Research Progress of Hippocampal Dopamine System Changes in Perioperative Neurocognitive Disorders.

Perioperative neurocognitive disorders (PND) are a cognitive impairment that occurs after anesthesia, especially in elderly patients and significantly affects their quality of life. The hippocampus, as a critical region for cognitive function and an important location in PND research, has recently attracted increasing attention. However, in the hippocampus the impact of anesthesia and its underlying mechanisms remain unclear. This review focuses on investigation of the effects of anesthesia on the hippocampal dopamine (DA) system and explores its potential association with PND. Through comprehensive review of existing studies, it was found that anesthesia affects the hippocampus through various pathways involved in metabolism, synaptic plasticity and oxygenation. Anesthesia may also influence the DA neurotransmitter system in the brain which plays a role in emotions, rewards, learning and memory functions. Specifically, anesthesia may participate in the pathogenesis of PND by affecting the DA system within the hippocampus. Future studies should explore the molecular mechanisms of these effects through techniques such as neuroimaging to study real-time effects to improve animal models to better simulate clinical observations. For clinical application, it is recommended that physicians exercise caution when selecting and managing anesthetic drugs by adopting comprehensive cognitive assessment methods to reduce post-anesthesia cognitive risk. Overall, this review provides a better understanding of the relationship between the hippocampal DA system and perioperative neurocognitive function and provides valuable guidance for prevention and treatment strategies for PND.

HIV-Associated Neurocognitive Disorder: A Look into Cellular and Molecular Pathology.

Despite combined antiretroviral therapy (cART) limiting HIV replication to undetectable levels in the blood, people living with HIV continue to experience HIV-associated neurocognitive disorder (HAND). HAND is associated with neurocognitive impairment, including motor impairment, and memory loss. HIV has been detected in the brain within 8 days of estimated exposure and the mechanisms for this early entry are being actively studied. Once having entered into the central nervous system (CNS), HIV degrades the blood-brain barrier through the production of its gp120 and Tat proteins. These proteins are directly toxic to endothelial cells and neurons, and propagate inflammatory cytokines by the activation of immune cells and dysregulation of tight junction proteins. The BBB breakdown is associated with the progression of neurocognitive disease. One of the main hurdles for treatment for HAND is the latent pool of cells, which are insensitive to cART and prolong inflammation by harboring the provirus in long-lived cells that can reactivate, causing damage. Multiple strategies are being studied to combat the latent pool and HAND; however, clinically, these approaches have been insufficient and require further revisions. The goal of this paper is to aggregate the known mechanisms and challenges associated with HAND.

Systemic inflammation, neuroinflammation and perioperative neurocognitive disorders.

Perioperative neurocognitive disorder (PND) is a common disorder following anesthesia and surgery, especially in the elderly. The complex cellular and molecular processes are involved in PND, but the underlying pathogenesis of which remains inconclusive due to conflicting data. A growing body of evidence has been shown that perioperative systemic inflammation plays important roles in the development of PND. We reviewed the relevant literature retrieved by a search in the PubMed database (on July 20, 2023). The search terms used were "delirium", "post operative cognitive dysfunction", "perioperative neurocognitive disorder", "inflammation" and "systemic", alone and in combination. All articles identified were English-language, full-text papers. The ones cited in the review are those that make a substantial contribution to the knowledge about systemic inflammation and PNDs. The aim of this review is to bring together the latest evidence for the understanding of how perioperative systemic inflammation mediates neuroinflammation and brain injury, how the inflammation is regulated and how we can translate these findings into prevention and/or treatment for PND.

Reversible large-scale network disruption correlates with neurocognitive improvement in HIV-associated minor neurocognitive disorder with combined anti-retroviral therapy intensification: a prospective longitudinal resting-state functional magnetic resonance imaging study.

