7 research outputs found
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Longitudinal changes in brain structure and integrity during acute HIV
Cognitive impairment persists in the form of HIV-associated neurocognitive disorder (HAND) among chronically infected individuals despite successful viral suppression. Widespread access to combination antiretroviral therapy (cART) has allowed infected individuals to initiate treatment at an earlier time point and effectively reduce the risk of HIV-related mortality and morbidity. The current study examines whether cART, when initiated within days to weeks following infection, can longitudinally preserve brain health. Quantitative magnetic resonance image (MRI) methodologies were used to analyze T1-weighted structural images and diffusion tensor imaging (DTI) metrics. Specifically, region of interest and voxel-wise volume and tensor-based spatial statistics (TBSS) approaches were performed to evaluate differences in brain volumes and white matter microstructure. We examined 31 acute HIV (AHI) participants who had paired month 0 (baseline) and month 24 (two-year follow-up) scans. Participants were comparatively analyzed in both a longitudinal manner to themselves, and a cross-sectional manner against 25 healthy control (CO) participants. As an indication of inflammation, CD8 t-lymphocyte counts was examined as a clinical covariate. The 31 AHI participants had a median (IQR) age of 26 (23-30) years at the time of enrollment and a median (IQR) baseline CD4 count of 576 (370-868) cells/μL. All immediately initiated cART. The 25 healthy controls had a median (IQR) age of 31 (26-37) years. Differences of brain integrity in the AHI group followed longitudinally were observed. Baseline CD8 count was significantly associated with increased mean diffusivity (MD) in the longitudinally infected, present in the genu and the splenium of the corpus callosum, the corona radiata, and the superior longitudinal fasciculus (all p<0.05). Structural analysis revealed enlarged corpus callosum (p<0.01) volumes, as well as enlarged caudate and thalamus subcortical gray matter volumes in the longitudinally infected AHI participants (both p<0.05). Differences of brain integrity in the AHI group after 24 months of treatment were observed compared to healthy controls. Specifically, fractional anisotropy (FA) was reduced in AHI at 24 months compared to controls in models adjusting for age in the corpus callosum, the corona radiata, and the left superior longitudinal fasciculus (all p<0.05). Structural analyses revealed enlarged putamen and the caudate volumes (both p<0.05). We conclude that differences in both brain integrity and structural volumes can be seen in AHI with successful viral suppression when compared to healthy controls. Future work will include longitudinal imaging data from healthy controls who are followed over two-year follow-up to ensure that observed changes are disease specific. We will also comparatively investigate longitudinally treated chronic HIV-infected participants (‘positive controls’) to examine if the differences are similar to those seen when therapy is initiated in the chronic stage of infection. We will examine inflammatory plasma and CSF biomarkers to inform potential mechanisms and, separately, cognitive testing to inform clinical significance
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Longitudinal changes in brain structure and integrity during acute HIV
Cognitive impairment persists in the form of HIV-associated neurocognitive disorder (HAND) among chronically infected individuals despite successful viral suppression. Widespread access to combination antiretroviral therapy (cART) has allowed infected individuals to initiate treatment at an earlier time point and effectively reduce the risk of HIV-related mortality and morbidity. The current study examines whether cART, when initiated within days to weeks following infection, can longitudinally preserve brain health. Quantitative magnetic resonance image (MRI) methodologies were used to analyze T1-weighted structural images and diffusion tensor imaging (DTI) metrics. Specifically, region of interest and voxel-wise volume and tensor-based spatial statistics (TBSS) approaches were performed to evaluate differences in brain volumes and white matter microstructure. We examined 31 acute HIV (AHI) participants who had paired month 0 (baseline) and month 24 (two-year follow-up) scans. Participants were comparatively analyzed in both a longitudinal