Lithium Exposure and Risk of Major Neurocognitive Disorders: A Systematic Review and Meta-analysis.

BACKGROUND: Published studies on the association between lithium use and the decreased risk of major neurocognitive disorders (MNCDs) have shown disparities in their conclusions. We aimed to provide updated evidence of this association. METHODS: A comprehensive literature search was performed in PubMed, EMBASE, and Cochrane Library from inception until August 31, 2023. All the observational studies evaluating the association between lithium use and MNCD risk were eligible for inclusion. Pooled odds ratios (ORs) and 95% prediction intervals were computed using random-effects models. RESULTS: Eight studies with 377,060 subjects were included in the analysis. In the general population on the association between lithium use versus nonuse and dementia, the OR was 0.94 (95% confidence interval [CI] = 0.77-1.24). Further analysis also demonstrated that lithium use was not associated with an increased risk of Alzheimer's disease (OR = 0.69, 95% CI: 0.31-1.65). When the analysis was restricted to individuals with bipolar disorder to reduce the confounding by clinical indication, lithium exposure was also not associated with a decreased risk of MNCD (OR = 0.9, 95% CI = 0.71-1.15). CONCLUSION: The results of this systematic review and meta-analysis do not support a significant association between lithium use and the risk of MNCD.

Diabetes mellitus in older persons with neurocognitive disorder: overtreatment prevalence and associated structural brain MRI findings.

BACKGROUND: Tight diabetes control is often applied in older persons with neurocognitive disorder resulting in increased hypoglycemic episodes but little is known about the pattern of brain injury in these overtreated patients. This study aims to: (a) quantify the prevalence of diabetes overtreatment in cognitively impaired older adults in a clinical population followed in an academic memory clinic (b) identify risk factors contributing to overtreatment; and (c) explore the association between diabetes overtreatment and specific brain region volume changes. METHODS: Retrospective study of older patients with type 2 diabetes and cognitive impairment who were diagnosed in a memory clinic from 2013 to 2020. Patients were classified into vulnerable and dependent according to their health profile. Overtreatment was defined when glycated hemoglobin was under 7% for vulnerable and 7.6% for dependent patients. Characteristics associated to overtreatment were examined in multivariable analysis. Grey matter volume in defined brain regions was measured from MRI using voxel-based morphometry and compared in patients over- vs. adequately treated. RESULTS: Among 161 patients included (median age 76.8 years, range 60.8-93.3 years, 32.9% women), 29.8% were considered as adequately treated, 54.0% as overtreated, and 16.2% as undertreated. In multivariable analyses, no association was observed between diabetes overtreatment and age or the severity of cognitive impairment. Among patients with neuroimaging data (N = 71), associations between overtreatment and grey matter loss were observed in several brain regions. Specifically, significant reductions in grey matter were found in the caudate (adj ß coeff: -0.217, 95%CI: [-0.416 to -0.018], p = .033), the precentral gyri (adj ßcoeff:-0.277, 95%CI: [-0.482 to -0.073], p = .009), the superior frontal gyri (adj ßcoeff: -0.244, 95%CI: [-0.458 to -0.030], p = .026), the calcarine cortex (adj ßcoeff:-0.193, 95%CI: [-0.386 to -0.001], p = .049), the superior occipital gyri (adj ßcoeff: -0.291, 95%CI: [-0.521 to -0.061], p = .014) and the inferior occipital gyri (adj ßcoeff: -0.236, 95%CI: [-0.456 to - 0.015], p = .036). CONCLUSION: A significant proportion of older patients with diabetes and neurocognitive disorder were subjected to excessively intensive treatment. The association identified with volume loss in several specific brain regions highlights the need to further investigate the potential cerebral damages associated with overtreatment and related hypoglycemia in larger sample.

Declining Prevalence of Human Immunodeficiency Virus (HIV)-Associated Neurocognitive Disorders in Recent Years and Associated Factors in a Large Cohort of Antiretroviral Therapy-Treated Individuals With HIV.

