Academic literature on the topic 'AIDS dementia complex - Pathogenesis'

We detected the cytokines interleukin-6 (IL-6) and granulocyte macrophage-CSF (GM-CSF) by ELISA in the CSF and serum of 30 HIV-infected patients classified as AIDS dementia complex (ADC), and 20 subjects with other neurological diseases (OND). We have found a high incidence of detectable IL-6 and GM-CSF in the CSF of ADC patients compared with OND patients. No statistical differences were observed between both groups for serum IL-6 and GM-CSF levels. These results suggest an intrathecal synthesis of these cytokines and a possible involvement in the pathogenesis of ADC.

In Eastern Europe, at least 130 thousand new cases of HIV infection have been registered, which undoubtedly reflects the urgency of this medical problem. In our country, the average rate of human immunodeficiency infection is 58 cases per 100 thousand people. It is known that the disease is caused by an RNA-containing human immunodeficiency virus. Two types of it have been studied — HIV-1 and HIV-2, which have many subtypes. An important clinical feature of this virus is its tropism to cells of the human nervous and immune systems. The main risk group for the disease is injecting drug users, blood recipients, and people with low social responsibility. The impairment of the nervous system in AIDS is represented by the AIDS-dementia complex, acute aseptic meningitis, HIV-associated myelopathy, pathology of the peripheral nervous system, as well as the influence of opportunistic infections and neoplasms. This article presents a clinical case of lesions of the nervous system associated with HIV infection and also considers the etiology, pathogenesis, features of the course, diagnosis, and treatment of patients with neuro-AIDS.

The kynurenine pathway (KP) is a major degradative pathway of tryptophan ultimately leading to the production of nicotinamide adenine dinucleotide (NAD+) and is also one of the major regulatory mechanisms of the immune response. The KP is known to be involved in several neuroinflammatory disorders including Alzheimer's disease, amyotrophic lateral sclerosis, AIDS dementia complex, Parkinson's disease, schizophrenia, Huntington's disease and brain tumours. However, the KP remains a relatively new topic for the field of multiple sclerosis (MS). Over the last 2–3 years, some evidence has progressively emerged suggesting that the KP is likely to be involved in the pathogenesis of autoimmune diseases especially MS. Some KP modulators are already in clinical trials for other inflammatory diseases and would potentially provide a new and important therapeutic strategy for MS patients. This review summarizes the known relationships between the KP and MS.

Tumor necrosis factor alpha (TNF-alpha) is a candidate human immunodeficiency virus type 1-induced neurotoxin that contributes to the pathogenesis of AIDS dementia complex. We report here on the effects of exogenous TNF-alpha on SK-N-MC human neuroblastoma cells differentiated to a neuronal phenotype with retinoic acid, TNF-alpha caused a dose-dependent loss of viability and a corresponding increase in apoptosis in differentiated SK-N-MC cells but not in undifferentiated cultures. Importantly, intracellular signalling via TNF receptors, as measured by activation of the transcription factor NF-kappa B, was unaltered by retinoic acid treatment. Finally, overexpression of bcl-2 or crmA conferred resistance to apoptosis mediated by TNF-alpha, as did the addition of the antioxidant N-acetylcysteine. These results suggest that TNF-alpha induces apoptosis in neuronal cells by a pathway that involves formation of reactive oxygen intermediates and which can be blocked by specific genetic interventions.

The aim of the thesis was to undertake an evaluation of the neuropsychological functioning of non-demented and demented patients with advanced HIV-infection who have been treated with Highly Active Antiretroviral Therapy (HAART) for several years. One hundred and one non-demented HIV-infected individuals and 23 patients with mild or moderate AIDS Dementia Complex (ADC), from the outpatient clinics and Neurology department at St. Vincent's Hospital, Sydney, Australia were randomly selected to participate in a prospective study of the neurological and neuropsychological complications of HIV disease. All had advanced HIV-infection and all had been on HAART for five years on average. Thirty-one seronegative controls were recruited as controls. All participants completed a standard neuropsychological examination assessing nine cognitive domains. Non-demented advanced HIV-infected individuals participated in three follow-up visits. In addition, we report the results of a multi-centre cohort of 78 patients with mild to moderate ADC on HAART (Abacavir ADC trial). The main findings of our research were that the prevalence of neuropsychological impairment in advanced HIV-infected individuals remains equivalent to the era that preceded the introduction of HAART. Moreover, while complex attention / psychomotor speed remained a marker of HIV-related neuropsychological impairment in the HAART era, impairment in learning, memory and aspects of complex attention may be new indicators of HIV-associated neurocognitive impairment. While progression of neuropsychological impairment is associated with past HIV-related history of brain involvement, we demonstrated that deterioration does not occur in a linear fashion and that over a 27 month period neuropsychological performance stabilizes in the majority. Stabilization of performance may be related to relapses in the course of HIV-associated neurocognitive impairment and HAART optimization especially with antiretrovirals that have good brain tissue penetrance. Our research showed that plasma viral load and current CD4 cell count were generally not associated with the neuropsychological performance, but rather that nadir CD4 cell count was associated with neuropsychological performance suggesting a relation between past immune deterioration and current cognitive status. Cerebrospinal markers of immune and virological activity were found to be partly dissociated from current neurological in contrast to what was observed in the pre-HAART era. Future studies will need to evaluate new factors for underlying HIV-associated neurocognitive impairment as well as factors for underlying partial recovery.

