Minor Cognitive Motor Disorder Research Articles

Circulating plasma-derived extracellular vesicles expressing bone and kidney markers are associated with neurocognitive impairment in people living with HIV.

Although effective antiretroviral therapy (ART) has improved the life expectancy of people with HIV (PWH), the prevalence of milder forms of HIV-associated neurocognitive disorders (HAND) persist, and it is associated with systemic and neuro-inflammatory processes that could impact other organ systems. However, the complex signaling mechanisms between the bone-kidney systems and the brain in HAND remain unknown. Extracellular vesicles (EVs) play a potential role in inter-organ communication and are involved in regulating cell activity in distant tissues. In this study, we examined whether levels of EVs from bone-and kidney-related cells associate with cognitive dysfunction and explored the relationship between kidney-bone EV axis in PWH experiencing cognitive deficits. EV subtypes were characterized in plasma from 61 PWH with either cognitive impairment (CI, n = 53) or normal cognition (NC, n = 8) based on the American Academy of Neurology criteria for HIV-associated dementia (HAD, n = 11), minor cognitive motor disorder (MCMD, n = 25) or asymptomatic neurocognitive impairment (ANI, n = 17) by spectral flow cytometry. EVs were profiled with markers reflecting bone and kidney cell origin. A support vector machine learning-based model was employed for analyses of EV phenotypes to predict the cognitive dysfunction. Plasma-EVs expressing osteocalcin, sclerostin, and nephrin were significantly higher in the cognitive impairment group compared to the normal cognition group. EVs bearing kidney cell markers correlated significantly with bone-derived EVs. A machine learning-based model, comprised of osteocalcin+, nephrin+, and CD24+ EVs predicted cognitive impairment in PWH on ART. Our study reveals that neurocognitive impairment in PWH is associated with increased levels of plasma EVs enriched with the bone markers osteocalcin and sclerostin and the kidney marker nephrin, suggesting that these EV subtypes may be novel candidate biomarkers for disease-spanning neurocognitive dysfunction. Moreover, the relationship between bone-derived EVs with kidney-derived EVs may suggest their role in mediating inter-organ crosstalk in the pathogenesis of HIV-associated cognitive impairment.

Free Papers Compiled

Human immunodeficiency virus HIV infected individuals on national AIDS control organization NACO India based highly active antiretroviral therapy (HAART) regimen often continue experiencing neurological complications referred to as HIV associated neurocognitive disorders (HAND).The cognitive impairment is attributed to HIV replication in the brain and liberation of inflammatory neurotoxins leading to neuronal dysfunction.The American academy of neurology task force on the acquired immune deficiency syndrome AIDS defined two level of neurological impairment in HIV patients: 1.HIV associated dementia(HAD)and 2.minor cognitive motor disorder (MCMD).A core difference between the two is the degree of functional impairment present . Patient with HAD have more impairment than those with MCMDTimely detection of Cognitive dysfunction in patients with HIV infection is very crucial as HAND could affect patient’s activities of daily living such as medication adherence, employment; driving and so on this worsens disease indirectly.Methods:A Cross sectional Study on Patients with immune compromised states infected by HIV/AIDS was the main aim. The study includes 75 HIV infected patients attending ART centre in Victoria hospital. Patients taken into study were aged above 18years, of both sexes, then MINI Screening for Psychiatric diagnosis will be applied to rule out Axis I Psychiatric illnessIHDS scale will be applied to know the neurocognitive severity (score less than <=10) patients will be considered.Results:More than half of the HIV patients had scored less in IHDS SCALE, reported.Conclusion:the results show that patients with HIV states have the high prevalence of prevalence of HIV associated neurocognitive impairment.Introduction:Electrolyte abnormalities are common in chronic alcoholics as a result of chronic alcohol consumption, acute alcohol intoxication. They are especially significant during alcohol withdrawal. We should be aware of these clinically important disturbances caused by alcohol abuse for their appropriate management.Material and methods:A cross-sectional observational study was conducted for a period of 18 months and 126 patients of alcohol dependence in withdrawal state were included. Diagnosis of alcohol withdrawal were confirmed using ICD-10 and patients were evaluated using CIWA-Ar. Venous blood was obtained for the determination of serum potassium, sodium and magnesium, calcium, phosphates, bicarbonates concentrations and LFT.Results:The prevalence of electrolyte imbalance was 71%. Hyponatraemia was noted in 28.6% and hypernatremia in 11.9% of individuals with alcohol dependence syndrome. Hypokalemia was noted in 42.1% and hyperkalemia was noted in 1.6% of individuals with alcohol dependence syndrome. 14.3% of the individuals have decreased magnesium levels and 15.1% have increased magnesium levels. 67.5% of individuals have normal calcium levels and hypocalcaemia was noted in 31.7%, while hypercalcaemia was noted in only one patient. Hypophosphatemia was present in 15.1% of individuals while in rest the serum phosphorous levels were normal. Metabolic acidosis was found in 19.8% and metabolic alkalosis in 3.2% patients.Conclusion:The prevalence of electrolyte imbalance in patients of alcohol dependance in alcohol withdrawal state was 71%. The most frequent electrolyte disturbances in these patients were hypokalemia (42.1%) followed by hypocalcemia (31.7%), hyponatremia (28.6%), and hypomagnesemia (14.3%). The metabolic disturbances ware present in 23% patients. The patients consuming 7/weeks were significantly more likely to have electrolyte imbalance and deaarranged liver function tests than in individuals consuming 4/weeks or less.

