Wpływ starzenia się i zakażenia wirusem HIV na związek pomiędzy stanem spoczynkowym mózgu a funkcjonowaniem poznawczym

Rationale and objective: The aging HIV seropositive (HIV+) population struggles with the brain functional and structural abnormalities. Consequently, HIV+ individuals can experience decline in neurocognitive performance. The current state of knowledge informs on the neuroinfectious actions of the HIV virus to a limited extent. However, with the new methods of brain imaging, such as resting state functional magnetic resonance imaging (RS-fMRI), we can now better understand the functional brain bases of the clinical neurocognitive portrait in this specific patient population. Up to date, few scientific reports addressed the effects of age and HIV infection on the resting state (RS) of the brain and cognitive functioning. Due to previous inconsistent findings, the issue remains unclear. This study aimed to examine the effects of aging and HIV infection on the RS of the brain in relationship to the cognitive functioning. Methods: This study analyzed data from a final number of 108 participants between 25 and 75 years of age, including 54 HIV+ individuals (age M=41; SD=12 years) and 54 demographically matched HIV-seronegative controls (age M=43; SD=12 years), with the mean of 16 years of education. All HIV+ participants were receiving HAART. The data retained for the current analyses included neuroimaging data of resting state functional magnetic resonance imaging (RS-fMRI), and neurocognitive data from a comprehensive battery of tests assessing attention, executive functions, memory, psychomotor functions, and semantic skills. RS data was analyzed using Regions of Interest-based approach, Independent Component Analysis, and Voxel-based analysis. Cognitive tests outcome T-scores were comprised into Neurocognitive Factor Scores. Between group differences in RS and neurocognitive data was assessed with T-unpaired test. Bivariate correlations examined relationships between age, RS measures, and neurocognitive factors. Multiple Linear Regression Analysis were performed in order to investigate the effects of age and HIV infection on the relationship between RS brain activity and neurocognitive performance. Results: Control group revealed patterns of aging in RS functional connectivity (FC) and neurocognitive decline comparable to the general population. HIV infection was related to decreases and increases in RS-FC and deterioration in attention and sematic skills as compared to controls. Interaction effects of age and HIV infection were exposed in terms of intra- and internetwork remote FC, which was weakening with age in HIV+ group, while strengthening with age in healthy comparators. No age-HIV interaction effects were observed on cognitive factors. Significant relationships were distinguished between RS-FC measures sensitive to age-HIV interaction effects and neurocognitive factors. Age had no significant moderator effects on majority of the revealed relationships in controls. HIV significantly moderated relationship between RS-FC and neurocognitive factors. Age in HIV+ group did not reveal significant moderator effects on the relationship between RS-FC and neurocognitive factors. Conclusions: Current study provides evidence that RS-fMRI is a sensitive technique to reveal not only additive but also interaction effects of age and HIV infection on the functioning of the brain. The results confirm that age and HIV infection lead to brain reorganization and decline in neurocognitive performance. Importantly, the study finds evidence for the employment of brain compensatory mechanisms in aging HIV+ patient population. The current findings support the hypothesis of rather accentuated than accelerated aging in the individuals aging with HIV.Uzasadnienie i cel: Osoby starzejące się z infekcją HIV (HIV+) zmagają sią z zaburzeniami w strukturze jak i funkcjonowaniu mózgu. W wyniku tego, osoby HIV+ mogą doświadczać deterioracji w funkcjonowaniu neuropoznawczym. Obecny stan wiedzy jest ograniczony na temat neuroinfekcyjnych działań wirusa HIV. Jednak przy użyciu nowych metod neuroobrazowania mózgu, takich jak badanie spoczynkowej aktywności mózgu w funkcjonalnym rezonansie magnetycznym (ang. resting state functional magnetic resonance imaging) możemy coraz lepiej opisać funkcjonalne podstawy mózgu przyczyniających się do klinicznego portretu zaburzeń neuropoznawczych w tej szczególnej grupie pacjentów. Do tej pory niewiele doniesień naukowych skierowanych było na badanie wpływu wieku i zakażenia wirusem HIV na stan spoczynkowy mózgu w odniesieniu do funkcji poznawczych. W związku z niespójnościami dotychczasowych doniesień, zagadnienie to pozostaje niewyjaśnione. To badanie miało na celu zbadanie efektów starzenia się i zakażenia wirusem HIV na stan spoczynkowy mózgu (RS) w stosunku do funkcjonowania poznawczego. Metoda: W badaniu przeanalizowano dane z ostatecznej liczby 108 uczestników między 25 a 75 rokiem życia, w tym 54 osoby HIV+ (średnia wieku = 41 lat; SD = 12 lat) oraz 54 demograficznie dopasowane osoby kontrolne HIV-seronegatywne (średnia wieku = 43 lata; SD = 12 lat), ze średnią 16 lat edukacji. Wszyscy uczestnicy HIV + byli na terapii HAART. Dane przeanalizowane w tym badaniu obejmowały dane spoczynkowego neuroobrazowania stanu mózgu (RS-fMRI) i dane neuropoznawcze z kompleksowego zestawu testów oceniających funkcje uwagi, funkcje wykonawcze, pamięć, funkcje psychomotoryczne i umiejętności semantyczne. Dane analizowano stosując podejście oparte na mózgowych regionach zainteresowania badawczego (ang. Regions of Interest-based analysis), analizy niezależnych komponentów (ang. Independent Component Analysis), i analizy opartej na wokselach (ang. Voxel-based analysis). Na podstawie wyników przekształconych (T) z testów poznawczych zostały skomponowane czynniki neuropoznawcze. Różnice pomiędzy grupami w RS i funkcjonowaniu poznawczym oceniano testem t. Dwuwymiarowe korelacje były użyte do zbadania relacji między wiekiem, RS, a czynnikami neuropoznawczymi. Wielokrotna analiza regresji liniowej przeprowadzona została w celu zbadania wpływu wieku i zakażenia wirusem HIV na relacje między spoczynkowa aktywnością mózgu (RS) a neuropoznawczą wydajnością. Wyniki: Grupa kontrolna, w zakresie połączeń funkcjonalnych (FC) w spoczynkowej aktywności mózgu oraz deterioracji funkcji neuropoznawczych, wykazała wzorce starzenia się porównywalne do ogólnej zdrowej populacji. Zakażenie wirusem HIV związane było z obniżeniem jak i z podwyższeniem RS-FC oraz pogorszeniem uwagi i umiejętności semantycznych w porównaniu z grupą kontrolną. Efekty interakcji wieku i zakażenia HIV były wykazane dla FC wewnątrz-sieciowych oraz między-sieciowych, które słabły wraz z wiekiem w grupie HIV+, a wzmacniały się wraz z wiekiem u zdrowych niezakażonych. Brak efektów interakcji wieku i wirusa HIV był wykazany dla czynników poznawczych. Wykazane zostały istotne relacje pomiędzy mocą połączeń RS-FC, które wykazały wrażliwość na skutki interakcji wieku i wirusa HIV, a wartością czynników neuropoznawczych. Wiek nie miał znaczącego wpływu jako moderator dla większości wykazanych relacji w grupie kontrolnej. Zakażenie wirusem HIV znacznie wpływało na związek między RS-FC a czynniki neuropoznawcze. Natomiast wiek w grupie HIV+ nie miał znaczących skutków jako moderator na relacje między RS-FC a czynnikami neuropoznawczymi. Wnioski: Obecne badanie dostarcza dowodów na to, że RS-fMRI jest czułą techniką mogącą ujawnić nie tylko efekty niezależne, ale również efekty interakcji wieku i zakażenia wirusem HIV na funkcjonowanie mózgu podczas braku jawnych procesów poznawczych. Wyniki tego badania dalej potwierdzają, że wiek i zakażenie wirusem HIV prowadzą do reorganizacji funkcjonalnej mózgu i spadku wydajności funkcji neuropoznawczych. Co ważne, badania to donosi o dowodach na wdrożenie kompensacyjnych mechanizmów mózgowych w populacji pacjentów starzejących się z wirusem HIV. Wyniki tego badania dowodzą o przeważającej słuszności hipotezy natężonego/skoncentrowanego (ang. accentuated) nad hipotezą przyspieszonego (ang. accelerated) starzenia się u osób żyjących z infekcją HIV