A major product of HIV-infected and cytokine-stimulated monocytic-lineage cells is quinolinic acid (QUIN), a neurotoxic metabolite of the kynurenine pathway (KP) of L-tryptophan (L-Trp) metabolism. Despite the large number of neurotoxins found in HIV patients with AIDS Dementia Complex (ADC), only QUIN correlates with both the presence and severity of ADC. With treatment, cerebrospinal fluid (CSF) QUIN concentrations decrease proportionate to the degree of clinical and neuropsychological improvement. As endothelial cells (EC) of the blood-brain barrier (BBB) are the first brain-associated cell that a bloodborne pathogen would encounter, this project examined the BBB response to KP metabolites, as these are implicated in damage of the CNS associated with ADC. Using RT-PCR and HPLC/gas chromatographymass spectrometry (GC-MS), I found that cultured primary human BBB EC and pericytes constitutively expressed the KP. EC synthesised kynurenic acid (KA) constitutively, and after immune activation, kynurenine (KYN). Pericytes produced small amounts of picolinic acid and after immune activation, KYN. An SV40-transformed BBB EC showed no KP expression. By contrast, human umbilical vein EC only expressed low levels of KA after immune activation, however human dermal microvascular EC showed a similar constitutive and inducible KP to that in BBB EC. As T cells are central to primary HIV infection, I also examined KP expression in two CD4+ and one CD4- cell lines, but none showed either constitutive or inducible KP expression. I next examined how QUIN might interact with BBB EC. There was no binding of 3H-QUIN to cultured primary human BBB EC, however a biologically relevant concentration of QUIN induced changes in gene expression which adversely affected EC function, possibly mediated by lipid peroxidation and oxidative stress. The upregulated genes were of the heat shock protein family, and the downregulated genes were associated with regulation of cell adhesion, tight junction and cytoskeletal stability, metalloproteinase (MMP) regulation, apoptosis and G protein signaling. Immunofluorescence showed that QUIN induced morphological changes in BBB EC consistent with the changes in gene expression. Gelatin zymography showed that this was not mediated by MMPs, as constitutive MMP expression was unchanged. These data provide strong evidence for QUIN directly damaging the BBB in the context of HIV infection.

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The objective of the present study was to evaluate the relationship between a set of cofactors and severity of cognitive impairment, to determine if there were any factors which significantly predicted more severe neurocognitive deficits in persons with AIDS. Twenty-four male volunteers recruited from community groups and physician referrals participated. Subjects completed several self-report questionnaires eliciting information regarding demographics and risk factor variables, in addition to a comprehensive battery of neuropsychological tests. A severity of cognitive impairment summary score was computed for each subject, reflecting both the number of impaired tests and their distance in the impaired direction from normative data. Neither CD4 count, number of months since diagnosis of AIDS, number of AIDS-related illnesses, number of recent stressors, history of head injury/LOC, history of substance use, current or past psychiatric disorder, history of learning disability nor history of other medical illness were found to be significantly related to severity of cognitive impairment in this sample, after controlling for the effects of age, level of education, estimated premorbid IQ and mood status. However, no reliable conclusions could be drawn from this study because the small sample size resulted in an unacceptably low level of statistical power for the desired regression analysis. Exploratory analyses of variance revealed no significant group differences for any of the covariate or cofactor variables when subjects falling at the low, middle, and high ranges of severity of impairment were compared, with the exception of a possible inverse relationship with CD4 count. This was consistent with an exploratory stepwise regression analysis in which only CD4 count entered the model. Some potential limitations of the operational definitions used for the variables in this study were identified, and modifications were suggested. The results of additional exploratory analyses comparing group differences between the "globally impaired" and "unimpaired" subjects (Maj et al., 1994 criteria) on both the covariate and cofactor variables, and neuropsychological test performance, were also discussed.