Alterations in brain metabolism during the first year of HIV infection

Migration of both uninfected and infected monocytes into the brain during acute HIV infection likely initiates metabolic changes that can be observed with magnetic resonance spectroscopy (MRS). Herein, we measured changes in brain metabolism during the first year of HIV infection and examined the relationship of these metabolite levels to CD16+ monocyte populations measured in the blood. MRS was performed on nine HIV+ subjects identified during acute HIV infection and nine seronegative control subjects. HIV+ subjects were examined within 90 days of an indeterminate Western blot, then again 2 and 6 months later, during early infection. Blood samples were collected for plasma viral RNA and monocyte subset quantification. HIV+ subjects were identified with acute viral ailment and did not display severe cognitive deficits such as dementia or minor cognitive motor disorder. Changes in lipid membrane metabolism (choline levels) in the frontal cortex and white matter were observed during the initial year of HIV infection. Greater numbers of CD16+ monocytes were associated with lower N-acetylaspartate levels and higher choline levels in the brain. These results suggest that HIV infection induces metabolic changes in the brain early during infection and that these changes may be related to monocyte dynamics in the periphery.

Cell Signaling Pathways and HIV-1 Therapeutics

Host-virus interactions permeate every aspect of both virus life cycle and host response and involve host cell macromolecular machinery and viral elements. It is these intimate interactions that mandate the outcomes of the infection and pathogenesis. It is also these intimate interactions that lay the foundation for the development of pharmaceutical interventions. HIV-1 is no exception in these regards. In the first two decades, HIV/AIDS research has led to the successful development of a number of antiviral inhibitors and the landmark formulation of the suppressive therapy. It has become apparent that this therapy does not offer a complete solution to cure and eradicate the virus. Meanwhile, this therapy has changed the overall landscape of HIV-associated neurological disorders to a more common and prevalent form so-called minor cognitive motor disorder. Thus, there is an important and continued need for new anti-HIV therapeutics. We believe that this is an excellent opportunity to compile and present the latest works being done during the last few years in this exciting field of HIV-host interactions, particularly cell signaling pathways. We hope that this special issue composed of one brief report, eight thematic reviews, and two original articles will serve to foster the exchange of new scientific ideas on HIV-host interactions and anti-HIV therapy and eventually contribute to HIV/AIDS eradication.

