Blood brain barrier disruption and glutamatergic excitotoxicity in post-acute sequelae of SARS COV-2 infection cognitive impairment: potential biomarkers and a window into pathogenesis.

Objective: To investigate the association between blood-brain barrier permeability, brain metabolites, microstructural integrity of the white matter, and cognitive impairment (CI) in post-acute sequelae of SARS-COV-2 infection (PASC). Methods: In this multimodal longitudinal MRI study 14 PASC participants with CI and 10 healthy controls were enrolled. All completed investigations at 3 months following acute infection (3 months ± 2 weeks SD), and 10 PASC participants completed at 12 months ± 2.22 SD weeks. The assessments included a standard neurological assessment, a cognitive screen using the brief CogState battery and multi-modal MRI derived metrics from Dynamic contrast enhanced (DCE) perfusion Imaging, Diffusion Tensor Imaging (DTI), and single voxel proton Magnetic Resonance Spectroscopy. These measures were compared between patients and controls and correlated with cognitive scores. Results: At baseline, and relative to controls, PASC participants had higher K-Trans and Myo-inositol, and lower levels of Glutamate/Glutamine in the frontal white matter (FWM) (p < 0.01) as well as in brain stem (p < 0.05), and higher FA and lower MD in the FWM (p < 0.05). In PASC participants, FA and MD decreased in the FWM at 12 months compared to baseline (p < 0.05). K-Trans and metabolite concentrations did not change significantly over time. Neurocognitive scores did not correlation with the increased permeability (K trans). Interpretation: PASC with CI is associated with BBB impairment, loss of WM integrity, and inflammation at 3 months which significantly but not uniformly improved at 12 months. The loss of WM integrity is possibly mediated by BBB impairment and associated glutamatergic excitotoxicity.

HIV associated neurocognitive disorder screening and diagnosis pathways in Australia: a scoping review and international implications.

Symptomatic HIV-associated neurocognitive disorder (HAND) is a complication of HIV (cognitive impairment, difficulties with everyday functioning). If detected early, interventions assist with optimizing care, avoiding rapid decline and enhancing coping. There remains inconsistency surrounding screening/diagnosis information within Australian healthcare professionals and community settings. A scoping review of academic literature, government policies and non-government organisations (NGOs) was conducted to map existing screening/diagnosis information using the guidelines of Joanna Briggs Institute. A literature search of EBSCOhost and Medline (dates: 2015-2021), the Australian government NGO web domains, Google and unpublished academic works was conducted (July 2021) and updated (December 2022) to identify Australian items (past 5 years). Seventeen items met the inclusion criteria. No government guidelines were identified. Various HIV-related organisations proposed different diagnostic guidelines. Most HAND research originated in Sydney. The most accessible information was from Dementia Australia, with some inaccuracies noted. There is scant Australian research/information on HAND screening/diagnosis. HAND translational research and screening/diagnosis standards are urgently needed to inform best practices. The Australian context is used to discuss international implications regarding higher-income countries with similar patterns/healthcare.

Factors associated with prolonged COVID-related PTSD-like symptoms among adults diagnosed with mild COVID-19 in Poland.

COVID-19 has been considered a possible cause of post-traumatic stress disorder (PTSD) or similar conditions. However, what specific disease symptoms may contribute most to prolonged PTSD-like symptoms in COVID-19 survivors is unclear. The study aimed to present the factor structure of COVID-19 symptoms and identify which symptoms of COVID-19 best explain the subsequent presence of PTSD-like symptoms in mild COVID-19 survivors. COVID-positive adults (n = 341) completed online self-report scales at the baseline assessment (T1) and after approximately 4 months (T2), including The Patient Health Questionnaire Anxiety-Depression Scale; The Scale of Psychosocial Experience Related to COVID-19, The Primary Care PTSD Screen for DSM-5; and self-designed questionnaires evaluating the severity of COVID-related medical and neurocognitive symptoms and pre-pandemic variables. Exploratory factor analysis revealed five factors of COVID-19 symptoms: flu-like, respiratory, cold, neurological, and neurocognitive. Hierarchical logistic regression showed that besides selected control variables (anxiety and depression, presence of PTSD-like symptoms, COVID-related stigma in T1), neurocognitive symptoms of COVID-19 in T1 but not other symptoms of the disease were a significant predictor of the presence of PTSD-like symptom in T2. Findings suggest a need for a comprehensive neurocognitive assessment of people diagnosed with COVID-19 and prompt interventions targeting the prevention of potential risks for long-term PTSD-like states at the community level.

