To evaluate relationships between HIV-associated neurocognitive disorder and metabolic variables in a subgroup of HIV+ participants examined in a prospective, observational, multicenter cohort study.
...In a cross-sectional substudy of the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort, 130 HIV+ participants provided fasting blood samples. Neurocognitive impairment (NCI) was defined by performance on neuropsychological tests adjusting for age, education, gender, and race/ethnicity. Global ratings and global deficit scores were determined. Demographics, biomarkers of HIV disease, metabolic variables, combination antiretroviral therapy (CART) history, other drug exposures, and self-reported diabetes were examined in multivariate models predicting NCI. Separate models were used for body mass index (BMI) alone (n = 90) and BMI and waist circumference (WC) together (n = 55).
NCI (global impairment rating ≥5) was diagnosed in 40%. In univariate analyses, age, longer duration of HIV infection, obesity, and WC, but not BMI, were associated with NCI. Self-reported diabetes was associated with NCI in the substudy and in those >55 in the entire CHARTER cohort. Multivariate logistic regression analyses demonstrated that central obesity (as measured by WC) increased the risk of NCI and that greater body mass may be protective if the deleterious effect of central obesity is accounted for.
As in HIV-uninfected persons, central obesity, but not more generalized increases in body mass (BMI), was associated with a higher prevalence of NCI in HIV+ persons. Diabetes appeared to be associated with NCI only in older patients. Avoidance of antiretroviral drugs that induce central obesity might protect from or help to reverse neurocognitive impairment in HIV-infected persons.
HIV enters the brain soon after infection causing neuronal damage and microglial/astrocyte dysfunction leading to neuropsychological impairment. We examined the impact of HIV on resting cerebral ...blood flow (rCBF) within the lenticular nuclei (LN) and visual cortex (VC).
This cross-sectional study used arterial spin labeling MRI (ASL-MRI) to measure rCBF within 33 HIV+ and 26 HIV- subjects. Nonparametric Wilcoxon rank sum test assessed rCBF differences due to HIV serostatus. Classification and regression tree (CART) analysis determined optimal rCBF cutoffs for differentiating HIV serostatus. The effects of neuropsychological impairment and infection duration on rCBF were evaluated.
rCBF within the LN and VC were significantly reduced for HIV+ compared to HIV- subjects. A 2-tiered CART approach using either LN rCBF < or =50.09 mL/100 mL/min or LN rCBF >50.09 mL/100 mL/min but VC rCBF < or =37.05 mL/100 mL/min yielded an 88% (29/33) sensitivity and an 88% (23/26) specificity for differentiating by HIV serostatus. HIV+ subjects, including neuropsychologically unimpaired, had reduced rCBF within the LN (p = 0.02) and VC (p = 0.001) compared to HIV- controls. A temporal progression of brain involvement occurred with LN rCBF significantly reduced for both acute/early (<1 year of seroconversion) and chronic HIV-infected subjects, whereas rCBF in the VC was diminished for only chronic HIV-infected subjects.
Resting cerebral blood flow (rCBF) using arterial spin labeling MRI has the potential to be a noninvasive neuroimaging biomarker for assessing HIV in the brain. rCBF reductions that occur soon after seroconversion possibly reflect neuronal or vascular injury among HIV+ individuals not yet expressing neuropsychological impairment.
Alzheimer's disease (AD) is the most common cause of dementia. Much is known concerning AD pathophysiology but our understanding of the disease at the systems level remains incomplete. Previous AD ...research has used resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) to assess the integrity of functional networks within the brain. Most studies have focused on the default-mode network (DMN), a primary locus of AD pathology. However, other brain regions are inevitably affected with disease progression. We studied rs-fcMRI in five functionally defined brain networks within a large cohort of human participants of either gender (n = 510) that ranged in AD severity from unaffected clinical dementia rating (CDR) 0 to very mild (CDR 0.5) to mild (CDR 1). We observed loss of correlations within not only the DMN but other networks at CDR 0.5. Within the salience network (SAL), increases were seen between CDR 0 and CDR 0.5. However, at CDR 1, all networks, including SAL, exhibited reduced correlations. Specific networks were preferentially affected at certain CDR stages. In addition, cross-network relations were consistently lost with increasing AD severity. Our results demonstrate that AD is associated with widespread loss of both intranetwork and internetwork correlations. These results provide insight into AD pathophysiology and reinforce an integrative view of the brain's functional organization.
Importance
Adults with Down syndrome (DS) are at high‐risk of revealing Alzheimer's disease (AD) pathology, in part due to the triplication of chromosome 21 encoding the amyloid precursor protein. ...Adults with DS are uniformly affected by AD pathology by their 30′s and have a 70% to 80% chance of clinical dementia by their 60′s. Our previous studies have assessed longitudinal changes in amyloid beta (Aβ) accumulation in DS.
Objective
The goal of the present study was to assess the presence of brain tau using 18FAV‐1451 positron emission tomography (PET) in DS and to assess the relationship of brain tau pathology to Aβ using Pittsburgh Compound B (PiB)‐PET.