AIDS Dementia Complex (ADC) is a neurodegenerative disorder implicated in HIV-1 infection that is associated with elevated levels of the neurotoxin, quinolinic acid (QA) which causes a cascade of events to occur, leading to the production of reactive oxygen species (ROS), these being ultimately responsible for oxidative neurotoxicity. In clinical studies, Non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz (EFV) and nevirapine (NVP) have been shown to potentially delay the progressive degeneration of neurons, thus reducing the frequency and neurological deficits associated with ADC. Despite these neuroprotective implications, there is still no biochemical data to demonstrate the mechanisms through which these agents offer neuroprotection. The present study aims to elucidate and further characterize the possible antioxidant and neuroprotective mechanisms of NVP and EFV in vitro and in vivo, using QA-induced neurotoxicity as a model. Research has demonstrated that antioxidants and metal chelators have the ability to offer neuroprotection against free radical induced injury and may be beneficial in the prevention or treatment of neurodegeneration. Hence the antioxidant and metal binding properties of these agents were investigated respectively. Inorganic studies, including the 1, 1-diphenyl-2 picrylhydrazyl (DPPH) assay, show that these agents readily scavenge free radicals in vitro, thus postulating the antioxidant property of these agents. The enhancement of superoxide radical generation and iron mediated Fenton reaction by QA is related to lipid peroxidation in biological systems, the extent of which was assayed using the nitroblue tetrazolium and thiobarbituric acid method respectively. Both agents significantly curtail QA-induced lipid peroxidation and potentially scavenge superoxide anions generated by cyanide in vitro. Furthermore, in vivo results demonstrate the ability of NVP and EFV to protect hippocampal neurons against lipid peroxidation induced by QA and superoxide radicals generated as a consequence thereof. The alleviation of QA-induced oxidative stress in vitro possibly occurs through the binding of iron (II) and / or iron (III), and this argument is further strengthened by the ability of EFV and not NVP to reduce iron (II)-induced lipid peroxidation in vitro directly. In addition the ferrozine and electrochemistry assay were used to measure the extent of iron (II) Fe[superscript 2+] and iron (III) Fe[superscript 3+] chelation activity. Both assays demonstrate that these agents bind iron (II) and iron (III), and prevent redox recycling of iron and subsequent complexation of Fe[superscript 2+] with QA which enhances neuronal damage. Both NNRTIs inhibit the endogenous biosynthesis of QA by inhibiting liver tryptophan 2, 3-dioxygenase activity in vivo and subsequently increasing hippocampal serotonin levels. Furthermore, these agents reduce the turnover of hippocampal serotonin to 5-hydroxyindole acetic acid. NVP and not EFV increase 5-hydroxyindole acetic acid and norepinephrine levels in the hippocampus. The results of the pineal indole metabolism study show that NVP increases the synthesis of melatonin, but decreases N-acetylserotonin, 5-hydroxyindole acetic acid and 5-hydroxytryptophol levels. Furthermore, it shows that EFV decreases 5-hydroxyindole acetic acid and melatonin synthesis. Behavioural studies using a Morris water maze show that the post-treatment of rats with NVP and EFV significantly improves QA-induced spatial memory deficits in the hippocampus. This study therefore provides novel information regarding the neuroprotective mechanisms of NVP and EFV. These findings strengthen the argument that these NNRTIs not only have antiviral effects but possess potential neuroprotective properties, which may contribute to the effectiveness of these drugs in the treatment of ADC.

