Development Of Neurocognitive Disorders Research Articles

Neurocognitive disorders in chronic kidney disease

Neurocognitive disorders (NCD) are common in patients with chronic kidney disease (CKD). It is essential to identify and characterize these disorders at an early stage, so as to be able to offer appropriate treatment. In a chronic disease such as CKD, the patient's involvement in decision-making is a major challenge, given the prospects for suppletive treatment: hemodialysis, peritoneal dialysis, kidney transplantation or non-dialytic drug therapy. Many factors are associated with the development and progression of NCD in patients with CKD, and a variety of conditions can influence the outcome of cognitive assessment in these patients.

Novel Allosteric Modulator Southern Research Institute-32743 Reverses HIV-1 Transactivator of Transcription-Induced Increase in Dopamine Release in the Caudate Putamen of Inducible Transactivator of Transcription Transgenic Mice.

Development of neurocognitive disorder in human immunodeficiency virus (HIV)-infected patients has been linked to dysregulation of dopamine by the HIV-1 transactivator of transcription (Tat) protein, a negative allosteric modulator of dopamine transporter (DAT). Using fast scan cyclic voltammetry, the present study determined the effects of in vivo Tat expression on dopamine release in the caudate putamen of inducible Tat transgenic (iTat-tg) mice and the impact of a novel DAT allosteric modulator, Southern Research Institute (SRI)-32743, on the Tat effect. We found that 7- or 14-day doxycycline (Dox)-induced Tat expression in iTat-tg mice resulted in a 2-fold increase in phasic but not tonic stimulated baseline dopamine release relative to saline control mice. To determine whether the Tat-induced increase in dopamine release is mediated by DAT regulation, we examined the effect of an in vitro applied DAT inhibitor, nomifensine, on the dopamine release. Nomifensine (1 nM-10 µM) concentration-dependently enhanced phasic stimulated dopamine release in both saline- and Dox-treated iTat-tg mice, while the magnitude of the nomifensine-mediated dopamine release was unchanged between saline and Dox treatment groups. A single systemic administration of SRI-32743 prior to animal sacrifice reversed the increased dopamine release in the baseline of phasic dopamine release and nomifensine-augmented dopamine levels in Dox-treated iTat-tg mice, while SRI-32743 alone did not alter baseline of dopamine release. These findings suggest that Tat expression induced an increase in extracellular dopamine levels by not only inhibiting DAT-mediated dopamine transport but also stimulating synaptic dopamine release. Thus, DAT allosteric modulators may serve as a potential therapeutic intervention for HIV infection-dysregulated dopamine system observed in HIV-1 positive individuals. SIGNIFICANCE STATEMENT: HIV infection-induced dysregulation of the dopaminergic system has been implicated in the development of neurocognitive impairments observed in HIV positive patients. Understanding the mechanisms underlying HIV-1 Tat protein-induced alteration of extracellular dopamine levels will provide insights into the development of molecules that can attenuate Tat interaction with targets in the dopaminergic system. Here, we determined whether Tat alters dopamine release and how the novel DAT allosteric modulator, SRI-32743, impacts dopamine neurotransmission to attenuate Tat-induced effects on extracellular dopamine dynamics.

Knockdown of P2Y4 ameliorates sepsis-induced acute kidney injury in mice via inhibiting the activation of the NF-κB/MMP8 axis.

Sepsis-induced acute kidney injury (S-AKI) has emerged as a frequent and life-threatening complication in critically ill patients, which is characterized by a systematic inflammatory response and a rapid decline in kidney function. P2Y4, a member of G protein–coupled P2Y nucleotide receptor family, has been reported to serve as a crucial player in inflammatory responses during the development of neurocognitive disorder and myocardial infarction. Nonetheless, the biological role of P2Y4 in S-AKI remains largely unclear. This study aimed to decipher the biological role of P2Y4 in S-AKI and illuminate the potential mechanisms. In this study, S-AKI models were successfully established in mice via cecal ligation and puncture. Results showed that the kidney tissues from S-AKI mouse models exhibited a higher P2Y4 expression level than from the sham-operated group. Knockdown of P2Y4 was found to remarkably alleviate kidney damage and reduce inflammatory response in mice of S-AKI models. Moreover, P2Y4 ablation inhibited the activation of the NF-κB/MMP-8 signaling axis. Additionally, mechanistic studies revealed that rescuing MMP-8 reversed the alleviating effects of P2Y4 knockdown against renal cell damage. Collectively, our findings indicate that P2Y4 knockdown ameliorated S-AKI in mice via inhibiting the activation of the NF-κB/MMP-8 axis and that P2Y4 may represent a novel therapeutic target for S-AKI patients.