Psychosocial risk factors and cognitive decline in people living with HIV: results from the Malaysian HIV and aging (MHIVA) study.

HIV-associated mortality has improved with the advent of antiretroviral therapy, yet neurocognitive decline persists. We assessed the association between psychosocial risk factors and cognitive function among Malaysian PLWH. Data of virally suppressed PLWH (n = 331) on stable ART, from the Malaysian HIV and Aging study was assessed. Psychosocial factors were assessed using the Lubben Social Network Scale-6 (social isolation) and Depression Anxiety Stress Scale-21 (DASS-21). The Montreal Cognitive Assessment (MoCA) with normative standards for the Malaysian population was used to determine cognitive function. Linear and logistic regression were used to assess the associations between cognition, and psychosocial risk factors. Median age of participants was 43.8 years (IQR 37.7-51.0). Participants were predominantly male (82.8%), with secondary education or higher (85.2%). Participants were on ART for 5.7 years (IQR 3.0-9.7), with a mean MoCA score of 24.6 (±3.7). Social isolation was found in 34.6% of participants, and severe depression, severe stress, and severe anxiety in 10.6%, 15.4%, and 6.0% respectively. After adjusting for demographic, clinical, and HIV parameters, MoCA scores were significantly associated with severe stress (ß = -0.11, p = 0.02) and having marginal friendship ties (ß = -0.13, p = 0.03). Social isolation and severe stress are associated with neurocognitive impairment in PLWH.

The kynurenine pathway relates to post-acute COVID-19 objective cognitive impairment and PASC.

OBJECTIVE: To determine the prevalence and natural history of post-acute COVID-19 objective cognitive impairment and function, and their relationship to demographic, clinical factors, post-acute sequelae of COVID-19 (PASC), and biomarkers. METHODS: A total of 128 post-acute COVID-19 patients (age = 46 ± 15; 42% women, acute disease severity: not hospitalized: 38.6% mild: 0-1 symptoms, 52% 2+ symptoms; 9.4% hospitalized) completed standard cognition, olfaction, and mental health examinations 2-, 4-, and 12-month post diagnosis. Over the same time frame, WHO-defined PASC was determined. Blood cytokines, peripheral neurobiomarkers, and kynurenine pathway (KP) metabolites were measured. Objective cognitive function was demographically/practice corrected, and impairment prevalence was determined using the evidence-based Global Deficit Score method to detect at least mild cognitive impairment (GDS > 0.5). Linear mixed effect regression models with time effect (month post diagnosis) evaluated the relationships to cognition. RESULTS: Across the 12-month study period, mild to moderate cognitive impairment ranged from 16% to 26%, and 46.5% were impaired at least once. Impairment associated with poorer work capacity (p < 0.05), and 2-month objectively tested anosmia (p < 0.05). PASC with (p = 0.01) and without disability (p < 0.03) associated with acute COVID-19 severity. KP measures showed prolonged activation (2 to 8 months) (p < 0.0001) linked to IFN-beta in those with PASC. Of the blood analytes, only the KP metabolites (elevated quinolinic acid, 3-hydroxyanthranilic acid, kynurenine, the kynurenine/tryptophan ratio) associated (p < 0.001) with poorer cognitive performance and greater likelihood of impairment. PASC, independent of disability associated with abnormal kynurenine/tryptophan (p < 0.03). INTERPRETATION: The kynurenine pathway relates to post-acute COVID-19 objective cognitive impairment and PASC, thereby enabling biomarker and therapeutic possibilities.

The comorbidity of depression and neurocognitive disorder in persons with HIV infection: call for investigation and treatment.

