Longitudinal Changes in Cognition and Brain Imaging in Persons With Human Immunodeficiency Virus.

OBJECTIVETo examine the associations of prediabetes, diabetes, and diabetes severity (as assessed by HbA1c and diabetes duration) with brain volumes and vascular pathology on brain MRI and to assess whether the associations of diabetes with brain volumes are mediated by brain vascular pathology.RESEARCH DESIGN AND METHODSCross-sectional study of 1,713 participants in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) (mean age 75 years, 60% female, 27% black, 30% prediabetes, and 35% diabetes) who underwent 3T brain MRI scans in 2011–2013. Participants were categorized by diabetes-HbA1c status as without diabetes (<5.7% [reference]), with prediabetes (5.7 to <6.5%), and with diabetes ([defined as prior diagnosis or HbA1c ≥6.5%] <7.0% vs. ≥7.0%), with further stratification by diabetes duration (<10 vs. ≥10 years).RESULTSIn adjusted analyses, compared with participants without diabetes and HbA1c <5.7%, participants with prediabetes and those with diabetes and HbA1c <7.0% did not have significantly different brain volumes or vascular pathology (all P > 0.05), but those with diabetes and HbA1c ≥7.0% had smaller total brain volume (β −0.20 SDs, 95% CI −0.31, −0.09), smaller regional brain volumes (including frontal, temporal, occipital, and parietal lobes; deep gray matter; Alzheimer disease signature region; and hippocampus [all P < 0.05]), and increased burden of white matter hyperintensities (WMH) (P = 0.016). Among participants with diabetes, those with HbA1c ≥7.0% had smaller total and regional brain volumes and an increased burden of WMH (all P < 0.05) compared with those with HbA1c <7.0%. Similarly, participants with longer duration of diabetes (≥10 years) had smaller brain volumes and higher burden of lacunes (all P < 0.05) than those with a diabetes duration <10 years. We found no evidence for mediation by WMH in associations of diabetes with smaller brain volumes by structural equation models (all P > 0.05).CONCLUSIONSMore-severe diabetes (defined by higher HbA1c and longer disease duration) but not prediabetes or less-severe diabetes was associated with smaller brain volumes and an increased burden of brain vascular pathology. No evidence was found that associations of diabetes with smaller brain volumes are mediated by brain vascular pathology, suggesting that other mechanisms may be responsible for these associations.

BackgroundType 2 diabetes mellitus (T2DM) is known to be associated with cognitive decline and brain structural changes. This study systematically reviews and estimates human brain volumetric differences and atrophy associated with T2DM.MethodsPubMed, PsycInfo and Cochrane Library were searched for brain imaging studies reporting on brain volume differences between individuals with T2DM and healthy controls. Data were examined using meta-analysis, and association between age, sex, diabetes characteristics and brain volumes were tested using meta-regression.ResultsA total of 14,605 entries were identified; after title, abstract and full-text screening applying inclusion and exclusion criteria, 64 studies were included and 42 studies with compatible data contributed to the meta-analysis (n=31,630; mean age 71.0 years; 44.4% male; 26,942 control; 4,688 diabetes). Individuals with T2DM had significantly smaller total brain volume, total grey matter volume, total white matter volume and hippocampal volume (approximately 1% to 4%); meta-analyses of smaller samples focusing on other brain regions and brain atrophy rate in longitudinal investigations also indicated smaller brain volumes and greater brain atrophy associated with T2DM. Meta-regression suggests that diabetes-related brain volume differences start occurring in early adulthood, decreases with age and increases with diabetes duration.ConclusionT2DM is associated with smaller total and regional brain volume and greater atrophy over time. These effects are substantial and highlight an urgent need to develop interventions to reduce the risk of T2DM for brain health.

