The role of lncRNAs related ceRNA regulatory network in multiple hippocampal pathological processes during the development of perioperative neurocognitive disorders.

Background: Perioperative neurocognitive disorders (PND) refer to neurocognitive abnormalities during perioperative period, which are a great challenge for elderly patients and associated with increased morbidity and mortality. Our studies showed that long non-coding RNAs (lncRNAs) regulate mitochondrial function and aging-related pathologies in the aged hippocampus after anesthesia, and lncRNAs are associated with multiple neurodegenerations. However, the regulatory role of lncRNAs in PND-related pathological processes remains unclear. Methods: A total of 18-month mice were assigned to control and surgery (PND) groups, mice in PND group received sevoflurane anesthesia and laparotomy. Cognitive function was assessed with fear conditioning test. Hippocampal RNAs were isolated for sequencing, lncRNA and microRNA libraries were constructed, mRNAs were identified, Gene Ontology (GO) analysis were performed, and lncRNA-microRNA-mRNA networks were established. qPCR was performed for gene expression verification. Results: A total of 312 differentially expressed (DE) lncRNAs, 340 DE-Transcripts of Uncertain Coding Potential (TUCPs), and 2,003 DEmRNAs were identified in the hippocampus between groups. The lncRNA-microRNA-mRNA competing endogenous RNA (ceRNA) network was constructed with 29 DElncRNAs, 90 microRNAs, 493 DEmRNAs, 148 lncRNA-microRNA interaction pairs, 794 microRNA-mRNA interaction pairs, and 110 lncRNA-mRNA co-expression pairs. 795 GO terms were obtained. Based on the frequencies of involved pathological processes, BP terms were divided into eight categories: neurological system alternation, neuronal development, metabolism alternation, immunity and neuroinflammation, apoptosis and autophagy, cellular communication, molecular modification, and behavior changes. LncRNA-microRNA-mRNA ceRNA networks in these pathological categories were constructed, and involved pathways and targeted genes were revealed. The top relevant lncRNAs in these ceRNA networks included RP23-65G6.4, RP24-396L14.1, RP23-251I16.2, XLOC_113622, RP24-496E14.1, etc., and the top relevant mRNAs in these ceRNA networks included Dlg4 (synaptic function), Avp (lipophagy), Islr2 (synaptic function), Hcrt (regulation of awake behavior), Tnc (neurotransmitter uptake). Conclusion: In summary, we have constructed the lncRNA-associated ceRNA network during PND development in mice, explored the role of lncRNAs in multiple pathological processes in the mouse hippocampus, and provided insights into the potential mechanisms and therapeutic gene targets for PND.

The impact of neurocognitive and psychiatric disorders on the risk of idiopathic normal pressure hydrocephalus: A bidirectional Mendelian randomization study.

BACKGROUND: Neurocognitive and psychiatric disorders have been proved that they can comorbid more often with idiopathic normal pressure hydrocephalus (iNPH) than general population. However, the potential causal association between these disorders and iNPH has not been assessed. Thus, our study aims to investigate the causal relationship between them based on a bidirectional Mendelian randomization (MR) analysis. METHODS: Random effects of the inverse variance weighted (IVW) method were conducted to obtain the causal association among the neurocognitive disorders, psychiatric disorders, and iNPH. Genome-wide association studies (GWAS) of 12 neurocognitive and psychiatric disorders were downloaded via the OpenGWAS database, GWAS Catalog, and Psychiatric Genomics Consortium, whereas GWAS data of iNPH were obtained from the FinnGen consortium round 9 release, with 767 cases and 375,610 controls of European ancestry. We also conducted the sensitivity analysis in these significant causal inferences using weighted median model, Cochrane's Q test, MR-Egger regression, MR Pleiotropy Residual Sum and Outlier detect and the leave-one-out analysis. RESULTS: For most of the neurocognitive and psychiatric disorders, no causal association was established between them and iNPH. We have found that iNPH (odds ratio [OR] = 1.030, 95% confidence interval [CI]: 1.011-1.048, p = .001) is associated with increased risk for schizophrenia, which failed in validation of sensitivity analysis. Notably, genetically predicted Parkinson's disease (PD) is associated with increased risk of iNPH (OR = 1.256, 95% CI: 1.045-1.511, p = .015). CONCLUSION: Our study has revealed the potential causal effect in which PD associated with an increased risk of iNPH. Further study is warranted to investigate the association between PD and iNPH and the potential underlying mechanism.