OBJECTIVE: HIV-associated neurocognitive disorder (HAND) affects multiple cognitive domains and currently, the neuropsychological testing is the gold standard to identify these deficits. The aim of this longitudinal 12-month pilot study is to determine the effect of intensified combination antiretroviral therapy (cART) on rs-fMRI in virally suppressed (both in CSF and blood) patients with active HAND (those who have progressive neurocognitive impairment) and correlated with neurocognitive function tests. METHODS: In this pilot study, we have evaluated sixteen patients with active HAND with viral suppression in both blood and CSF to study the effect of cART on functional connectivity. Participants underwent rs-fMRI at the baseline (time point-1 (TP-1) and 12-month visits (time point-2 (TP-2)). Connectivity in the five major networks was measured at TP-1 and TP-2 using the seed-based approach. All the participants underwent a five-domain neuropsychological battery at TP-1 and TP-2. Neurocognitive scores (NC) as well as blood and CSF markers were correlated with functional connectivity (FC). RESULTS: There was a significant increase in the FC between the two time points within the executive, salience, default mode, dorsal attention, and visual networks at voxel level threshold of p < 0.001 and cluster level threshold of p < 0.05 and corrected for false detection rate (FDR). The neurocognitive scores were positively correlated with all the networks at similar cluster and voxel level thresholds. CONCLUSIONS: These results indicate that rs-fMRI can be potentially used as one of the biomarkers for treatment efficacy in HAND.

De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome.

Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE, where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions.

Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders.

HIV-associated neurocognitive disorder (HAND) is characterized by cognitive and behavioral deficits in people living with HIV. HAND is still common in patients that take antiretroviral therapies, although they tend to present with less severe symptoms. The continued prevalence of HAND in treated patients is a major therapeutic challenge, as even minor cognitive impairment decreases patient's quality of life. Therefore, modern HAND research aims to broaden our understanding of the mechanisms that drive cognitive impairment in people with HIV and identify promising molecular pathways and targets that could be exploited therapeutically. Recent studies suggest that HAND in treated patients is at least partially induced by subtle synaptodendritic damage and disruption of neuronal networks in brain areas that mediate learning, memory, and executive functions. Although the causes of subtle neuronal dysfunction are varied, reversing synaptodendritic damage in animal models restores cognitive function and thus highlights a promising therapeutic approach. In this review, we examine evidence of synaptodendritic damage and disrupted neuronal connectivity in HAND from clinical neuroimaging and neuropathology studies and discuss studies in HAND models that define structural and functional impairment of neurotransmission. Then, we report molecular pathways, mechanisms, and comorbidities involved in this neuronal dysfunction, discuss new approaches to reverse neuronal damage, and highlight current gaps in knowledge. Continued research on the manifestation and mechanisms of synaptic injury and network dysfunction in HAND patients and experimental models will be critical if we are to develop safe and effective therapies that reverse subtle neuropathology and cognitive impairment.

Modification of lipid rafts by extracellular vesicles carrying HIV-1 protein Nef induces redistribution of amyloid precursor protein and Tau, causing neuronal dysfunction.

HIV-associated neurocognitive disorders (HANDs) are a frequent outcome of HIV infection. Effective treatment of HIV infection has reduced the rate of progression and severity but not the overall prevalence of HANDs, suggesting ongoing pathological process even when viral replication is suppressed. In this study, we investigated how HIV-1 protein Nef secreted in extracellular vesicles (exNef) impairs neuronal functionality. ExNef were rapidly taken up by neural cells in vitro, reducing the abundance of ABC transporter A1 (ABCA1) and thus cholesterol efflux and increasing the abundance and modifying lipid rafts in neuronal plasma membranes. ExNef caused a redistribution of amyloid precursor protein (APP) and Tau to lipid rafts and increased the abundance of these proteins, as well as of Aß42 ExNef further potentiated phosphorylation of Tau and activation of inflammatory pathways. These changes were accompanied by neuronal functional impairment. Disruption of lipid rafts with cyclodextrin reversed the phenotype. Short-term treatment of C57BL/6 mice with either purified recombinant Nef or exNef similarly resulted in reduced abundance of ABCA1 and elevated abundance of APP in brain tissue. The abundance of ABCA1 in brain tissue of HIV-infected human subjects diagnosed with HAND was lower, and the abundance of lipid rafts was higher compared with HIV-negative individuals. Levels of APP and Tau in brain tissue correlated with the abundance of Nef. Thus, modification of neuronal cholesterol trafficking and of lipid rafts by Nef may contribute to early stages of neurodegeneration and pathogenesis in HAND.