Comparison of Scales to Evaluate the Progression of Hiv-Associated Neurocognitive Disorder

AIM: First, to compare the characterization of neurocognitive deficits in milder stages of HIV-associated neurocognitive disorder (HAND) derived from existing dementia rating scales of the American Academy of Neurology (AAN) and Memorial Sloan Kettering (MSK) with the 2007 consensus ('Frascati') classification. Second, to identify potential sociodemographic and clinical predictors of HAND progression during 1-year follow-up. METHODS: 104 HIV-infected subjects in an existing cohort system were evaluated with a medical history, exam, neuropsychological test battery and functional assessments. The degree of HAND was rated using the AAN, MSK and Frascati scales. The degree of concordance among these scales was determined. In addition, 45 subjects were reassessed for changes in their neurocognitive status at 1-year follow-up. Associations between age, education, sex, depression ratings, substance abuse, race, hepatitis C serostatus, CD4 count and progression of HAND were examined. RESULTS: There was excellent concordance (gamma > 0.8) among the Frascati, MSK and AAN ratings. Subjects rated as having minor cognitive motor disorder on the AAN scale (n = 45) were evenly split between Frascati rating of asymptomatic neurocognitive impairment (n = 24) and mild neurocognitive disorder (n = 21). At 1-year follow-up of 45 subjects, 31% had worsened, 13% had improved and 56% were stable. Predictors of progression included age older than 50 years (odds ratio: 5.57; p = 0.013) and female gender (odds ratio: 3.13; p = 0.036). CONCLUSION: The Frascati HAND rating scale has excellent concordance with previous neurocognitive rating scales and can be used to better characterize milder stages of cognitive impairment. Older individuals and women appeared to be more likely to show neurocognitive progression.

The HIV-1 viral protein Tat modulates glutamate and GABA exocytosis from human and mouse neocortical nerve endings by acting at different binding sites

Background Central Nervous System (CNS) disorders often accompany the acquired immunodeficiency syndrome (AIDS) and are typified by neuropsychiatric symptoms, such as cognitive and motor impairments, sometimes paralleled by neuropathological hallmarks. Collectively, these events are referred to as HIV-1 associated dementia (HAD). Before the advent of the Highly Active Antiretroviral Therapy (HAART), about 20% of adult patients, but as many as 40% of children/adolescent infected subjects developed HAD. Nowadays, in the era of HAART, the prevalence of HAD has decreased, but a more subtle form of disorder, referred to as Minor Cognitive Motor Disorder (MCMD), has emerged in about 20% of symptomatic HIV-1 seropositive patients, including those receiving HAART. This work was aimed at investigating the impact of the HIV-1 viral protein Tat on central neurotransmission since this protein has been proposed as one of the viral component involved in the onset of central neuropsychiatric symptoms. Methods The approach used was the up-down superfusion of purified synaptosomes isolated from human neocortical specimens removed during neurosurgery from consenting patients suffering of brain tumours. Experiments were also carried out by using mouse purified synaptosomes or slices in an attempt to propose an animal model suitable to investigate Tat-induced modification to central nervous system. Functional studies were paralleled by biochemical investigation on the existence of receptor protein potential involved in the effects observed and changes to second messenger production. Results

HIV and Neurocognitive Impairment

HIV-associated neurocognitive disorders (HAND) range from mild (neuropsychologically impaired) to moderate (minor cognitive motor disorder) to severe

CSF biomarkers in HIV dementia

A reliable biomarker for HIV-associated dementia (HIV-D) has eluded neuro-AIDS investigators for more than 2 decades. An urgent need remains, because although the incidence of HIV-D has declined among patients treated with highly active antiretroviral therapy, prevalence has increased, and a more insidious cognitive decline, minor cognitive motor disorder (MC/MD), has become common.1,2 Efforts to diagnose, evaluate treatments, and identify risk factors are held back by lack of disease-specific biomarkers. Routine radiographic findings of “HIV encephalitis” do not correlate strongly with cognitive dysfunction, and although advanced imaging modalities such as magnetic resonance spectroscopy (MRS), magnetization transfer imaging, and diffusion tensor imaging show promising, sometimes striking, correlations, these modalities will likely remain impractical in most settings where costs are prohibitive and interpretive expertise is limited.3–5 An ideal biomarker for HIV-associated brain disease would be objective, quantitative, and scalable for wide use. Operationally, it would serve 1) diagnosis of HIV-D and MC/MD, 2) identification of patients at risk, 3) detection of disease progression, 4) confirmation of arrested or static encephalopathy, and 5) measurement of treatment response. A single biomarker sufficient for all these aims is implausible; rather, complementary markers likely will be required. Moving from bedside to bench, biomarkers ideally should further the science of neuro-AIDS by means of transparent associations with HIV neuropathogenesis. Numerous viral and host factors have been implicated; how these elements interact and converge to produce the particular patterns of HIV-associated brain injury remains unclear. The most attractive grand narrative is also the oldest, namely, …