Predicting the Emergence of Major Neurocognitive Disorder Within Three Months After a Stroke.

Background: Neurocognitive disorder (NCD) is common after stroke, with major NCD appearing in about 10% of survivors of a first-ever stroke. We aimed to classify clinical- and imaging factors related to rapid development of major NCD 3 months after a stroke, so as to examine the optimal composition of factors for predicting rapid development of the disorder. We hypothesized that the prediction would mainly be driven by neurodegenerative as opposed to vascular brain changes.Methods: Stroke survivors from five Norwegian hospitals were included from the “Norwegian COgnitive Impairment After STroke” (Nor-COAST) study. A support vector machine (SVM) classifier was trained to distinguish between patients who developed major NCD 3 months after the stroke and those who did not. Potential predictor factors were based on previous literature and included both vascular and neurodegenerative factors from clinical and structural magnetic resonance imaging findings. Cortical thickness was obtained via FreeSurfer segmentations, and volumes of white matter hyperintensities (WMH) and stroke lesions were semi-automatically gathered using FSL BIANCA and ITK-SNAP, respectively. The predictive value of the classifier was measured, compared between classifier models and cross-validated.Results: Findings from 227 stroke survivors [age = 71.7 (11.3), males = (56.4%), stroke severity NIHSS = 3.8 (4.8)] were included. The best predictive accuracy (AUC = 0.876) was achieved by an SVM classifier with 19 features. The model with the fewest number of features that achieved statistically comparable accuracy (AUC = 0.850) was the 8-feature model. These features ranked by their weighting were; stroke lesion volume, WMH volume, left occipital and temporal cortical thickness, right cingulate cortical thickness, stroke severity (NIHSS), antiplatelet medication intake, and education.Conclusion: The rapid (<3 months) development of major NCD after stroke is possible to predict with an 87.6% accuracy and seems dependent on both neurodegenerative and vascular factors, as well as aspects of the stroke itself. In contrast to previous literature, we also found that vascular changes are more important than neurodegenerative ones. Although possible to predict with relatively high accuracy, our findings indicate that the development of rapid onset post-stroke NCD may be more complex than earlier suggested.

Abstract P66: Prediction of Early Post-Stroke Major Neurocognitive Disorder Using Support Vector Machines

Neurocognitive disorder (NCD) appears in 10% of survivors of a first-ever stroke and in 30% after a recurrent one. We aimed to classify clinical- and imaging factors related to the development of major NCD 3 months post stroke, so as to examine whether early development (&lt;1 yr) is mainly of a neurodegenerative or vascular origin. Based on previous literature we hypothesized that early post-stroke major NCD would mainly be of neurodegenerative origin. 227 stroke survivors (age = 71.69 (11.25), NIHSS = 3.79 (4.75), females (43,61%)) were included from the ‘Norwegian COgnitive Impairment After STroke’ study. Clinical- and MRI data at baseline, and neuropsychological data at baseline and 3 months was used. Cortical thicknesses were automatically measured using Freesurfer and white matter hyperintensity (WMH) volumes were semi-automatically measured using FSL Bianca. Stroke lesion volumes were semi-automatically measured using ITK-snap. Support Vector Machine (SVM) classification was used in order to investigate the prognostic value of the neuroimaging findings and the clinical factors. Model performance was measured using Area Under Receiving Operating Characteristics (ROC) and -Curve (AUC). The best model correctly predicted major NCD in 88% of the patients and was driven by 19 features, with the top five features being stroke volume, WMH volume, left hemisphere occipital- and temporal thickness, and right hemisphere cingulate thickness. In conclusion, clinical- and MRI findings may be used in prediction of cognitive outcome for stroke patients. Various meta-studies of post-stroke major NCD prediction show levels ranging from .48 to .91, showing that the current model is performing well. Early development of major NCD seems dependent not on neurodegenerative causes alone, but also on vascular factors, as well as aspects of the stroke itself. This highlights the complexity of post-stroke NCD and thus also its prediction. Figure 1: ROC curve of SVM model, with an AUC of .88.

