Longitudinal Morphometric Study of Genetic Influence of APOE e4 Genotype on Hippocampal Atrophy - An N=1925 Surface-based ADNI Study

abstract: The apolipoprotein E (APOE) e4 genotype is the most prevalent known genetic risk factor for Alzheimer's disease (AD). In this paper, we examined the longitudinal effect of APOE e4 on hippocampal morphometry in Alzheimer's Disease Neuroimaging Initiative (ADNI). Generally, atrophy of hippocampus has more chance occurs in AD patients who carrying the APOE e4 allele than those who are APOE e4 noncarriers. Also, brain structure and function depend on APOE genotype not just for Alzheimer's disease patients but also in health elderly individuals, so APOE genotyping is considered critical in clinical trials of Alzheimer's disease. We used a large sample of elderly participants, with the help of a new automated surface registration system based on surface conformal parameterization with holomorphic 1-forms and surface fluid registration. In this system, we automatically segmented and constructed hippocampal surfaces from MR images at many different time points, such as 6 months, 1- and 2-year follow up. Between the two different hippocampal surfaces, we did the high-order correspondences, using a novel inverse consistent surface fluid registration method. At each time point, using Hotelling's T^2 test, we found significant morphological deformation in APOE e4 carriers relative to noncarriers in the entire cohort as well as in the non-demented (pooled MCI and control) subjects, affecting the left hippocampus more than the right, and this effect was more pronounced in e4 homozygotes than heterozygotes.Dissertation/ThesisMasters Thesis Computer Science 201

Influence of APOE Genotype on Hippocampal Atrophy over Time - An N=1925 Surface-Based ADNI Study

abstract: The apolipoprotein E (APOE) e4 genotype is a powerful risk factor for late-onset Alzheimer’s disease (AD). In the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, we previously reported significant baseline structural differences in APOE e4 carriers relative to non-carriers, involving the left hippocampus more than the right—a difference more pronounced in e4 homozygotes than heterozygotes. We now examine the longitudinal effects of APOE genotype on hippocampal morphometry at 6-, 12- and 24-months, in the ADNI cohort. We employed a new automated surface registration system based on conformal geometry and tensor-based morphometry. Among different hippocampal surfaces, we computed high-order correspondences, using a novel inverse-consistent surface-based fluid registration method and multivariate statistics consisting of multivariate tensor-based morphometry (mTBM) and radial distance. At each time point, using Hotelling’s T[superscript 2] test, we found significant morphological deformation in APOE e4 carriers relative to non-carriers in the full cohort as well as in the non-demented (pooled MCI and control) subjects at each follow-up interval. In the complete ADNI cohort, we found greater atrophy of the left hippocampus than the right, and this asymmetry was more pronounced in e4 homozygotes than heterozygotes. These findings, combined with our earlier investigations, demonstrate an e4 dose effect on accelerated hippocampal atrophy, and support the enrichment of prevention trial cohorts with e4 carriers.The article is published at http://journals.plos.org/plosone/article?id=10.1371/journal.pone.015290

Disrupted cerebral metabolite levels and lower nadir CD4+ counts are linked to brain volume deficits in 210 HIV-infected patients on stable treatmentpatients on stable treatment

AbstractCognitive impairment and brain injury are common in people with HIV/AIDS, even when viral replication is effectively suppressed with combined antiretroviral therapies (cART). Metabolic and structural abnormalities may promote cognitive decline, but we know little about how these measures relate in people on stable cART. Here we used tensor-based morphometry (TBM) to reveal the 3D profile of regional brain volume variations in 210 HIV+ patients scanned with whole-brain MRI at 1.5T (mean age: 48.6±8.4years; all receiving cART). We identified brain regions where the degree of atrophy was related to HIV clinical measures and cerebral metabolite levels assessed with magnetic resonance spectroscopy (MRS). Regional brain volume reduction was linked to lower nadir CD4+ count, with a 1–2% white matter volume reduction for each 25-point reduction in nadir CD4+. Even so, brain volume measured by TBM showed no detectable association with current CD4+ count, AIDS Dementia Complex (ADC) stage, HIV RNA load in plasma or cerebrospinal fluid (CSF), duration of HIV infection, antiretroviral CNS penetration-effectiveness (CPE) scores, or years on cART, after controlling for demographic factors, and for multiple comparisons. Elevated glutamate and glutamine (Glx) and lower N-acetylaspartate (NAA) in the frontal white matter, basal ganglia, and mid frontal cortex — were associated with lower white matter, putamen and thalamus volumes, and ventricular and CSF space expansion. Reductions in brain volumes in the setting of chronic and stable disease are strongly linked to a history of immunosuppression, suggesting that delays in initiating cART may result in imminent and irreversible brain damage