Trastornos neurocognitivos en la infección por el virus de la inmunodeficiencia humana

Disruption of neurocognitive functioning is one of most frequent complications in patients with HIV infection nowadays. The Highly Active Antiretroviral Therapy (HAART) has demonstrated an improvement associated with its use, although there are different works that show this improvement is achieved in a low proportion of individuals who initiate therapy. The most known characterization of neurocognitive dysfunction is the HIV-associated Dementia (HAD), yet there may also exist the asymptomatic neurocognitive impairment (ANI) or the Minor Cognitive-Motor Disorder (MCMD). This review describes the disorders related to HIV infection, and comments on possible interventions focused on the protection of neurocognitive functioning in HIV-infected people.

Amount of HIV DNA in Peripheral Blood Mononuclear Cells is Proportional to the Severity of HIV-1-Associated Neurocognitive Disorders

Human immunodeficiency virus (HIV) DNA in peripheral blood mononuclear cells was previously associated with neuropsychological function. By including individuals encompassing the full range of HIV-1-associated neurocognitive disorders, this study reports results from subjects with normal cognition, minor cognitive motor disorder, and HIV-1-associated dementia. Individuals with normal cognition had relatively low HIV DNA levels compared to those with minor cognitive motor disorder and HIV-1-associated dementia. Neuropsychological deficits were significantly associated with entry HIV DNA in all domains. These findings demonstrate for the first time that the severity of HIV-1-associated neurocognitive disorders is proportional to the amount of circulating HIV DNA.

Amount of HIV DNA in Peripheral Blood Mononuclear Cells is Proportional to the Severity of HIV-1-Associated Neurocognitive Disorders

Human immunodeficiency virus (HIV) DNA in peripheral blood mononuclear cells was previously associated with neuropsychological function. By including individuals encompassing the full range of HIV-1-associated neurocognitive disorders, this study reports results from subjects with normal cognition, minor cognitive motor disorder, and HIV-1-associated dementia. Individuals with normal cognition had relatively low HIV DNA levels compared to those with minor cognitive motor disorder and HIV-1-associated dementia. Neuropsychological deficits were significantly associated with entry HIV DNA in all domains. These findings demonstrate for the first time that the severity of HIV-1-associated neurocognitive disorders is proportional to the amount of circulating HIV DNA.

Cerebral immune activation in chronic hepatitis C infection: A magnetic resonance spectroscopy study

Abnormal cerebral metabolism and cognitive impairments have been reported in patients with chronic hepatitis C (HCV) but studies have failed to demonstrate a relationship between these findings. Twenty-five HCV-positive patients with histologically-mild liver disease were studied with cerebral proton magnetic resonance spectroscopy (MRS), using acquisition parameters to quantify myo-inositol (mI) and other metabolites in frontal white matter (FWM). Patients underwent automated attention and working memory tests (Cognitive Drug Research test system). The mean mI/ creatine ratio in the HCV+ve patients (0.64, SD 0.21) was significantly higher (p=0.02) than in healthy controls (0.52, SD 0.10). On cognitive testing, the HCV+ve patients showed impairments in 2/4 composite scores, reflecting working memory and attention, compared to normative data from healthy volunteers (p<0.005) and HCV-ve controls (p=0.03). There was a significant association between elevated FWM mI/creatine and prolonged working memory reaction times (R=0.72, p=0.002). Elevated FWM mI/ creatine is a feature of HIV-related minor cognitive-motor disorder. It is associated with infection and immune activation of microglial cells. The similar findings in this study suggest that cerebral immune activation may also occur in HCV infection. This may underlie the mild neurocognitive impairment and neuropsychological symptoms observed in a proportion of patients.