Depression and neurocognitive disorder continue to be the major neuropsychiatric disorders affecting persons with HIV (PWH). The prevalence of major depressive disorder is two to fourfold higher among PWH than the general population (∼6.7%). Prevalence estimates of neurocognitive disorder among PWH range from 25 to over 47% - depending upon the definition used (which is currently evolving), the size of the test battery employed, and the demographic and HIV disease characteristics of the participants included, such as age range and sex distribution. Both major depressive disorder and neurocognitive disorder also result in substantial morbidity and premature mortality. However, though anticipated to be relatively common, the comorbidity of these two disorders in PWH has not been formally studied. This is partly due to the clinical overlap of the neurocognitive symptoms of these two disorders. Both also share neurobehavioral aspects - particularly apathy - as well as an increased risk for non-adherence to antiretroviral therapy. Shared pathophysiological mechanisms potentially explain these intersecting phenotypes, including neuroinflammatory, vascular, and microbiomic, as well as neuroendocrine/neurotransmitter dynamic mechanisms. Treatment of either disorder affects the other with respect to symptom reduction as well as medication toxicity. We present a unified model for the comorbidity based upon deficits in dopaminergic transmission that occur in both major depressive disorder and HIV-associated neurocognitive disorder. Specific treatments for the comorbidity that decrease neuroinflammation and/or restore associated deficits in dopaminergic transmission may be indicated and merit study.

The Evolution of Assessing Central Nervous System Complications in Human Immunodeficiency Virus: Where Do We Go From Here?

In this fifth decade of the human immunodeficiency virus (HIV) epidemic, central nervous system (CNS) complications including cognitive impairment and mental health remain a burden for people with HIV (PWH) on antiretroviral therapy. Despite the persistence of these complications, which often co-occur, the underlying pathophysiology remains elusive and consequently treatments remain limited. To continue to grow our understanding of the underlying mechanisms of CNS complications among PWH, there is a need to reexamine our current approaches, which are now more than 2 decades old. At the 2021 National Institutes of Health-sponsored meeting on Biotypes of CNS Complications in PWH, the Neurobehavioral Working Group addressed the following: (1) challenges inherent to determining CNS complications; (2) heterogeneity in CNS complications; and (3) problems and solutions for examining integrated biotypes. The review below provides a summary of the main points presented and discussed by the Neurobehavioral Working Group at the meeting.

Novel magnetic resonance KTRANS measurement of blood-brain barrier permeability correlated with covert HE.

BACKGROUND: Using dynamic contrast-enhanced (DCE) MR perfusion and MR spectroscopy this study aimed to characterize the blood-brain barrier permeability and metabolite changes in patients with cirrhosis and without covert HE. METHODS: Covert HE was defined using psychometric HE score (PHES). The participants were stratified into 3 groups: cirrhosis with covert HE (CHE) (PHES<-4); cirrhosis without HE (NHE) (PHES≥-4); and healthy controls (HC). Dynamic contrast-enhanced MRI and MRS were performed to assess KTRANS, a metric derivative of blood-brain barrier disruption, and metabolite parameters. Statistical analysis was performed using IBM SPSS (v25). RESULTS: A total of 40 participants (mean age 63 y; male 71%) were recruited as follows: CHE (n=17); NHE (n=13); and HC (n=10). The KTRANS measurement in the frontoparietal cortex demonstrated increased blood-brain barrier permeability, where KTRANS was 0.01±0.02 versus 0.005±0.005 versus 0.004±0.002 in CHE, NHE, and HC patients, respectively (p = 0.032 comparing all 3 groups). Relative to HC with a value of 0.28, the parietal glutamine/creatine (Gln/Cr) ratio was significantly higher in both CHE 1.12 mmoL (p < 0.001); and NHE 0.49 (p = 0.04). Lower PHES scores correlated with higher glutamine/Cr (Gln/Cr) (r=-0.6; p < 0.001) and lower myo-inositol/Cr (mI/Cr) (r=0.6; p < 0.001) and lower choline/Cr (Cho/Cr) (r=0.47; p = 0.004). CONCLUSION: The dynamic contrast-enhanced MRI KTRANS measurement revealed increased blood-brain barrier permeability in the frontoparietal cortex. The MRS identified a specific metabolite signature with increased glutamine, reduced myo-inositol, and choline, which correlated with CHE in this region. The MRS changes were identifiable in the NHE cohort.

Meaningful cognitive decline is uncommon in virally suppressed HIV, but sustained impairment, subtle decline and abnormal cognitive aging are not.