Neuroimaging biomarkers of neurodegenerative diseases and dementia

Neurodegenerative disorders leading to dementia are common diseases that affect many older and some young adults. Neuroimaging methods are important tools for assessing and monitoring pathological brain changes associated with progressive neurodegenerative conditions. In this review, the authors describe key findings from neuroimaging studies (magnetic resonance imaging and radionucleotide imaging) in neurodegenerative disorders, including Alzheimer's disease (AD) and prodromal stages, familial and atypical AD syndromes, frontotemporal dementia, amyotrophic lateral sclerosis with and without dementia, Parkinson's disease with and without dementia, dementia with Lewy bodies, Huntington's disease, multiple sclerosis, HIV-associated neurocognitive disorder, and prion protein associated diseases (i.e., Creutzfeldt-Jakob disease). The authors focus on neuroimaging findings of in vivo pathology in these disorders, as well as the potential for neuroimaging to provide useful information for differential diagnosis of neurodegenerative disorders

Structural brain connectivity of HIV-positive children: a graph network analysis study

Vertical transmission of human immunodeficiency virus (HIV) from mother to child is a major problem in sub-Saharan Africa. As in adults, a variety of cognitive impairments may be evident in HIV infected children being treated with combined antiretroviral therapy (ART). The HIV virus compromises visual perception, attention, memory, language and executive functioning. Prior imaging studies have shown abnormal brain structure in adults and children infected by HIV. Graph theory analyses have been applied to HIV neuropathogenesis previously, these have demonstrated significant disruptions to brain connectivity in older HIV+ adults on treatment. However, no previous studies have investigated the same topological organization or structural connectivity of brain structure in infected children, or correlated this with markers of disease severity. The aims of this project were first, to delineate the topological organization of brain structure in children living with HIV currently on treatment and contrast it with healthy HIV negative children, second to investigate differences in measures of brain structure between healthy controls and children living with HIV and third to correlate brain imaging measures with markers of disease severity. The studies presented here examine the structural connectivity between nodes in the brain by utilizing magnetic resonance imaging and graph theory methods, and also investigated gray matter structure and cortical complexity. Children living with HIV displayed abnormal structural connectivity in regions of the dorsal posterior cingulate and inferior frontal gyrus of the frontal lobe, as well as in superior regions of the temporal lobe when compared to healthy HIV negative children. Significantly decreased cortical thickness was found in precentral and postcentral regions and the superior and middle frontal regions of children living with HIV compared to the healthy group. Deficits in cortical complexity of the inferior frontal gyrus and fusiform gyri were also apparent in the HIV infected group. Cortical thickness, surface area and gyrification were positively associated with CD4 count as a marker of disease severity. In conclusion, this project demonstrated abnormal brain structure and structural connectivity of brain structure in regions involved with motor development, executive function, and language fluency and generation in treated children living with HIV. Abnormal structural connectivity may indicate disruption to brain network integrity in developing children. Even in the post-ART era, infected children remain at risk for abnormal brain development. Longitudinal studies in larger cohorts are needed to address the issue of changes in brain structure and topology over time during adolescent brain development

What can imaging tell us about cognitive impairment and dementia?

Peer reviewedPublisher PD

MR Imaging Biomarkers in HIV associated Neurocognitive Impairment in the Era of cART

HIV associated neurocognitive disorder (HAND) continues to occur despite virally suppressive combination of antiretroviral therapy. The viral toxins, neuroinflammation secondary to host factor (ARV toxicity, immune reconstitution are additional factors) and the comorbidities in combination or individually appear to drive the ongoing HAND. Although in the pre-cART era the biomarkers of HIV dementia were clearly laid out in terms of clinical, biochemical and imaging criteria, in the cART era this has become more blurred. Some of the observations drawn from the imaging studies to identify the pathological underpinnings have shown conflicting results by different authors. The cause of these contradictory imaging observations are multifocal but principally linked to the observation that “HIV neural injury is not a one-time event”. Therefore, the paradigm of imaging should be tailored to the diversity of the disease spectrum. I have used the advanced imaging techniques to identify if there are any imaging techniques which can demonstrate the ongoing neural injury as well as monitor the response to the therapy in this research using both cross sectional and longitudinal experiments. I have also explored if there is any imaging equivalent to identify the neuroinflammation

