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

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

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

What can imaging tell us about cognitive impairment and dementia?

Peer reviewedPublisher PD

Aspects of Subcortical Ischaemic Vascular Disease : Early clinical manifestations and associations with Type 2 diabetes mellitus

Summary Subcortical ischaemic vascular disease (SIVD) is an important cause of cognitive impairment in elderly patients. Screening and diagnostic tests are needed to identify these patients. The HIV dementia scale (HDS) is a reliable and quantitative scale for identifying HIV dementia1. The cognitive profile of HIV dementia has subcortical features that resemble subcortical ischaemic vascular disease (SIVD). The clinical syndrome is characterized by early impairment of attention and executive function, accompanied by a slowing of motor performance and information processing, while memory functions remain relatively intact2. Chapter 2 reported the results of an attempt to validate the HDS for elderly SIVD patients. The primary hypotheses were that the HDS could be used as a screening test in SIVD patients and that it could be used as a screening test for patients who have vascular risk factors. The HDS consists of four items and is easy to administer. All items of the HDS represent characteristics of subcortical cognitive functions, (i.e. psychomotor speed, concentration, executive functions and memory skills). Because the neuropsychological profiles of patients with normal pressure hydrocephalus (NPH) are identical to those of SIVD patients, NPH patients were also included in the study population2,3. The results of the study indicated that the HDS is capable of discriminating between patients with cognitive impairments due to SIVD or a NPH and normal control subjects in an older population. Patients had HDS scores of 5.1 ± 3.5 (maximum score 16), and control subjects had scores of 13.0± 2.4 (p < 0.0001). The results further showed that the HDS is of additional value for subjects whose Mini Mental State Examination (MMSE) scores fall within the normal range. The results of this study suggest that the HDS is capable of detecting cognitive impairment in SIVD patients and may therefore be used in clinical trials in SIVD patients or those who are at risk for SIVD. The central hypothesis of Chapter 3 was that a clinical neurophysiological test could be helpful for detecting cognitive impairment in SIVD patients. The late responses that are elicited by the auditory oddball paradigm are considered to be related to cognitive processing4. It has been shown that the latency of the N2 complex and the P3 is prolonged in patients with Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Binswanger’s disease and depression5-7. Several studies have investigated the auditory oddball paradigm in patients with vascular white matter disease (i.e. leukoaraiosis or lacunar infarcts)6,8-11. These studies, however, used either a definition of cognitive decline that was based on DSM-IV criteria for Alzheimer’s dementia12 or tests of cognitive function that were not described in detail. In addition, these studies analyzed only the P3 wave. We attempted to determine whether the various deflections of the event-related potential (N1, N2 complex and P3) that are evoked by the auditory oddball paradigm could differentiate between patients who have vascular cognitive impairment (VCI) caused by SIVD in an early phase of the disease and age-matched control subjects. We demonstrated that N2 latency was significantly longer in patients with VCI (254.6 ± 25.1 milliseconds) than it was in age-matched control subjects (235 ± 28.6 milliseconds) (p = 0.001), whereas the latencies of P3 and N1 were not significantly different. The peak-to-peak amplitude of the N2 complex to the P3 wave was significantly lower in the patient group (patients 11.5 ± 7.0 microvolt vs. controls 15.4 ± 9.4 microvolt, p = 0.02). White-matter lesions revealed by MRI were not correlated with N2 latency (r = -0.255, p = 0.3). These data show that the latency of the N2 complex is longer and the peak-to-peak amplitude of the N2 to P3 wave is lower for a well-defined group of VCI patients than it is for healthy control subjects. Subcortical ischaemic vascular disease incorporates both white-matter lesions and lacunar infarcts. While hypertension is the most important and consistent risk factor for white-matter lesions and lacunar infarcts, the data on the relation between these lesions and diabetes mellitus (DM) are not consistent. Because of the frequency of both SIVD and DM among elderly subjects we investigated the relation between DM and SIVD. Chapter 4 reports the result of a systematic review addressing the association between DM and structural brain-imaging abnormalities. It is known that DM increases the risk of cerebral large-vessel disease two to threefold. Whether DM is a risk factor for SIVD, including white-matter lesions and lacunar infarcts, remains unclear. Our systematic review addressed available data on brain-imaging changes in diabetic patients, as revealed by computer tomo-graphy (CT) and magnetic resonance imaging (MRI); it also analysed studies that use magnetic resonance spectroscopy (MRS), positron emission tomo-graphy (PET) and single-photon emission computer tomography (SPECT) to investigate the relationship between DM and abnormalities. We also assessed the relationship of these cerebral changes to cognition, and related disease variables, including DM subtype, age and hypertension, DM duration, medi-ation use and glycaemic control. Eligible studies were evaluated according to predefined inclusion criteria (i.e. clear imaging-outcome measures, a clear definition of DM and a sample size of at least 20 DM patients). Data on study design, DM type, treatment and associated comorbidity, imaging modality (MRI, MRS, CT, SPECT or PET) and imaging findings were extracted from the fifty-five articles that were included in the review. The methodology of these studies with regard to population selection, DM assessment, neuro-imaging rating methods and data analyses were heterogeneous. DM was associated with cerebral atrophy in eight out of ten studies that investigated this relationship. Eight of nineteen studies reported an association between DM and lacunar infarcts. We found little evidence of an association with white-matter lesions. Studies that used PET and SPECT reported regional abnormalities of cerebral blood flow and cerebral glucose metabolism. None of the studies assessed the relationship between imaging findings and cognition. Data on the relationship between imaging findings and disease variables (e.g. age, hypertension, medication use, glycaemic control) were scarce as well. We concluded that DM is associated with cerebral atrophy and lacunar infarcts, but that the association with white-matter lesions is equivocal. Chapter 