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.

Selective peroxisome proliferator-activated receptor-gamma modulator, INT131 exhibits anti-inflammatory effects in an EcoHIV mouse model.

Despite the use of antiretroviral therapy for the treatment of HIV-1 infection, cognitive impairments, that is, HIV-1-associated neurocognitive disorders remain prevalent potentially due to persistent viral replication, production of viral proteins, associated brain inflammation or in certain instances, antiretroviral neurotoxicity. Cellular targets in the brain include microglia which in response to infection release inflammatory markers and viral proteins. Evidence suggests that PPARγ agonists exert anti-inflammatory properties in neurological disorders. However, these agonists namely, thiazolidinediones have limited use in the clinic due to reported adverse side effects. INT131 is a novel non-thiazolidinedione compound that belongs to a new class of drugs known as selective PPARγ modulators. INT131 is considered to have a safer profile; however, its neuroprotective role in vivo is not known.The goal of this study was to examine the effect of INT131 in the context of EcoHIV-induced inflammation in vitro, in primary cultures of mouse glial cells and in vivo, in a mouse model of EcoHIV-associated brain inflammation, as well as characterize its pharmacokinetic properties and brain penetration. In primary cultures of glial cells and in the in vivo mouse model, EcoHIV exposure resulted in a significant elevation of inflammatory markers such as TNFα, IL-1ß, CCL3, and C3 which were attenuated with INT131 treatment. Pharmacokinetic analyses revealed that INT131 penetrates into the brain with a brain to blood partition ratio Kp value of 8.5%. Overall, this is the first report to demonstrate that INT131 could be a potential candidate for the treatment of HIV-1-associated brain inflammation.

Atypical 7q11.23 deletions excluding ELN gene result in Williams-Beuren syndrome craniofacial features and neurocognitive profile.

Williams-Beurens syndrome (WBS) is a rare genetic disorder caused by a recurrent 7q11.23 microdeletion. Clinical characteristics include typical facial dysmorphisms, weakness of connective tissue, short stature, mild to moderate intellectual disability and distinct behavioral phenotype. Cardiovascular diseases are common due to haploinsufficiency of ELN gene. A few cases of larger or smaller deletions have been reported spanning towards the centromeric or the telomeric regions, most of which included ELN gene. We report on three patients from two unrelated families, presenting with distinctive WBS features, harboring an atypical distal deletion excluding ELN gene. Our study supports a critical role of CLIP2, GTF2IRD1, and GTF2I gene in the WBS neurobehavioral profile and in craniofacial features, highlights a possible role of HIP1 in the autism spectrum disorder, and delineates a subgroup of WBS individuals with an atypical distal deletion not associated to an increased risk of cardiovascular defects.

Activation of CD200-CD200R1 Axis Attenuates Perioperative Neurocognitive Disorder Through Inhibition of Neuroinflammation in Mice.

Perioperative neurocognitive disorder (PND) is the mild cognitive impairment associated with surgery and anesthesia. It is a common surgical complication in the elderly. An important mechanism of PND is the surgically induced neuroinflammation. The interaction between the neuronal surface protein CD200 and its receptor in microglia, CD200R1, is an important regulatory pathway to control neuroinflammation. However, the potential role of the CD200-CD200R1 pathway in the acute period of PND has not been fully investigated. In this study, in a PND mouse model, we first measured the protein expression level of CD200, CD200R1, and the related pro- and anti-inflammatory cytokines in the hippocampus. Then, we investigated cognitive function, neuroinflammation and postsynaptic density protein 95 (PSD-95) expression after the injection of CD200-Fc (agonist), CD200R1-Fc (antagonist) or IgG1-Fc (vehicle) into lateral ventricle in PND models. Compared with the control group, the expression of CD200 was up-regulated at day 1 after surgery in PND models. The injection of the CD200-Fc into the lateral ventricle could mitigate primed neuroinflammation and cognitive decline, increase the expression of PSD-95 at day 1 after surgery in PND models. In conclusion, we have demonstrated that CD200-CD200R1 signaling was involved in the acute inflammatory process of PND, and activating CD200R1 can inhibit neuroinflammation and attenuate PND. Thus, the CD200-CD200R1 axis is a potential novel target for PND prevention and treatment.