Imaging of brain structural and functional effects in people with human immunodeficiency virus

Before the introduction of antiretroviral therapy, human immunodeficiency virus (HIV) infection was often accompanied by central nervous system (CNS) opportunistic infections and HIV encephalopathy marked by profound structural and functional alterations detectable with neuroimaging. Treatment with antiretroviral therapy nearly eliminated CNS opportunistic infections, while neuropsychiatric impairment and peripheral nerve and organ damage have persisted among virally suppressed people with HIV (PWH), suggesting ongoing brain injury. Neuroimaging research must use methods sensitive for detecting subtle HIV-associated brain structural and functional abnormalities, while allowing for adjustments for potential confounders, such as age, sex, substance use, hepatitis C coinfection, cardiovascular risk, and others. Here, we review existing and emerging neuroimaging tools that demonstrated promise in detecting markers of HIV-associated brain pathology and explore strategies to study the impact of potential confounding factors on these brain measures. We emphasize neuroimaging approaches that may be used in parallel to gather complementary information, allowing efficient detection and interpretation of altered brain structure and function associated with suboptimal clinical outcomes among virally suppressed PWH. We examine the advantages of each imaging modality and systematic approaches in study design and analysis. We also consider advantages of combining experimental and statistical control techniques to improve sensitivity and specificity of biotype identification and explore the costs and benefits of aggregating data from multiple studies to achieve larger sample sizes, enabling use of emerging methods for combining and analyzing large, multifaceted data sets. Many of the topics addressed in this article were discussed at the National Institute of Mental Health meeting Biotypes of CNS Complications in People Living with HIV, held in October 2021, and are part of ongoing research initiatives to define the role of neuroimaging in emerging alternative approaches to identifying biotypes of CNS complications in PWH. An outcome of these considerations may be the development of a common neuroimaging protocol available for researchers to use in future studies examining neurological changes in the brains of PWH

HIV and Early Life Stress on Neuroimaging and Risky Behavior

This study examined the interactive effects of early life stress (ELS) and HIV on brain morphometry, diffusion-basis-spectrum-imaging (DBSI), risky decision-making, and sex-risk behavior. 122 people with HIV (PWH) and 113 people without HIV (PWoH), free of major psychiatric illness and neurological confounds, were stratified into high (≥ 3 events) vs. low (\u3c 3 events) ELS [PWoH/low ELS (n = 57), PWoH/high ELS (n =56), PWH/low ELS (n = 43), PWH/high ELS (n = 79)] and underwent structural magnetic resonance imaging, DBSI, neuropsychological, and risky-behavior assessment; all PWH were virologically controlled. Compared to PWoH, PWH had smaller orbitofrontal cortex (OFC), parietal lobes, insula, caudate and anterior cingulate. No ELS effects were detected in volumetric measures. Significant interactions were found between HIV serostatus and ELS on the OFC and on cellularity of the inferior fronto-occipital fasciculus after multiple comparisons adjustment. Specifically, PWH/high ELS exhibited significantly smaller OFC and PWoH/high ELS show significantly larger OFC than the other groups. PWoH/high ELS exhibited higher DBSI cellularity (neuroinflammation proxy) of the inferior-occipital-fasciculus compared to PWoH/high ELS. Regardless of HIV status, executive function moderated the relationship between the OFC and sex-risk behavior such that individuals within the sample who performed above average on a measure of executive function and had a larger OFC reported fewer sex partners in past six months than individuals with smaller volumes. No interaction was found between HIV serostatus and ELS on risky behavior measures. Clustering analyses defined ELS subgroups in PWH that were determined by demographic characteristics, duration of infection, recent CD4+ T-cell count, nadir CD4+ T-cell count and high/low ELS.Even in PWH that are virologically controlled, without major current psychiatric comorbidities, there is evidence of a synergistic impact of ELS and HIV on OFC volumes. Higher volumes in the OFC were detrimental when associated with lower executive function scores or advantageous when associated with higher executive function. Findings suggest that ELS is associated with different brain signatures among PWoH and virally suppressed PWH. However, ELS was not directly associated with risky behaviors, and subgroups in PWH were characterized by demographic variables, past substance use and HIV clinical variables