Background: High antiretroviral therapy (ART) coverage and viral suppression among people with HIV (PWH) in Australia provide a unique context to study individual cognitive trajectories, cognitive aging and factors associated with longitudinal cognitive function during chronic and stable HIV disease. Methods: Participants from the Predictors of Adherence to Antiretroviral Therapy study (n = 457, recruited between September 2013 and November 2015, median age = 52 years, and all with HIV RNA <50 copies mL) completed a cognitive assessment with CogState Computerized Battery (CCB) at baseline, Month-12, and Month-24. Demographics, psycho-social and socioeconomic factors, healthcare seeking behaviors, HIV disease characteristics and comorbidities were assessed. The CCB data were corrected for age, sex and practice effect and averaged into a global z-score (GZS). Cognitive impairment was defined with the global deficit score method (GDS>0.5). Meaningful cognitive change was statistically defined (decline or improvement versus stability, i.e., 90% CI, that is p < 0.05, 2-tailed) using a novel evidence-based change score: the linear mixed-effect regression (LMER)-based GZS change score. A separate LMER model with a top-down variable selection approach identified the independent effects of age and other demographic, HIV disease characteristics, socioeconomic and health-related factors on the demographically corrected GZS. The combined definitions of change and cross-sectional impairment enabled the identification of cognitive trajectories. Findings: At Month-12 and Month-24, 6% and 7% showed meaningful cognitive decline and 4% and 3% improved respectively. Only 1% showed sustained decline. Incident impairment due to subtle cognitive decline (i.e., below the threshold of meaningful cognitive decline) was 31% and 25% at Month-12 and Month-24, while 14% showed sustained impairment (i.e., cognitively impaired at all study visits). Older age (≥50 years) and time interaction was associated with lower demographically corrected GZS (ß = -0.31, p < 0.001). Having a regular relationship, excellent English proficiency, and perceived stigma (avoidance) were associated with higher GZS (all p < 0.05). Relying on government subsidy, severe depression, and lower belief in ART necessity and higher concerns were associated with lower GZS (all p < 0.05). No HIV disease characteristics had a significant effect. Interpretations: Meaningful cognitive decline was not different from normal expectation in chronic stable HIV disease. Despite this, subtle cognitive decline, sustained cognitive impairment, and greater than normative-age cognitive aging were evident. Funding: Funding for the PAART study was provided in part by unrestricted educational grants from Gilead Sciences (www.gilead.com) (Grant Number: IN-AU-264- 0131), the Balnaves Foundation (www.balnavesfoundation.com), the Victorian Department of Health and Human Services (Australia) (www.dhs.vic.gov.au/home), Western Australia Health (www.health.wa.gov.au), the ACT Ministry of Health (Australia) (www.health.act.gov.au), and in-kind support from the Queensland Department of Health (Australia) (www.health.qld.gov.au), and NHMRC Partnership grant APP1058474 (PI: Carr, Andrew).

Low incidence of advanced neurological burden but high incidence of age-related conditions that are dementia risk factors in aging people living with HIV: a data-linkage 10-year follow-up study.

Although increasing research is focusing on age-related comorbidities (ARC) among people living with HIV (PLHIV), no studies have concomitantly assessed non-HIV age-related neurological disorders (e.g., Alzheimer's dementia). A total of 254 PLHIV and 69 HIV-negative controls completed baseline medical history and cognitive testing. ARC data were collected from medical records over the subsequent 9-10 years and included all types of strokes, all types of dementia, mild cognitive impairment, Parkinson's disease, motor neuron disease (grouped into a non-HIV age-related neurological category), cardiovascular disease, chronic kidney disease, chronic liver disease, chronic lung disease, non-AIDS cancers, osteoporosis, and diabetes. Kaplan-Meier curves assessed differences in the incident rates (per 1000 person year) of groups of ARC as defined above and combined ARC (i.e., development of any of the ARC) among younger (baseline age < 50) and older (baseline age ≥ 50) PLHIV and younger and older controls. Cox-proportional hazard models assessed the individual and interaction effects of HIV status and chronological age, in addition to a range of demographic and clinical variables including historical and baseline HIV brain involvement on the risk of developing combined ARC. Older PLHIV had a higher incidence of cardiovascular disease, osteoporosis, and combined ARC compared to other groups (p < 0.05). Incident rate of non-HIV age-related neurological disorders was 2.3 [0.93, 4.79] per 1000 person year. While this incident rate was higher in older PLHIV (5.37 [1.97, 11.92]) than older HIV-negative participants (3.58 [0.18-17.67]), this was not significant. In multivariate analyses, HIV status and chronological age, but not their interaction, and smoking were associated with higher risk of combined ARC (p < 0.05). In analyses focusing on PLHIV, older age and taking abacavir/efavirenz/atazanavir/darunavir containing antiretroviral treatments at the time of diagnosis were associated with greater ARC (p < 0.05). Non-HIV age-related neurological disorders are uncommon in older PLHIV, where the majority were < 70 years of age at the end of follow-up. However, the greater burden of ARC among older PLHIV, most of which are established dementia risk factors, warrants the establishment of commensurate prevention strategies and greater attention to neurocognitive screening.