Differences in resting state functional networks in HIV infected and uninfected children at age 7 years

Includes bibliographical referencesAlthough early administration of highly active antiretroviral therapy (HAART) in infants provides the brain some protection against HIV damage, few studies have examined the long-term effects of HIV infection and HAART on neurodevelopment, and none have measured their impact on functional brain networks in young children. We use resting state functional magnetic resonance imaging (RS-fMRI) to explore differences in functional connectivity (FC) in HIV infected children stable on HAART and in HIV uninfected children. The 9 resting state networks (RSNs) identified using independent component analysis (ICA) included the visual lingual gyrus, visual occipital gyrus, salience, dorsal attention, auditory, motor, executive control, posterior default mode network (pDMN) and default mode network (DMN) . No significant group level differences were found in any RSNs using ICA. However, seed-based correlation analysis ( SCA ) revealed two regions where uninfected children had a higher FC compared to infected children (p < 0. 05 corrected for multiple comparison); specifically, between a seed in the left cingulate gyrus of the DMN and the left middle frontal gyrus, and between a seed in the right middle frontal gyrus of the executive control network and the right supramarginal gyrus. Consistent with our findings, previous RS-fMRI studies in HIV infected adults have reported reduced connectivity compared to uninfected adults in numerous DMN regions and executive control network. However, in contrast to the adult literature, in which a number of areas within the networks have been implicated, we only observed a focal effect in each of the two RSNs. Given that some of the RSNs are still undergoing major developments at age 7 years (i.e . time of scan for the children), the reduced FC may represent delayed network maturation within the infected cohort , with potential effects on cognitive functioning, information processing and memory recall abilities . Furthermore, positive associations were found between the clinical CD4/CD8 at time of enrollment and two regions within the dorsal attention and auditory networks. These results were independent of treatment arm and suggest that reduced FC in these networks at age 7 years are a result of poor immune function in early infancy (6-8 weeks of age), supporting the notion of in itiating ART immediately in HIV infected infants