Design
Cohort study
Setting
Multi‐center study
Participants
Participants consisted of a sample of individuals with DS and sibling controls recruited from the community; exclusion criteria included contraindications for magnetic resonance imaging (MRI) and/or a medical or psychiatric condition that impaired cognitive functioning.
Exposures
PET brain scans to assess Aβ (11CPiB) and tau (18FAV‐1451) burden.
Main outcomes and measures
Multiple linear regression models (adjusted for chronological age, sex and performance site) were used to examine associations between regional 18FAV‐1451 standard uptake value ratio (SUVR) (based on regions associated with Braak stages 1‐6) and global 11CPiB SUVR (as both a continuous and dichotomous variable).
Results
A cohort of 156 participants (mean age = 39.05, SD(8.4)) were examined. These results revealed a significant relationship between in vivo Aβ and tau pathology in DS. As a dichotomous variable, 18FAV‐1451 retention was higher in each Braak region in PiB(+) participants. We also found, based on our statistical models, starting with the Braak 3 region of interest (ROI), an acceleration of 18FAV‐1451 SUVR deposition with 11CPiB SUVR increases.
Background and purpose
AV‐1451 (18F‐AV‐1451, flortaucipir) positron emission tomography was performed in C9orf72 expansion carriers to assess tau accumulation and disease manifestation.
Methods
Nine ...clinically characterized C9orf72 expansion carriers and 18 age‐ and gender‐ matched cognitively normal individuals were psychometrically evaluated and underwent tau positron emission tomography imaging. The regional AV‐1451 standard uptake value ratios from multiple brain regions were analyzed. Spearman correlation was performed to relate the AV‐1451 standard uptake value ratio to clinical, psychometric and cerebrospinal fluid measures.
Results
C9orf72 expansion carriers had increased AV‐1451 binding in the entorhinal cortex compared to controls. Primary age‐related tauopathy was observed postmortem in one patient. AV‐1451 uptake did not correlate with clinical severity, disease duration, psychometric performance or cerebrospinal fluid markers.
Conclusion
C9orf72 expansion carriers exhibited increased AV‐1451 uptake in entorhinal cortex compared to cognitively normal controls, suggesting a propensity for primary age‐related tauopathy. However, AV‐1451 accumulation was not associated with psychometric performance in our cohort.
Diagnostic challenges exist for differentiating HIV dementia from Alzheimer disease (AD) in older HIV-infected (HIV+) individuals. Similar abnormalities in brain amyloid-beta42 (Alphabeta42) ...metabolism may be involved in HIV-associated neuropathology and AD. We evaluated the amyloid-binding agent (11)C-Pittsburgh compound B ((11)C-PiB), a biomarker for Alphabeta42 deposition, in cognitively unimpaired HIV+ (n = 10) participants and matched community controls without dementia (n = 20).
In this case-control study, all participants had an (11)C-PiB scan within 2 years of concomitant CSF studies and neuropsychometric testing. Statistical differences between HIV+ and community controls for demographic and clinical values were assessed by chi(2) tests. Participants were further divided into either low (<500 pg/mL) or normal (>or=500 pg/mL) CSF Alphabeta42 groups with Student t tests performed to determine if regional differences in fibrillar amyloid plaque deposition varied with CSF Alphabeta42.
Regardless of CSF Alphabeta42 level, none of the HIV+ participants had fibrillar amyloid plaques as assessed by increased (11)C-PiB mean cortical binding potential (MCBP) or binding potential within 4 cortical regions. In contrast, some community controls with low CSF Alphabeta42 (<500 pg/mL) had high (11)C-PiB MCBP with elevated binding potentials (>0.18 arbitrary units) within cortical regions.
Cognitively unimpaired HIV+ participants, even with low CSF Alphabeta42 (<500 pg/mL), do not have (11)C-PiB parameters suggesting brain fibrillar amyloid deposition. The dissimilarity between unimpaired HIV+ and preclinical AD may reflect differences in Abeta42 production and/or formation of diffuse plaques. Future longitudinal studies of HIV+ participants with low CSF Abeta42 and normal (11)C-PiB are required.
To evaluate the effects of HIV-associated neurocognitive impairment on caudate blood flow and volume.
The authors performed continuous arterial spin labeled MRI on 42 HIV+ patients (23 subsyndromic ...and 19 HIV neurosymptomatic) on highly active antiretroviral therapy and 17 seronegative controls. They compared caudate blood flow and volume among groups.
A stepwise decrease in both caudate blood flow and volume was observed with increasing HIV-associated neurocognitive impairment. Compared with seronegative controls, baseline caudate blood flow was reduced in HIV+ neurosymptomatic patients (p = 0.001) with a similar decreasing trend for subsyndromic HIV+ patients (p = 0.070). Differences in caudate volume were observed only for neurosymptomatic HIV+ patients compared with controls (p = 0.010). A Jonckheere-Terpstra test for trends was significant for both caudate blood flow and volume for each of the three subgroups. Pearson product moment correlation coefficients were not significant between caudate blood flow and volume for each group.