Aging exacerbates extrapyramidal motor signs in the era of highly active antiretroviral therapy

The phenotype of human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) in the developed world has changed with the broad institution of highly active antiretroviral therapy (HAART) and with aging of the HIV+ population. Extrapyramidal motor signs were a prominent feature of HAND as defined in the early stages of the epidemic but has not been reevaluated in the era of HAART. Moreover, the contribution of aging to extrapyramidal motor signs in the context of HIV remains undefined. We examined these questions among the 229 HIV+ participants in the Hawaii Aging with HIV Cohort compared to age-, gender-, and ethnicity-matched HIV-negative controls. Extrapyramidal motor signs were quantified using the motor exam of the Unified Parkinson's Disease Rating Scale (UPDRSmotor) and compared to concurrent neuropsychological and clinical cognitive diagnostic categorization. The mean UPDRSmotor score increased with older age (1.68 versus 3.35; P<.001) and with HIV status (1.18 versus 3.56; P<.001). Age group (P=.024), HIV status (P<.001), and the interaction between age and HIV (P=.026) were significantly associated with UPDRSmotor score. Among HIV+ patients, the mean UPDRSmotor score increased with worsening cognitive diagnostic category (P<.001) where it was 2.06 (2.31) in normal cognition (n=110), 3.21 (3.48) in minor cognitive motor disorder (MCMD) (n=84), and 5.72 (5.01) in HIV-associated dementia (HAD) (n=37). We conclude that extrapyramidal motor signs are increased in HIV in the era of HAART and that the impact of HIV on extrapyramidal motor signs is exacerbated by aging. These results highlight the importance of a careful neurological examination in the evaluation of HIV patients.

NeuroAIDS

The neurological complications of AIDS (NeuroAIDS) include neurocognitive impairment and HIV-associated dementia (HAD; also known as AIDS dementia and HIV encephalopathy). HAD is the most significant and devastating central nervous system (CNS) complications associated with HIV infection. Despite recent advances in our knowledge of the clinical features, pathogenesis, and neurobiological aspects of HAD, it remains a formidable scientific and therapeutic challenge. An understanding of the mechanisms of HIV neuroinvasion, CNS proliferation, and HAD pathogenesis provide a basis for the interpretation of the diagnostic features of HAD and its milder form, HIV-associated minor cognitive/motor disorder (MCMD). Current diagnostic strategies are associated with significant limitations, but it is hoped that the use of biomarkers may assist researchers and clinicians in predicting the onset of the disease process and in evaluating the effects of new therapies.

Book Review: HIV and Psychiatry: HIV and Psychiatry: A Training and Resource Manual

