Journal of neurology & neuromedicine最新文献

Background: While clinical studies have documented sex differences in emotional, behavioral, and cognitive function of children with Attention Deficit and Hyperactive Disorder (ADHD), it is unknown if these sex differences are due to differences in referral and diagnosis or if they can be also seen when we screen a community sample for ADHD. If these sex differences exist in populations with a diagnosis history but cannot be seen in screening, then they are unfair, preventable, and due to gender (social processes in referral and diagnosis) rather than sex.

Aim: Using the data from a community sample of 9-10-year-old healthy developing children, we explored sex differences in the associations between cognitive, emotional, behavioral, and health status with positive screening vs. history of diagnosed ADHD.

Methods: The Adolescent Brain Cognitive Development (ABCD) study included a national sample of 10,171 American children between ages 9 and 10 years old. This sample included 1,488 children with a history of psychiatric diagnosis and 8,683 children without a diagnosis. The two independent variables were screening and history of ADHD. The following variables were outcomes: symptom severity, cognitive function, body mass index (BMI), internalizing, externalizing, and total behavioral disorders. Sex was the moderator, and age, race, ethnicity, education, household income, and family structure were covariates. Mixed-effects regression models were used to adjust for the nested nature of the data.

Results: Positive screening for ADHD and a history of diagnosis were both associated with worse cognitive function, higher internalizing, externalizing, total problem behaviors, higher inattention (ADHD symptoms), and lower BMI. Sex altered the association between history of diagnosis but not positive screening for ADHD with externalizing, and total behavioral problems as well as cognitive function. Sex did not affect the associations between positive screening for ADHD or a history of diagnosis with BMI or ADHD symptoms. Both history of diagnosis and positive screening for ADHD were associated with higher internalizing for boys than girls.

Conclusion: History of diagnosis, but not positive screening for ADHD, is differently associated with behavioral and cognitive performance of males and females. As sex differences are seen in correlates of history of diagnosis but not positive screening, some of the observed sex differences are due to differential referral and diagnosis rather than differential presentation of ADHD in the community. This finding suggests that some of the so-called "sex differences" that are believed to be due to biology and heritable may be "gender differences" and modifiable. This is important because while gender differences are preventable and modifiable, sex differences are not.

Gulf War Illness (GWI) is a chronic debilitating disease of unknown etiology that affects the brain and has afflicted many veterans of the 1990-91 Gulf War (GW). We showed recently¹ that blood serum from patients suffering from GWI exerts detrimental effects on neural cultures, including reduced growth, increased apoptosis, and disruption of neural network function. Remarkably, these adverse effects were prevented by the concomitant addition to the culture of serum from healthy Gulf War (GW) era veterans. We interpreted those findings¹ in the context of our hypothesis that GWI is, at least partly, due to circulating pathogenic persistent antigens², probably coming from vaccines administered to GW veterans who lacked crucial Human Leukocyte Antigen (HLA) class 2 alleles³ and, therefore, could not make antibodies against those antigens; by contrast, healthy GW veterans who received the same vaccines and possessed HLA protection³ made antibodies that neutralized the various antigens. Thus, we hypothesized that the beneficial effect of the healthy serum on preventing the adverse GWI serum effects was due to the presence of antibodies against the persistent antigens. Here we tested this hypothesis by assessing the effect of pooled human immunoglobulin G (IgG) on ameliorating the GWI adverse effects on neural growth and apoptosis in neuroblastoma N2A cultures. We tested this effect in 14 GWI patients and found that IgG exerted a potent ameliorating effect by inhibiting the reduction in growth and increased apoptosis of GWI serum. These results lend support to our persistent antigen hypothesis^1,2 and suggest an immunotherapy approach for treating GWI. This approach is further strengthened by our finding that the severity of GWI neurocognitive/mood (NCM) symptoms was positively correlated with the degree of apoptosis caused by GWI serum on the neural culture, thus validating the relevance of the apoptotic effect to NCM symptomatology. Finally, we used this relation to predict NCM scores based on the reduced apoptosis effected by IgG addition and found a predicted reduction in NCM symptom severity by ~60%. Altogether, these findings point to the possible beneficial use of IgG in treating GWI.