Neurocognitive outcomes beyond childhood in people with a Fontan circulation are not well defined. This study aimed to investigate neurocognitive functioning in adolescents and adults with a Fontan circulation and associations with structural brain injury, brain volumetry, and postnatal clinical factors. In a binational study, participants with a Fontan circulation without a preexisting major neurological disability were prospectively recruited from the Australia and New Zealand Fontan Registry. Neurocognitive function was assessed by using Cogstate software in 107 participants with a Fontan circulation and compared with control groups with transposition of the great arteries (n=50) and a normal circulation (n=41). Brain MRI with volumetric analysis was performed in the participants with a Fontan circulation and compared with healthy control data from the ABIDE I and II (Autism Brain Imaging Data Exchange) and PING (Pediatric Imaging, Neurocognition, and Genetics) data repositories. Clinical data were retrospectively collected. Of the participants with a Fontan circulation who had a neurocognitive assessment, 55% were male and the mean age was 22.6 years (SD 7.8). Participants with a Fontan circulation performed worse in several areas of neurocognitive function compared with those with transposition of the great arteries and healthy controls (P<0.05). Clinical factors associated with worse neurocognitive outcomes included more inpatient days during childhood, younger age at Fontan surgery, and longer time since Fontan procedure (P<0.05). Adults with a Fontan circulation had more marked neurocognitive dysfunction than adolescents with a Fontan circulation in 2 domains (psychomotor function, P=0.01 and working memory, P=0.02). Structural brain injury was present in the entire Fontan cohort; the presence of white matter injury was associated with worse paired associate learning (P<0.001), but neither the presence nor severity of infarct, subcortical gray matter injury, and microhemorrhage was associated with neurocognitive outcomes. Compared with healthy controls, people with a Fontan circulation had smaller global brain volumes (P<0.001 in all regions) and smaller regional brain volumes in most cerebral cortical regions (P<0.05). Smaller global brain volumes were associated with worse neurocognitive functioning in several domains (P<0.05). A significant positive association was also identified between global brain volumes and resting oxygen saturations (P≤0.04). Neurocognitive impairment is common in adolescents and adults with a Fontan circulation and is associated with smaller gray and white matter brain volume. Understanding modifiable factors that contribute to brain injury to optimize neurocognitive function is paramount.

Persons with HIV (PWH) are at increased risk of chronic obstructive pulmonary disease. The seroprevalence of cytomegalovirus (CMV) is high among PWH, and CMV serology has been associated with accelerated lung function decline in the general population. To determine whether CMV IgG concentrations were associated with lower lung function in PWH. : PWH aged 25 years or older and with viral suppression were included from the Copenhagen Comorbidity in HIV infection (COCOMO) study. CMV IgG concentrations were measured using indirect chemiluminescent immunoassay, and high CMV IgG concentrations defined as values above the upper limit of detection (>180 U/mL). Lung function was measured by spirometry as forced expiratory volume in 1 second (FEV1). Among 987 PWH, 937 (95%) had positive CMV IgG serostatus, and 313 (33%) of the CMV seropositive had high CMV IgG concentrations. High CMV IgG concentrations were associated with lower FEV1 in a linear regression model adjusted for age, sex, smoking status, height, ethnicity and BMI (-86.7 mL [95% CI: -164.5; -8.9], P = .029), but the association was attenuated when additionally adjusted for CD4 + T cell nadir (-67.4 mL [95% CI: -147.0; 12.2], P = .097). Smoking modified the association (p-interaction = 0.001), and the association was more pronounced among current smokers, even in the fully adjusted model (-292.8 mL [-446.5; -139.0], P < .001). High CMV IgG concentrations were associated with lower lung function among PWH, especially among those who smoke. Further studies are needed to verify CMV as a causal factor in reduced lung function of PWH.