Genomic Factors and Therapeutic Approaches in HIV-Associated Neurocognitive Disorders: A Comprehensive Review.

HIV-associated neurocognitive disorders (HANDs) still persist despite improved life expectancy, reduced viral loads, and decreased infection severity. The number of patients affected by HANDs ranges from (30 to 50) % of HIV-infected individuals. The pathological mechanisms contributing to HANDs and the most serious manifestation of the disease, HIV-associated dementia (HAD), are not yet well understood. Evidence suggests that these mechanisms are likely multifactorial, producing neurocognitive complications involving disorders such as neurogenesis, autophagy, neuroinflammation, and mitochondrial dysfunction. Over the years, multiple pharmacological approaches with specific mechanisms of action acting upon distinct targets have been approved. Although these therapies are effective in reducing viral loading to undetectable levels, they also present some disadvantages such as common side effects, the need for administration with a very high frequency, and the possibility of drug resistance. Genetic studies on HANDs provide insights into the biological pathways and mechanisms that contribute to cognitive impairment in people living with HIV-1. Furthermore, they also help identify genetic variants that increase susceptibility to HANDs and can be used to tailor treatment approaches for HIV-1 patients. Identification of the genetic markers associated with disease progression can help clinicians predict which individuals require more aggressive management and by understanding the genetic basis of the disorder, it will be possible to develop targeted therapies to mitigate cognitive impairment. The main goal of this review is to provide details on the epidemiological data currently available and to summarise the genetic (specifically, the genetic makeup of the immune system), transcriptomic, and epigenetic studies available on HANDs to date. In addition, we address the potential pharmacological therapeutic strategies currently being investigated. This will provide valuable information that can guide clinical care, drug development, and our overall understanding of these diseases.

Role of APOC3 3238C/G polymorphism in HIV-associated neurocognitive disorder.

Apolipoprotein not only have a role in cholesterol metabolism but also play a role in normal brain function. Apolipoprotein gene polymorphisms are known risk factors for a number of mental and neurological disorders. The expression of brain apolipoproteins is significantly altered in several brain disorders. Therefore, we assed ApoC33238 C/G polymorphism in a total of 248 patient infected with HIV (45 with HAND, 89 without HAND, 114 without ART) and 134 healthy controls using PCR-RFLP. ApoC3 3238CG, 3238 GG genotypes and 3238G allele showed a non-significant increased risk for severity of HAND (P = 0.16, OR = 1.83; P = 0.32, OR = 2.78; P = 0.10, OR = 1.65) while comparing individuals with and without HAND. ApoC3 3238 GG genotype and 3238G allele revealed an increased risk for disease progression when compared between HIV patients with and without ART (P = 0.55, OR = 1.76; P = 0.65, OR = 1.12) though risk could not reach statistical significance. ApoC3 3238 GG genotype and 3238G allele were associated with the reduced risk of acquiring HIV infection when comparing HIV patients who are not on ART with healthy controls (P = 0.05, OR = 0.29; P = 0.04, OR = 0.66). In HIV patients on ART,ApoC3 3238 GG genotype showed an increased susceptibility to development of HAND (P = 0.48, OR = 2.24) when comparing alcohol drinkers and non-drinkers however risk could not reach statistical significance. In conclusion, the genotype ApoC33238GG displayed an inclination of risk for the severity of HAND and HIV disease progression. The polymorphism of APOC3 3238C/G may have a role to reduce the risk for acquisition of HIV infection. ApoC33238GG genotype in presence of alcohol may increase susceptibility to development of HAND.

Acceptability and Feasibility of Genetic Testing to Assess Risk of HIV-Associated Neurocognitive Impairment Among Thai Adolescents and Young Adults.