Daily rhythms in behavior and physiology are coordinated by an endogenous clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. This central pacemaker also relays day length information to allow for seasonal adaptation, a process for which melatonin signaling is essential. How the SCN encodes day length is not fully understood. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression by directing target mRNAs for degradation or translational repression. The miR-132/212 cluster plays a key role in facilitating neuronal plasticity, and miR-132 has been shown previously to modulate resetting of the central clock. A recent study from our group showed that miR-132/212 in mice is required for optimal adaptation to seasons and non-24-hour light/dark cycles through regulation of its target gene, methyl CpG-binding protein (MeCP2), in the SCN and dendritic spine density of SCN neurons. Furthermore, in the seasonal rodent Mesocricetus auratus (Syrian hamster), adaptation to short photoperiods is accompanied by structural plasticity in the SCN independently of melatonin signaling, thus further supporting a key role for SCN structural and, in turn, functional plasticity in the coding of day length. In this commentary, we discuss our recent findings in context of what is known about day length encoding by the SCN, and propose future directions.

Gulf War Illness (GWI) is a chronic debilitating disease of unknown etiology that affects the brain and has afflicted many veterans of the 1990-91 Gulf War (GW). Here we tested the hypothesis that brain damage may be caused by circulating harmful substances to which GW veterans were exposed but which could not be eliminated due to lack of specific immunity. We assessed the effects of serum from GWI patients on function and morphology of brain cultures in vitro, including cultures of embryonic mouse brain and neuroblastoma N2A line. Blood serum from GWI and healthy GW veterans was added, alone and in combination, to the culture and its effects on the function and morphology of the culture assessed. Neural network function was assessed using electrophysiological recordings from multielectrode arrays in mouse brain cultures, whereas morphological assessments (neural growth and cell apoptosis) were done in neuroblastoma cultures. In contrast to healthy serum, the addition of GWI serum disrupted neural network communication and caused reduced cell growth and increased apoptosis. All of these detrimental effects were prevented or ameliorated by the concomitant addition of serum from healthy GW veterans. These findings indicate that GWI serum contains neuropathogenic factors that can be neutralized by healthy serum. We hypothesize that these factors are persistent antigens circulating in GWI blood that can be neutralized, possibly by specific antibodies present in the healthy serum, as proposed earlier¹.

The cerebellar ataxias are a group of incurable brain disorders that are caused primarily by the progressive dysfunction and degeneration of cerebellar Purkinje cells. The lack of reliable disease models for the heterogeneous ataxias has hindered the understanding of the underlying pathogenic mechanisms as well as the development of effective therapies for these devastating diseases. Recent advances in the field of induced pluripotent stem cell (iPSC) technology offer new possibilities to better understand and potentially reverse disease pathology. Given the neurodevelopmental phenotypes observed in several types of ataxias, iPSC-based models have the potential to provide significant insights into disease progression, as well as opportunities for the development of early intervention therapies. To date, however, very few studies have successfully used iPSC-derived cells to model cerebellar ataxias. In this review, we focus on recent breakthroughs in generating human iPSC-derived Purkinje cells. We also highlight the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.

Nitric oxide derived from endothelial nitric oxide synthase (eNOS) has been shown to be a major mediator of endothelium-dependent responses in cerebral blood vessels. Loss of a single eNOS gene is not associated with any apparent negative consequences on endothelial function in most blood vessels. In contrast, we have recently demonstrated that heterozygous eNOS gene deficiency in combination with a high fat diet is associated with marked impairment of endothelial function. These findings provide an important example of eNOS haploinsufficiency and one that directly impacts the cerebral vasculature. A major mechanism associated with the impairment of endothelial function with eNOS deficiency and a high fat diet appears to be related to increases in plasma IL-6 that serves to further reduce the bioavailability of NO either directly or indirectly via reductions in eNOS expression or activity and via increases in vascular superoxide. Taken together, these findings provide important insights into genetic and molecular mechanisms that promote endothelial dysfunction in response to a high fat diet in cerebral blood vessels with inherent reductions in eNOS gene expression, such as those due to eNOS gene polymorphisms. These findings also highlight the importance of eNOS+/- mice to study the effects of eNOS haploinsufficiency on cerebral blood vessels.