Little is known about the impact of HIV infection on the clinical presentation and outcomes after stroke in the modern antiretroviral therapy (ART) era. We aimed to compare stroke characteristics and outcomes between persons with HIV (PWH) and without HIV (PWOH) presenting with stroke in Uganda. We conducted a matched cohort study at Mulago National Referral Hospital and Mbarara Regional Referral Hospital between January 2018 and November 2020. We enrolled consecutive PWH presenting with CT-confirmed acute or subacute stroke (symptom onset ≤14 days) and matched them by sex and stroke type to 2 consecutive available PWOH admitted to the same hospital. We obtained baseline clinical data and followed participants for 90 days from the day of clinical presentation. We compared stroke severity (defined by the NIH stroke scale [NIHSS]) and 90-day all-cause mortality and morbidity (using the modified Rankin Scale [mRS]) by HIV serostatus with and without adjustment for confounders. We enrolled 105 PWH and 157 PWOH with stroke. PWH were younger (mean [SD] age 49 [14] vs 59 [16] years, p < 0.001), and nearly 80% (82/105) were on ART for a median of 5 years and a median CD4 count of 214 cells/uL (interquartile range 140, 337). Compared with PWOH, PWH presented with a 3-point lower median NIHSS (16 vs 19, p = 0.011), a 20% lower proportion of all-cause mortality at 90 days (p = 0.001), and had less disability at 90 days (median mRS 4 vs 5, p = 0.004). Age and NIHSS-adjusted odds ratio of 90-day all-cause mortality in PWH compared with PWOH was 0.45 (95% CI 0.22-0.96, p = 0.037). In the modern ART era, PWH with acute stroke in Uganda present with modest stroke and are significantly less likely to die within 90 days than PWOH. This potentially reflects the protective effects of ART, enhanced health care access, and their younger age at stroke presentation.

Delirium duration is predictive of long-term cognitive impairment in intensive care unit survivors. Hypothesizing that a neuroanatomical basis may exist for the relationship between delirium and long-term cognitive impairment, we conducted this exploratory investigation of the associations between delirium duration, brain volumes, and long-term cognitive impairment. A prospective cohort of medical and surgical intensive care unit survivors with respiratory failure or shock. Quantitative high resolution 3-Tesla brain magnetic resonance imaging was used to calculate brain volumes at discharge and 3-month follow-up. Delirium was evaluated using the confusion assessment method for the intensive care unit; cognitive outcomes were tested at 3- and 12-month follow-up. Linear regression was used to examine associations between delirium duration and brain volumes, and between brain volumes and cognitive outcomes. A total of 47 patients completed the magnetic resonance imaging protocol. Patients with longer duration of delirium displayed greater brain atrophy as measured by a larger ventricle-to-brain ratio at hospital discharge (0.76, 95% confidence intervals [0.10, 1.41]; p = .03) and at 3-month follow-up (0.62 [0.02, 1.21], p = .05). Longer duration of delirium was associated with smaller superior frontal lobe (-2.11 cm(3) [-3.89, -0.32]; p = .03) and hippocampal volumes at discharge (-0.58 cm(3) [-0.85, -0.31], p < .001)--regions responsible for executive functioning and memory, respectively. Greater brain atrophy (higher ventricle-to-brain ratio) at 3 months was associated with worse cognitive performances at 12 months (lower Repeatable Battery for the Assessment of Neuropsychological Status score -11.17 [-21.12, -1.22], p = .04). Smaller superior frontal lobes, thalamus, and cerebellar volumes at 3 months were associated with worse executive functioning and visual attention at 12 months. These preliminary data show that longer duration of delirium is associated with smaller brain volumes up to 3 months after discharge, and that smaller brain volumes are associated with long-term cognitive impairment up to 12 months. We cannot, however, rule out that smaller preexisting brain volumes explain these findings.