manner to themselves, and a cross-sectional manner against 25 healthy control (CO) participants. As an indication of inflammation, CD8 t-lymphocyte counts was examined as a clinical covariate. The 31 AHI participants had a median (IQR) age of 26 (23-30) years at the time of enrollment and a median (IQR) baseline CD4 count of 576 (370-868) cells/μL. All immediately initiated cART. The 25 healthy controls had a median (IQR) age of 31 (26-37) years. Differences of brain integrity in the AHI group followed longitudinally were observed. Baseline CD8 count was significantly associated with increased mean diffusivity (MD) in the longitudinally infected, present in the genu and the splenium of the corpus callosum, the corona radiata, and the superior longitudinal fasciculus (all p<0.05). Structural analysis revealed enlarged corpus callosum (p<0.01) volumes, as well as enlarged caudate and thalamus subcortical gray matter volumes in the longitudinally infected AHI participants (both p<0.05). Differences of brain integrity in the AHI group after 24 months of treatment were observed compared to healthy controls. Specifically, fractional anisotropy (FA) was reduced in AHI at 24 months compared to controls in models adjusting for age in the corpus callosum, the corona radiata, and the left superior longitudinal fasciculus (all p<0.05). Structural analyses revealed enlarged putamen and the caudate volumes (both p<0.05). We conclude that differences in both brain integrity and structural volumes can be seen in AHI with successful viral suppression when compared to healthy controls. Future work will include longitudinal imaging data from healthy controls who are followed over two-year follow-up to ensure that observed changes are disease specific. We will also comparatively investigate longitudinally treated chronic HIV-infected participants (‘positive controls’) to examine if the differences are similar to those seen when therapy is initiated in the chronic stage of infection. We will examine inflammatory plasma and CSF biomarkers to inform potential mechanisms and, separately, cognitive testing to inform clinical significance
Data-driven physical actigraphy patterns relate to cognitive and vascular health in older adults
Health benefits of physical activity (PA) are well known; however, specific PA patterns that relate most strongly to cognitive aging outcomes are poorly understood. We characterized latent profiles of PA among older adults and examined associations with cognition and vascular burden. 124 functionally normal older adults wore a Fitbit™ for 30 days. Daily average step count, sedentary time (0 steps/min), and high-intensity time (≥120 steps/min) were calculated. Participants completed neurocognitive testing assessing cognitive domains of executive functioning and memory; medical history, from which vascular burden (i.e., a count of cardiovascular conditions) was calculated; and brain MRI (n = 44). Subgroups with similar PA patterns were identified via latent profile analysis. Three latent PA classes emerged: Class 1Low PA (n = 49), Class 2Average PA (n = 59), and Class 3High-intensity PA (n = 16). PA class related to executive functioning and vascular burden, driven by better outcomes in Class 3 than Class 1. Sex-stratified analyses revealed these associations were strongest in males. Post hoc analyses showed a positive association between high-intensity PA and white matter integrity among males. High-intensity PA related to better cognitive and vascular health, particularly among males. Findings inform physical activity-specific and person-specific recommendations for optimal cognitive aging
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Enlarged perivascular spaces are associated with white matter injury, cognition and inflammation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