UVOD: Neurokognitivni poremećaj udružen sa HIVinfekcijom (HIV associated neurocognitive disorder- HAND) javlja se u oko polovine pacijenata sa HIV-om. HAND obuhvata spektar neuroloških poremećaja koji variraju od asimptomatskog neurokognitivnog poremećaja(ANI), preko blagog kognitivnog oštećenja, koje se naziva blagi kognitivni poremećaj (MND) do demencije udružene sa HIV-om (HAD). U evaluaciji i dijagnostici ovog poremećaja koriste se razne laboratorijske, kliničke i metode imidžinga, među kojima magnetno-rezonantni imidžing (MRI) zauzima posebno mesto u pogledu dijagnostike strukturnih poremećaja. Međutim, za dijagnostiku suptilnih supcelularnih neurobiohemijskih poremećaja neophodno je korišćenje magnetno-rezonantne spektroskopije (MRS). Klasično shvatanje promena u neurobiohemijskom profilu kod pacijenata sa HIV infekcijom uključuje: sniženje NAA (neuronskog markera) kao odraz neurodegeneracije, povišenje Cho (markera razgradnje membrana) kao odraz inflamacije/ apoptoze, povišenje mI (markera proliferacije mikroglije) kao odraz inflamacije i povišenje Glx+Gln (markera glutaminergične ravnoteže) kao odraz ekscitotoksičnosti. Do sada u literaturi nije opisano korišćenje multivokselske MRS mozga na HIV+ pacijentima. CILJEVI: Ciljevi studije su bili: utvrditi da li postoje promene u odnosima koncentracija metabolita u mozgu dobijenih metodom multivokselske MRS u neurološki asimptomatskih HIV+ pacijenata u poređenju sa zdravim kontrolnim ispitanicima,zatim da li postoje razlike između pacijenata na kombinovanoj antiretroviralnoj terapiji (cART) i pacijenata bez cART; utvrditi da li postoji i kakva je povezanost odnosa metabolita dobijenih MRS sa imunološkim parametrima HIV+ pacijenata i nivoom nadir CD4+ T-limfocita; i konačno, utvrditi da li postoji i kakva je povezanost dobijenih odnosa metabolita sa parametrima penetracije antiretroviralne terapije u centralni nervni sistem. ISPITANICI I METODE: U studiju je uključeno ukupno 114 ispitanika (32 HIV+ pacijenta na cART, prosečne starosti 41.97 godina (25-61); 28 HIV+ pacijenata bez cART, prosečne starosti 35.21 godina (24-52); 50 kontrolnih, zdravih subjekata prosečne starosti 36.56.godina (19-53)). Svi ispitanici su potpisali informisani pristanak za učešće u studiji. Ispitivanje je odobreno od strane Etičke komisije Instituta za onkologiju Vojvodine, kao i Etičke komisije Medicinskog fakulteta Univerziteta u Novom Sadu. Kriterijum za uključenje pacijenata u studiju je bio prisustvo HIV infekcije. Kriterijumi za isključivanje pacijenata iz studije su bili: prisustvo aktivne oportunističke infekcije, prisustvo aktivnog neurološkog oboljenja, podatak o aktivnoj zloupotrebi narkotika, koinfekcija virusom hepatitisa B i C, prisustvo lezija bele ili sive mase i kontraindikacije za snimanje na aparatu za magnetnu rezonancu. 4 ispitanika su isključena iz ispitivanja. Svim ispitanicima urađeni su skrining neurokognitivni testovi, kao i rutinska laboratorijska ispitivanja (broj CD4+, CD3+ i CD8+ limfocita). Nakon toga, svim ispitanicima urađen je konvencionalni MRI praćen multivokselskom MRS supratentorijalne suprakalozalne bele mase. Ispitivano je ukupno 12 voksela (6 u sivoj i 6 u beloj masi), odnosno preko 7900 spektara. Određeni su pikovi karakterističnih metabolita. Na metodi dugog eha analizirana su tri glavna pika: NAA na 2.0ppm, Cho na 3.2ppm i tCr na 3.ppm, izražena preko odnosa koncentracija NAA/Cr i Cho/Cr. Na metodi kratkog eha analizirani su signali NAA, Cho, Cr te mI na 3.5ppm i Glx+Gln na 2.2-2.4ppm. Ovi signali su izraženi kroz odnose koncentracija NAA/Cr, Cho/Cr, mI/Cr i (Glx+Gln)/Cr. Za statističku obradu podataka korišćen je IBM SPSS ver. 21.0. Deskriptivna statistika je uključila određivanje srednje vrednosti, minimuma, maksimuma i standardne devijacije. Razlike između posmatranih grupa ispitanika za sve kontinuirane varijable ispitivane su jednofaktorskom analizom varijanse (ANOVA) sa naknadnim (post-hoc) testovima za koje je korišćena metoda po Tukey-ju. Rezultati su prikazani u vidu srednjih vrednosti, standardne devijacije, najviše i najniže izmerene vrednosti (maksimum i minimum), i za svaki ispitivani parametar pridružena je vrednost F i p. Veza između kontinuiranih varijabli je ispitivana pomoću koeficijenta Pirsonove linearne korelacije, uz prethodnu proveru zadovoljavanja uslova o homogenosti varijansi, normalnosti raspodele i linearnosti. Vrednosti p<0.05 su uzimane kao statistički značajne. REZULTATI: Pokazano je da su HIV+ pacijenti na cART značajno stariji od druge dve grupe ispitanika. Nije pokazana značajna razlika u stepenu