BackgroundTo explore whether baseline “AN” features in SCD, including brain Aβ deposition, hippocampal volume, and glucose metabolism in the hippocampus and parahippocampal gyrus, can predict longitudinal cognitive changes, thus identifying imaging biomarkers for SCD progression.MethodThis study included 95 subjects with follow‐up (59 SCD patients and 36 normal controls). Baseline imaging included 18F‐Florbetapir PET/CT (brain Aβ), 18F‐FDG PET/CT (hippocampal and parahippocampal glucose metabolism), and T1‐weighted MRI (hippocampal volume). Cognitive function was assessed with neuropsychological tests at baseline and after two years. Cognitive change rates (Δchange = (follow‐up ‐ baseline) / baseline) were used as the primary outcome. A general linear model analyzed the relationship between baseline “AN” features and cognitive change rates, with Bonferroni correction for multiple comparisons.ResultCompared to the NC group, SCD subjects showed a trend toward accelerated decline in executive function (Shape Trail Test (STT)‐A score, β= ‐0.04, p = 0.083). Baseline whole‐brain Aβ deposition predicted longitudinal changes in the Boston Naming Test (BNT, β= ‐0.38, p = 0.00435) and STT‐A score (β= 0.25, p = 0.053). Baseline hippocampal volume predicted changes in Montreal Cognitive Assessment‐Basic (MoCA‐B, β= 0.43, p = 0.00449). Baseline FDG SUVr in the left parahippocampal gyrus predicted MoCA‐B (β= 0.36, p = 0.021) and STT‐B scores (β= ‐0.38, p = 0.0223). FDG SUVr in the right hippocampus predicted changes in BNT scores (β= 0.46, p = 0.00407).ConclusionThe 2‐year follow‐up indicated that SCD subjects experienced accelerated executive function decline. Baseline “A” and “N” imaging features predicted longitudinal cognitive changes in language, executive, and overall cognitive function in SCD. This study identifies baseline “AN” features as key imaging biomarkers for SCD progression.

Associations of cumulative Pb exposure and longitudinal changes in Mini-Mental Status Exam scores, global cognition and domains of cognition: The VA Normative Aging Study

BackgroundSeminal studies on exposure to life course social determinants of health, such as neighborhood racial segregation and neighborhood poverty, suggest detrimental associations with poorer cognitive function. We aimed to test the opposite by examining the relationship between self‐reported exposure to health‐promoting neighborhood environments over the life course and cognitive function among older adults.MethodParticipants were persons living without dementia at three US Alzheimer’s Disease Research Centers (University of California, Davis in Sacramento (UCD); Washington University in Saint Louis (WU); and Wake Forest University in Winston‐Salem (WFU)). An ancillary study (K01AG063895, PI: Besser) included the Life Course Sociodemographics and Neighborhood Questionnaire (LSNEQ) comprised of indices like neighborhood measures of socioeconomic status (NSES), walking and biking frequency, and greenness from childhood, midlife, and late life. LSNEQ data were linked with late‐life cognitive test z‐scores (Animals and Vegetables Category Fluency, Trail Making Parts A and B) from the National Alzheimer’s Coordinating Center Uniform Data Set. Multivariable linear mixed effects models tested associations between the LSNEQ index scores (composite values over childhood and mid‐ and late‐life) and baseline and longitudinal change in cognitive function controlling for demographics, Center, and baseline global Clinical Dementia Rating (0 or 0.5).ResultThe sample (n = 322) included 65% women, 17% Black, 76% White, and 7% other/mixed racialized group participants and was, on average, 70±7 years old and followed for 2.5±3.2 years. Life Course NSES was lower for UCD (mean = 12.7, SD = 3.5) versus WU (mean = 13.9, SD = 3.2) and WFU (mean = 14.3, SD = 3.2). Life Course Neighborhood Walking and Biking frequency did not differ by Center. Life Course Neighborhood Greenness differed across Centers, and was lowest for WU (mean = 4.8, SD = 1.3) and highest for WFU (mean = 5.6; SD = 1.2). In multivariable analyses, greater Life Course Neighborhood Walking and Biking was associated with higher baseline Trail A scores (estimate = 0.83, 95% CI = 0.08‐1.58) and slower decline on Animals over time (estimate = 0.024, 95% CI = 0.002‐0.045). Greater Life Course Neighborhood Greenness was associated with slower decline on Vegetables over time (estimate = 0.035, 95% CI = 0.001‐0.069).ConclusionThese preliminary findings suggest self‐reported, life course neighborhood exposures and behaviors (i.e., greenness and neighborhood walking/biking) may be associated with better cognition and slower decline in later life.