Decreasing trends in caudate blood flow and volume were associated with significantly increasing HIV-associated neurocognitive impairment (HNCI), with the greatest decreases observed for more severely impaired patients. However, reductions in caudate blood flow and volume were poorly correlated. Changes in residual caudate blood flow may act as a surrogate biomarker for classifying the degree of HNCI.
The purpose of the present study is to examine the integrity of white matter microstructure among individuals coinfected with HIV and HCV using diffusion tensor imaging (DTI). Twenty-five HIV+ ...patients, 21 HIV+/HCV+ patients, and 25 HIV− controls were included in this study. All HIV+ individuals were stable on combination antiretroviral therapy (cART; ≥3 months). All participants completed MRI and neuropsychological measures. Clinical variables including liver function, HIV-viral load, and CD4 count were collected from the patient groups. DTI metrics including mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA) from five subregions of the corpus callosum were compared across groups. The HIV+/HCV+ group and HIV+ group were similar in terms of HIV clinical variables. None of the participants met criteria for cirrhosis or fibrosis. Within the anterior corpus callosum, significant differences were observed between both HIV+ groups compared to HIV− controls on DTI measures. HIV+ and HIV+/HCV+ groups had significantly lower FA values and higher MD and RD values compared to HIV− controls; however, no differences were present between the HIV+ and HIV+/HCV+ groups. Duration of HIV infection was significantly related to DTI metrics in total corpus callosum FA only, but not other markers of HIV disease burden or neurocognitive function. Both HIV+ and HIV+/HCV+ individuals had significant alterations in white matter integrity within the corpus callosum; however, there was no evidence for an additive effect of HCV coinfection. The association between DTI metrics and duration of HIV infection suggests that HIV may continue to negatively impact white matter integrity even in well-controlled disease.
Background and purpose
Sporadic Creutzfeldt–Jakob disease (sCJD) is a rapidly progressive neurodegenerative disease caused by an abnormal isoform of the human prion protein. Structural magnetic ...resonance imaging in patients with pathologically confirmed sCJD was compared with cognitively normal individuals to identify a cortical thickness signature of sCJD.
Methods
This retrospective cross‐sectional study compared patients with autopsy‐confirmed sCJD with dementia (n = 11) with age‐ and sex‐matched cognitively normal individuals (n = 22). We identified regions of interest (ROIs) in which cortical thickness was most affected by sCJD. Within patients with sCJD, the relationship between ROI cortical thickness and clinical measures (disease duration, cerebrospinal fluid tau and diffusion‐weighted imaging abnormalities) was evaluated.
Results
Compared with cognitively normal individuals, patients with sCJD had significantly reduced cortical thickness in multiple ROIs, including the fusiform gyrus, precentral gyrus, precuneus and superior temporal gyrus bilaterally; the caudal middle frontal gyrus, superior frontal gyrus, postcentral gyrus, inferior temporal gyrus and transverse temporal gyrus in the left hemisphere; and the superior parietal lobule in the right hemisphere. Only one patient with sCJD had co‐pathology consistent with Alzheimer's disease. Reduced cortical thickness did not correlate with disease duration, presence of diffusion restriction or elevated cerebrospinal fluid tau.
Conclusion
Cortical signature changes in sCJD may reflect brain changes not captured by standard clinical measures. This information may be used with clinical measures to inform the progression of sCJD and patterns of prion protein spread throughout the brain. These results may have implications for prediction of symptomatic progression and plausibly for development of therapeutic strategies.
Longitudinal brain changes in treated and untreated individuals with primary HIV infection were examined. Before treatment, significant brain volume loss and cortical thinning were observed. After ...treatment, no further brain atrophy was found. This highlights the importance of early treatment.
Abstract
Background
Human immunodeficiency virus (HIV) penetrates the brain in early infection. We used neuroimaging to longitudinally examine the impact of HIV and combination antiretroviral therapy (cART) on the brain in treated and untreated HIV-infected participants, starting in primary HIV infection (PHI).
Methods
Sixty-five participants, enrolled during PHI, underwent longitudinal magnetic resonance imaging, 30 of whom commenced cART during follow-up. Cross-sectional data from 16 patients with chronic HIV infection (CHI) and 19 HIV-uninfected participants were included for comparison. Brain volume and cortical thickness were estimated using tensor-based morphometry and cortical modeling, respectively. Mixed-effects models longitudinally mapped structural brain changes before and after cART. The relationship between brain morphometry estimates and blood and cerebrospinal fluid (CSF) biomarkers were also tested. Region-of-interest analyses were performed to compare brain morphometry estimates between the groups.
Results
Prior to cART, longer duration of untreated infection in PHI correlated with volume loss in the thalamus, caudate, and cerebellum, and with cortical thinning in the frontal and temporal lobes and cingulate cortex. After cART, no further volume loss was observed. However, small increases of cortical thickness in the frontal and temporal lobe correlated with longer cART duration. No correlations were observed with blood or CSF measures. The PHI group did not have different brain morphometric measures compared to the HIV-uninfected group, but had larger volumes in the thalamus, caudate, putamen, and cortical gray matter compared with CHI participants.
Conclusions
Subcortical atrophy and cortical thinning occur during untreated infection but may be arrested by cART. These findings emphasize the importance of early cART.
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