Sirtuins Modulation: A Promising Strategy for HIV-Associated Neurocognitive Impairments

HIV-Associated neurocognitive disorder (HAND) is one of the major concerns since it persists in 40% of this population. Nowadays, HAND neuropathogenesis is considered to be caused by the infected cells that cross the brain–blood barrier and produce viral proteins that can be secreted and internalized into neurons leading to disruption of cellular processes. The evidence points to viral proteins such as Tat as the causal agent for neuronal alteration and thus HAND. The hallmarks in Tat-induced neurodegeneration are endoplasmic reticulum stress and mitochondrial dysfunction. Sirtuins (SIRTs) are NAD+-dependent deacetylases involved in mitochondria biogenesis, unfolded protein response, and intrinsic apoptosis pathway. Tat interaction with these deacetylases causes inhibition of SIRT1 and SIRT3. Studies revealed that SIRTs activation promotes neuroprotection in neurodegenerative diseases such Alzheimer’s and Parkinson’s disease. Therefore, this review focuses on Tat-induced neurotoxicity mechanisms that involve SIRTs as key regulators and their modulation as a therapeutic strategy for tackling HAND and thereby improving the quality of life of people living with HIV.

Computational basis of decision-making impairment in multiple sclerosis

Background: Multiple sclerosis (MS) is commonly associated with decision-making, neurocognitive impairments, and mood and motivational symptoms. However, their relationship may be obscured by traditional scoring methods. Objectives: To study the computational basis underlying decision-making impairments in MS and their interaction with neurocognitive and neuropsychiatric measures. Methods: Twenty-nine MS patients and 26 matched control subjects completed a computer version of the Iowa Gambling Task (IGT). Participants underwent neurocognitive evaluation using an expanded version of the Brief Repeatable Battery. Hierarchical Bayesian Analysis was used to estimate three established computational models to compare parameters between groups. Results: Patients showed increased learning rate and reduced loss-aversion during decision-making relative to control subjects. These alterations were associated with: (1) reduced net gains in the IGT; (2) processing speed, executive functioning and memory impairments; and (3) higher levels of depression and current apathy. Conclusion: Decision-making deficits in MS patients could be described by the interplay between latent computational processes, neurocognitive impairments, and mood/motivational symptoms.

Prediction Models for Radiation-Induced Neurocognitive Decline in Adult Patients with Primary or Secondary Brain Tumors: A Systematic Review

Purpose: Although an increasing body of literature suggests a relationship between brain irradiation and deterioration of neurocognitive function, it remains as the standard therapeutic and prophylactic modality in patients with brain tumors. This review was aimed to abstract and evaluate the prediction models for radiation-induced neurocognitive decline in patients with primary or secondary brain tumors.Methods: MEDLINE was searched on October 31, 2021 for publications containing relevant truncation and MeSH terms related to “radiotherapy”, “brain”, “prediction model”, and “neurocognitive impairments”. Risk of bias was assessed using the Prediction model Risk Of Bias ASsessment Tool.Results: Of 3,580 studies reviewed, 23 prediction models were identified. Age, tumor location, education level, baseline neurocognitive score, and radiation dose to the hippocampus were the most common predictors in the models. The Hopkins verbal learning (n=7) and the trail making tests (n=4) were the most frequent outcome assessment tools. All studies used regression (n=14 linear, n=8 logistic, and n=4 Cox) as machine learning method. All models were judged to have a high risk of bias mainly due to issues in the analysis.Conclusion: Existing models have limited quality and are at high risk of bias. Following recommendations are outlined in this review to improve future models: develop a standardized instrument for neurocognitive assessment in patients with brain tumors; adherence to model development and validation guidelines; careful choice of candidate predictors according to the literature and domain expert consensus; and considering radiation dose to brain substructures as they can provide important information on specific neurocognitive impairments.