Current Challenges and Solutions for Clinical Management and Care of People with HIV: Findings from the 12th Annual International HIV and Aging Workshop.

People with HIV on combination antiretroviral therapy (ART) have longer life expectancy and are increasingly experiencing age-related comorbidities. Thus, aging with HIV has become a central issue in clinical care and research, which has been particularly challenging with the intersection of the ongoing coronavirus (COVID)-19 pandemic. Since 2009, the International Workshop on HIV and Aging has served as a multidisciplinary platform to share research findings from cross-disciplinary fields along with community advocates to address critical issues in HIV and aging. In this article, we summarize the key oral presentations from the 12th Annual International Workshop on HIV and Aging, held virtually on September 23rd and 24th, 2021. The topics ranged from basic science research on biological mechanisms of aging to quality of life and delivery of care under the COVID-19 pandemic. This workshop enriched our understanding of HIV and aging under the COVID-19 pandemic, identified challenges and opportunities to combat the impact of COVID-19 on HIV communities, and also provided updated research and future directions of the field to move HIV and aging research forward, with the ultimate goal of successful aging for older people with HIV.

Elevation of cell-associated HIV-1 transcripts in CSF CD4+ T cells, despite effective antiretroviral therapy, is linked to brain injury.

Antiretroviral therapy (ART) can attain prolonged undetectable HIV-1 in plasma and cerebrospinal fluid (CSF), but brain injury remains prevalent in people living with HIV-1 infection (PLHIV). We investigated cell-associated (CA)-HIV-1 RNA transcripts in cells in CSF and blood, using the highly sensitive Double-R assay, together with proton Magnetic Resonance Spectroscopy (1H MRS) of major brain metabolites, in sixteen PLHIV. 14/16 CSF cell samples had quantifiable CA-HIV-1 RNA, at levels significantly higher than in their PBMCs (median 9,266 vs 185 copies /106 CD4+ T-cells; p<0.0001). In individual PLHIV, higher levels of HIV-1 transcripts in CSF cells were associated with greater brain injury in the frontal white matter (Std ß=-0.73; p=0.007) and posterior cingulate (Std ß=-0.61; p=0.03). 18-colour flow cytometry revealed that the CSF cells were 91% memory T-cells, equally CD4+ and CD8+ T-cells, but fewer B cells (0.4 %), and monocytes (3.1%). CXCR3+CD49d+integrin ß7-, CCR5+CD4+ T-cells were highly enriched in CSF, compared with PBMC (p <0.001). However, CA-HIV-1 RNA could not be detected in 10/16 preparations of highly purified monocytes from PBMC, and was extremely low in the other six. Our data show that elevated HIV-1 transcripts in CSF cells were associated with brain injury, despite suppressive ART. The cellular source is most likely memory CD4+ T cells from blood, rather than trafficking monocytes. Future research should focus on inhibitors of this transcription to reduce local production of potentially neurotoxic and inflammatory viral products.

Prognostic indicators and outcomes of hospitalised COVID-19 patients with neurological disease: An individual patient data meta-analysis.

BACKGROUND: Neurological COVID-19 disease has been reported widely, but published studies often lack information on neurological outcomes and prognostic risk factors. We aimed to describe the spectrum of neurological disease in hospitalised COVID-19 patients; characterise clinical outcomes; and investigate factors associated with a poor outcome. METHODS: We conducted an individual patient data (IPD) meta-analysis of hospitalised patients with neurological COVID-19 disease, using standard case definitions. We invited authors of studies from the first pandemic wave, plus clinicians in the Global COVID-Neuro Network with unpublished data, to contribute. We analysed features associated with poor outcome (moderate to severe disability or death, 3 to 6 on the modified Rankin Scale) using multivariable models. RESULTS: We included 83 studies (31 unpublished) providing IPD for 1979 patients with COVID-19 and acute new-onset neurological disease. Encephalopathy (978 [49%] patients) and cerebrovascular events (506 [26%]) were the most common diagnoses. Respiratory and systemic symptoms preceded neurological features in 93% of patients; one third developed neurological disease after hospital admission. A poor outcome was more common in patients with cerebrovascular events (76% [95% CI 67-82]), than encephalopathy (54% [42-65]). Intensive care use was high (38% [35-41]) overall, and also greater in the cerebrovascular patients. In the cerebrovascular, but not encephalopathic patients, risk factors for poor outcome included breathlessness on admission and elevated D-dimer. Overall, 30-day mortality was 30% [27-32]. The hazard of death was comparatively lower for patients in the WHO European region. INTERPRETATION: Neurological COVID-19 disease poses a considerable burden in terms of disease outcomes and use of hospital resources from prolonged intensive care and inpatient admission; preliminary data suggest these may differ according to WHO regions and country income levels. The different risk factors for encephalopathy and stroke suggest different disease mechanisms which may be amenable to intervention, especially in those who develop neurological symptoms after hospital admission.

