatase in serum. Finally, superoxide dismutase activity and the total antioxidation capacity were evidently increased, while the malondialdehyde level and the distribution of lipid droplets were reduced in liver cells of BEA-treated mice. Taken together, the findings of this study suggested that BEA had a strong hypolipidemic function and could be used as a supplement in healthcare foods and drugs or in combination with other hypolipidemic drugs.

BACKGROUND: Asparagus (Asparagus officinalis L.) by-products, i.e. the parts of the spears discarded during industrial processing, might have potential use as food supplements for their therapeutic effects. In this study the hypolipidaemic and hepatoprotective effects of ethanolic (EEA) and aqueous (AEA) extracts from asparagus by-products were evaluated in mice fed a high-fat diet (HFD). RESULTS: Continuous HFD feeding caused obvious hyperlipidaemia and liver damage in mice. However, both EEA and AEA significantly decreased the levels of body weight gain, serum total cholesterol and serum low-density lipoprotein cholesterol in hyperlipidaemic mice when administered at a daily dose of 200 mg kg−1 for 8 weeks. Also, serum high-density lipoprotein cholesterol levels were evidently increased in the AEA-treated group. Moreover, both EEA and AEA dramatically decreased the activities of alanine and aspartate transaminases in serum. Finally, superoxide dismutase activity and total antioxidant capacity were increased and malondialdehyde level and the distribution of lipid droplets decreased in liver cells of both EEA- and AEA-treated mice. CONCLUSION: The findings of this study suggest that both EEA and AEA have strong hypolipidaemic and hepatoprotective properties and could be used as supplements in healthcare foods and drugs or in combination with other hypolipidaemic drugs. Copyright © 2010 Society of Chemical Industry

An extract of seabuckthorn (Hippophae rhamnoides L.) seed residues has been shown to possess hypoglycemic and hypolipidemic properties in normal mice. The present study investigated the effects of an aqueous extract of seabuckthorn seed residues (ASSR) on serum glucose, lipid profiles and antioxidant parameters in streptozotocin-induced diabetic rats. Male Sprague-Dawley rats were divided into four groups: a normal control group; diabetic control group; diabetic groups supplemented with 5 mg/kg body weight glibenclamide (reference drug) and 400 mg/kg body weight ASSR. Diabetes in rats was induced by intraperitoneal injection of streptozotocin (45 mg/kg body weight). Vehicle (distilled water), glibenclamide and ASSR were administered orally to normal and diabetic rats once a day lasting for 4 weeks. The data showed that administration of ASSR significantly lowered the serum glucose, triglyceride and nitric oxide levels in diabetic rats. Moreover, ASSR treatment also increased serum superoxide dismutase activity and glutathione level markedly. These results show that ASSR has hypoglycemic, hypotriglyceridemic and antioxidant effects in streptozotocin-induced diabetic rats, suggesting that ASSR supplementation can be useful in preventing diabetic complications associated with hyperlipidemia and oxidative stress.

Increased studies have revealed that core mammalian clock genes regulate immune functions. Previously, we reported Per2m/m mice displayed a down-regulated circadian immune response to lipopolysaccharide (LPS) challenge. However, the mediators between Per2 and immune function and their underlying mechanisms remain unclear. In this study, serum corticosterone (CORT), a hormone which played a crucial role in immune suppression, was found to be significantly increased in Per2m/m mice compared with the one in wild-type mice following LPS administration at ZT3 and ZT8. The elevated level of serum CORT was correlated with their higher survival rate, which could be further suppressed by glucocorticoid receptor antagonist. Expression of StAR, a rate-limiting enzyme in CORT synthesis, as well as the expression of core clock genes (Clock/Bmal1), was more strongly induced and longer lasting in Per2m/m mice in contrast to the ones in control mice after LPS injection. Additionally, the binding of CLOCK and BMAL1 to StAR’s promoter was elevated after LPS administration, and the binding was higher in Per2m/m mice. Furthermore, loss of Clock function resulted in lower survival and failed to induce the serum CORT production and StAR expression in Clockm/m mice following LPS administration. Our results revealed that CORT, regulated by Bmal1/Clock transcriptional activation of StAR’s expression, could function as a mediator between clock system and immune response and contribute to the endotoxemia resistance in Per2m/m mice.