Enlarged perivascular spaces have been previously reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, but their significance and pathophysiology remains unclear. We investigated associations of white matter enlarged perivascular spaces with classical imaging measures, cognitive measures and plasma proteins to better understand what enlarged perivascular spaces represent in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and whether radiographic measures of enlarged perivascular spaces would be of value in future therapeutic discovery studies for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Twenty-four individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and 24 age- and sex-matched controls were included. Disease status was determined based on the presence of NOTCH3 mutation. Brain imaging measures of white matter hyperintensity, brain parenchymal fraction, white matter enlarged perivascular space volumes, clinical and cognitive measures as well as plasma proteomics were used in models. White matter enlarged perivascular space volumes were calculated via a novel, semiautomated pipeline, and levels of 7363 proteins were quantified in plasma using the SomaScan assay. The relationship of enlarged perivascular spaces with global burden of white matter hyperintensity, brain atrophy, functional status, neurocognitive measures and plasma proteins was modelled with linear regression models. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and control groups did not exhibit differences in mean enlarged perivascular space volumes. However, increased enlarged perivascular space volumes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy were associated with increased white matter hyperintensity volume (β = 0.57, P = 0.05), Clinical Dementia Rating Sum-of-Boxes score (β = 0.49, P = 0.04) and marginally with decreased brain parenchymal fraction (β = -0.03, P = 0.10). In interaction term models, the interaction term between cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease status and enlarged perivascular space volume was associated with increased white matter hyperintensity volume (β = 0.57, P = 0.02), Clinical Dementia Rating Sum-of-Boxes score (β = 0.52, P = 0.02), Mini-Mental State Examination score (β = -1.49, P = 0.03) and marginally with decreased brain parenchymal fraction (β = -0.03, P = 0.07). Proteins positively associated with enlarged perivascular space volumes were found to be related to leukocyte migration and inflammation, while negatively associated proteins were related to lipid metabolism. Two central hub proteins were identified in protein networks associated with enlarged perivascular space volumes: CXC motif chemokine ligand 8/interleukin-8 and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. The levels of CXC motif chemokine ligand 8/interleukin-8 were also associated with increased white matter hyperintensity volume (β = 42.86, P = 0.03), and levels of C-C motif chemokine ligand 2/monocyte chemoattractant protein 1 were further associated with decreased brain parenchymal fraction (β = -0.0007, P < 0.01) and Mini-Mental State Examination score (β = -0.02, P < 0.01) and increased Trail Making Test B completion time (β = 0.76, P < 0.01). No proteins were associated with all three studied imaging measures of pathology (brain parenchymal fraction, enlarged perivascular spaces, white matter hyperintensity). Based on associations uncovered between enlarged perivascular space volumes and cognitive functions, imaging and plasma proteins, we conclude that white matter enlarged perivascular space volumes may capture pathologies contributing to chronic brain dysfunction and degeneration in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
Abstract QS40: A Novel Bioactive Suture That Accelerates Wound Tensile Strength Re-establishment And Enhances Wound Healing
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Multi-Modal Biomarkers of Repetitive Head Impacts and Traumatic Encephalopathy Syndrome: A Clinicopathological Case Series
Traumatic encephalopathy syndrome (TES) criteria were developed to aid diagnosis of chronic traumatic encephalopathy (CTE) pathology during life. Interpreting clinical and biomarker findings in patients with TES during life necessitates autopsy-based determination of the neuropathological profile. We report a clinicopathological series of nine patients with previous repetitive head impacts (RHI) classified retrospectively using the recent TES research framework (100% male and white/Caucasian, age at death 49-84) who completed antemortem neuropsychological evaluations, T1-weighted magnetic resonance imaging, diffusion tensor imaging (n = 6), (18)F-fluorodeoxyglucose-positron emission tomography (n = 5), and plasma measurement of neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and total tau (n = 8). Autopsies were performed on all patients. Cognitively, low test scores and longitudinal decline were relatively consistent for memory and executive function. Medial temporal lobe atrophy was observed in all nine patients. Poor white matter integrity was consistently found in the fornix. Glucose hypometabolism was most common in the medial