Changes in resting-state functional brain activity are associated with waning cognitive functions in HIV-infected children.

Delayed brain development in perinatally HIV-infected children may affect the functional brain activity and subsequently cognitive function. The current study evaluated the functional brain activity in HIV-infected children by quantifying the amplitude of low frequency fluctuations (ALFF) and functional connectivity (FC). Additionally, correlation of ALFF and FC with cognitive measures was performed. Twenty-six HIV-infected children and 20 control children underwent neuropsychological (NP) assessment and resting-state functional magnetic resonance imaging (rs-fMRI). ALFF and FC maps were generated and group differences were analyzed using two-sample t-test. Furthermore, ALFF and FC showing significant group differences were correlated with NP scores using Pearson's correlation. Significantly lower ALFF in the left middle temporal gyrus, precentral and post central gyrus was observed in HIV-infected children compared to controls. FC was significantly reduced in the right inferior parietal, vermis, middle temporal and left postcentral regions, and significantly increased in the right precuneus, superior parietal and left middle frontal regions in HIV-infected children as compared to control. HIV-infected children showed significantly lower NP scores in various domains including closure, exclusion, memory, verbal meaning, quantity and hidden figure than controls. These waning cognitive functions were significantly associated with changes in ALFF and FC in HIV-infected children. The findings suggest that abnormal ALFF and FC may responsible for cognitive deficits in HIV-infected children. ALFF and FC in association with cognitive evaluation may provide a clinical biomarker to evaluate functional brain activity and to plan neurocognitive intervention in HIV-infected children undergoing standard treatment.This study was funded by Department of Science and Technology, New Delhi, India (Grant number: SR/CSI/02/2 0 10, G) and Sidra Medicine, Doha, Qatar, has provided the workstation for image processing

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

Alteration of brain network topology in HIV-associated neurocognitive disorder: A novel functional connectivity perspective

HIV is capable of invading the brain soon after seroconversion. This ultimately can lead to deficits in multiple cognitive domains commonly referred to as HIV-associated neurocognitive disorders (HAND). Clinical diagnosis of such deficits requires detailed neuropsychological assessment but clinical signs may be difficult to detect during asymptomatic injury of the central nervous system (CNS). Therefore neuroimaging biomarkers are of particular interest in HAND. In this study, we constructed brain connectivity profiles of 40 subjects (20 HIV positive subjects and 20 age-matched seronegative controls) using two different methods: a non-linear mutual connectivity analysis approach and a conventional method based on Pearson's correlation. These profiles were then summarized using graph-theoretic methods characterizing their topological network properties. Standard clinical and laboratory assessments were performed and a battery of neuropsychological (NP) tests was administered for all participating subjects. Based on NP testing, 14 of the seropositive subjects exhibited mild neurologic impairment. Subsequently, we analyzed associations between the network derived measures and neuropsychological assessment scores as well as common clinical laboratory plasma markers (CD4 cell count, HIV RNA) after adjusting for age and gender. Mutual connectivity analysis derived graph-theoretic measures, Modularity and Small Worldness, were significantly (p < 0.05, FDR adjusted) associated with the Executive as well as Overall z-score of NP performance. In contrast, network measures derived from conventional correlation-based connectivity did not yield any significant results. Thus, changes in connectivity can be captured using advanced time-series analysis techniques. The demonstrated associations between imaging-derived graph-theoretic properties of brain networks with neuropsychological performance, provides opportunities to further investigate the evolution of HAND in larger, longitudinal studies. Our analysis approach, involving non-linear time-series analysis in conjunction with graph theory, is promising and it may prove to be useful not only in HAND but also in other neurodegenerative disorders