Subjective cognitive decline, anxiety symptoms, and the risk of mild cognitive impairment and dementia

AbstractBackgroundSubjective cognitive decline (SCD) and anxiety symptoms both predict neurocognitive disorders, but the two correlate strongly with each other. It is unclear whether they reflect two independent disease processes in the development of neurocognitive disorders, and hence deserve separate attention. This cohort study examined whether SCD and anxiety symptoms demonstrate independent risks of mild cognitive disorder and dementia (MCI/dementia).MethodThe study included 11,522 participants aged ≥60 years and diagnosed with normal cognition at baseline, recruited from Alzheimer’s Disease Centers across USA. The participants were evaluated for SCD and anxiety symptoms at baseline, and followed‐up almost annually for incident MCI/dementia (median follow‐up 4.5 years; interquartile range 2.3–7.4 years). SCD and anxiety symptoms were included in Cox‐regression to investigate their independent risks of MCI/dementia.ResultSCD and anxiety symptoms demonstrated independent risks of MCI/dementia, with HR 1.3 (95% CI 1.1–1.6) and 1.9 (95% CI 1.7–2.1) respectively. Co‐occurring SCD and anxiety symptoms demonstrated the highest risk (HR 2.6, 95% CI 2.0–3.4) – half of the participants in this group developed MCI/dementia within 6.2 years of follow‐up (95% 4.4–8.1), compared to 12.3 years in participants without SCD or anxiety (95% CI 12.1–12.6).ConclusionThe findings suggest that clinicians should not dismiss one over the other when patients present with both SCD and anxiety, and that both constructs may potentially be useful to identify high‐risk populations for preventive interventions and trials. The findings also point to the need for further research to clarify on the neurobiological distinctions between SCD and anxiety symptoms, which may potentially enrich our understanding on the pathogenesis of neurocognitive disorders.

Subjective cognitive decline, anxiety symptoms, and the risk of mild cognitive impairment and dementia

BackgroundSubjective cognitive decline (SCD) and anxiety symptoms both predict neurocognitive disorders, but the two correlate strongly with each other. It is unclear whether they reflect two independent disease processes in the development of neurocognitive disorders and hence deserve separate attention. This cohort study examined whether SCD and anxiety symptoms demonstrate independent risks of mild cognitive disorder and dementia (MCI/dementia).MethodsThe study included 14,066 participants aged ≥ 50 years and diagnosed with normal cognition at baseline, recruited from Alzheimer’s Disease Centers across the USA. The participants were evaluated for SCD and anxiety symptoms at baseline and followed up almost annually for incident MCI/dementia (median follow-up 4.5 years; interquartile range 2.2–7.7 years). SCD and anxiety symptoms were included in Cox regression to investigate their independent risks of MCI/dementia.ResultsSCD and anxiety symptoms demonstrated independent risks of MCI/dementia, with HR 1.9 (95% CI 1.7–2.1) and 1.3 (95% CI 1.2–1.5), respectively. Co-occurring SCD and anxiety symptoms demonstrated the highest risk (HR 2.4, 95% CI 1.9–2.9)—participants in this group had a 25% probability of developing MCI/dementia by 3.1 years (95% 2.4–3.7), compared to 8.2 years among those without SCD or anxiety (95% CI 7.9–8.6). The results remained robust even in the sensitivity analyses that took into account symptom severity and consistency of symptoms in the first 2 annual visits.ConclusionsThe findings suggest that clinicians should not dismiss one over the other when patients present with both SCD and anxiety and that both constructs may potentially be useful to identify high-risk populations for preventive interventions and trials. The findings also point to the need for further research to clarify on the neurobiological distinctions between SCD and anxiety symptoms, which may potentially enrich our understanding on the pathogenesis of neurocognitive disorders.