Clinically accessible neuroimaging predictors of post-stroke neurocognitive disorder: a prospective observational study.

BACKGROUND: Neurocognitive disorder (NCD) is common in stroke survivors. We aimed to identify clinically accessible imaging markers of stroke and chronic pathology that are associated with early post-stroke NCD. METHODS: We included 231 stroke survivors from the "Norwegian Cognitive Impairment after Stroke (Nor-COAST)" study who underwent a standardized cognitive assessment 3 months after the stroke. Any NCD (mild cognitive impairment and dementia) and major NCD (dementia) were diagnosed according to "Diagnostic and Statistical Manual of Mental Disorders (DSM-5)" criteria. Clinically accessible imaging findings were analyzed on study-specific brain MRIs in the early phase after stroke. Stroke lesion volumes were semi automatically quantified and strategic stroke locations were determined by an atlas based coregistration. White matter hyperintensities (WMH) and medial temporal lobe atrophy (MTA) were visually scored. Logistic regression was used to identify neuroimaging findings associated with major NCD and any NCD. RESULTS: Mean age was 71.8 years (SD 11.1), 101 (43.7%) were females, mean time from stroke to imaging was 8 (SD 16) days. At 3 months 63 (27.3%) had mild NCD and 65 (28.1%) had major NCD. Any NCD was significantly associated with WMH pathology (odds ratio (OR) = 2.73 [1.56 to 4.77], p = 0.001), MTA pathology (OR = 1.95 [1.12 to 3.41], p = 0.019), and left hemispheric stroke (OR = 1.8 [1.05 to 3.09], p = 0.032). Major NCD was significantly associated with WMH pathology (OR = 2.54 [1.33 to 4.84], p = 0.005) and stroke lesion volume (OR (per ml) =1.04 [1.01 to 1.06], p = 0.001). CONCLUSION: WMH pathology, MTA pathology and left hemispheric stroke were associated with the development of any NCD. Stroke lesion volume and WMH pathology were associated with the development of major NCD 3 months after stroke. These imaging findings may be used in the routine clinical setting to identify patients at risk for early post-stroke NCD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02650531 , Registered 8 January 2016 - Retrospectively registered.

Physical fitness and neurocognitive outcomes in adult survivors of childhood acute lymphoblastic leukemia: A report from the St. Jude Lifetime cohort.

BACKGROUND: Survivors of childhood acute lymphoblastic leukemia (ALL) are at increased risk for both treatment-related exercise intolerance and neurocognitive deficits. This analysis aimed to identify the association between exercise intolerance and neurocognitive impairments in ALL survivors. METHODS: Cardiopulmonary exercise testing, results from a 2-hour standardized neuropsychological assessment, and self-report questionnaires were obtained for 341 adult survivors of childhood ALL and 288 controls. Multivariable modeling was used to test associations between oxygen uptake at 85% estimated heart rate (rpkVO2 ) and neuropsychological test and self-reported questionnaire domains, adjusted for sex, age at diagnosis, cranial radiation, anthracycline, and methotrexate exposure and tobacco smoking status. RESULTS: Compared with controls, survivors had worse rpkVO2 and performance on verbal intelligence, focused attention, verbal fluency, working memory, dominant/nondominant motor speed, visual-motor speed, memory span, and reading and math measures (all P < .001). In adjusted models, exercise intolerance was associated with decreases in performance of verbal ability, focused attention, verbal fluency, working memory, dominant motor speed, nondominant motor speed, visual-motor speed, memory span, reading academics, and math academics in survivors. CONCLUSION: This study demonstrates an association between exercise intolerance and neurocognitive outcomes. Research is needed to determine whether interventions that improve exercise tolerance impact neurocognitive function in ALL survivors.