obrazovanja među grupama. Pokazano je da godine života statistički značajno utiču samo na koncentracije NAA/Cr, dok na odnose drugih metabolita ne utiču značajno. Utvrđeno je statistički značajno sniženje (p<0.05) koncentracija NAA/Cr dobijenih metodom dugog eha između tri grupe ispitanika na svim posmatranim vokselima. Naknadnim analizama utvrđena je statistički značajna razlika na 10/12 voksela između HIV+ pacijenata sa cART i zdravih, kao i između HIV+ pacijenata bez terapije i zdravih, dok su se koncentracije NAA/Cr značajno razlikovale između HIV+ pacijenata sa i bez cART samo na jednom vokselu (duboka frontalna bela masa levo). Utvrđena je statistički značajna razlika u smislu sniženja Cho/Cr odnosa dobijenih metodom dugog eha u 5/12 voksela, sa pojedinačnim vokselima koji su prikazivali razlike između grupa. Na metodi kratkog eha utvrđeno je značajno sniženje odnosa koncentracija NAA/Cr kod HIV+ pacijenata samo na tri voksela, pri čemu nisu prikazane značajne razlike između dve grupe pacijenata sa HIV infekcijom (sa i bez cART). Rezultati odnosa koncentracija Cho/Cr između tri gurpe pacijenata dobijeni metodom kratkog eha slični su rezultatima dobijenim na metodi dugog eha (statistički značajna razlika dobijena je na 5/12 voksela). Što se tiče odnosa koncentracija mI/Cr, uočeno je značajno povišenje ovog odnosa kod HIV+ pacijenata u odnosu na zdrave na 6/12 voksela. Prikazano je statistički značajno povišenje ovog markera kod pacijenata bez cART u odnosu na pacijente sa cART samo u regiji levog dorzalnog anteriornog cinguluma. Statistički značajno povišenje (Glx+Gln)/Cr odnosa je prikazano u regiji zadnjeg cinguluma desno kod pacijenata na terapiji u odnosu na pacijente bez terapije, dok na drugim vokselima nije prikazana značajna razlika. Vokseli 4, 7 i 10 su dali najviše informacija(supkortikalna bela masa frontalno levo, dorzalni prednji cingulum levo te parijetalni supkorteks leve cerebralne hemisfere), sa prikazanim značajnim razlikama u bar 4 odnosa metabolita. Prikazana je značajna pozitivna korelacija nadir CD4 + broja limfocita sa koncentracijama NAA/Cr, a negativna sa odnosima Cho/Cr i mI/Cr, što čini nadir CD4+ najboljim serološkim prediktorom neurodegenerativnog oštećenja. Pokazana je pozitivna korelacija indeksa penetracije lekova u monocite (ME) sa odnosima NAA/Cr i negativna korelacija indeksa penetracije lekova u centralni nervni sistem (CPE) sa Cho/Cr i mI/Cr. Došli smo do zakljulka da je ME indeks bolji marker neurodegenerativnog odgovora a CPE indeks bolji u monitoringu kontrole inflamacije. ZAKLJUČAK: Smatra se da HIV virus uzrokuje prerano starenje mozgašto je prvenstveno posledica direktnog oštećenja nervnih ćelija samim virusom (preko viralnih proteina, indukovanih citokina i hemokina). Pokazali smo da su neuronski gubitak i neurodegeneracija proces koji zahvata celokupan volumen mozga, dok su procesi inflamacije i proliferacije mikroglije svedeni na tačno određene regione, pretežno sive mase. Visoka senzitivnost multivokselske 1H-MRS sa korišćenjem senzitivnih površinskih kalemova omogućava mapiranje metabolita sa prostornom rezolucijom. MRS može dati ključni uvid u promene koncentracija metabolita mozga tokom razvoja infekcije od akutne i primarne do hronične. Vrlo brzo nakon serokonverzije, dolazi do detektabilnih promena u metabolitima mozga u smislu neuronskog oštećenja i inflamacije. U našem istraživanju su po prvi put analizirani rezultati protonske multivokselske MRS bele i sive mase velikog mozga u suprakalozalnom regionu. Utvrđeno je da postoje difuzne, ali ipak visoko regionalno-zavisne promene u odnosima neurometabolita kod pacijenata koji dobijaju antiretroviralnu terapiju i kod pacijenata koji je ne dobijaju, u poređenju sa zdravim kontrolnim ispitanicima (odgovarajućim po polu i starosti). Dodatne studije sa posmatranjem apsolutnih koncentracija neurometabolita, kao i longitudinalne studije u koje su uključeni HIV+ pacijenti u različitim fazama bolesti, su neophodne za dalje i bolje razumevanje neuropatogeneze HAND-a. MRS se pokazala uspešnom u detekciji efikasnosti određenih terapijskih opcija. Dva postojeća indeksa za procenu efikasnosti antiretroviralne terapije (CPE, ME) odvojeno pogađaju dva puta neuropatogeneze kognitivnog poremećaja, sa različitim uspehom u sveobuhvatnoj proceni efekta i efikasnosti terapije. U budućnosti je potrebna njihova pojedinačna modulacija ili kreiranje jedinstvenog indeksa, koji bi obuhvatio i efikasnost prolaza leka kroz hematoencefalnu barijeru i dejstvo na latentni rezervoar HIV-a u ćelijama monocitno-makrofagne loze.