A modern strategy of combined surgical and radiation treatment in patients with brain metastases

The treatment standards for patients with brain metastases have been developed for several decades. An important element in the evolution of approaches to the treatment of these patients is the development of microsurgery, stereotactic radiotherapy, and targeted therapy and introduction of these techniques into clinical practice. Surgery is an effective treatment option in patients having single brain metastases and/or occuring in life-threatening clinical situations. Irradiation of the whole brain after surgical treatment is a necessary step in achieving satisfactory local control of intracranial metastatic foci, but the development of neurocognitive disorders and deterioration of life quality after this irradiation necessitate the search for alternative radiotherapy techniques in this clinical situation. Currently, an alternative to postoperative irradiation of the whole brain is stereotactic radiotherapy, which is used before or after surgical treatment. Stereotactic radiotherapy improves local control of intracranial metastatic foci and reduces the risk of neurotoxicity. In this review, we analyze the literature data on outcomes of stereotactic irradiation as a component of combined treatment of patients with metastatic brain lesions.

The Role of Sleep and Sleep Disorders in the Development, Diagnosis, and Management of Neurocognitive Disorders.

It is becoming increasingly apparent that sleep plays an important role in the maintenance, disease prevention, repair, and restoration of both mind and body. The sleep and wake cycles are controlled by the pacemaker activity of the superchiasmic nucleus in the hypothalamus but can be disrupted by diseases of the nervous system causing disordered sleep. A lack of sleep has been associated with an increase in all-cause mortality. Likewise, sleep disturbances and sleep disorders may disrupt neuronal pathways and have an impact on neurological diseases. Sleep deprivation studies in normal subjects demonstrate that a lack of sleep can cause attention and working memory impairment. Moreover, untreated sleep disturbances and sleep disorders such as obstructive sleep apnoe (OSA) can also lead to cognitive impairment. Poor sleep and sleep disorders may present a significant risk factor for the development of dementia. In this review, the underlying mechanisms and the role of sleep and sleep disorders in the development of neurocognitive disorders [dementia and mild cognitive impairment (MCI)] and how the presence of sleep disorders could direct the process of diagnosis and management of neurocognitive disorders will be discussed.

Propofol Compared with Isoflurane Inhibits Mitochondrial Metabolism in Immature Swine Cerebral Cortex

Anesthetics used in infants and children are implicated in the development of neurocognitive disorders. Although propofol induces neuroapoptosis in developing brain, the underlying mechanisms require elucidation and may have an energetic basis. We studied substrate utilization in immature swine anesthetized with either propofol or isoflurane for 4 hours. Piglets were infused with 13-Carbon-labeled glucose and leucine in the common carotid artery to assess citric acid cycle (CAC) metabolism in the parietal cortex. The anesthetics produced similar systemic hemodynamics and cerebral oxygen saturation by near-infrared spectroscopy. Compared with isoflurane, propofol depleted ATP and glycogen stores. Propofol decreased pools of the CAC intermediates, citrate, and α-ketoglutarate, while markedly increasing succinate along with decreasing mitochondrial complex II activity. Propofol also inhibited acetyl-CoA entry into the CAC through pyruvate dehydrogenase, while promoting glycolytic flux with marked lactate accumulation. Although oxygen supply appeared similar between the anesthetic groups, propofol yielded a metabolic phenotype that resembled a hypoxic state. Propofol impairs substrate flux through the CAC in the immature cerebral cortex. These impairments occurred without systemic metabolic perturbations that typically accompany propofol infusion syndrome. These metabolic abnormalities may have a role in the neurotoxity observed with propofol in the vulnerable immature brain.

HIV associated neurocognitive disorders

Human immunodeficiency virus type 1 is associated with the development of neurocognitive disorders in many infected individuals, including a broad spectrum of motor impairments and cognitive deficits. Despite extensive research, the pathogenesis of HIV-associated neurocognitive disorders (HAND) is still not clear. This review provides a comprehensive view of HAND, including HIV neuroinvasion, HAND diagnosis and different level of disturbances, influence of highly-active antiretroviral therapy to HIV-associated dementia (HAD), possible pathogenesis of HAD, etc. Together, this review will give a thorough and clear understanding of HAND, especially HAD, which will be vital for future research, diagnosis and treatment.