Adenosine A3 receptor as a novel therapeutic target to reduce secondary events and improve neurocognitive functions following traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a common pathological condition that presently lacks a specific pharmacological treatment. Adenosine levels rise following TBI, which is thought to be neuroprotective against secondary brain injury. Evidence from stroke and inflammatory disease models suggests that adenosine signaling through the G protein-coupled A3 adenosine receptor (A3AR) can provide antiinflammatory and neuroprotective effects. However, the role of A3AR in TBI has not been investigated. METHODS: Using the selective A3AR agonist, MRS5980, we evaluated the effects of A3AR activation on the pathological outcomes and cognitive function in CD1 male mouse models of TBI. RESULTS: When measured 24 h after controlled cortical impact (CCI) TBI, male mice treated with intraperitoneal injections of MRS5980 (1 mg/kg) had reduced secondary tissue injury and brain infarction than vehicle-treated mice with TBI. These effects were associated with attenuated neuroinflammation marked by reduced activation of nuclear factor of kappa light polypeptide gene enhancer in B cells (NFκB) and MAPK (p38 and extracellular signal-regulated kinase (ERK)) pathways and downstream NOD-like receptor pyrin domain-containing 3 inflammasome activation. MRS5980 also attenuated TBI-induced CD4+ and CD8+ T cell influx. Moreover, when measured 4-5 weeks after closed head weight-drop TBI, male mice treated with MRS5980 (1 mg/kg) performed significantly better in novel object-placement retention tests (NOPRT) and T maze trials than untreated mice with TBI without altered locomotor activity or increased anxiety. CONCLUSION: Our results provide support for the beneficial effects of small molecule A3AR agonists to mitigate secondary tissue injury and cognitive impairment following TBI.

Nitrosative Stress Is Associated with Dopaminergic Dysfunction in the HIV-1 Transgenic Rat.

Advances in antiretroviral therapy have resulted in significantly decreased HIV-related mortality. HIV-associated neurocognitive disorders, however, continue to be a major problem in infected patients. The neuropathology underlying HIV-associated neurocognitive disorders has not been well characterized, and evidence suggests different contributing mechanisms. One potential mechanism is the induction of oxidative stress. Using the HIV-1 transgenic (Tg) rat model of HIV, we found increased striatal NADPH oxidase-4 and neuronal nitric oxide synthase expression in the adult (7- to 9-month-old) Tg rat compared with control rats but not in the young (1-month-old) Tg rats. This was accompanied by increased 3-nitrotyrosine (3-NT) immunostaining in the adult Tg rats, which worsened significantly in the old Tg rats (18 to 20 months old). There was, however, no concurrent induction of the antioxidant systems because there was no change in the expression of the nuclear factor-erythroid 2-related factor 2 and its downstream targets (thioredoxin and glutathione antioxidant systems). Colocalization of 3-NT staining with neurofilament proteins and evidence of decreased tyrosine hydroxylase and dopamine transporter expression in the old rats support dopaminergic involvement. We conclude that the HIV-1 Tg rat brain shows evidence of nitrosative stress without appropriate oxidation-reduction adaptation, whereas 3-NT modification of striatal neurofilament proteins likely points to the ensuing dopaminergic neuronal loss and dysfunction in the aging HIV-1 Tg rat.

Nitroxides affect neurological deficits and lesion size induced by a rat model of traumatic brain injury.