temporal lobe and thalamus. Most patients had elevated plasma GFAP, NfL, and total tau at their initial visit and a subset showed longitudinally increasing concentrations. Neuropathologically, five of the nine patients had CTE pathology (n = 4 "High CTE"/McKee Stage III-IV, n = 1 "Low CTE"/McKee Stage I). Primary neuropathological diagnoses (i.e., the disease considered most responsible for observed symptoms) were frontotemporal lobar degeneration (n = 2 FTLD-TDP, n = 1 FTLD-tau), Alzheimer disease (n = 3), CTE (n = 2), and primary age-related tauopathy (n = 1). In addition, hippocampal sclerosis was a common neuropathological comorbidity (n = 5) and associated with limbic-predominant TDP-43 proteinopathy (n = 4) or FTLD-TDP (n = 1). Memory and executive function decline, limbic system brain changes (atrophy, decreased white matter integrity, hypometabolism), and plasma biomarker alterations are common in RHI and TES but may reflect multiple neuropathologies. In particular, the neuropathological differential for patients with RHI or TES presenting with medial temporal atrophy and memory loss should include limbic TDP-43. Researchers and clinicians should be cautious in attributing cognitive, neuroimaging, or other biomarker changes solely to CTE tau pathology based on previous RHI or a TES diagnosis alone
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Evaluation of Plasma Phosphorylated Tau217 for Differentiation Between Alzheimer Disease and Frontotemporal Lobar Degeneration Subtypes Among Patients With Corticobasal Syndrome
ImportancePlasma phosphorylated tau217 (p-tau217), a biomarker of Alzheimer disease (AD), is of special interest in corticobasal syndrome (CBS) because autopsy studies have revealed AD is the driving neuropathology in up to 40% of cases. This differentiates CBS from other 4-repeat tauopathy (4RT)-associated syndromes, such as progressive supranuclear palsy Richardson syndrome (PSP-RS) and nonfluent primary progressive aphasia (nfvPPA), where underlying frontotemporal lobar degeneration (FTLD) is typically the primary neuropathology.ObjectiveTo validate plasma p-tau217 against positron emission tomography (PET) in 4RT-associated syndromes, especially CBS.Design, setting, and participantsThis multicohort study with 6, 12, and 24-month follow-up recruited adult participants between January 2011 and September 2020 from 8 tertiary care centers in the 4RT Neuroimaging Initiative (4RTNI). All participants with CBS (n = 113), PSP-RS (n = 121), and nfvPPA (n = 39) were included; other diagnoses were excluded due to rarity (n = 29). Individuals with PET-confirmed AD (n = 54) and PET-negative cognitively normal control individuals (n = 59) were evaluated at University of California San Francisco. Operators were blinded to the cohort.Main outcome and measuresPlasma p-tau217, measured by Meso Scale Discovery electrochemiluminescence, was validated against amyloid-β (Aβ) and flortaucipir (FTP) PET. Imaging analyses used voxel-based morphometry and bayesian linear mixed-effects modeling. Clinical biomarker associations were evaluated using longitudinal mixed-effect modeling.ResultsOf 386 participants, 199 (52%) were female, and the mean (SD) age was 68 (8) years. Plasma p-tau217 was elevated in patients with CBS with positive Aβ PET results (mean [SD], 0.57 [0.43] pg/mL) or FTP PET (mean [SD], 0.75 [0.30] pg/mL) to concentrations comparable to control individuals with AD (mean [SD], 0.72 [0.37]), whereas PSP-RS and nfvPPA showed no increase relative to control. Within CBS, p-tau217 had excellent diagnostic performance with area under the receiver operating characteristic curve (AUC) for Aβ PET of 0.87 (95% CI, 0.76-0.98; P < .001) and FTP PET of 0.93 (95% CI, 0.83-1.00; P < .001). At baseline, individuals with CBS-AD (n = 12), defined by a PET-validated plasma p-tau217 cutoff 0.25 pg/mL or greater, had increased temporoparietal atrophy at baseline compared to individuals with CBS-FTLD (n = 39), whereas longitudinally, individuals with CBS-FTLD had faster brainstem atrophy rates. Individuals with CBS-FTLD also progressed more rapidly on a modified version of the PSP Rating Scale than those with CBS-AD (mean [SD], 3.5 [0.5] vs 0.8 [0.8] points/year; P = .005).Conclusions and relevanceIn this cohort study, plasma p-tau217 had excellent diagnostic performance for identifying Aβ or FTP PET positivity within CBS with likely underlying AD pathology. Plasma P-tau217 may be a useful and inexpensive biomarker to select patients for CBS clinical trials