Host genetic factors may modify the risk of developing HIV-associated neurocognitive impairment (HIV-NCI), and genetic research has the potential to inform novel treatments for HIV-NCI. However, there is a need to better understand the acceptability of genetic testing among distinct populations of people living with HIV at increased risk for HIV-NCI, such as young people living with perinatally acquired HIV (PHIV) in low- and middle-income countries, to gauge the feasibility of genetic research within these populations. This pilot study evaluated the acceptability and feasibility of genetic testing to assess risk of future neurocognitive problems in 50 Thai adolescents and young adults (13-24 years; Meanage = 19.16 [standard deviation = 3.09]; 52% female) with PHIV and demographically similar HIV-negative controls. Participants (25 PHIV; 25 controls) completed a survey assessing acceptability of and concerns about genetic testing and were asked to provide blood samples for genetic testing. Descriptive statistics and blood draw completion rates were produced and calculated. Reported concerns about genetic testing were grouped thematically and tallied. Independent t tests and chi-squares explored demographic differences between participants who reported concerns and peers. Results indicated 46 participants (92%) rated genetic testing as "acceptable" or "completely acceptable." Eight participants (16%) reported concerns about genetic testing. The most common concerns were related to genetic information being shared or misused. Compared with participants without concerns, participants who reported concerns had more years of education and were more likely to have postsecondary schooling. Regarding completion rates, 49 participants (98%) agreed to genetic testing and provided blood samples. Overall, results support the acceptability and feasibility of incorporating genetic testing into research investigating HIV-NCI among adolescents and young adults in Thailand. Findings provide important considerations for planning future genetic studies among young people in Thailand.

Research Progress on Exosomes and MicroRNAs in the Microenvironment of Postoperative Neurocognitive Disorders.

Postoperative neurocognitive disorder (PND) is a disease that frequently develops in older patients during the perioperative period. It seriously affects the quality of life of the affected patients. Despite advancements in understanding PND, this disorder's mechanisms remain unclear, including pathophysiological processes such as central synaptic plasticity and function, neuroinflammation, excitotoxicity, and neurotrophic support. Growing evidence suggests that microenvironmental changes are major factors for PND induction in older individuals. Exosomes are carriers for transporting different bioactive molecules between nerve cells in the microenvironment and maintaining intercellular communication and tissue homeostasis. Studies have shown that exosomes and microRNAs (miRNAs) are involved in various physiological and pathological processes, including neural processes related to PND, such as neurogenesis and cell death, neuroprotection, and neurotrophy. This article reviews the effects of exosomes and miRNAs on the brain microenvironment in PND and has important implications to improve PND diagnosis, as well as to develop targeted therapy of this disorder.

A (GCC) repeat in SBF1 reveals a novel biological phenomenon in human and links to late onset neurocognitive disorder.

The human SBF1 (SET binding factor 1) gene, alternatively known as MTMR5, is predominantly expressed in the brain, and its epigenetic dysregulation is linked to late-onset neurocognitive disorders (NCDs), such as Alzheimer's disease. This gene contains a (GCC)-repeat at the interval between + 1 and + 60 of the transcription start site (SBF1-202 ENST00000380817.8). We sequenced the SBF1 (GCC)-repeat in a sample of 542 Iranian individuals, consisting of late-onset NCDs (N = 260) and controls (N = 282). While multiple alleles were detected at this locus, the 8 and 9 repeats were predominantly abundant, forming > 95% of the allele pool across the two groups. Among a number of anomalies, the allele distribution was significantly different in the NCD group versus controls (Fisher's exact p = 0.006), primarily as a result of enrichment of the 8-repeat in the former. The genotype distribution departed from the Hardy-Weinberg principle in both groups (p < 0.001), and was significantly different between the two groups (Fisher's exact p = 0.001). We detected significantly low frequency of the 8/9 genotype in both groups, higher frequency of this genotype in the NCD group, and reverse order of 8/8 versus 9/9 genotypes in the NCD group versus controls. Biased heterozygous/heterozygous ratios were also detected for the 6/8 versus 6/9 genotypes (in favor of 6/8) across the human samples studied (Fisher's exact p = 0.0001). Bioinformatics studies revealed that the number of (GCC)-repeats may change the RNA secondary structure and interaction sites at least across human exon 1. This STR was specifically expanded beyond 2-repeats in primates. In conclusion, we report indication of a novel biological phenomenon, in which there is selection against certain heterozygous genotypes at a STR locus in human. We also report different allele and genotype distribution at this STR locus in late-onset NCD versus controls. In view of the location of this STR in the 5' untranslated region, RNA/RNA or RNA/DNA heterodimer formation of the involved genotypes and alternative RNA processing and/or translation should be considered.