HIV and Psychiatry: A Training and Resource Manual Kenneth Citron, Marie-Josee Brouillette, Alexandre Beckett, editors. 2nd edition. New York (NY): Cambridge University Press; 2005. 346 p. US$65.00. Reviewer rating: Excellent Review by Raymond Tempier, MD Saskatoon, Saskatchewan Human Immunodeficiency Virus (HIV) was first reported to be associated with AIDS in 1984. Since then, HIV has caused the worst worldwide epidemic in recent times and HIV infection is still progressing. At the end of 2005, according to the Public Health Agency of Canada, 58 000 Canadians were infected with HIV, a 16% increase since 2002.' The prevalence rate of HIV infection is also increasing as patients stay alive owing to treatment progress, but many (27%) ignore that they are infected. HIV infection is affecting psychological health but is also related to mental illness. It is now well known that HIV damages the brain, as 10% to 20% of infected individuals have some cognitive impairment. As we all know, HIV infection is devastating in sub-Saharan Africa, and in a recent study in Uganda, researchers found that, in a cohort of patients hospitalized for manic episode, 55% were HIV positive.2 These findings are consistent with the hypothesis that HIV infection can lead to the development of secondary mania.3 Such results are examples of the dramatic impact that HIV infection has on psychiatric disorders. This training manual comes at quite an opportune time as HIV infection and its consequences on mental health are still burning issues to deal with. My review is of the second edition of this training manual, which was prompted by the availability of new treatments such as antiretroviral medications and, most recently, highly active antiretroviral therapy. These drugs have changed the prognosis of HIV-infected patients. Nevertheless, azidothymidine (AZT) and related medications are heavy treatments requiring strict adherence to the treatment schedule; as well, they interact with psychotropic medications. As shown before, several mental disorders, not only cognitive deficits, are related to HIV infection. Therefore, this book aims to present the knowledge base necessary for psychiatrists and mental health professionals to better help, support, and treat those infected with HIV and its effects on mental health. The book starts with an extensive medical overview of the HIV infection. Practical tables show necessary baseline laboratory tests. A summary table lists the neuropsychiatrie side effects of medications used to treat HIV infection. This first chapter is also filled with details on antiretroviral therapies and their relation to psychotropic medications. The lipodystrophy syndrome, a consequence of antiretroviral therapy, is presented here through several pictures that are, unfortunately, of rather poor quality. The suggested websites are a useful addition to this basic information. The second chapter focuses on cognitive disorders that are becoming a common complaint of HIV patients, according to the authors. We also learn that up to 25% of patients have some sort of minor cognitive motor disorder. In each chapter of this book, there is a primary case history, with the chapter structured according to the pertinent questions that could arise for a practising physician faced with such a situation. …

HIV-1 Associated Dementia In Pre And Post HAART Era

Patients infected with human immunodeficiency virus (HIV-1) invariably experience a wide range of neurological complications associated with AIDS that are collectively referred to as HIV associated dementia (HAD). HIV associated dementia usually develops in advanced stages of HIV-1 disease. Clinically HAD involves varying degree of neurological and psychiatric symptoms like – cognitive impairment, motor disturbances, hallucinations, delirium and behavioural changes, often leading to progressive deterioration of cognitive and motor skills. The worldwide incidence of HAD is up to 40% of AIDS population. The advent of highly active anti-retroviral therapy (HAART) had a significant negative impact on HAD, nevertheless neurological complications had shown persistence. Variability in drug penetration, distribution, drug resistance, optimal dosage levels and toxicity, hinder the success of HAART in countering the neuronal cell death or damages to the brain. In the post HAART period a subtle form of HAD has evolved which is referred as minor cognitive motor disorder (MCMD). Hence the HIV-1 induced neurological complications continue to be a clinical problem amongst AIDS affected individuals. The aim of this review is to describe the cellular and molecular basis of neuropathogenesis of HAD, list the most common therapeutic regimens used in HAART, discuss briefly the advantages and limitations of HAART agents and describe how HAD has evolved in post HAART era. doi: 10.5214/ans.0972.7531.2007.140204

Insulin Resistance Is Associated With Cognition Among HIV-1-Infected Patients

To determine if insulin resistance (IR) is associated with lower cognitive performance among HIV-1-infected adults and to determine if advanced age magnifies risk. Cross-sectional analysis within the Hawaii Aging With HIV Cohort. We calculated the homeostasis model assessment of insulin resistance (HOMA-IR) among 145 cohort participants. Values were compared to concurrent neuropsychological test performance and cognitive diagnoses. Hypertension, body mass index (BMI), and non-Caucasian self-identity were directly related to insulin resistance (IR); however, age, CD4 lymphocyte count, and rates of treatment with HAART were not. In logistic regression analyses and stratifying cognition status on a 3-tiered scale (normal, minor cognitive motor disorder (MCMD), and HIV-associated dementia (HAD)), we identified an increased risk of meeting a higher diagnostic category as HOMA-IR increased (OR, 1.12; 95% CI: 1.003 to 1.242 per unit of HOMA-IR, P = 0.044). In linear regression models and among nondiabetic participants, an increasing degree of IR was associated with lower performance on neuropsychological summary scores. IR is associated with cognitive dysfunction in this contemporary HIV-1 cohort enriched with older individuals. Metabolic dysfunction may contribute to the multifactorial pathogenesis of cognitive impairment in the era of HAART.