BACKGROUND: HIV-associated neurocognitive disorders (HAND) have been suggested as persistent even with effective antiretroviral therapy (ART). Aims were to evaluate HAND prevalence and associated factors, in a large cohort of people-with-HIV (PWH). METHODS: ART-treated PWH, underwent a neuropsychological examination through a battery of 12 tests exploring 5 different domains, between 2009 and 2020, were included in this cross-sectional analysis. HAND were classified according to Frascati's criteria. Participants were defined as complaining or not-complaining if a cognitive complaint was reported or not. Chi-square for trend and multivariable logistic regression were fitted. RESULTS: Overall, 1424 PWH were enrolled during four three-years periods. HAND prevalence was 24%; among complainers (572/1424), it was 38%, higher than among not-complainers (15%). Over the study period, a decreasing HAND prevalence was found in the entire population (P < 0.001) and in complaining (P < 0.001); in not-complaining it remained stable (P = 0.182). Factors associated with HAND were older age, lower educational level, lower current CD4+ T-cell count and HCV co-infection. Compared to nonnucleoside reverse transcriptase inhibitors, receiving dual and integrase strand transfer inhibitor (INSTI)-based therapies was associated with a decreased risk of HAND, as well as being tested in more recent years. CONCLUSIONS: In this large cohort of ART-treated PWH, mostly virologically suppressed, a remarkable decreasing HAND prevalence was observed. Besides HIV- and patient-related factors, the reduced risk of HAND found with dual and INSTI-based regimens along with a more recent ART initiation, could suggest a potential role of new treatment strategies in this decline, due to their greater virologic efficacy and better tolerability.

The Association Between Somatic Symptom Disorders and Neurocognitive Disorders: A Systematic Review.

OBJECTIVE: Onset of neuropsychiatric symptoms in older adults may represent prodromal manifestations of neurodegenerative disorders. The association between the onset of somatic symptom and related disorders (SSRD) and the subsequent development of neurodegenerative disorders remains unclear. A critical review of studies describing the association between SSRD and neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Frontotemporal dementia, and Lewy body dementia was performed. OBJECTIVE: To critically review studies describing the association between SSRD and neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Frontotemporal dementia, and Lewy body dementia. METHODS: A systematic review of Web of Science Core databases was carried out from inception of databases up to May 2021 to identify observational studies pertaining to both SSRD and neurodegenerative disorders. Data was extracted and compiled regarding subjects enrolled, age at onset of the SSRD and at onset of the neurodegenerative disorders, and specific SSRD manifestations and underlying neuropathologies reported. RESULTS: Thirteen articles were included. Of the 123 identified subjects with SSRD at baseline, 34.1% developed a neurodegenerative disorder, with 80.9% of these being a Lewy body spectrum disorder. The interval between onset of SSRD manifestations and subsequent development of a neurodegenerative disorder was less than 3 years for half of the cases. Of the 1,494 subjects with a neurodegenerative disorder at baseline retrieved, SSRD manifestations were reported in 33.4% of Lewy body spectrum disorders cases. Onset of SSRD manifestations antedated or was concomitant to the diagnosis of the Lewy body spectrum disorder in 65.6% of cases. CONCLUSION: While limited, current evidence suggests a possible association between late-onset SSRD and the subsequent development of neurodegenerative disorders, notably Lewy body spectrum disorders.

Prevalence and 1-year incidence of HIV-associated neurocognitive disorder (HAND) in adults aged ≥50 years attending standard HIV clinical care in Kilimanjaro, Tanzania.