5 elaborated on the conclusions that were drawn in Chapter 4 by reporting results from a cross-sectional study that compared a well-defined population of independently living elderly patients with Type 2 DM to healthy control subjects in order to investigate the association between DM, white-matter lesions, lacunar infarcts and brain atrophy. We also compared DM patients who had hypertension to those who did not, in order to determine whether concomitant hypertension could be defined as a relevant disease variable in DM patients. In addition, we investigated the relationship of DM to other disease determinants. The study population consisted of forty-five patients who suffered from Type 2 DM without hypertension (mean age 73.2 ± 5.1 years, mean duration of DM 16.7 ± 11.4 years), forty-five patients with type 2 DM and hypertension (mean age 73.3 ± 5.9 years, mean duration of DM 11.3 ± 9.1 years) and forty-four control subjects (mean age 73.0 ± 5.3 years). All patients and control subjects underwent MRI brain scans. White-matter lesions (WML), cerebral atrophy and medial temporal lobe atrophy (MTA) were rated using a standardized visual rating scale. WML occurred more frequently among DM patients (both with hypertension and without hypertension) than it did among healthy control subjects. Significantly more DWML (deep white-matter lesions) were found among DM patients (with and without hypertension) than were found among control subjects, although no difference was found in the occurrence of periventricular hyperintensities (PVH). Although higher atrophy scores were seen among DM patients than among control subjects, this result was not significant. The association between Type 2 DM and DWML is supported by significant positive correlations between the severity of DWML and the value of glycolysated haemoglobin (HbA1c) and the duration of DM. Data from this cross-sectional study suggest that Type 2 DM is an independent risk factor for DWML in independently living elderly patients. Chapter 6 addressed the detailed neuropsychological profiles of independently functioning patients who have Type 2 DM. It also examined correlations between cognitive impairment and brain lesions (i.e. SIVD, atrophy and lacunar infarcts) that were revealed by MRI. The chapter discusses the influence of relevant disease variables. After adjusting for hypertension neuro-psychological scores for each cognitive domain except for memory functions were worse for a group of elderly patients with Type 2 DM than they were for healthy control subjects. Periventricular hyperintensities (PVH) were an inde-pendent predictor of motor speed, while none of the other MRI measures was independently associated with cognitive impairment. No interactions between the various MRI measures were found. HbA1c and duration of DM were both significantly associated with cognitive dysfunction. Data from this cross-sectional study show that Type 2 DM is associated with diminished cognitive functioning in various cognitive domains, while memory is less affected, after adjusting for hypertension. The association of cognitive impairment with MRI measures is equivocal, although HbA1c and duration of DM were significantly associated with cognitive dysfunction. General discussion Four major conclusions can be drawn from this thesis. First, we demonstrated that the HIV dementia scale (HDS) is a sensitive screening test for detecting cognitive impairment in patients with SIVD, and it may be useful as a screening test for a population of patients who have vascular risk factors. Second, we investigated the auditory oddball paradigm in SIVD patients, showing that the latency of the N2 complex is longer and the peak-to-peak amplitude of the N2 to P3 wave is lower among a well-defined group of VCI patients than among healthy control subjects. Third, Type 2 DM is an indepen-ent risk factor for deep white-matter lesions in independently living elderly patients who visit an outpatient clinic. Fourth, although patients with Type 2 DM exhibit global cognitive deterioration with memory function being less affected after adjustment for hypertension, independent correlations with SIVD or atrophy are equivocal. The concept of SIVD was introduced as a homogeneous subtype of vascular cognitive impairment. This condition is a frequent cause of vascular cognitive impairment, and it is caused by small-vessel disease, which includes cerebral white-matter lesions (WML) and lacunar infarcts in subcortical white and grey matter13-15. Vascular cognitive impairment due to SIVD covers a wide spectrum of cognitive dysfunction, ranging from subtle and clinically often undetected deficits to overt dementia16. The neuropsychological profile is characterized by early impairment of attention and executive function, with a slowing of motor performance and information processing. Episodic memory is believed to be relatively unaffected13. Subtle clinical symptoms are often neglected by physi-cians and both patients and physicians often consider these symptoms as normal signs of ageing. Most screening tests, such as the Mini Mental State Examination (MMSE), are not sensitive enough to detect cognitive impairment in such patients, as they were designed to identify cognitive symptoms, as in Alzheimer’s disease (AD)17. Because of the frequency with which SIVD is identified as a cause of vascular cognitive impairment, a brief and simple cognitive screening test should enable physicians to make early diagnoses and should facilitate the recognition of cognitive problems in patients who are at risk for SIVD. We demonstrated that the HIV dementia scale (HDS) discriminates between elderly patients with subcortical cognitive impairment due to SIVD and normal control subjects. The difference was still significant in a sub-analysis of patients who had MMSE scores of 27 or higher (Chapter 2). Nonetheless, we cannot exclude the possibility that the cognitive deficits in these patients were caused by concomitant AD. Patients with AD present with a different clinical picture, however, and they generally have lower MMSE scores. Our findings suggest that the HDS may be useful as a screening test for SIVD and that it is of additional value for subjects whose MMSE scores fall within the normal range. Second, the auditory oddball paradigm is a neurophysiological method for eliciting an event-related potential (ERP); it contains different deflections with the highest amplitude, usually measured at about 300 milliseconds (P3)4. The late responses elicited by the auditory oddball paradigm are considered related to cognitive processing4. Although several studies have evaluated the diagnostic value of the ERP for patients with dementia, these studies primarily investigated patients with advanced disease, even though early diagnosis is needed to provide adequate care and therapy5-7,18,19. In the present thesis, we showed that the latency of the N2 complex is prolonged and the peak-to-peak