INTRODUCTION: HIV associated neurocognitive disorder- HAND appears in about half of the HIV+ patients. HAND represents a spectrum of neurological disorders varying from asymptomatic neurocognitive impairment (ANI), over mild neurocognitive disorder (MND) to HIV associated dementia (HAD). For evaluation and diagnostics of this disorder, many laboratory, clinical and imaging methods are used, first of all magnetic resonance imaging (MRI). Nevertheless, for detecting subtle subcellullar neurobiochemical disorders, the use of magnetic resonance spectroscopy (MRS) is necessary. Classical pattern of neurobiochemical changes in HIV infection consist of: decrease in NAA (neuronal marker) depicting neurodegeneration, increase in Cho (metabolism on membrane marker) depicting inflammation/ apoptosis, increase in mI (marker of microglial proliferation) depicting inflammation and increase in Glx+Gln (glutaminergic balance marker) depicting the effect of excytotoxicity. To the best of our knowledge, this is the first study using multivoxel MRS of the brain in HIV+ patients. AIMS: The aims of this study were: to show whether there are differences in metabolites' ratios on multivoxel MRS in neurologically asymptomatic HIV+ patients compared to control subjects; whether there are differences in metabolites' ratios between patients on combined antiretroviral therapy (cART) and therapy-naive ones; whether there are correlations between matebolites' ratios and immunological parameters in HIV+ patients as well as with nadir CD4+ count; whether there are correlations between metabolites' ratios with parameters of drugs' penetration in central nervous system (CNS). SUBJECTS AND METHODS: Overall of 114 subjects were enrolled in the study (32 HIV+ paients on cART, average age 41.97 years (25-61); 28 HIV+ patients off cART, average age 35.21 years (24-52); 50 control subjects, average age 36.56 years (19-53)). All the subjects signed the informed consent. The study was ethically approved by Ethical committee of Vojvodina Oncology Institute and Ethical committee of Faculty of Medicine, University of Novi Sad. Inclusion criteria for HIV+ subjects were: the presence of HIV infection. Exclusion criteria included: active opportunistic infection, active neurological illness, usage of drugs of abuse, hepatitis B or C coinfection, presence of both white or grey matter lesions, and contraindications that apply for magnetic resonance (MR) examination. 4 subjects were excluded from the study due to the presence of white matter lesions (3 HIV+ and one control subject). Each patient performed International HIV Dementia Scale (IHDS), a screening test for evaluation of global cognitive status in HIV-infected patients. Baseline study laboratory variables were assessed (CD4+ T-lymphocyte count and plasma HIV RNA, nadir CD4+ counts and CD4+ T-cell counts at the moment of MR scan. Conventional MRI scan was followed by multivoxel MRS with both long and short echo. We analyzed 12 voxels (6 in grey and 6 in white matter) with overall of over 7900 spectra. Finally, we analyzed following dominant signals: on the long echo tCr (creatine plus phosphocreatine) at 3.0 ppm, NAA (N-acetyl-aspartate) at 2.0 ppm and Cho (choline containing compounds) at 3.2ppm (ratios of NAA/Cr and Cho/Cr were assessed); on the short echo tCr, NAA, Cho, (Glx+Gln) at 2.2-2.4ppm and mI (myoinositol) at 3.5ppm (ratios of NAA/Cr, Cho/Cr, (Glx+Gln)/Cr and mI/Cr were assessed. All statistical calculations were performed using IBM SPSS software (version 21.0, Chicago, IL, USA). Descriptive statistics included determination of mean values, minimum, maximum and standard deviation. Among-group differences (HIV infected subjects versus healthy controls) in acquired metabolite ratios were evaluated using ANOVA with post hoc Tukey test to determine the differences between separate groups. Due to a known impact of age and education on the NAA concentrations, differences in NAA/Cr ratios among groups were tested using ANCOVA, with age as a covariate variable. Testing relationships between continuous variables was performed using Pearson linear correlation. Statistical significance was set at value p<0.05. RESULTS: We showed that HIV+ patients on therapy were significantly older than the other two groups of patients. There was no significant difference in the level of education. We confirmed that the age significantly affects the level of NAA/Cr only.There was significant decrease (p<0.05) in NAA/Cr level on long echo MRS among three groups on all the observed voxels. Post hoc analysis showed that there was significant difference in 10/12 voxels between HIV+ patients on cART and healthy controls and between HIV+ patients off cART and controls, while NAA/Cr differed significantly between HIV+ patients on and off cART in only one voxel (deep frontal white matter on the left). There was decrease in Cho/Cr levels on long echo MRS in 5/12 voxels among three groups. On short echo MRS, we showed decrease in NAA/Cr level in 3/12 voxels, while there were no differences between two groups of HIV+ patients. Results of short echo MRS in the means of Cho/Cr resembled long echo MRS. There was significant increase in mI/Cr level in HIV+ patients in 6/12 voxels compared to healthy controls, while there was difference in only one voxel between HIV+ patients on and off therapy (dorsal part of anterior cingulate on the left). Significant increase in (Glx+Gln)/Cr level was present between HIV+ patients on and off therapy in the region of right posterior cingulate. Voxels 4, 7 and 10 were the most informative ones (subcortical frontal white matter on the left, dorsal part of left anterior cingulate and right posterior cingulate), showing significant differences in 4 metabolites' ratios. We showed positive correlation between nadir CD4+ count and NAA/Cr and negative correlation between nadir CD4+ count and Cho/Cr, and nadir CD4+ count and mI/Cr, which made nadir CD4+ count the best serological predictor of neurodegeneration. Positive correlation was showed between monocyte efficacy (ME) index and NAA/Cr, while negative correlation was present between CNS penetration efficacy (CPE), Cho/Cr and mI/Cr. We concluded that ME better depicted neurodegenerative process while CPE was better in monitoring of inflammation. CONCLUSIONS: HIV causes premature ageing of the brain, in the means of cognition, attention, working memory and executive function. These effects are due to direct affection of neurons by virus per se (viral proteins, induced cytokines and chemokynes). We showed tha neuronal loss and neurodegeneration affect the whole volume of the brain while inflammation and glial proliferation affect restricted areas predominantly in grey matter. High sensitivity of multivoxel MRS with use of sensitive surface coils enables metabolite mapping with high spatial resolution. MRS can give essential data on metabolites' changes during the evolution of the infection from acute, over primary to chronic. Early after seroconversion, metabolites' changes can be detected (neuronal dysfunction and inflammation).To the best of our knowledge, this is the first study using multivoxel MRS of the brain in HIV infection in human population, analyzing data from supracallosal grey and white matter. We showed the presence of diffuse but regionally highly specific changes in metabolites' ratios in patients on cART and off cART, compared to age and gender matched healthy controls. Additional studies with absolute concentrations of metabolites, as well as longitudinal studies with HIV+ patients in different stages of the disease, are necessary for better understanding of neuropathogenesis of HAND. We showed that MRS can be useful tool in evaluation of therapy regimens efficacy. Two available indices for evaluation of cART efficacy target two separate pathways of cognitive disorder pathogenesis, with different reliability in evaluation of effect and efficacy of applied therapy. In the future, their modulation or creation of new index is needed, in order to include drug delivery through the blood-brain barrier as well as the effect on latent reservoir of HIV in monocyte/macrophage cells.

Thesis (MScMedSc (Biomedical Sciences. Medical Physiology))--University of Stellenbosch, 2010.
ENGLISH ABSTRACT: HIV/AIDS is a global epidemic that accounts for a large percentage of the mortality in South Africa every year. Since the implementation of anti-retroviral treatment, HIV positive individuals have been living longer, and the cognitive impairment associated with the disease is becoming increasingly apparent. During the initial systemic infection of HIV, the virus migrates through the blood-brain barrier and inflicts axonal injury by causing upregulation of cytokines and neurotoxic proteins. HIV-associated dementia is a neuropsychological classification of cognitive impairment in HIV and a variety of symptoms have been classified as a part of the dementia complex. One of these is apathy, which is thought to be a precursor for dementia in HIV patients. Three groups of individuals have been recruited and scanned using magnetic resonance imaging (MRI) to examine changes in the brain. These are an HIV non-apathetic cohort, an HIV apathetic cohort and a healthy control cohort. Diffusion tensor imaging (DTI) is an MRI technique used to quantitatively assess white matter (WM) integrity using metrics such as fractional anisotropy (FA). Voxel-based analysis, tract-based spatial statistics (TBSS) and tractography are three established DTI analysis methods that have been applied in numerous studies. However, there are certain methodological strengths and limitations associated with each technique and therefore all three of these techniques were used to compare WM differences across groups. The frontal-subcortical pathways are known to be abnormal in apathy, and this has been demonstrated in a number of imaging studies. Most of these studies have examined apathy in the context of neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s. However, to our knowledge this is the first DTI study in HIV apathetic patients. With the tractography method, the anterior thalamic radiation and the corpus callosum were reconstructed for each individual to determine whether there were any global changes in these tracts. No significant changes were found. However, a variety of regions in the WM were significantly abnormal in the HIV cohorts when comparing the data at a voxel-based level and using TBSS. This included areas such as the genu and splenium of the corpus callosum, the internal capsule and corona radiata. Changes in frontal WM for the HIV apathy group are an indication of dysfunction in the frontal-striatal circuits, and previous literature has implicated these circuits in the neuropathology of apathy in a variety of central nervous system (CNS) disorders.