OBJECTIVES: HIV-associated neurocognitive disorders (HANDs) are prevalent in older people living with HIV (PLWH) worldwide. HAND prevalence and incidence studies of the newly emergent population of combination antiretroviral therapy (cART)-treated older PLWH in sub-Saharan Africa are currently lacking. We aimed to estimate HAND prevalence and incidence using robust measures in stable, cART-treated older adults under long-term follow-up in Tanzania and report cognitive comorbidities. DESIGN: Longitudinal study. PARTICIPANTS: A systematic sample of consenting HIV-positive adults aged ≥50 years attending routine clinical care at an HIV Care and Treatment Centre during March-May 2016 and followed up March-May 2017. MEASUREMENTS: HAND by consensus panel Frascati criteria based on detailed locally normed low-literacy neuropsychological battery, structured neuropsychiatric clinical assessment, and collateral history. Demographic and etiological factors by self-report and clinical records. RESULTS: In this cohort (n = 253, 72.3% female, median age 57), HAND prevalence was 47.0% (95% CI 40.9-53.2, n = 119) despite well-managed HIV disease (Mn CD4 516 (98-1719), 95.5% on cART). Of these, 64 (25.3%) were asymptomatic neurocognitive impairment, 46 (18.2%) mild neurocognitive disorder, and 9 (3.6%) HIV-associated dementia. One-year incidence was high (37.2%, 95% CI 25.9 to 51.8), but some reversibility (17.6%, 95% CI 10.0-28.6 n = 16) was observed. CONCLUSIONS: HAND appear highly prevalent in older PLWH in this setting, where demographic profile differs markedly to high-income cohorts, and comorbidities are frequent. Incidence and reversibility also appear high. Future studies should focus on etiologies and potentially reversible factors in this setting.

Neurocognitive Disorders in HIV-positive Patients.

Human immunodeficiency viruses (HIV) associated neurocognitive disorders (HAND) encompasses a group of syndromes of various degrees of impairment in cognition and daily functioning of HIV positive individuals. Although the widespread use of highly active antiretroviral therapy (HAART) has drastically reduced the prevalence of severe form of HAND, like HIV associated dementia (HAD), the prevalence of HAND and associated morbidity remains high. OBJECTIVES: (1) To know the prevalence of HAND in HIV-infected patients of a multi-ethnic population. (2) To describe various types of neurocognitive impairment among patients of HAND and study the factors affecting HAND. STUDY DESIGN: This study was a cross-sectional descriptive study conducted on 250 HIV-positive patients in outpatient department (OPD) of a tertiary care center in Mumbai, conducted over a period of 12 months. Patients with HIV-1 attending the OPD and having a minimal formal education of 4 years were included. Patients with concomitant delirium, any known central nervous system (CNS) disorder, any psychiatric disorder, and pregnant females were excluded. Outcome measures-the test batteries used were (1) International HIV Dementia Scale (IHDS) and (2) Addenbrookes cognitive examination-revised (ACE-R) scale. RESULTS: Of 250 subjects studied, 55.6% (139) were males and 44.4 % (111) were females. The mean age of study population was 39.42 years. The mean years of education were 8.32 years. The mean duration of infection (diagnosis of HIV-positive state) was 64.49 months and the mean duration of HAART intake in our patients was 52.30 months. The mean cluster of differentiation 4 (CD4) counts of our subjects were 527.13 per cumm [standard deviation (SD) of 234.13]. The mean nadir CD4 counts were 224.35 per cumm (SD of 115.09). Using the ACE-R scale, the prevalence of HAND was 71.60%, of which 37.20% had an asymptomatic neurological impairment, 29.60% had mild cognitive dysfunction, and 4.80% had HAD. Memory, verbal fluency and visuospatial abilities were the most affected domains on the ACE-R and memory recall and psychomotor speed were affected more on the IHDS. The prevalence of HAND was more with increasing age (p = 0.020), lesser education (p < 0.00) and lesser nadir CD4 counts (p < 0.00). However, it was not affected by the duration of the disease and the current CD4 counts (p > 0.05). CONCLUSION: Human immunodeficiency viruses (HIV) associated neurocognitive disorders HAND is common in HIV-positive patients, most of whom are asymptomatic. Older patients with less education and severe disease, having lower nadir counts are at the highest risk of HAND. Memory, verbal fluency, and visuospatial abilities were the most commonly affected domains.

Childhood Neurotoxicity and Brain Resilience to Adverse Events during Adulthood.