Defining Acute Traumatic Encephalopathy: Methods of the “HEAD Injury Serum Markers and Multi-Modalities for Assessing Response to Trauma” (HeadSMART II) Study

Despite an estimated 2.8 million annual ED visits, traumatic brain injury (TBI) is a syndromic diagnosis largely based on report of loss of consciousness, post-traumatic amnesia, and/or confusion, without readily available objective diagnostic tests at the time of presentation, nor an ability to identify a patient's prognosis at the time of injury. The recognition that “mild” forms of TBI and even sub-clinical impacts can result in persistent neuropsychiatric consequences, particularly when repetitive, highlights the need for objective assessments that can complement the clinical diagnosis and provide prognostic information about long-term outcomes. Biomarkers and neurocognitive testing can identify brain injured patients and those likely to have post-concussive symptoms, regardless of imaging testing results, thus providing a physiologic basis for a diagnosis of acute traumatic encephalopathy (ATE). The goal of the HeadSMART II (HEAD injury Serum markers and Multi-modalities for Assessing Response to Trauma) clinical study is to develop an in-vitro diagnostic test for ATE. The BRAINBox TBI Test will be developed in the current clinical study to serve as an aid in evaluation of patients with ATE by incorporating blood protein biomarkers, clinical assessments, and tools to measure, identify, and define associated pathologic evidence and neurocognitive impairments. This protocol proposes to collect data on TBI subjects by a multi-modality approach that includes serum biomarkers, clinical assessments, neurocognitive performance, and neuropsychological characteristics, to determine the accuracy of the BRAINBox TBI test as an aid to the diagnosis of ATE, defined herein, and to objectively determine a patient's risk of developing post-concussive symptoms.

Exploring Paradoxical Lucidity Stories: Working Towards Promoting Meaningful Engagement when Least Expected

Lucidity is the typical cognitive state of adults. However, conditions such as Alzheimer Disease and major neurocognitive disorders can rob people of their usual clarity. Episodes of “paradoxical lucidity” (PL) happen when there is a spontaneous return of lucidity in people who are assumed to have lost the capacity to engage and communicate. These often take place near the end of life. Anecdotal stories depicting PL have been shared for centuries, but the etiology and mechanisms of PL rarely have been examined scientifically. The purpose of this mixed-methods project was to “gather the stories,” of witnessed episodes of PL, to describe them, including potential triggers and contextual supports. Sixty witnesses of episodes have shared their experiences. Two-thirds those displaying PL were female. Most had died within six months of the episode. Episodes generally lasted under an hour (range: “moments” up to 5+ hours). Illustrative descriptions about PL emerged: 1) A trusted person or professional, perhaps unknowingly, saying or doing the right thing could trigger an episode; 2) PL frequently took place in a sacred environment involving ritual spiritual practices (e.g., saying the rosary and singing hymns); 3) meaningful music was often a trigger; and 4) PL sometimes involved the return of one’s professional or familial/friend role. Familiar sounds (e.g., music, voices) were the most common sensory antecedents. A deeper understanding of PL events could potentially drive interventions to promote these valued episodes. The possibility that end-stage neurocognitive impairments could be reversible, even for a short period, is thought-provoking and inspiring.

Silent Strokes May Be Involved in Neurocognitive Impairment in Children With Sickle Cell Disease

Neurological complications are frequent occurrences in children and adolescents with sickle cell disease (SCD). This research has investigated the prevalence of neurovascular and neurocognitive impairments in 17 patients with SCD from Northern Brazil, with aged 6-16 years. Transcranial Doppler Ultrasound (TDU) examinations were performed on patients employing the STOP protocol as a risk score to predict stroke. Neuropsychological assessments were also performed: the Wechsler Intelligence Scale for Children - 4th Edition (WISC-IV). Fisher's Exact Test was used for statistical analyses (p ≤0.05) of the collected dataset. Frequent headaches were a common clinical finding, occurring in over 75% of the children. There were no alterations in cerebral hemodynamics on TDU for over 70% of the patients. In general, patients had below-average scores on most cognitive domains. There was a tendency for correlation between transcranial Doppler results and the WISC-IV indices of total Intelligence Quotient (p = 0.069) and Processing Speed Index (p = 0.082). Conclusion: Most SCD patients showed impairments on cognitive tests, but there was no statistically significant correlation between the presence of neurovascular damage and worse performance on the tests.