amplitude of the N2 complex to P3 wave is lowered in patients who suffer from VCI caused by SIVD (Chapter 3). One of the limitations of this study was that we did not include patients with Alzheimer’s disease. Although Goodin and Aminoff reported that the N1 latency is prolonged in subcortical dementia as compared to cortical dementia, we found no prolonged N1 wave in our patients, as compared to the control subjects20. The patients in the study by Goodin and Aminoff were already suffering from advanced disease, while the patients in our study were clinically characterized by cognitive impairment and not dementia. Further studies are therefore necessary to compare the ERP that it evoked by the auditory oddball paradigm in patients with early Alzheimer’s disease to that which is evoked in patients who suffer from cognitive impairment due to SIVD. We could not demonstrate a significant positive cor-relation between the severity of white-matter abnormalities, the presence of lacunar infarcts and the N2 latency in a subgroup of our study population who underwent MRI. Although this result may be explained by the small sample size, it may also suggest that the functional difference in N2 complex between the two groups is not accompanied by anatomical changes that are revealed by MRI. The lack of correlation is not completely surprising, as the clinical impact of the severity of WML on cognition is also a subject of discussion21. Third, age and hypertension have been shown to be clearly associated with WML on MRI. The association of WML with DM, however, is much weaker than its association with any of the other risk factors. Chapter 4 presented a review of the literature on the association between DM and brain-imaging changes. Studies using CT and MRI provide evidence of a relationship between DM and cerebral atrophy, and they suggest that lacunar infarcts are more common in DM patients, although the association with WML is equivocal. Many of these studies, however, have major methodological limitations, including small sample size, inability to adjust for confounding factors, unclear operationalization of DM and insensitive rating scales for structural brain changes22-26. Because of these inconsistencies and methodological shortcomings, we investigated MRI abnormalities in independently living elderly patients with Type 2 DM who were visiting an outpatient clinic. The results presented in this thesis confirm that Type 2 DM in elderly patients is an independent risk factor for deep WML (Chapter 5). In contrast to other studies, our study population consisted of a well-defined patient group with Type 2 DM, taking comorbid hypertension into account as well. In addition, we used a semi-quantitative rating scale to assess WML; this scale is more sensitive for detecting small amounts of WML than are the rating scales that have been used in many previous studies. Most of the WML scales that have been applied in previous studies were originally developed for patients with cerebrovascular disease or vascular dementia, and they are relatively crude and insensitive. Although these scales discriminates adequately between patients with severe WML and those with modest or subtle abnormalities, they may not be sensitive enough to detect the modest differences in WML that are expected between patients with DM and control subjects (especially in small study populations). Nonetheless, although true volumetric scales claimed higher sensitivity, very few studies have used these techniques27,28. Furthermore, these studies revealed no more WML in DM patients than they did for control subjects. These studies also suffer from other methodological shortcomings (e.g. undefined DM subtype, no adjustment for other disease variables)27,28. Results regarding the association between DM and atrophy are more consistent in the literature23,26,29,30. We also found more atrophy among the DM group, but this difference was not statistically signi-ficant. Although this lack of difference may be due to the visual rating scale that was used, a comparative study between visual rating and volumetry concluded that visual rating is as clinically useful and sometimes even more accurate than volumetry31. Lacunar infarcts occurred sporadically in both DM patients and control subjects. This finding may be attributable to the fact that we investigated independently living patients who were visiting an outpatient clinic in the early phase of vascular disease. Fourth, Type 2 DM is common among the elderly, and it has been associated with cognitive impairment and dementia32-35. Study populations tend to be small, however, and they do not take into account possible differences in educational level. They also do not usually adjust for age, sex and co-morbid hypertension32. In addition, most studies do not include extensive neuropsychological test batteries, and most population studies use global cogni-tive screenings tests, such as the MMSE. We investigated neuropsychological profiles in a well-defined group of elderly patients with Type 2 DM, as well as correlations with brain-imaging abnormalities. In particular, we hypothesized that cognitive impairment in Type 2 DM was caused by SIVD (Chapter 6). When we started our study, the association between cognition and MRI findings in the DM population was not known. We administered an extensive neuropsychological test battery to Type 2 DM patients and investigated associations with MRI lesions, in order to clarify the pathological mechanisms of cognitive impairment among these patients. We demonstrated that global cognitive test scores and neuropsychological scores for each cognitive domain except for memory functions after adjustment for hypertension were worse for a group of independently living elderly patients with Type 2 DM than they were for healthy control subjects. This result has been confirmed by other studies32. Nonetheless, although we have demonstrated that Type 2 DM is an independent risk factor for deep WML, these lesions are not independently associated with cognitive impairment in the diabetic population. Only PVH was an independent predictor for motor speed: none of the other MRI measures was associated with cognitive impairment. Interactions between the various MRI measures were also not present. One of the limitations of this study was that we used a semi-quantitative visual rating scale to assess WML and a visual rating scale to determine atrophy. More sophisticated MRI analyses (e.g. volumetrics) may reveal significant correlations with structural brain changes and cognitive impairment in DM patients. We concluded that the association of cognitive impairment with MRI measures is equivocal in Type 2 DM, but that it may support a dual pathology involving both vascular disease and cerebral atrophy. It is possible that other factors that are not yet known play a role in cognitive impairment in patients with Type 2 DM.Scheltens, P. [Promotor]Weinstein, H. [Copromotor