Role of MMP-13-77A/G polymorphism in HIV-associated neurocognitive disorders patients.

Many diseases including HIV-Associated Neurocognitive Disorder (HAND) are impacted by matrix metalloproteinases (MMPs). MMP-13 play a role to cleave the collagen. MMP-13 contributes to peripheral neuropathy and induces unmyelinated axon degeneration. MMP-13-77A/G polymorphism has been associated to a lower level of MMP-13. MMP-13 have been linked to increased expression in a number of diseases including neurological disease. Hence we analyzed the effect of MMP-13-77A/G polymorphism in pateints with and without HAND. The PCR-Restriction fragment length polymorphism approach was used to genotype MMP-13-77A/G polymorphism. The MMP-13-77AG genotype was shown to be more prevalent in HAND patients than in controls and showed a risk for severe HAND (44.4% vs. 34.8%, P = 0.16, OR = 1.79). When compared to healthy controls, the MMP-13-77AG genotype was found to be prevalent in HAND patients (44.4 %vs. 38.2%, P = 0.66, OR = 1.26). MMP-13-77AG genotype was overrepresented (51.5% vs. 38.2%, OR = 1.70, P = 0.29) in HAND patients who had advanced HIV disease. In without HAND patients, the MMP-13-77AG genotype was found be lessor in advanced stage of HIV disease when compared with healthy controls and it was associated with a reduced risk for advancement in disease (38.2% vs. 11.82%, P = 0.03, OR = 0.18). Smokers were more likely to have the MMP-13-77AG genotype than non-smokers, indicating an elevated risk of HAND severity (60.0% vs. 40.0%, P = 0.50, OR = 2.29, 95%). In patients with and without HAND, alcohol intake enhanced the risk for developing HAND and its severity when the MMP-13-77GG genotype was present (P = 0.78, OR = 2.10, P = 0.78, OR = 2.10). In conclusion, Individuals with alcohol usage and the MMP-13-77GG genotype may have additive effect on HAND development and its severity. Individuals of without HAND and MMP-13-77AG genotype showed reduced risk for advancement of HIV disease.

MiR-214-3p Prevents the Development of Perioperative Neurocognitive Disorders in Elderly Rats.

OBJECTIVE: This study aimed to identify microRNAs (miRNAs) involved in the development of perioperative neurocognitive disorders (PND). METHODS: Plasma exosomal miRNA expression was examined in patients before and after cardiopulmonary bypass (CPB) using microarray and qRT-PCR and these patients were diagnosed as PND later. Elderly rats were subjected to CPB, and the cognitive functions were examined. Bioinformatics analysis was conducted to predict the targets of miR-214-3p. Rats were administered rno-miR-214-3p agomir before or after CPB to investigate the role of miR-214-3p in PND development. RESULTS: We identified 76 differentially expressed plasma exosomal miRNAs in PND patients after surgery (P<0.05, ∣log2FC∣>0.58), including the upregulated hsa-miR-214-3p (P=0.002399392). Prostaglandin-endoperoxide synthase 2 (PTGS2) was predicted as a miR-214-3p target. In rats, CPB reduced the platform crossing numbers and target quadrant stay time, accompanied with hippocampal neuronal necrosis. The rno-miR-214-3p level was significantly increased in plasma exosomes but decreased in rat hippocampus after surgery, exhibiting a negative correlation (P<0.001, r=-0.762). A negative correlation between miR-214-3p and PTGS2 protein expression was also observed in the hippocampus after surgery. Importantly, rno-miR-214-3p agomir treatment, before or after surgery, significantly increased the platform crossing numbers (P=0.035) and target quadrant stay time (P=0.029) compared with negative control. Hippocampal PTGS2 protein level was increased in the untreated surgery group and decreased in response to rno-miR-214-3p agomir treatment before or after surgery (both P<0.05 vs. negative control). CONCLUSION: These data suggest that miR-214-3p/PTGS2 signaling contributes to the development of PND, serving as a potential therapeutic target for PND.