Herpes simplex-1 as an additive risk factor for cognitive decline in apolipoprotein E4 carriers

textThe identification of early, modifiable risk factors for cognitive decline presents the most promising opportunity for intervention. To date one of the most robustly replicated risk factors for the most common form of dementia, Alzheimer’s disease (AD), is the Apolipoprotein E4 (ApoE4) allele. Risk for sporadic and familial late onset AD increases nearly threefold for each E4 allele an individual carries. However some E4 carriers do not develop cognitive decline, and many non-E4 carriers do, highlighting the role of environmental variables in the progression to clinical symptoms. There is evidence that herpes simplex-1 (HSV-1), a common neurotropic viral infection with affinity for the same brain structures affected in AD, is an acquired risk factor that may compound the genetic risk associated with ApoE4. We examined the interaction between the ApoE4 allele and HSV-1 in cognitively normal middle-aged adults using neuropsychological testing and structural and functional neuroimaging. Neuropsychological assessments were used to determine cognitive differences between groups. Structural neuroimaging was used to measure group differences in bilateral hippocampal volumes, and cortical thickness in brain regions most likely to be affected by AD and HSV-1. Functional neuroimaging was used to examine differences in resting- state brain activity within the default mode network (DMN), a network known for alterations in functional connectivity during the progression from normal aging to AD. With regard to cognition we found that ApoE4 carriers performed significantly lower on tests of executive functioning when they were infected with HSV-1. HSV-1 infection alone also correlated with significantly lower full scale IQ (FSIQ). Within the structural domain we found that individuals with ApoE4 had significantly smaller bilateral hippocampal volumes compared to individuals without the virus, regardless of HSV-1 status. Within the functional domain we failed to find any group differences in functional connectivity within the DMN. Together these findings suggest that HSV-1 may contribute to cognitive changes linked to cognitive vulnerability, and that ApoE4 may contribute to structural brain vulnerability. Because these factors are identifiable prior to the onset of frank cognitive decline, antiviral intervention could be considered as a means of mitigating risk for cognitive decline.Psycholog

A multimodal approach to investigate brain reorganization after spinal cord injury using functional magnetic resonance imaging and functional near-infrared spectroscopy

Traumatic Spinal Cord Injury (SCI) results in structural and functional neurological changes at both the brain and the level of the spinal cord. Anatomical studies indicate decreased grey matter volume in sensorimotor and non-sensorimotor regions of the cortex following SCI; whereas, neurophysiological findings mostly report altered functional activity in the sensorimotor nodes of the cortex, subcortex, and cerebellum. Therefore, it is currently unknown whether tissue atrophy observed in non-motor related areas has any concomitant functional consequences. Furthermore, the neural underpinnings of adaptive neuroplasticity after SCI is not well-defined in the current literature. Hence, this dissertation is a pioneer study investigating the structural and functional changes in the whole brain after SCI, with particular focus on subcortical regions, using a multimodal approach employing magnetic resonance imaging (MRI), resting-state functional MRI (fMRI) and functional near-infrared spectroscopy (fNIRS), that may take best advantage of each of these three tools. MRI scans from 23 healthy controls (HC) and 36 individuals with complete SCI within two years of injury were used to demonstrate that both injury level and duration since injury are important factors contributing to recovery. Specifically, cervical level injury when compared to thoracolumbar level injury exhibits a greater loss of cortical grey matter volume in the orbitofrontal cortex, insula, and anterior cingulate cortex. Next, using the fMRI scans of the same participants during a resting-state scan, the intrinsic functional connectivity of the mediodorsal, pulvinar and ventrolateral nuclei of the thalamus to the regions of salient network and the fronto-parietal network is observed to be dynamic and altered in the SCI group. Lastly, a continuous-wave fNIRS is used to reliably measure brain function in individuals with SCI during both dynamic and static tasks while accounting for cerebrovascular reactivity. Five min of resting-state data and 26 min of motor data including finger tapping, finger tapping imagery and ankle tapping were acquired to identify the spatial activation pattern unique to each of the movement type. A breath-hold paradigm is also used to quantify cerebrovascular reactivity as a means to calibrate task activity from neurovascular constraints. Sixteen HC were scanned at two separate visits to determine the sensitivity and test-retest reliability of fNIRS data from the sensorimotor cortex. Following validation, the same procedure was repeated in 13 individuals with paraplegia resulting from SCI and 13 HC to quantify alterations in the cortical activity of the motor cortex and cerebrovascular reactivity between the two groups. Results indicate that SCI group exhibit altered cerebrovascular reactivity with greater delay in response and greater pre-stimulus undershoot. As hypothesized, the hemodynamic response to ankle movement resulted in only a small change in oxyhemoglobin concentration in the sensorimotor cortex of SCI group when compared to HC. The application of fNIRS to assess cortical reorganization following SCI is unique and expands our understanding of the neurophysiology after SCI. It paves the groundwork for extending the implementation of fNIRS to rehabilitation research and other clinical populations with vascular dysfunction. This dissertation is one of the first studies to comprehensively examine both the structural and functional alterations of the brain in humans with complete SCI and opens promising avenues for SCI research using fNIRS modality