OBJECTIVE: This study used childhood cancer survivors as a novel model to study whether children who experience central nervous system (CNS) injury are at higher risk for neurocognitive impairment associated with subsequent late onset chronic health conditions (CHCs). METHODS: Adult survivors of childhood cancer (n = 2,859, ≥10 years from diagnosis, ≥18 years old) completed a comprehensive neurocognitive battery and clinical examination. Neurocognitive impairment was defined as age-adjusted z score < 10th percentile. Participants impaired on ≥3 tests had global impairment. CHCs were graded using the Common Terminology Criteria for Adverse Events v4.3 (grade 1, mild; 2, moderate; 3, severe/disabling; 4, life-threatening) and were combined into a severity/burden score by frequency and grade (none/low, medium, high, and very high). A total of 1,598 survivors received CNS-directed therapy including cranial radiation, intrathecal methotrexate, or neurosurgery. Logistic regression estimated the odds of neurocognitive impairment associated with severity/burden score and grade 2 to 4 conditions, stratified by CNS treatment. RESULTS: CNS-treated survivors performed worse than non-CNS-treated survivors on all neurocognitive tests and were more likely to have global neurocognitive impairment (46.9% vs 35.3%, p < 0.001). After adjusting for demographic and treatment factors, there was a dose-response association between severity/burden score and global neurocognitive impairment, but only among CNS-treated survivors (high odds ratio [OR] = 2.24, 95% confidence interval [CI] = 1.42-3.53; very high OR = 4.07, 95% CI = 2.30-7.17). Cardiovascular and pulmonary conditions were associated with processing speed, executive function, and memory impairments in CNS-treated but not non-CNS-treated survivors who were impacted by neurologic conditions. INTERPRETATION: Reduced cognitive/brain reserve associated with CNS-directed therapy during childhood may make survivors vulnerable to adverse cognitive effects of cardiopulmonary conditions during adulthood. ANN NEUROL 2021;89:534-545.

Sex-specific cytokine responses and neurocognitive outcome after blood transfusions in preterm infants.

BACKGROUND: The objective of this study was to determine sex-specific differences in inflammatory cytokine responses to red blood cell (RBC) transfusion in preterm infants in the neonatal period and their relationship to later neurocognitive status. METHODS: Infants with a birth weight <1000 g and gestational age 22-29 weeks were enrolled in the Transfusion of Prematures (TOP) trial. The total number of transfusions was used as a marker of transfusion status. Nineteen cytokines and biomarkers were analyzed from 71 infants longitudinally during the neonatal period. Twenty-six infants completed the Bayley Scales of Infant & Toddler Development, 3rd Edition (Bayley-III) at 12 months' corrected age. RESULTS: Nine cytokine levels were significantly elevated in proportion to the number of transfusions received. Of those, one cytokine showed a sex-specific finding (p = 0.004): monocyte chemoattractant protein-1, MCP-1, rose substantially in females (8.9% change per additional transfusion), but not in males (-0.8% change). Higher concentrations of MCP-1 exclusively were associated with worse Bayley-III scores: decreased cognitive raw scores (p = 0.0005) and motor scaled scores (p < 0.0001). CONCLUSIONS: This study provides evidence of a sex-specific difference in the inflammatory response to RBC transfusions during neonatal life, with MCP-1 levels rising only in females and inversely correlating with neurocognitive status at 12 months old. IMPACT: It is important to understand the risk factors for abnormal neurodevelopment in preterm infants, including anemia and RBC transfusion, in order to improve outcomes and provide potential targets for therapy. Our study investigates and provides the first evidence of sex-specific differences in inflammatory cytokine responses to RBC transfusions in preterm infants in the neonatal period, and their relationship to later cognitive outcomes. This study critically suggests that different transfusion thresholds may have a sex-specific effect on neurodevelopment: females have worse cognitive outcomes with increased number of transfusions, while males have worse outcomes with lower number of transfusions.

"Emergency Room Evaluation and Recommendations" and Incident Hospital Admissions in Older People with Major Neurocognitive Disorders Visiting Emergency Department: Results of an Experimental Study.