Cannabinoid receptor type 2 agonist JWH-133 decreases cathepsin B secretion and neurotoxicity from HIV-infected macrophages.

HIV-associated neurocognitive disorders (HAND) are prevalent despite combined antiretroviral therapy (cART), affecting 52% of people living with HIV. Our laboratory has demonstrated increased expression of cathepsin B (CATB) in postmortem brain tissue with HAND. Increased secretion of CATB from in vitro HIV-infected monocyte-derived macrophages (MDM) induces neurotoxicity. Activation of cannabinoid receptor type 2 (CB2R) inhibits HIV-1 replication in macrophages and the neurotoxicity induced by viral proteins. However, it is unknown if CB2R agonists affect CATB secretion and neurotoxicity in HIV-infected MDM. We hypothesized that HIV-infected MDM exposed to CB2R agonists decrease CATB secretion and neurotoxicity. Primary MDM were inoculated with HIV-1ADA and treated with selective CB2R agonists JWH-133 and HU-308. HIV-1 p24 and CATB levels were determined from supernatants using ELISA. MDM were pre-treated with a selective CB2R antagonist SR144528 before JWH-133 treatment to determine if CB2R activation is responsible for the effects. Neuronal apoptosis was assessed using a TUNEL assay. Results show that both agonists reduce HIV-1 replication and CATB secretion from MDM in a time and dose-dependent manner and that CB2R activation is responsible for these effects. Finally, JWH-133 decreased HIV/MDM-CATB induced neuronal apoptosis. Our results suggest that agonists of CB2R represent a potential therapeutic strategy against HIV/MDM-induced neurotoxicity.

Brief Report: Polymorphisms in CAMKK2 may Influence Domain-Specific Neurocognitive Function in HIV+ Indonesians Receiving ART.

BACKGROUND: Despite effective antiretroviral therapy (ART), milder forms of HIV-associated neurocognitive disorders remain prevalent and are characterized by neuroinflammation, synaptic dysfunction, and neuronal loss. METHODS: We explore associations between neurocognitive impairment in HIV+ Indonesians and 17 polymorphisms in adjacent genes involved in inflammation and neuronal growth/repair pathways, P2X4R and CAMKK2. HIV+ Indonesians (n = 59) who had received ART for 12 months were assessed to derive Z-scores for the attention, fluency, memory, executive, and motor speed domains relative to local control subjects. These were used to determine total cognitive scores. RESULTS: No alleles of P2X4R displayed significant associations with neurocognition in bivariate or multivariable analyses. In CAMKK2, rs2686344 influenced total cognitive scores in bivariate analyses (P = 0.04). Multivariable linear regression modeling independently associated rs2686344 with higher executive function Z-scores (P = 0.05) after adjusting for CD4 T-cell counts (adjusted R2 = 0.103, model P = 0.034), whereas rs1653588 associated with lower and rs1718120 (P = 0.05) with higher fluency Z-scores (P = 0.05) after adjusting for education and log10 HIV RNA copies/mL (adjusted R2 = 0.268, model P = 0.001). CONCLUSIONS: Polymorphisms in CAMKK2 may influence neurocognitive outcomes in specific domains in HIV+ Indonesians receiving ART for 12 months.

Genetic modulation of longitudinal change in neurocognitive function among adult glioma patients.