AFRIKAANSE OPSOMMING: MIV/VIGS is `n wêreldwye epidemie wat verantwoordelik is vir `n hoë sterftesyfer in Suid- Afrika elke jaar. Sedert die inleiding van anti-retrovirale behandeling, het die MIV-positiewe populasie se lewensduur verleng. Tesame met langer lewensduur, het die kognitiewe verswakking wat geassosieer word met die siekte ook meer prominent na vore gekom. Gedurende die beginstadium van sistemiese infeksie in MIV is daar `n migrasie van die virus deur die bloed-breinskans. MIV kan indirek verantwoordelik wees vir aksonale beskadiging deur verhoging van neurotoksiese proteine en sitokinien te induseer. MIV-geassosieerde demensie is `n neurosielkundige klassifikasie van kognitiewe verswakking in MIV en verskeie simptome is al geïdentifiseer as deel van die demensie kompleks. Een van die simptome is apatie en daar word gespekuleer dat dit `n voorloper is vir demensie in MIV pasiënte. Drie groepe individue was gewerf vir die studie en geskandeer deur magnetiese resonansie beeldvorming (MRB) om sodoende veranderinge in die brein te ondersoek. Die groepe was onderskeidelik `n HIV nie-apatiese kohort, `n HIV apatiese kohort en `n gesonde kontrole kohort. Diffusie tensor beelding (DTB) is `n MRB tegniek wat toegepas word om witstof integriteit te meet deur gebruik te maak van maatstawwe soos fraksionele anisotropie (FA). “Voxel-based analysis”, “tract-based spatial statistics (TBSS)” en “tractography” is drie gevestigde DTB analitiese metodes wat al in talle studies toegepas was. Daar is egter sekere metodologiese voordele en beperkings verbonde aan elke tegniek en daarom is al drie tegnieke gebruik om witstof verskille tussen groepe te vergelyk. Die frontale-subkortikale roetes in die brein is bekend vir abnormaliteite in apatie en dit was ook al gedemonstreer in verskeie studies. Die meeste van die studies het apatie ondersoek in die konteks van neurodegeneratiewe siektes soos Alzheimer se siekte en Parkinson se siekte. Maar sover ons weet is hierdie die eerste DTB studie in MIV pasiënte met apatie. Met die “tractography” metode was die anterior thalamic radiation en corpus callosum herbou vir elke individu. Dit was om te bepaal of daar enige globale veranderinge is in hierdie gebiede, maar geen beduidende veranderinge is gevind nie.`n Verskeidenheid van gebiede in die witstof was beduidend abnormaal in die MIV kohorte wanneer die data vergelyk was met “TBSS” en “voxel-based analysis.” Dit het gebiede ingesluit soos die genu en splenium van die corpus callosum, die internal capsule en die corona radiata. Veranderinge in die frontale witstof vir die MIVapatie groep is `n aanduiding van disfunksie in die frontale-striatale bane. Vorige literatuur impliseer dat hierdie bane betrokke is in die neuro-patologie van apatie in verskeie sentrale senuweestelsel (SS) steurings.

The first description of a syndrome consisting of cognitive, motor, and behavioural disturbances in patients with AIDS was published in 1986. The syndrome was named ‘AIDS dementia complex’. In 1990, the World Health Organization (WHO) introduced the term ‘HIV-associated dementia’, pointing out that subclinical or mild cognitive and/or motor dysfunctions without impairment of performance in daily living activities cannot be subsumed under the term ‘dementia’. The expression ‘mild cognitive/motor disorder’ was proposed for those conditions. The same distinction was made in 1991 by the American Academy of Neurology, which identified an ‘HIV-associated dementia complex’ and an ‘HIV-associated minor cognitive/motor disorder’. The present chapter focuses on the dementia syndrome associated with HIV infection.