INTRODUCTION: Older people with major neurocognitive disorders (MNCDs) visiting the emergency department (ED) are at high risk of hospital admissions. The "Emergency Room Evaluation and Recommendations" (ER2) tool decreases the length of stay (LOS) in the hospital when older people visiting ED are hospitalized after an index ED visit, regardless of their cognitive status. Its effect on hospital admissions has not yet been examined in older people with MNCD visiting ED. This study aimed to examine whether ER2 recommendations were associated with incident hospital admissions and LOS in ED in older people with MNCD visiting ED. METHODS: A total of 356 older people with MNCD visiting ED of the Jewish General Hospital (Montreal, Quebec, Canada) were recruited in this non-randomized, pre-post-intervention, single arm, prospective and longitudinal open label trial. ED staff and patients were blinded of the ER2 score, and patients received usual ED care during the observation period, whereas ED staff were informed about the ER2 score, and patients had ER2 tailor-made recommendations in addition to usual care during the intervention period. Hospital admissions and the LOS in ED were the outcomes. RESULTS: There were less incident hospital admissions (odds ratio ≤ 0.61 with p ≤ 0.022) and longer LOS in ED (coefficient beta ≥4.28 with p ≤ 0.008) during the intervention period compared to the observation period. DISCUSSION/CONCLUSION: ER2 recommendations have mixed effects in people with MNCD visiting ED. They were associated with reduced incident hospital admissions and increased LOS in ED, suggesting that they may have benefits in addition to usual ED care.

Screening Accuracy of Mini Addenbrooke's Cognitive Examination Test for HIV-Associated Neurocognitive Disorders in People Ageing with HIV.

Aging and increased cardiovascular risk are major drivers for HIV-associated neurocognitive disorders (HAND), for which accurate screenings are lacking. Mini-Addenbrooke's Cognitive Examination (MACE) reliably detects vascular and neurodegenerative cognitive decline among HIV-negative patients. We evaluated MACE diagnostic accuracy in detecting HAND in people living with HIV (PLWH) and we compared it with the International HIV Dementia Scale (IHDS). A single-centre double-blind study of diagnostic accuracy on adult outpatient PLWH without neurocognitive confounding was performed. MACE and IHDS were administered in 5 and 10 min by clinicians, followed by the reference standard battery (14 tests) by neuropsychologists. HAND diagnosis was based on the modified version of Frascati's criteria by Gisslén to reduce false positives. Exploratory cut-offs were evaluated for MACE. Diagnostic accuracy and clinical utility parameters were assessed. 231 patients were enrolled. 75.7% men with a median age, education, and length of infection of 54 (48-59), 10 (8-13) and 16 (5-25) years. HAND prevalence was 48.5% (38.9% asymptomatic impairment). Compared to IHDS, MACE sensitivity (89.3% vs 70.5%), specificity (94.1% vs 63.0%), correct classification rate (86.5% vs 66.7%), J index (0.83 vs 0.34), AUROC (0.97 vs 0.79), agreement with the gold standard (k 0.84 vs 0.33) and effect size in distinguishing HAND vs non-HAND (d 2.11 vs 1.15) were higher. Among PLWH aged 65 years and above (n = 37) MACE performance was consistently better than IHDS. The quick and easy-to-perform MACE could possess an accurate and useful screening performance for HAND in otherwise neurocognitively healthy cohorts of PLWH.

Perioperative platelet count in peripheral blood is associated with the early stage of PND after major orthopedic surgery: a prospective observational study.

BACKGROUND: Perioperative neurocognitive disorders (PND) are common complications of major surgery among elderly patients, remarkably decreasing patients' life quality. Platelet count has been proved to be an essential factor in inflammation. However, as far as we know, the relationship between platelet count and PND is not clear yet in the orthopedic area. PND could be a long-term disease, which sometimes lasts for several years, and it is meaningful to find a biomarker of PND at the early stage. Thus, we designed this study to find out the association between perioperative platelet count and occurrence of PND, and determine whether preoperative platelet count could be a biomarker of the early stage of PND. METHODS: A prospective observational study was performed on the patients who would take total knee arthroplasty or total hip arthroplasty. Their peripheral platelets were counted by blood routine examination 1 day before and 3 days after the surgery. And we assessed their neurocognitive functions 1 day before and 3 days after the surgery. These data were recorded and analyzed to find out the relationship between platelet count and the occurrence of PND. RESULTS: Eventually, 70 patients finished the whole process, and 14 of them developed PND. The median preoperative platelet count in the PND group was significantly higher than that in the non-PND group (239 vs 168 × 10^9/L, p = 0.009). Preoperative platelet count was an independent risk factor for PND (odds ratio = 1.014, 95% confidence interval [CI] 1.000-1.027, P = 0.043) in the logistic multivariable regression, while the area under the curve of the receiver operating characteristic curve of the prediction model was 0.796 (95% CI 0.676-0.916). CONCLUSIONS: The higher preoperative and postoperative level of platelet count in the peripheral blood were associated with the early stage of PND, and preoperative platelet count could be a potential predictor of the early stage of PND in patients undergoing major orthopedic surgeries. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2000033001 , registration date: 17 May 2020.