PURPOSE: Impaired neurocognitive function (NCF) is extremely common in patients with higher grade primary brain tumor. We previously reported evidence of genetic variants associated with NCF in glioma patients prior to treatment. However, little is known about the effect of genetic variants on NCF decline after adjuvant therapy. METHODS: Patients (N = 102) completed longitudinal NCF assessments that included measures of verbal memory, processing speed, and executive function. Testing was conducted in the postoperative period with an average follow up interval of 1.3 years. We examined polymorphisms in 580 genes related to five pathways (inflammation, DNA repair, metabolism, cognitive, and telomerase). RESULTS: Five polymorphisms were associated with longitudinal changes in processing speed and 14 polymorphisms with executive function. Change in processing speed was strongly associated with MCPH1 rs17631450 (P = 2.2 × 10-7) and CCDC26 rs7005206 (P = 9.3 × 10-7) in the telomerase pathway; while change in executive function was more strongly associated with FANCF rs1514084 (P = 2.9 × 10-6) in the DNA repair pathway and DAOA rs12428572 (P = 2.4 × 10-5) in the cognitive pathway. Joint effect analysis found significant genetic-dosage effects for longitudinal changes in processing speed (Ptrend = 1.5 × 10-10) and executive function (Ptrend = 2.1 × 10-11). In multivariable analyses, predictors of NCF decline included progressive disease, lower baseline NCF performance, and more at-risk genetic variants, after adjusting for age, sex, education, tumor location, histology, and disease progression. CONCLUSION: Our longitudinal analyses revealed that polymorphisms in telomerase, DNA repair, and cognitive pathways are independent predictors of decline in NCF in glioma patients.

Current and Future Perspectives of Noncoding RNAs in Brain Function and Neuropsychiatric Disease.

Noncoding RNAs (ncRNAs) represent the majority of the transcriptome and play important roles in regulating neuronal functions. ncRNAs are exceptionally diverse in both structure and function and include enhancer RNAs, long ncRNAs, and microRNAs, all of which demonstrate specific temporal and regional expression in the brain. Here, we review recent studies demonstrating that ncRNAs modulate chromatin structure, act as chaperone molecules, and contribute to synaptic remodeling and behavior. In addition, we discuss ncRNA function within the context of neuropsychiatric diseases, particularly focusing on addiction and schizophrenia, and the recent methodological developments that allow for better understanding of ncRNA function in the brain. Overall, ncRNAs represent an underrecognized molecular contributor to complex neuronal processes underlying neuropsychiatric disorders.

High-Mobility Group Box-1 and Its Potential Role in Perioperative Neurocognitive Disorders.

Aseptic surgical trauma provokes the release of HMGB1, which engages the innate immune response after binding to pattern-recognition receptors on circulating bone marrow-derived monocytes (BM-DM). The initial systemic inflammation, together with HMGB1, disrupts the blood-brain barrier allowing penetration of CCR2-expressing BM-DMs into the hippocampus, attracted by the chemokine MCP-1 that is upregulated by HMGB1. Within the brain parenchyma quiescent microglia are activated and, together with the translocated BM-DMs, release proinflammatory cytokines that disrupt synaptic plasticity and hence memory formation and retention, resulting in postoperative cognitive decline (PCD). Neutralizing antibodies to HMGB1 prevents the inflammatory response to trauma and PCD.

Natural selection at the RASGEF1C (GGC) repeat in human and divergent genotypes in late-onset neurocognitive disorder.

Expression dysregulation of the neuron-specific gene, RASGEF1C (RasGEF Domain Family Member 1C), occurs in late-onset neurocognitive disorders (NCDs), such as Alzheimer's disease. This gene contains a (GGC)13, spanning its core promoter and 5' untranslated region (RASGEF1C-201 ENST00000361132.9). Here we sequenced the (GGC)-repeat in a sample of human subjects (N = 269), consisting of late-onset NCDs (N = 115) and controls (N = 154). We also studied the status of this STR across various primate and non-primate species based on Ensembl 103. The 6-repeat allele was the predominant allele in the controls (frequency = 0.85) and NCD patients (frequency = 0.78). The NCD genotype compartment consisted of an excess of genotypes that lacked the 6-repeat (divergent genotypes) (Mid-P exact = 0.004). A number of those genotypes were not detected in the control group (Mid-P exact = 0.007). The RASGEF1C (GGC)-repeat expanded beyond 2-repeats specifically in primates, and was at maximum length in human. We conclude that there is natural selection for the 6-repeat allele of the RASGEF1C (GGC)-repeat in human, and significant divergence from that allele in late-onset NCDs. STR alleles that are predominantly abundant and genotypes that deviate from those alleles are underappreciated features, which may have deep evolutionary and pathological consequences.

The natural history of neurocognition in MPS disorders: A review.