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

Psychobiological factors of resilience and depression in late life.

In contrast to traditional perspectives of resilience as a stable, trait-like characteristic, resilience is now recognized as a multidimentional, dynamic capacity influenced by life-long interactions between internal and environmental resources. We review psychosocial and neurobiological factors associated with resilience to late-life depression (LLD). Recent research has identified both psychosocial characteristics associated with elevated LLD risk (e.g., insecure attachment, neuroticism) and psychosocial processes that may be useful intervention targets (e.g., self-efficacy, sense of purpose, coping behaviors, social support). Psychobiological factors include a variety of endocrine, genetic, inflammatory, metabolic, neural, and cardiovascular processes that bidirectionally interact to affect risk for LLD onset and course of illness. Several resilience-enhancing intervention modalities show promise for the prevention and treatment of LLD, including cognitive/psychological or mind-body (positive psychology; psychotherapy; heart rate variability biofeedback; meditation), movement-based (aerobic exercise; yoga; tai chi), and biological approaches (pharmacotherapy, electroconvulsive therapy). Additional research is needed to further elucidate psychosocial and biological factors that affect risk and course of LLD. In addition, research to identify psychobiological factors predicting differential treatment response to various interventions will be essential to the development of more individualized and effective approaches to the prevention and treatment of LLD