Neurodevelopmental Processes in the Prefrontal Cortex Derailed by Chronic HIV-1 Viral Protein Exposure

Due to the widespread access to, and implementation of, combination antiretroviral therapy, individuals perinatally infected with human immunodeficiency virus type 1 (HIV-1) are living into adolescence and adulthood. Perinatally infected adolescents living with HIV-1 (pALHIV) are plagued by progressive, chronic neurocognitive impairments; the pathophysiological mechanisms underlying these deficits, however, remain understudied. A longitudinal experimental design from postnatal day (PD) 30 to PD 180 was utilized to establish the development of pyramidal neurons, and associated dendritic spines, from layers II-III of the medial prefrontal cortex (mPFC) in HIV-1 transgenic (Tg) and control animals. Three putative neuroinflammatory markers (i.e., IL-1β, IL-6, and TNF-α) were evaluated early in development (i.e., PD 30) as a potential mechanism underlying synaptic dysfunction in the mPFC. Constitutive expression of HIV-1 viral proteins induced prominent neurodevelopmental alterations and progressive synaptodendritic dysfunction, independent of biological sex, in pyramidal neurons from layers II-III of the mPFC. From a neurodevelopmental perspective, HIV-1 Tg rats exhibited prominent deficits in dendritic and synaptic pruning. With regards to progressive synaptodendritic dysfunction, HIV-1 Tg animals exhibited an age-related population shift towards dendritic spines with decreased volume, increased backbone length, and decreased head diameter; parameters associated with a more immature dendritic spine phenotype. There was no compelling evidence for neuroinflammation in the mPFC during early development. Collectively, progressive neuronal and dendritic spine dysmorphology herald synaptodendritic dysfunction as a key neural mechanism underlying chronic neurocognitive impairments in pALHIV.

Altered Functional Connectivity of the Nucleus Accumbens Network Between Deficit and Non-deficit Schizophrenia

Deficit schizophrenia (DS), which is marked by stable negative symptoms, is regarded as a homogeneous subgroup of schizophrenia. While DS patients have structurally altered nucleus accumbens (NAcc) compared to non-deficit schizophrenia (NDS) patients and healthy individuals, the investigation of NAcc functional connectivity (FC) with negative symptoms and neurocognition could provide insights into the pathophysiology of schizophrenia. 58 DS, 93 NDS, and 113 healthy controls (HCs) underwent resting-state functional magnetic resonance (rsfMRI). The right and left NAcc were respectively used as seed points to construct the functional NAcc network in whole-brain FC analysis. ANCOVA compared the differences in NAcc network FC and partial correlation analysis explored the relationships between altered FC of NAcc, negative symptoms and neurocognition. Compared to HCs, both DS and NDS patients showed decreased FC between the left NAcc (LNAcc) and bilateral middle cingulate gyrus, and between the right NAcc (RNAcc) and right middle frontal gyrus (RMFG), as well as increased FC between bilateral NAcc and bilateral lingual gyrus. Moreover, the FC between the LNAcc and bilateral calcarine gyrus (CAL) was lower in the DS group compared to NDS patients. Correlation analysis indicated that FC value of LNAcc-CAL was negatively correlated to negative symptoms. Furthermore, aberrant FC values within the NAcc network were correlated with severity of clinical symptoms and neurocognitive impairments in DS and NDS patients. This study demonstrated abnormal patterns of FC in the NAcc network between DS and NDS. The presence of altered LNAcc-CAL FC might be involved in the pathogenesis of negative symptoms in schizophrenia.

Synergistic Impairment of the Neurovascular Unit by HIV-1 Infection and Methamphetamine Use: Implications for HIV-1-Associated Neurocognitive Disorders

The neurovascular units (NVU) are the minimal functional units of the blood­–brain barrier (BBB), composed of endothelial cells, pericytes, astrocytes, microglia, neurons, and the basement membrane. The BBB serves as an important interface for immune communication between the brain and peripheral circulation. Disruption of the NVU by the human immunodeficiency virus-1 (HIV-1) induces dysfunction of the BBB and triggers inflammatory responses, which can lead to the development of neurocognitive impairments collectively known as HIV-1-associated neurocognitive disorders (HAND). Methamphetamine (METH) use disorder is a frequent comorbidity among individuals infected with HIV-1. METH use may be associated not only with rapid HIV-1 disease progression but also with accelerated onset and increased severity of HAND. However, the molecular mechanisms of METH-induced neuronal injury and cognitive impairment in the context of HIV-1 infection are poorly understood. In this review, we summarize recent progress in the signaling pathways mediating synergistic impairment of the BBB and neuronal injury induced by METH and HIV-1, potentially accelerating the onset or severity of HAND in HIV-1-positive METH abusers. We also discuss potential therapies to limit neuroinflammation and NVU damage in HIV-1-infected METH abusers.