MPS disorders are associated with a wide spectrum of neurocognitive effects, from mild problems with attention and executive functions to progressive and degenerative neuronopathic disease. Studies of the natural history of neurocognition are necessary to determine the profile of abnormality and the rates of change, which are crucial to select endpoints for clinical trials of brain treatments and to make clinical recommendations for interventions to improve patients' quality of life. The goal of this paper is to review neurocognitive natural history studies to determine the current state of knowledge and assist in directing future research in all MPS disorders. There are seven different types of MPS diseases, each resulting from a specific enzyme deficiency and each having a separate natural history. MPS IX, will not be discussed as there are only 4 cases reported in the literature without cognitive abnormality. For MPS IH, hematopoietic cell transplant (HCT) is standard of care and many studies have documented the relationship between age at treatment and neurocognitive outcome, and to a lesser extent, neurocognitive status at baseline. However, the mortality and morbidity associated with the transplant process and residual long-term problems after transplant, have led to renewed efforts to find better treatments. Rather than natural history, new trials will likely need to use the developmental trajectories of the patients with HCT as a comparators. The literature has extensive data regarding developmental trajectories post-HCT. For attenuated MPS I, significant neurocognitive deficits have been documented, but more longitudinal data are needed in order to support a treatment directed at their attention and executive function abnormalities. The neuronopathic form of MPS II has been a challenge due to the variability of the trajectory of the disease with differences in timing of slowing of development and decline. Finding predictors of the course of the disease has only been partially successful, using mutation type and family history. Because of lack of systematic data and clinical trials that precede a thorough understanding of the disease, there is need for a major effort to gather natural history data on the entire spectrum of MPS II. Even in the attenuated disease, attention and executive function abnormalities need documentation. Lengthy detailed longitudinal studies are needed to encompass the wide variability in MPS II. In MPS IIIA, the existence of three good natural history studies allowed a quasi-meta-analysis. In patients with a rapid form of the disease, neurocognitive development slowed up until 42 to 47 months, halted up to about 54 months, then declined rapidly thereafter, with a leveling off at an extremely low age equivalent score below 22 months starting at about chronological age of 6. Those with slower or attenuated forms have been more variable and difficult to characterize. Because of the plethora of studies in IIIA, it has been recommended that data be combined from natural history studies to minimize the burden on parents and patients. Sufficient data exists to understand the natural history of cognition in MPS IIIA. MPS IIIB is quite similar to IIIA, but more attenuated patients in that phenotype have been reported. MPS IIIC and D, because they are so rare, have little documentation of natural history despite the prospects of treatments. MPS IV and VI are the least well documented of the MPS disorders with respect to their neurocognitive natural history. Because, like attenuated MPS I and II, they do not show progression of neurocognitive abnormality and most patients function in the range of normality, their behavioral, attentional, and executive function abnormalities have been ignored to the detriment of their quality of life. A peripheral treatment for MPS VII, extremely rare even among MPS types, has recently been approved with a post-approval monitoring system to provide neurocognitive natural history data in the future. More natural history studies in the MPS forms with milder cognitive deficits (MPS I, II, IV, and VI) are recommended with the goal of improving these patients' quality of life with and without new brain treatments, beyond the benefits of available peripheral enzyme replacement therapy. Recommendations are offered at-a-glance with respect to what areas most urgently need attention to clarify neurocognitive function in all MPS types.

Pathways to understanding psychosis through rare - 22q11.2DS - and common variants.

The 22q11.2 Deletion Syndrome has significant impact on brain and behavior, with about 25% of individuals developing schizophrenia. The condition offers a model for prospective studies on the emergence of psychosis and advancing mechanistic hypotheses on gene-environment interactions, with magnified power for examining genome-phenome association. Here, we highlight findings that build on the International 22q11.2 Brain and Behavior Consortium and relate to several key domains in the study of psychosis-risk and schizophrenia. We examine neurocognition, olfaction and neuroimaging data that indicate similar impairment patterns in this rare syndrome and idiopathic presentation of schizophrenia. We conclude that the converging paradigms, studying psychosis dimensionally in rare and common variants samples, provide complementary approaches that will propel precision medicine in psychiatry.

Immunomodulatory lipid mediator profiling of cerebrospinal fluid following surgery in older adults.

Arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) derived lipids play key roles in initiating and resolving inflammation. Neuro-inflammation is thought to play a causal role in perioperative neurocognitive disorders, yet the role of these lipids in the human central nervous system in such disorders is unclear. Here we used liquid chromatography-mass spectrometry to quantify AA, DHA, and EPA derived lipid levels in non-centrifuged cerebrospinal fluid (CSF), centrifuged CSF pellets, and centrifuged CSF supernatants of older adults obtained before, 24 h and 6 weeks after surgery. GAGE analysis was used to determine AA, DHA and EPA metabolite pathway changes over time. Lipid mediators derived from AA, DHA and EPA were detected in all sample types. Postoperative lipid mediator changes were not significant in non-centrifuged CSF (p > 0.05 for all three pathways). The AA metabolite pathway showed significant changes in centrifuged CSF pellets and supernatants from before to 24 h after surgery (p = 0.0000247, p = 0.0155 respectively), from before to 6 weeks after surgery (p = 0.0000497, p = 0.0155, respectively), and from 24 h to 6 weeks after surgery (p = 0.0000499, p = 0.00363, respectively). These findings indicate that AA, DHA, and EPA derived lipids are detectable in human CSF, and the AA metabolite pathway shows postoperative changes in centrifuged CSF pellets and supernatants.

Association of MGAT4C with major neurocognitive disorder in the Mexican population.

BACKGROUND: Neurocognitive disorders (NCDs) are characterized by cognitive decline. Most genetic studies of NCDs have been focused on single-nucleotide polymorphism; other genetic variations, such as copy number variants (CNV), have been less explored. The aim of the present study was to explore CNVs associated with NCDs in a small sample of Mexican individuals and search for the frequency in a larger replication sample of individuals at high-risk for or diagnosed with NCDs. METHOD: The exploratory analysis analyzed whole-genome CNVs associated with NCDs in 1335 individuals, of whom 35 were diagnosed with NCDs and 1300 were population-based controls. Whole-genome CNVs were derived from PsychArray and the PennCNV algorithm. The frequency of associated CNVs in a sample of 277 individuals diagnosed with NCDs and 70 high-risk individuals was then determined using RT-PCR. RESULTS: The exploratory analysis identified one deletion associated with NCDs (p = 0.007) affecting the gene MGAT4C (Mannosyl (Alpha-1,3-)-Glycoprotein Beta-1,4-N-Acetylglucosaminyltransferase, Isozyme C). In the replication sample, a frequency of 3.97% was found in individuals diagnosed with NCDs and 1.43% in high-risk individuals. CONCLUSIONS: An association between a rare CNV on MGAT4C and cognitive impairment was found in this sample of the Mexican population. Nevertheless, studies with larger sample sizes are needed in order to further explore the association.

Neurocognitive, adaptive, and psychosocial functioning in individuals with Robinow syndrome.

It has been estimated that 10-15% of people with Robinow syndrome (RS) show delayed development, but no studies have formally assessed developmental domains. The objective of this study is to provide the first description of cognitive, adaptive, and psychological functioning in RS. Thirteen participants (10 males) aged 4-51 years were seen for neuropsychological screening. Eight had autosomal-dominant RS (DVL1, n = 5; WNT5A, n = 3), four had autosomal-recessive RS (NXN, n = 2; ROR2, n = 2), and one had a mutation on an RS candidate gene (GPC4). Participants completed measures of intellectual, fine-motor, adaptive, executive, and psychological functioning. Findings indicated generally average intellectual functioning and low-average visuomotor skills. Adaptive functioning was average in autosomal-recessive RS (RRS) but low average in autosomal-dominant RS (DRS). Parent-report indicated executive dysfunction and attention problems in 4/8 children, 3/4 of whom had a DVL1 variant; adult self-report did not indicate similar difficulties. Learning disabilities were also reported in 4/8 individuals with DRS, 3/4 of whom had a DVL1 variant. Peer problems were reported for a majority of participants, many of whom also reported emotional concerns. Altogether, the findings indicate average neurocognitive functioning in RRS. In contrast, DRS, especially DVL1 pathogenic alleles, may confer specific risk for neurodevelopmental disability.