INTRODUCTIONWith anti‐amyloid beta (Aβ) therapies approved for Alzheimer's disease (AD), surrogate biomarkers are needed to monitor clinical treatment efficacy. Therefore, we systematically compared longitudinal changes in A/T/N biomarkers (amyloid‐positron emission tomography [PET], tau‐PET, plasma phosphorylated tau at threonine 217 [p‐tau217], and magnetic resonance imaging) for tracking cognitive changes.METHODSWe analyzed longitudinal biomarker and cognitive change rates from the Alzheimer's Disease Neuroimaging Initiative (N = 141) and Anti‐Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) (N = 151), estimated using linear mixed models. Using linear models, we tested biomarker changes as predictors of cognitive changes, comparing predictive strengths across biomarkers using bootstrapping.RESULTSTau‐PET, plasma p‐tau217, and cortical thickness changes accurately tracked change rates in Mini‐Mental State Examination, Alzheimer's Disease Assessment Scale‐Cognitive Subscale 13‐item version, Clinical Dementia Rating‐Sum of Boxes, and Preclinial Alzheimer Cognitive Composite scores. In contrast, amyloid‐PET change rates were not linked to cognitive changes.DISCUSSIONPlasma p‐tau217 offers a cost‐effective AD‐specific alternative to tau‐PET and could potentially be implemented for monitoring cognitive changes in AD trials, while amyloid‐PET lacks utility. Cortical thickness changes accurately track cognitive changes but may be confounded by pseudo‐atrophy in anti‐Aβ treatments.HighlightsLongitudinal changes in tau‐PET, plasma p‐tau217, cortical thickness – but not amyloid‐PET – effectively track cognitive decline.Cortical thickness may be confounded by pseudo‐atrophy in anti‐Aβ trials.Plasma p‐tau217 is a robust and cost‐effective alternative to tau‐PET as an AD‐specific surrogate biomarker for monitoring cognitive changes.

Schizophrenia patients (SZH) often show impaired cognition and reduced brain structural volumes; these deficits are also detectable in healthy relatives of SZH. However, there is considerable heterogeneity: a sizable percentage of SZH are relatively cognitively intact; clustering strategies have proved useful for categorising into cognitive subgroups. We used a clustering strategy to investigate relationships between subgroup assignment and brain volumes, in 102 SZH (N = 102) and 32 siblings of SZH (SZH-SIB), alongside 92 controls (CON) and 48 of their siblings. SZH had poorer performance in all cognitive domains, and smaller brain volumes within prefrontal and temporal regions compared to controls. We identified three distinct cognitive clusters (‘neuropsychologically normal’, ‘intermediate’, ‘cognitively impaired’) based on age- and gender-adjusted cognitive domain scores. The majority of SZH (60.8%) were assigned to the cognitively impaired cluster, while the majority of SZH-SIB (65.6%) were placed in the intermediate cluster. Greater right middle temporal volume distinguished the normal cluster from the more impaired clusters. Importantly, the observed brain volume differences between SZH and controls disappeared after adjustment for cluster assignment. This suggests an intimate link between cognitive performance levels and regional brain volume differences in SZH. This highlights the importance of accounting for heterogeneity in cognitive performance within SZH populations when attempting to characterise the brain structural abnormalities associated with the disease.

During childhood, the brain can consume up to 65% of total calories, and a steady supply of the brain's main fuel glucose needs to be maintained. Although the brain itself is not dependent on insulin for the uptake of glucose, insulin plays an important role in energy homeostasis. Thus, the risk for insulin resistance during brain development may negatively impact the whole brain volume. We investigated the link between the insulin resistance and the whole brain volume as measured by structural Magnetic resonance imaging (MRI) in 46 unmedicated depressed and overweight youths between the ages of 9 and 17 years. Smaller whole brain volumes were associated with insulin resistance independent of age, sex, depression severity, body mass index, socioeconomic status, Tanner Stage, and Intelligence quotient (IQ) (r = 0.395, P = .014) There may be a significant cost for developing insulin resistance on the developing brain. Disentangling the precise relationship between the insulin resistance and the developing brain is critical.