Evolving paradigms in the pathogenesis of HIV-1-associated dementia

HIV-1-associated dementia (HIV-D) remains a significant consequence of HIV-1 infection and AIDS. Since the clinical introduction of highly active antiretroviral therapy (HAART), the incidence of HIV-D has decreased, yet the prevalence has increased as patients are living longer under treatment. Additionally, a less severe form of HIV-D, minor cognitive motor disorder, has become an increasing issue. Two different models have been proposed for virus entry in the central nervous system (CNS) in HIV-D. In the 'Trojan horse' model, the virus enters the CNS early carried by macrophages and infects resident glia; later in the course of infection, virus replication is activated and additional monocyte/macrophages are recruited into the CNS via cytokine/chemokine networks and endothelial-cell-leukocyte interactions at the blood-brain barrier. In the 'late invasion' model, an inherently invasive activated monocyte subset is expanded from bone marrow as a result of immune dysregulation in the periphery in the setting of AIDS. In this review we discuss these two separate, although not mutually exclusive, means for virus entry and persistence in the CNS. Additionally, we explore mechanisms for neuronal injury and apoptosis, including the role of virus, viral and host proteins, oxidative stress and products of infected or uninfected activated microglia and astrocytes. Potential therapeutic strategies are also briefly discussed.

The decline of incident cases of HIV-associated neurological disorders in San Francisco, 1991–2003

Neuropsychological impairment as a result of HIV infection and the development of other central nervous system (CNS) disorders associated with HIV disease has been well documented since the early days of the epidemic [1]. Although the mechanism by which HIV causes cognitive–motor impairment is unresolved [2,3], cognitive decline has been demonstrated to be a ‘function of disease progression’ [4]. The prevalence of AIDS dementia is not known. However, the World Health Organization reported that “of 35 million HIV infected individuals worldwide, one-third of adults will develop a dementive illness” [4]. Estimates of the prevalence of the disorder range from 16 to 25%, with more recent data pointing towards 7–10% [2]. Among only those with advanced HIV disease, the prevalence of dementia has been estimated at 15–66% [2]. The prevalence of minor cognitive motor disorder has been estimated at 25–30%, and is usually seen in symptomatic HIV infection [4]. The annual incidence of AIDS dementia has been estimated at 7% [5]. The prevalence of the disorder has proved much more difficult to estimate. Nevertheless, because of the degree of morbidity associated with these disorders, a small change in their incidence or prevalence could mean a substantial change in the demands on the healthcare system. Since the advent of widely available highly active antiretroviral therapy (HAART) in 1996, several studies have reported a decrease in the incidence of AIDS dementia [6]. Among HAART-treated patients, a decrease in AIDS dementia has also been observed, along with improved cognitive functioning and neuroimaging markers [6]. Furthermore, autopsy analysis has revealed significant reductions in HIV-related brain lesions in HAART-treated patients compared with patients receiving either no therapy, monotherapy or dual therapy [7]. However, no difference in the presence of lesions was noted between untreated and treated patients who died in the post-HAART era, suggesting that the incidence of AIDS dementia among advanced-stage HIV patients may not decrease [7]. We report here on changes in the incidence of CNS disorders in San Francisco, a city in which AIDS case reporting has been shown to be over 95% complete [8], and where the proportion of individuals living with AIDS who receive HAART increased from 5% in 1995 to 76% in 2003 [9]. In San Francisco, the Department of Public Health conducts AIDS case surveillance activities, in which health department personnel review pathology, laboratory, and death reports to identify and report diseases among individuals with AIDS. The initial and subsequent occurrences of AIDS-related opportunistic infections, including cryptococcosis and HIV encephalopathy, are collected. We analysed the annual incidence of CNS diagnoses (AIDS dementia, cryptococcosis, toxoplasmosis, progressive multifocal leukoencephalopathy and primary brain lymphoma) among AIDS cases in San Francisco from 1991 to 2003. The annual incidence of AIDS dementia declined from 3.71 per 100 persons living with AIDS in 1992, to 0.34 per 100 persons living with AIDS in 2002 and to 0.24 per 100 persons living with AIDS in 2003 (Fig. 1). Although not as dramatic, declines in other CNS opportunistic illnesses were also observed. These data strongly support the notion that after the advent and wider use of HAART, the incidence of newly diagnosed AIDS dementia and other HIV-associated neurological problems in San Francisco has fallen sharply.Fig. 1: Incidencea of central nervous system diagnoses among AIDS cases 1991–2003b. All central nervous system causes;dementia;toxoplasmosis;cryptococcosis;brain lymphoma;progressive multifocal leukoencephalopathy. aIncidence per 100 individuals living with AIDS per year. bLikelihood ratio for trend, P < 0.001 for all central nervous system diagnoses.When interpreting these data it is important to note that diagnoses of CNS opportunistic illnesses may have been missed because of insufficient access to medical records at selected facilities, or to records of local AIDS cases who received some or all of their medical care at facilities outside San Francisco. Reports of opportunistic illnesses occurring in 2003 may be incomplete because of reporting delays, and thus the decline observed between 2002 and 2003 may not be as great as depicted. Nevertheless, consistent with reported declines in other opportunistic diseases among patients with HIV here in San Francisco [10], we conclude that the advent of HAART has resulted in a dramatic decrease in the incidence of each one of the five CNS disorders reported here among patients with AIDS. Whereas the actual mechanism of action of this protective effect is not fully understood, reduced viral load and protection against the destruction of immune competent cells associated with HAART appears to be responsible for reducing HIV-associated cognitive disorders and other CNS opportunistic diseases. Fewer new cases, as well as a decrease in the number of living cases with one or more of these debilitating CNS disorders, may indicate a decreasing burden on the system of care; an important consideration as we experience an increasing volume of patients living with chronic HIV infection into older age.