Research has attributed tissue damage post-traumatic brain injury (TBI) to two-pronged effects, increased reactive oxygen species (ROS) and impairment of endogenous antioxidant defence systems, underpinned by manganese superoxide dismutase (MnSOD). Novel antioxidant nitroxides have been shown to mimic MnSOD to ameliorate oxidative stress related disorders. This study aimed to investigate the effects of two nitroxides, CTMIO and DCTEIO, on the neurological outcomes following moderate TBI in rats induced by a weight drop device. The rats were immediately treated with CTMIO and DCTEIO (40 mM in drinking water) post-injury for up to 2 weeks. The brains were histologically examined at 24 h and 6 weeks post injury. DCTEIO reduced the lesion size at both 24h and 6 weeks, with normalised performance in sensory, motor and cognitive tests at 24h post-injury. Astrogliosis was heightened by DCTEIO at 24h and still elevated at 6 weeks in this group. In TBI brains, cellular damage was evident as reflected by changes in markers of mitophagy and autophagy (increased fission marker dynamin-related protein (Drp)-1, and autophagy marker light chain 3 (LC3)A/B and reduced fusion marker optic atrophy (Opa)-1). These were normalised by DCTEIO treatment. CTMIO, on the other hand, seems to be toxic to the injured brains, by increasing injury size at 6 weeks. In conclusion, DCTEIO significantly improved tissue repair and preserved neurological function in rats with TBI possibly via a mitophagy mechanism. This study provides evidence for DCTEIO as a promising new option to alleviate lesion severity after moderate TBI, which is not actively treated.

Neurocognitive changes after awake surgery in glioma patients: a retrospective cohort study.

PURPOSE: Deficits in neurocognitive functioning (NCF) frequently occur in glioma patients. Both treatment and the tumor itself contribute to these deficits. In order to minimize the harmful effects of surgery, an increasing number of patients undergo awake craniotomy. To investigate whether we can indeed preserve cognitive functioning after state-of-the art awake surgery and to identify factors determining postoperative NCF, we performed a retrospective cohort study. METHODS: In diffuse glioma (WHO grade 2-4) patients undergoing awake craniotomy, we studied neurocognitive functioning both pre-operatively and 3-6 months postoperatively. Evaluation covered five neurocognitive domains. We performed analysis of data on group and individual level and evaluated the value of patient-, tumor- and treatment-related factors for predicting change in NCF, using linear and logistic regression analysis. RESULTS: We included 168 consecutive patients. Mean NCF-scores of psychomotor speed and visuospatial functioning significantly deteriorated after surgery. The percentage of serious neurocognitive impairments (- 2 standard deviations) increased significantly for psychomotor speed only. Tumor involvement in the left thalamus predicted a postoperative decline in NCF for the domains overall-NCF, executive functioning and psychomotor speed. An IDH-wildtype status predicted decline for overall-NCF and executive functioning. CONCLUSIONS: In all cognitive domains, except for psychomotor speed, cognitive functioning can be preserved after awake surgery. The domain of psychomotor speed seems to be most vulnerable to the effects of surgery and early postoperative therapies. Cognitive performance after glioma surgery is associated with a combination of structural and biomolecular effects from the tumor, including IDH-status and left thalamic involvement.

Multi-domain neurocognitive classification of primary brain tumor patients prior to radiotherapy on a prospective clinical trial.

INTRODUCTION: We investigated multi-domain baseline neurocognition of primary brain tumor patients prior to radiotherapy (RT), including clinical predictors of function and association between pre-RT and post-RT impairment on a prospective trial. METHODS: A multi-domain neuropsychological battery (memory, executive functioning, language, attention, processing) was performed on 37 patients, pre-RT and 3-(n = 21), 6-(n = 22) and 12-(n = 14) months post-RT. Impairment rate was the proportion of patients with standardized T-scores ≤ 1.5 standard deviations below normative means. Per-patient impairment across all domains was calculated using a global deficit score (GDS; higher value indicates more impairment). Associations between baseline GDS and clinical variables were tested. Global GDS impairment rate at each time point was the fraction of patients with GDS scores > 0.5. RESULTS: Statistically significant baseline neurocognitive impairments were identified on 4 memory (all p ≤ 0.03) and 2 out of 3 (p = 0.01, p = 0.027) executive functioning tests. Per-patient baseline GDS was significantly associated with tumor volume (p = 0.048), tumor type (p = 0.043), seizure history (p = 0.007), and use of anti-epileptics (p = 0.009). The percentage of patients with the same impairment status at 3-, 6-, and 12-months as at baseline were 88%, 85%, and 85% respectively. CONCLUSIONS: Memory and executive functioning impairment were the most common cognitive deficits prior to RT. Patients with larger tumors, more aggressive histology, and use of anti-epileptics had higher baseline GDS values. GDS is a promising tool to encompass multi-domain neurocognitive function, and baseline GDS can identify those at risk of cognitive impairment.