Moving on From HAND: Why We Need New Criteria for Cognitive Impairment in Persons Living With Human Immunodeficiency Virus and a Proposed Way Forward.

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) criteria are frequently used to describe cognitive impairment in persons living with HIV (PLWH) across diverse populations globally. These criteria typically find 20-60% of PLWH meet criteria for HAND, which does not tally with clinical observations in the modern era that cognitive disorders present relatively infrequently. Most with HAND have asymptomatic neurocognitive impairment; however, the significance of low cognitive test performance without symptoms is uncertain. Methods underlying HAND criteria carry a false-positive rate that can exceed 20%. Comorbidities, education, and complex socioeconomic factors can influence cognitive test performance, further increasing the potential for misclassification. We propose a new framework to characterize cognitive impairment in PLWH that requires a clinical history and acknowledges the multifactorial nature of low cognitive test performance. This framework is intended to be applicable across diverse populations globally, be more aligned with clinical observations, and more closely represent HIV brain pathology.

Neurocognitive impairment in Asian childhood cancer survivors: a systematic review.

Childhood cancer survivors are at higher risk of developing neurocognitive deficits due to the intensive treatment they received at an early age. Most studies on childhood cancer survivorship have so far focused on the Western populations. Due to the ethnic, genetic, environmental, and cultural differences, clinical data of the Western populations may not be representative of Asian countries. This scoping review systematically summarized the existing clinical evidence of the neurocognitive impairment of Asian childhood cancer survivors. We searched the Embase and Medline databases for studies assessing the neurocognitive functions of survivors in Asia, who were diagnosed with cancer before the age of 19 and completed active treatment. The literature search identified 13 studies involving 2212 participants from five Asian countries: South Korea (n = 4, 30.8%), Taiwan (n = 3, 23.1%), Japan (n = 3, 23.1%), Hong Kong (n = 2, 15.4%), and Thailand (n = 1, 7.7%). The included studies focused on CNS tumors (n = 10, 76.9%), hematological malignancies (n = 7, 53.8%), or heterogeneous cancer diagnoses (n = 3, 23.1%). Collectively, mild-to-moderate impairment in intelligence was observed in 10.0 to 42.8% of survivors, which seemed higher than the reported rate in Western survivors. We speculate that the ethnic and genetic variations in drug responses and susceptibility to adverse chronic toxicities may have contributed to the differences in the prevalence and severity of neurocognitive impairment between these two populations. To better understand the effects of culturally relevant and region-specific environmental risk factors on the post-treatment neurocognitive development in cancer survivors, a holistic approach that addresses the complex interactions between biological, physical, and psychosocial factors is needed. This will aid the development of effective intervention strategies to improve the functional and psychosocial outcomes of cancer survivors in Asian societies.

Metabolic Inflammation-A Role for Hepatic Inflammatory Pathways as Drivers of Comorbidities in Nonalcoholic Fatty Liver Disease?