Abnormal cognitive aging in people with HIV: evidence from data integration between two countries' cohort studies.

OBJECTIVES: Previous research has shown inconsistent results on whether cognitive aging is abnormal in people with HIV (PWH) because of low sample size, cross-sectional design, and nonstandard neuropsychological methods. To address these issues, we integrated data from two longitudinal studies: Australian HIV and Brain Ageing Research Program ( N  = 102) and CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study ( N  = 924) and determined the effect of abnormal aging on neurocognitive impairment (NCI) among PWH. METHODS: Both studies used the same neuropsychological test battery. NCI was defined based on demographically corrected global deficit score (≥0.5 = impaired). Both studies also assessed comorbidities, neuropsychiatric conditions and functional status using similar tools. To determine the cross-sectional and longitudinal effects of age on the risk of NCI, a generalized linear mixed-effect model tested main and interaction effects of age group (young, <50 vs. old, ≥50) and time on NCI adjusting the effects of covariates. RESULTS: Older PWH had 83% higher chance of NCI compared with younger PWH [odds ratio (OR) = 1.83 (1.15-2.90), P  < 0.05]. Older participants also had a greater risk of increases in NCI over the follow-up [OR = 1.66 (1.05-2.64), P  < 0.05] than younger participants. Nonwhite ethnicity ( P  < 0.05), having a contributing ( P  < 0.05) or confounding ( P  < 0.001) comorbidity, greater cognitive symptoms ( P  < 0.001), and abnormal creatinine level ( P  < 0.05), plasma viral load greater than 200 copies/ml ( P  < 0.05), being from the Australian cohort ( P  < 0.05) were also associated with a higher risk of NCI. CONCLUSION: Data integration may serve as a strategy to increase sample size and study power to better assess abnormal cognitive aging effect in PWH, which was significant in the current study.

Blood pressure change and cognition in childhood and early adulthood: a systematic review.

Introduction: High blood pressure in midlife is an established risk factor for cognitive decline and dementia but less is known about the impact of raised blood pressure on cognition in childhood and early adulthood. Method: We systematically reviewed and quantified the existing evidence base relating to blood pressure in early life and subsequent cognitive performance. Medline, Embase, PsycINFOo, Scopus, and Web of Science were searched from inception to July 2020. We included longitudinal cohort and case-control studies involving participants aged 0-40 years with a baseline and at least one follow-up blood pressure assessment alongside at least one measure of cognition, occurring at the same time as, or subsequent to blood pressure measures. Risk of bias was assessed independently by two reviewers. PROSPERO registration CRD42020214655. Results: Of a total of 5638 records identified, three cohort and two case-control studies were included with ages ranging from 3 to early 30s. Repeated blood pressure measurements averaged over 25 years or cumulative blood pressure in the 25-30 years prior to assessment of cognitive function were associated with poorer cognitive performance in the two largest cohort studies. The smallest cohort study reported no evidence of an association and the results from the two case-control studies were contradictory. All studies were at risk of bias. Conclusion: Overall, the evidence in this area is lacking and study quality is mixed. Our review highlights an urgent need for studies evaluating the potential for a relationship between raised blood pressure and poorer cognition in early life given the potential for possible risk reduction if such a relationship exists.

Lack of cognitive impairment in long-term survivors of colorectal cancer.