Formaldehyde Impairs Learning and Memory Involving the Disturbance of Hydrogen Sulfide Generation in the Hippocampus of Rats

Formaldehyde (FA), a well-known indoor and outdoor pollutant, has been implicated as the responsible agent in the development of neurocognitive disorders. Hydrogen sulfide (H(2)S), the third gasotransimitter, is an endogenous neuromodulator, which facilitates the induction of hippocampal long-term potentiation, involving the functions of learning and memory. In the present study, we analyzed the effects of intracerebroventricular injection of FA on the formation of learning and memory and the generation of endogenous H(2)S in the hippocampus of rats. We found that the intracerebroventricular injection of FA in rats impairs the function of learning and memory in the Morris water maze and novel object recognition test and increases the formation of apoptosis and lipid peroxidation in the hippocampus. We also showed that FA exposure inhibits the expression of cystathionine β-synthase, the major enzyme responsible for endogenous H(2)S generation in hippocampus and decreases the production of endogenous H(2)S in hippocampus in rats. These results suggested that FA-disturbed generation of endogenous H(2)S in hippocampus leads to the oxidative stress-mediated neuron damage, ultimately impairing the function of learning and memory. Our findings imply that the disturbance of endogenous H(2)S generation in hippocampus is a potential contributing mechanism underling FA-caused learning and memory impairment.

Deregulation of microRNAs by HIV-1 Vpr leads to the development of neurocognitive disorders

Studies have shown that HIV-infected patients develop neurocognitive disorders that are marked by neuronal dysfunction. The lack of productive infection of neurons by HIV suggests that viral and cellular proteins, with neurotoxic activities, released from HIV-1 infected target cells cause this neuronal deregulation. The viral protein R, a protein encoded by HIV-1, has been shown to alter the expression of various important cytokines and inflammatory proteins in infected and uninfected cells, however the mechanisms involved remain unclear. Using human neuronal cell line, we found that Vpr can be taken up by neurons causing i- deregulation of calcium homeostasis, ii- endoplasmic reticulum-calcium release, iii-activation of the oxidative stress pathway, iv- mitochondrial dysfunction and v- synaptic retraction. In search for the cellular factors involved, we performed microRNAs and gene array assays using human neurons (primary cultures or cell line, SH-SY5Y) that we treated with recombinant Vpr proteins. Interestingly, Vpr deregulates the levels of several miRNAs (e.g. miR-34a) and their target genes (e.g. CREB), which could lead to neuronal dysfunctions. Therefore, we conclude that Vpr is a major player in neuronal dysfunction through deregulating miRNAs and their target genes, a phenomenon that could lead to the development of HAND.

Development of neurocognitive disorders in HIV/AIDS

Development of neurocognitive disorders in HIV/AIDS Brandon C Dennis1,2, Sidney A Houff1, Dong Y Han1, Frederick A Schmitt1,2,31Department of Neurology, 2Sanders-Brown Center on Aging, 3Departments of Psychiatry, Psychology, and Behavioral Science, University of Kentucky College of Medicine, Lexington, KY, USAAbstract: The introduction of highly active antiretroviral therapy has had an enormous impact on the management of human immunodeficiency virus (HIV) infection and has led to an increase in survival and decrease in HIV-associated dementia. However, minor neurocognitive disturbances across various neurocognitive domains remain common in 50% or more of HIV patients according to recent estimates. Increased longevity has led to the investigation of several moderating and complicating factors, including vascular disease, neurotoxicity, aging, substance abuse, hepatitis C coinfection, and psychiatric illness. This article provides a review of the history of HIV-associated neurocognitive disorders (HAND), revised diagnostic terminology, factors moderating development of HAND, assessment techniques and neurocognitive profiles, current treatment and limitations, and future research directions.Keywords: HIV-associated neurocognitive disorders, HIV dementia, AIDS dementia, AIDS