Nonalcoholic fatty liver disease (NAFLD) is a global and growing health concern. Emerging evidence points toward metabolic inflammation as a key process in the fatty liver that contributes to multiorgan morbidity. Key extrahepatic comorbidities that are influenced by NAFLD are type 2 diabetes, cardiovascular disease, and impaired neurocognitive function. Importantly, the presence of nonalcoholic steatohepatitis and advanced hepatic fibrosis increase the risk for systemic comorbidity in NAFLD. Although the precise nature of the crosstalk between the liver and other organs has not yet been fully elucidated, there is emerging evidence that metabolic inflammation-in part, emanating from the fatty liver-is the engine that drives cellular dysfunction, cell death, and deleterious remodeling within various body tissues. This review describes several inflammatory pathways and mediators that have been implicated as links between NAFLD and type 2 diabetes, cardiovascular disease, and neurocognitive decline.

Prevalence of HIV-associated neurocognitive disorder (HAND) in Turkey and assessment of Addenbrooke's Cognitive Examination Revised (ACE-R) test as a screening tool.

OBJECTIVES: We aimed to assess the Addenbrooke's Cognitive Examination Revised (ACE-R) and three questions (3Qs, European Aids Clinical Society Guidelines) as potential screening tools for HIV-associated neurocognitive disorder (HAND). In addition, we tried to determine the prevalence and associated factors for HAND among people living with HIV (PLWH) in Turkey. METHODS: Persons living with HIV were enrolled from two teaching hospitals between March 2018 and September 2018. Participants underwent screening tools, a neuropsychological test battery (NTB) and an assessment of activities of daily living. HAND was diagnosed according to Frascati's criteria and applying the Global Deficit Score (GDS) approach. A receiver operating characteristic (ROC) curve analysis was performed to compare the predictive accuracy of ACE-R to that of the NP test battery. Factors associated with HAND were evaluated using multivariate logistic regression analysis. RESULTS: The study sample included 162 participants (94% male). The HAND prevalence was 45.7% [asymptomatic neurocognitive impairment (ANI), 37.7%; mild neurocognitive disorder (MND), 7.4%; HIV-associated dementia (HAD), 0.6%] according to the Frascati criteria and 31.5% (ANI, 25.9%; MND, 4.9%; HAD, 0.6%) using the GDS. In the ROC analysis, the ACE-R showed an area under the curve of 0.68 at a cut-off score of 89. The sensitivity, specificity and correct classification rate of screening tests for HAND diagnosis were as follows: ACE-R (62.2%, 67%, 64.8%) and 3Qs (10.8%, 88.6%, 53%). In multivariate analysis, only education level (adjusted odds ratio [aOR] = 0.84, 95% CI: 0.76-0.92, P ≤ 0.001) was an independent risk factor for HAND. CONCLUSIONS: HAND is a common comorbidity in PLWH in Turkey. The sensitivities and specificities of 3Qs and the ACE-R as screening tools are lower than desired.

Assessment, prevalence, and correlates of frailty among middle-aged adults with HIV in rural Uganda.

We investigated the prevalence and risk factors for frailty among people with HIV (PWH) in rural Uganda (n = 55, 47% male, mean age 44 years). Frailty was defined according to the Fried criteria with self-reported physical activity level replacing the Minnesota Leisure Time Activity Questionnaire. Alternate classifications for physical activity utilized were the sub-Saharan Africa Activity Questionnaire and the International Physical Activity Questionnaire. Eleven participants (19%) were frail. Frail participants were older (p < 0.001), less likely to be on antiretroviral therapy (p = 0.03), and had higher rates of depression (p < .001) and HIV-associated neurocognitive disorder (p = 0.003). Agreement between physical activity measures was sub-optimal. Prevalence of frailty was high among PWH in rural Uganda, but larger sample sizes and local normative data are needed.

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

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

Long-term impact of systematic pain and sedation management on cognitive, motor, and behavioral outcomes of extremely preterm infants at preschool age.