BACKGROUND: Our longitudinal study reported cognitive impairment in 43% of people following diagnosis of localised colorectal cancer (CRC) versus 15% in healthy controls (p < 0.001) and 50% versus 13% 1-2 years later (p < 0.001). Here we evaluate cognitive function and neuroimaging in a subgroup at long-term follow-up. PATIENTS AND METHODS: Cancer-free Australian participants in the study, and controls, completed cognitive and functional assessments. Neuroimaging was optional. Blood tests included inflammatory markers, clotting factors, sex hormones and apolipoprotein E genotype. The primary endpoint was demographically and practice effect-corrected cognitive scores comparing CRC survivors with controls over time examined using a linear mixed model, adjusted for baseline performance. Secondary endpoints included cognitive impairment rate using the Global Deficit Score [GDS > 0.5], Functional Deficit Score, blood results and neuroimaging. RESULTS: The study included 25 CRC survivors (60% men, median age 72) at mean 9 years after baseline (9 received adjuvant chemotherapy) and 25 controls (44% men, median age 68) at mean 6 years after baseline. There were no significant differences in cognitive scores or proportion with cognitive impairment (16 vs. 8%) between survivors and controls and no evidence of accelerated ageing in CRC survivors. Baseline cognitive performance predicted for subsequent cognitive function. There were no differences in functional tests or blood tests between groups. In 18 participants undergoing neuroimaging, 10 CRC survivors had higher myoinositol levels than 8 controls, and lower volume in the right amygdala and caudate and left hippocampal regions. CONCLUSIONS: There was no difference in cognitive capacity and function between CRC survivors and controls 6-12 years after diagnosis. Differences in neuroimaging require confirmation in a larger sample. HIGHLIGHTS: • No evidence of long term cognitive impairment in colorectal cancer survivors compared to controls 6-12 years after diagnosis • No evidence of accelerated cognitive ageing in colorectal cancer survivors • No evidence of long-term functional impairment in colorectal cancer survivors.

Brain aging and cardiovascular factors in HIV: a longitudinal volume and shape MRI study.

OBJECTIVE: We aimed to examine the relative contributions of HIV infection, age, and cardiovascular risk factors to subcortical brain atrophy in people with HIV (PWH). DESIGN: Longitudinal observational study. METHODS: Virally suppressed PWH with low neuropsychological confounds (n  = 75) and demographically matched HIV-negative controls (n = 31) completed baseline and 18-month follow-up MRI scans, neuropsychological evaluation, cardiovascular assessments, and HIV laboratory tests. PWH were evaluated for HIV-associated neurocognitive disorder (HAND). Subcortical volumes were extracted with Freesurfer after removal of white matter hyperintensities. Volumetric and shape analyses were conducted using linear mixed-effect models incorporating interactions between age, time, and each of HIV status, HAND status, HIV disease factors, and cardiovascular markers. RESULTS: Across baseline and follow-up PWH had smaller volumes of most subcortical structures compared with HIV-negative participants. In addition, over time older PWH had a more rapid decline in caudate volumes (P  = 0.041), predominantly in the more severe HAND subgroups (P = 0.042). Higher CD4+ cell counts had a protective effect over time on subcortical structures for older participants with HIV. Increased cardiovascular risk factors were associated with smaller volumes across baseline and follow-up for most structures, although a more rapid decline over time was observed for striatal volumes. There were no significant shape analyses findings. CONCLUSION: The study demonstrates a three-hit model of general (as opposed to localized) subcortical injury in PWH: HIV infection associated with smaller volumes of most subcortical structures, HIV infection and aging synergy in the striatum, and cardiovascular-related injury linked to early and more rapid striatal atrophy.

Prevalence, Demographic Correlates, and Medical Correlates of Cognitive Impairment Among Iranian People Living With HIV: A Cross-sectional Survey Study.

ABSTRACT: While taking antiretroviral therapy, 30%-60% of people living with HIV (PLWH) experience neurocognitive impairment (NCI). To determine NCI prevalence among Iranian PLWH, by the computerized Vienna Test System, 63 adults living without HIV and 63 Iranian PLWH aged 18-50 years ( M = 35.3, SD = 7.9) were assessed for cognitive function. NCI was determined by receiver operating characteristic curve cutoff points based on the adults living without HIV. Associations between demographics, HIV serostatus markers, and mean T-scores were investigated. Performance differences were tested by including significant covariates in an analysis of covariance. NCI prevalence rates were 57.14% in PLWH and 19.05% in adults living without HIV. Global neurocognitive performance and all cognitive domains were significantly different between the groups, except for visual memory and selective attention. In Iran, NCI prevalence parallels that reported in PLWH worldwide. There should be a strategy to screen Iranian PLWH for NCI.