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

Brain Effective Connectivity During Motor-Imagery and Execution Following Stroke and Rehabilitation

Brain areas within the motor system interact directly or indirectly during motor-imagery and motor-execution tasks. These interactions and their functionality can change following stroke and recovery. How brain network interactions reorganize and recover their functionality during recovery and treatment following stroke are not well understood. To contribute to answering these questions, we recorded blood oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI) signals from10 stroke survivors and evaluated dynamical causal modeling (DCM)-based effective connectivity among three motor areas: primary motor cortex (M1), premotor cortex (PMC) and supplementary motor area (SMA), during motor-imagery and motor-execution tasks. We compared the connectivity between affected and unaffected hemispheres before and after mental practice and combined mental practice and physical therapy as treatments. The treatment (intervention) period varied in length between 14 to 51 days but all patients received the same dose of 60 h of treatment. Using Bayesian model selection (BMS) approach in the DCMapproach, wefound that, after intervention, the same network dominated during motor-imagery and motor-execution tasks butmodulatory parameters suggested a suppressive influence of SM A on M1 during the motor-imagery task whereas the influence of SM A on M1 was unrestricted during themotor-execution task.We found that the intervention caused a reorganization of the network during both tasks for unaffected as well as for the affected hemisphere. Using Bayesian model averaging (BMA) approach, we found that the intervention improved the regional connectivity among the motor areas during both the tasks. The connectivity between PMCandM1was stronger inmotor-imagery taskswhereas the connectivity from PMC to M1, SM A to M1 dominated in motor-execution tasks. There was significant behavioral improvement (p = 0.001) in sensation and motor movements because of the intervention as reflected by behavioral Fugl-Meyer (FMA)measures,whichwere significantly correlated (p=0.05)with a subset of connectivity. These findings suggest that PMC andM1 play a crucial role duringmotor-imagery aswell as during motorexecution task. In addition,M1 causesmore exchange of causal information amongmotor areas during a motorexecution task than during a motor-imagery task due to its interaction with SM A. This study expands our understanding of motor network involved during two different tasks, which are commonly used during rehabilitation following stroke. A clear understanding of the effective connectivity networks leads to a better treatment in helping stroke survivors regain motor ability

The effects of HIV-1 infection on subcortical brain structures in children receiving ART : a structural MRI study

INTRODUCTION This project investigated volumetric differences in certain subcortical structures as measured on high-resolution structural Magnetic Resonance Imaging (MRI) scans traced manually. The sample comprised 79 5-year old children, 52 with HIV and 27 uninfected controls. Infected children were all stable on antiretroviral therapy (ART) and were from the Children with HIV early antiretroviral (CHER) cohort who have been followed since birth. The study aimed to investigate the long-term effects of HIV and ART on the developing brain. While high-resolution structural data has been analysed using automated FreeSurfer to determine volume and cortical thickness, manual tracing remains the gold standard. Thus, manual tracing was used to validate automated measures and investigate subtle group differences in selected regions of interest. METHODS Extensive clinical data were available for all participants in the study. MR images were AC-PC transformed and converted to analyse format. Structures were traced using MultiTracer software. Structures selected included the caudate, nucleus accumbens (NA), putamen (Pu), globus pallidus (GP) and corpus callosum (CC). Four of these structures occur bilaterally. Tracing was performed in 79 subjects. Three subjects were excluded due to poor quality images or pathology; 5 HIV-1 infected children were excluded as they were not randomized between treatment groups. Certain subjects were retraced for inter and intrarater reliabilities. The effect and association of ethnicity, age, birthweight and sex as possible confounders were investigated. As the groups were not well matched for ethnicity, all Cape Coloured children were excluded from further analyses. Analysis of variance was used to test the effect on structure size between HIV-1 infected children and controls, as well as between 3 treatment arms (ART deferred until clinical criteria were met, early ART for 40 weeks, early ART for 96 weeks) and uninfected controls. Analysis of covariance was used to control for the possible confounding effects of sex and age. Each structure was tested for possible association with clinical variables (CD4, CD8, CD4/CD8 ratio and CD4%) both at enrolment and time of scanning. Linear regressions were modelled using clinical variables that showed significant correlation with structure size whilst controlling for covariates. Congruence between automated FreeSurfer and manual segmentation were evaluated via Bland-Altman, Pearson r and Cronbach's alpha