Amyotrophic lateral sclerosis (ALS) is an adult-onset, progressive, fatal neurodegenerative disease. Several genes are associated with ALS. Copper-zinc superoxide dismutase 1 (SOD1) is one of the most commonly mutated genes in ALS, and more than 160 mutations in SOD1 have been reported. We reported a novel heterozygous insertion mutation that led to a frameshift and a premature termination at position 136 in exon 5 of the SOD1 gene (c.392_393insGCAAAGGTGG; p.N132Qfs*5) in a Chinese familial ALS pedigree. This mutation in the pedigree demonstrated an autosomal dominant pattern of inheritance and a phenotype characterized by an early onset (approximately 34 years old) with a relatively rapid course (approximately 2 years) and limb onset with respiratory involvement. The clinical feature of the p.N132Qfs*5 mutation was nearly identical to a previously reported mutation (Gly127insTGGG). Experiments in G127X mice demonstrated that the G127X mutation was pathogenic. SOD1 activity in the p.N132Qfs*5 mutation carriers in the family decreased significantly compared with normal family members. In conclusion, we identified a novel SOD1 mutation in an ALS family, which is an important addition to the catalog of SOD1 mutations in ALS.

The present study was designed to investigate the hypolipidaemic and hypoglycaemic effects of total flavonoids from seed residues of Hippophae rhamnoides L. (FSH) in a high-fat diet fed mouse model. Consumption of a high-fat diet (HFD) for 4 weeks caused a significant rise of serum total cholesterol in mice. These hypercholesterolaemic mice then were orally administrated with different doses of FSH (50, 100 and 150 mg kg⁻¹ body weight) and simvastatin (20 mg kg⁻¹ body weight) for another 12 weeks under continuous HFD feeding.FSH administration markedly reduced total mouse body, liver, and epididymal fat pad weights. Serum total cholesterol and low density of lipoprotein-cholesterol levels were also significantly decreased by FSH treatment. Additionally, FSH significantly lowered total cholesterol and triglyceride concentrations in liver, and the results were corroborated by transmission electron microscope findings. The rise in serum glucose was significantly suppressed by FSH treatment while improving impaired glucose tolerance.These results suggest that FSH possesses hypolipidaemic and hypoglycaemic properties in mice fed a high-fat diet and could be developed as a supplement in healthcare foods and drugs.

During industrial processing of Asparagus (Asparagus officinalis L.), around half of each spear is discarded. However, these discarded asparagus (by-products) might be used as food supplements for their potential therapeutic effects. This study evaluated the hypolipidemic effect of n-butanol extract (BEA) from asparagus by-products in mice fed a high-fat diet (HFD). Continuous HFD feeding caused hyperlipidemia, oxidative stress and liver damage in mice. Interestingly, while BEA significantly decreased the levels of body weight gain, serum total cholesterol and low density lipoprotein cholesterol, it dramatically increased the high density lipoprotein level when administered at three different doses (40, 80 or 160 mg/kg body weight) for 8 weeks in hyperlipidemic mice. In addition, BEA decreased the levels of alanine transaminase, aspartate transaminase and alkaline phosphatase in serum. Finally, superoxide dismutase activity and the total antioxidation capacity were evidently increased, while the malondialdehyde level and the distribution of lipid droplets were reduced in liver cells of BEA-treated mice. Taken together, the findings of this study suggested that BEA had a strong hypolipidemic function and could be used as a supplement in healthcare foods and drugs or in combination with other hypolipidemic drugs.