Evaluation of HIV RNA and markers of immune activation as predictors of HIV-associated dementia

To evaluate whether baseline levels of plasma and CSF HIV RNA, tumor necrosis factor alpha (TNFalpha), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-2 (MMP-2), or macrophage colony stimulating factor (M-CSF) are predictors of incident HIV-associated dementia (HIVD) in a cohort with advanced HIV infection. A total of 203 nondemented subjects with CD4 lymphocyte counts less than 200/muL, or <300/microL but with cognitive impairment, underwent semiannual neurologic, cognitive, functional, and laboratory assessments. HIVD and minor cognitive motor disorder (MCMD) were defined using American Academy of Neurology criteria. The cumulative incidence of HIVD was estimated using Kaplan-Meier curves. Cox proportional hazards regression models were used to examine the associations between biologic variables and time to HIVD, adjusting for age, sex, years of education, duration of HIV infection, type of antiretroviral use, premorbid IQ score, and presence of MCMD. After a median follow-up time of 20.7 months, 74 (36%) subjects reached the HIVD endpoint. The dementia was mild in 70% of cases. The cumulative incidence of HIVD was 20% at 1 year and 33% at 2 years. Highly active antiretroviral therapy (HAART) was used by 73% of subjects at baseline. A plasma HIV RNA level was undetectable in 23% of subjects and a CSF HIV RNA level was undetectable in 48% of subjects. In adjusted analyses, neither plasma nor CSF HIV RNA levels (log10) were associated with time to HIVD; log10 levels of plasma TNFalpha (HR 3.07, p = 0.03) and CSF MCP-1 (HR = 3.36, p = 0.06) tended to be associated with time to HIVD. The lack of association between baseline plasma and CSF HIV RNA levels and incident dementia suggests highly active antiretroviral therapy may be affecting CNS viral dynamics, leading to lower HIV RNA levels, and therefore weakening the utility of baseline HIV RNA levels as predictors of HIV-associated dementia.