Effect of sensorineural hearing loss on neurocognitive and adaptive functioning in survivors of pediatric embryonal brain tumor.

PURPOSE: Survivors of pediatric embryonal brain tumors (BT) are at high risk for sensorineural hearing loss (SNHL) associated with neurocognitive decline. However, previous studies have not assessed the relationship between SNHL and adaptive functioning. We examined neurocognitive and adaptive functioning in patients with and without SNHL. METHODS: Participants included 36 patients treated for an embryonal BT with craniospinal irradiation (CSI) and cisplatin chemotherapy who were assessed 6.7 years post-treatment on average. The impact of SNHL on neurocognitive performance and parent-rated adaptive functioning was assessed in univariate and multivariate analyses. RESULTS: There were 17 cases with SNHL (mean age at evaluation = 14.4) and 19 cases with NH (mean age at evaluation = 13.8). After accounting for age at diagnosis and additional covariates in multivariable analyses, SNHL was associated with worse overall intellectual functioning (p = 0.027) and perceptual reasoning (p = 0.016) performance. There was no effect of SNHL on adaptive functioning in multivariable models. Age at diagnosis and sex were associated with performance on neurocognitive measures. CONCLUSIONS: SNHL in pediatric embryonal BT is associated with increased risk for neurocognitive deficits in conjunction with other demographic and treatment-related factors.

Use of Neuroimaging to Inform Optimal Neurocognitive Criteria for Detecting HIV-Associated Brain Abnormalities.

OBJECTIVE: Frascati international research criteria for HIV-associated neurocognitive disorders (HAND) are controversial; some investigators have argued that Frascati criteria are too liberal, resulting in a high false positive rate. Meyer et al. recommended more conservative revisions to HAND criteria, including exploring other commonly used methodologies for neurocognitive impairment (NCI) in HIV including the global deficit score (GDS). This study compares NCI classifications by Frascati, Meyer, and GDS methods, in relation to neuroimaging markers of brain integrity in HIV. METHOD: Two hundred forty-one people living with HIV (PLWH) without current substance use disorder or severe (confounding) comorbid conditions underwent comprehensive neurocognitive testing and brain structural magnetic resonance imaging and magnetic resonance spectroscopy. Participants were classified using Frascati criteria versus Meyer criteria: concordant unimpaired [Frascati(Un)/Meyer(Un)], concordant impaired [Frascati(Imp)/Meyer(Imp)], or discordant [Frascati(Imp)/Meyer(Un)] which were impaired via Frascati criteria but unimpaired via Meyer criteria. To investigate the GDS versus Meyer criteria, the same groupings were utilized using GDS criteria instead of Frascati criteria. RESULTS: When examining Frascati versus Meyer criteria, discordant Frascati(Imp)/Meyer(Un) individuals had less cortical gray matter, greater sulcal cerebrospinal fluid volume, and greater evidence of neuroinflammation (i.e., choline) than concordant Frascati(Un)/Meyer(Un) individuals. GDS versus Meyer comparisons indicated that discordant GDS(Imp)/Meyer(Un) individuals had less cortical gray matter and lower levels of energy metabolism (i.e., creatine) than concordant GDS(Un)/Meyer(Un) individuals. In both sets of analyses, the discordant group did not differ from the concordant impaired group on any neuroimaging measure. CONCLUSIONS: The Meyer criteria failed to capture a substantial portion of PLWH with brain abnormalities. These findings support continued use of Frascati or GDS criteria to detect HIV-associated CNS dysfunction.