The present study was designed to investigate the antihyperglycemic activity of the aqueous extract of sea buckthorn (Hippophae rhamnoides L.) seed residues (ASSR) in streptozotocin (STZ) and high-fat diet (HFD)-induced type 2 diabetic rats. Male Sprague-Dawley rats were divided into a normal control group (control), diabetic group and diabetic group supplemented with ASSR. Type 2 diabetes was induced by intravenous injection of low-dose STZ (25 mg/kg b.w.) and feeding with HFD for 10 weeks. Vehicle (distilled water) and ASSR (400 mg/kg b.w.) were orally administered once a day for 6 weeks. Our results showed that administration of ASSR significantly lowered the body weight, serum glucose, total cholesterol and low-density lipoprotein cholesterol levels in diabetic rats. Meanwhile, ASSR also significantly increased insulin sensitivity index in diabetic rats. These results suggest that ASSR might exhibit hypoglycemic and hypolipidemic effects in the STZ–HFD-induced type 2 diabetic rats. PRACTICAL APPLICATIONS Sea buckthorn (Hippophae rhamnoides L.) bush, bearing delicious and nutritious orange-colored berries, is locally called “Shaji” in China. The berry of sea buckthorn is one of the edible crude herbs that have been in use in Tibetan and Mongolian traditional medicines for a long time. In addition to medicinal use, the berries are processed into various products such as juice and marmalade, and are used for flavoring of dairy products. As a part of sea buckthorn berry, its seed is a by-product of the berry processing industry and also contains many bioactive substances. It was demonstrated in this study that ASSR was of hypoglycemic and hypolipidemic properties in experimental type 2-like diabetic rats. Therefore, seed residues of sea buckthorn and its aqueous extract could be added as supplement in health-care food or drugs or combined with other hypoglycemic drugs.

An extract of seabuckthorn (Hippophae rhamnoides L.) seed residues has been shown to possess hypoglycemic and hypolipidemic properties in normal mice. The present study investigated the effects of an aqueous extract of seabuckthorn seed residues (ASSR) on serum glucose, lipid profiles and antioxidant parameters in streptozotocin-induced diabetic rats. Male Sprague-Dawley rats were divided into four groups: a normal control group; diabetic control group; diabetic groups supplemented with 5 mg/kg body weight glibenclamide (reference drug) and 400 mg/kg body weight ASSR. Diabetes in rats was induced by intraperitoneal injection of streptozotocin (45 mg/kg body weight). Vehicle (distilled water), glibenclamide and ASSR were administered orally to normal and diabetic rats once a day lasting for 4 weeks. The data showed that administration of ASSR significantly lowered the serum glucose, triglyceride and nitric oxide levels in diabetic rats. Moreover, ASSR treatment also increased serum superoxide dismutase activity and glutathione level markedly. These results show that ASSR has hypoglycemic, hypotriglyceridemic and antioxidant effects in streptozotocin-induced diabetic rats, suggesting that ASSR supplementation can be useful in preventing diabetic complications associated with hyperlipidemia and oxidative stress.

The study was designed to investigate the antihypertensive effect of total flavones extracted from seed residues of Hippophae rhamnoides L. (TFH-SR) and its underlying mechanism in chronic sucrose-fed rats by evaluating its ability to regulate insulin and angiotensin || levels. Feeding of high-sucrose diet (HS: 77% of kcal from carbohydrate, 16% from protein and 6% from lipid, respectively) for 6 weeks resulted in significant rise in systolic blood pressure (SBP) by 25.60%, plasma insulin by 114.24%, triglycerides by 85.14% and activated angiotensin || contents in heart and kidney. However, TFH-SR treatment significantly suppressed the elevated hypertension, hyperinsulinemia and dyslipidemia. Furthermore, TFH-SR (especially at the dose of 150mg/kg/day) increased the circulatory blood angiotensin || level as effective as angiotensin || receptor blocker. These results indicated that TFH-SR exerted its antihypertensive effects at least in part by improving insulin sensitivity and blocking angiotensin || signal pathway. Findings of the present study suggested that TFH-SR might prove to be of potential use in the management of hyperinsulinemia in non-diabetic state with cardiovascular diseases.

Mutations of Cu-Zn superoxide dismutase (SOD1) have rarely been identified in Chinese patients with amyotrophic lateral sclerosis (ALS). We recently initiated a program to screen mutations of SOD1, TARDBP, and C9orf72 genes, the most commonly mutated genes in ALS patients in Western countries, in Chinese ALS patients. In this study, we report a novel missense SOD1 mutation with a substitution of tryptophan for cysteine at the seventh amino acid (p.C7W, traditionally named p.C6W) based on HUGO Gene Nomenclature in a familial ALS pedigree. We also found that the activities of SOD1 were significantly decreased in the C7W patient and the carriers of the family, compared with the SOD1 activities of normal family members. Compared with reported C7G and C7S patients, analysis of phenotype revealed relatively mild disease phenotypes in C7W patients, which is correlated with less deteriorated alteration in protein structure. Like those of many other familial ALS families, variable clinical phenotypes in the C7W intrafamily suggest that potential genetic modifiers may contribute to this disease.