BACKGROUND: Providing optimal pain relief is a challenging task when caring for premature infants. The aim of this study was to compare the long-term cognitive, motor, and behavioral outcomes of preterm infants before and after the implementation of a pain and sedation protocol. In addition, we investigated whether the increased opiate administration resulting after the implementation process had an impact on these outcomes. METHODS: Cognitive outcomes were evaluated using the Kaufman Assessment Battery for Children (KABC), neuromotor examinations were based on Amiel-Tison, and behavioral outcomes were assessed using the parent-reported Child Behavior Checklist (CBCL). RESULTS: One hundred extremely preterm infants were included in the study (control group, n = 53; intervention group, n = 47). No significant differences were found in cognitive and motor outcomes at preschool age. However, every increase in the cumulative opiate exposure for each 100 mg/kg was weakly significantly associated with a higher risk for autism spectrum features (adjusted odds ratio (aOR) = 1.822, 95% confidence interval (CI) [1.231-2.697]; P = 0.03) and withdrawn behavior (aOR = 1.822, 95% CI [1.231-2.697]; P = 0.03) at preschool age. CONCLUSION: Increased neonatal cumulative opiate exposure did not alter cognitive and motor outcomes but may represent a risk factor for autism spectrum and withdrawn behavior at preschool age. IMPACT: The implementation of a protocol for the management of pain and sedation in preterm infants resulted in increased cumulative opiate exposure. Our study adds further evidence that increased neonatal opiate exposure did  not alter cognitive and motor outcomes but may yield a potential risk factor for autism spectrum disorders and withdrawn behavior at preschool age. A vigilant use of opiates is recommended. Further studies are needed looking for novel pain management strategies and drugs providing optimal pain relief with minimal neurotoxicity.

Neuroimaging and Cognitive Evidence for Combined HIV-Alcohol Effects on the Central Nervous System: A Review.

Alcohol use disorder (AUD) among people living with HIV (PLWH) is a significant public health concern. Despite the advent of effective antiretroviral therapy, up to 50% of PLWH still experience worsened neurocognition, which comorbid AUD exacerbates. We report converging lines of neuroimaging and neuropsychological evidence linking comorbid HIV/AUD to dysfunction in brain regions linked to executive function, learning and memory, processing speed, and motor control, and consequently to impairment in daily life. The brain shrinkage, functional network alterations, and brain metabolite disruption seen in individuals with HIV/AUD have been attributed to several interacting pathways: viral proteins and EtOH are directly neurotoxic and exacerbate each other's neurotoxic effects; EtOH reduces antiretroviral adherence and increases viral replication; AUD and HIV both increase gut microbial translocation, promoting systemic inflammation and HIV transport into the brain by immune cells; and HIV may compound alcohol's damaging effects on the liver, further increasing inflammation. We additionally review the neurocognitive effects of aging, Hepatitis C coinfection, obesity, and cardiovascular disease, tobacco use, and nutritional deficiencies, all of which have been shown to compound cognitive changes in HIV, AUD, and in their comorbidity. Finally, we examine emerging questions in HIV/AUD research, including genetic and cognitive protective factors, the role of binge drinking in HIV/AUD-linked cognitive decline, and whether neurocognitive and brain functions normalize after drinking cessation.

Is the use of the QPC cognitive complaints questionnaire relevant for the screening strategy of HIV-Associated neurocognitive disorders?

BACKGROUND: The screening strategy for HIV-Associated Neurocognitive Disorders (HAND) is challenging. The French Expert Report recommend the use of the Cognitive Complaints Questionnaire (QPC) and the Montreal Cognitive assessment. However, the QPC has never been studied in People Living with HIV (PLWH). This study aims to determine the degree of agreement between QPC and the presence of HAND according to Frascati criteria, established by a battery of neuropsychological tests. METHODS: Data from patients who performed both a QPC and a battery of neuropsychological tests over a six-month follow-up period were evaluated retrospectively. RESULTS: A total of 121 patients were selected, with a median age of 53.1 years old. Among participants, 92.6% had an undetectable plasma viral load, 49.6% had a nadir CD4 less than 200/mm3 and 23.1% had a CDC stage C. Median CD4 cell count was 686/mm3. Prevalence of HAND was 57%, including 28.9% of Asymptomatic Neurocognitive Impairment, 24.8% of Mild Neurocognitive Disorder and 3.3% of HIV-associated Dementia. This analyze shows no agreement between QPC and HIV-associated neurocognitive disorders (kappa = -0.007). CONCLUSIONS: The QPC is not relevant in the screening for HAND. Thus, it urges to develop a specific tool to assess cognitive complaints among PLWH.