Background: Cognitive impairment affects 50%–75% of people with secondary progressive multiple sclerosis (PwSPMS). Improving our ability to predict cognitive decline may facilitate earlier intervention. Objective: The main aim of this study was to assess the relationship between longitudinal changes in cognition and baseline serum neurofilament light chain (sNfL) in PwSPMS. In a multi-modal analysis, MRI variables were additionally included to determine if sNfL has predictive utility beyond that already established through MRI. Methods: Participants from the MS-STAT trial underwent a detailed neuropsychological test battery at baseline, 12 and 24 months. Linear mixed models were used to assess the relationships between cognition, sNfL, T2 lesion volume (T2LV) and normalised regional brain volumes. Results: Median age and Expanded Disability Status Score (EDSS) were 51 and 6.0. Each doubling of baseline sNfL was associated with a 0.010 [0.003–0.017] point per month faster decline in WASI Full Scale IQ Z-score (p = 0.008), independent of T2LV and normalised regional volumes. In contrast, lower baseline volume of the transverse temporal gyrus was associated with poorer current cognitive performance (0.362 [0.026–0.698] point reduction per mL, p = 0.035), but not change in cognition. The results were supported by secondary analyses on individual cognitive components. Conclusion: Elevated sNfL is associated with faster cognitive decline, independent of T2LV and regional normalised volumes.

In this observational study, we assessed the extent to which a community-created pilot intervention, providing trauma-informed care for persons with HIV (PWH), affected HIV care retention and viral suppression among PWH attending an HIV Services Organization in the Southern US. PWH with trauma exposure and/or trauma symptoms (N = 166) were offered a screening and referral to treatment (SBIRT)session. Per self-selection, 30 opted-out, 29 received SBIRT-Only, 25 received SBIRT-only but reported receiving other behavioral health care elsewhere, and 82 participated in the Safety and Stabilization (S&S) Intervention. Estimates from multivariable logistic regression analyses indicated S&S Intervention participants had increased retention in HIV care (adjusted odds ratio [aOR] 5.46, 95% CI 1.70-17.50) and viral suppression (aOR 17.74, 95% CI 1.83-172), compared to opt-out participants. Some evidence suggested that PTSD symptoms decreased for intervention participants. A randomized controlled trial is needed to confirm findings.

The aim of this study was to evaluate the effectiveness of five intervention strategies: patient navigation, appointment help/alerts, psychosocial support, transportation/appointment accompaniment, and data-to-care on HIV care outcomes among persons with HIV (PWH) who are out of care (OOC). A systematic review with meta-analysis. We searched CDC's Prevention Research Synthesis (PRS) Project's cumulative HIV database to identify intervention studies conducted in the U.S., published between 2000 and 2020 that included comparisons between groups or prepost, and reported at least one relevant outcome (i.e. re-engagement or retention in HIV care, and viral suppression). Effect sizes were meta-analyzed using random-effect models to assess intervention effectiveness. Thirty-nine studies reporting on 42 unique interventions met the inclusion criteria. Overall, intervention strategies are effective in improving re-engagement in care [odds ratio (OR) = 1.79;95% confidence interval (95% CI): 1.36-2.36, k = 14], retention in care (OR = 2.01; 95% CI: 1.64-2.64, k = 22), and viral suppression (OR = 2.50;95% CI: 1.87-3.34, k = 27). Patient navigation, appointment help/alerts, psychosocial support, and transportation/appointment accompaniment improved all three HIV care outcomes. Data-to-care improved re-engagement and retention but had insufficient evidence for viral suppression. Several strategies are effective for improving HIV care outcomes among PWH who are OOC. More work is still needed for consistent definitions of OOC and HIV care outcomes, better reporting of intervention and cost data, and identifying how best to implement and scale-up effective strategies to engage and retain OOC PWH in care and reach the ending the HIV epidemic goals.