neurocognitive and motor disorders in hiv infection ...

In: Research Focus on Cognitive Disorders Editor: Valerie N. Plishe, pp. 133-147

ISBN 1-60021-483-5 © 2007 Nova Science Publishers, Inc.

Chapter 6

NEUROCOGNITIVE AND MOTOR DISORDERS IN HIV INFECTION. ASSESSMENT AND INTERVENTIONS Jose A. Muñoz-Moreno∗ Lluita contra la SIDA Foundation - HIV Unit, Germans Trias i Pujol University Hospital, Ctra. de Canyet, S/N 08916, Badalona, Barcelona, Catalonia, Spain.

ABSTRACT Neurocognitive and motor functioning may be progressively affected in HIV-infected patients. This disruption starts with impairment on neuropsychological performance, usually with subtle changes, but it may also lead to important neurocognitive complications. The current anti-HIV treatments may improve these neuropsychological disorders, although a total recovery is not completely achieved. In addition, in clinical practice, people living with HIV frequently report problems with their cognitive functioning in their routine clinical visits, pointing attention and memory as the main functions affected. Though many different studies assessing neurocognitive impairment in HIV infection have been published, an standard approach to optimally assess neuropsychological deficits does not currently exist. Moreover, when HIV-infected patients present a good immunological status, neuropsychological changes are usually subtle and affect few neurocognitive domains. For these reasons, it is necessary a rigorous and adequate assessment of impaired neurocognitive functioning. Until now, few strategies have been recommended for the improvement of cognitive disorders in patients with HIV infection. This chapter describes the most common neurocognitive and motor disorders associated with HIV infection, provides a summarized approach for an adequate assessment of these manifestations, and discusses possible clinical interventions focused on the preservation of neuropsychological functioning in the HIV infected population.

∗

Correspondence concerning this article should be addressed to Jose A. Muñoz-Moreno, Lluita contra la SIDA Foundation - HIV Unit, Germans Trias i Pujol University Hospital, Ctra. de Canyet, S/N 08916, Badalona, Barcelona, Catalonia, Spain. Tel: +34 93 465 78 97; Fax: +34 93 465 76 02; e-mail: [email protected].

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Jose A. Muñoz-Moreno

1. INTRODUCTION The alteration of neurocognitive and motor functioning is currently one of the most important disruptions caused by the Human Immunodeficiency Virus (HIV). This is so, not only for the interference that it may produce on an individual's life [1], but also because HIVrelated neurological diseases continue to be major causes of morbidity and mortality [2]. Changes in neuropsychological performance are presented more clearly at the most advanced stages of HIV infection, although certain cognitive or motor deficits may also exist throughout the asymptomatic stages of the infection. In any case, an increase in HIV-related neurocognitive impairment is a sign of a more severe deterioration of the Central Nervous System (CNS) and, if maintained, this complication may lead to a fatal progression. The most severe form of neurocognitive impairment is HIV-related Dementia (HIV-D), which is characterized by the presence of the Acquired Immunodeficiency Syndrome (AIDS) Dementia Complex (ADC). Similarly, mild cognitive impairment, or the Minor CognitiveMotor Disorder (MCMD), may appear in prior phases. The use of current anti-HIV treatments, or Highly Active Antiretroviral Therapy (HAART) regimens, has helped to control the viral replication, and consequently, to improve the restoration of the human immune system. This has resulted in a meaningful decrease in the most common HIV-related diseases, especially decreasing the incidence of opportunistic infections, maternal transmission rates, and AIDS death rates [2]. Regarding HIV-related neurocognitive impairment, HAART regimens have also been shown to produce benefits on impaired neuropsychological functioning [3]. However, until the present, HIV-infected individuals frequently continue to report problems in their cognitive functioning. Confirming this, recent findings show that neurocognitive recovery is not achieved in all impaired individuals receiving HAART. In fact, it has been seen that the change may only be achieved by a minor proportion of them [4].

2. COGNITIVE DISORDERS AND CLINICAL MANIFESTATIONS The presence of HIV-1-related neurocognitive disorders has been perceived since the beginning of the HIV epidemic. The initial cases detected with a gay-related immunodeficiency disorder, later renamed as AIDS, were characterized by the presentation of neuropsychiatric pathology including complications from psychosis to dementia [5]. A few years later, some investigators showed an early effort to conceptualize the neurocognitive disorder which characterized that syndrome [6]. Thus, HIV-D was defined, identifying the ADC as the neurobehavioral pattern observed. ADC was characterized by cognitive, motor and emotional changes, including mental slowing, weakness, decreased coordination, depressive mood and loss of motivation. Simultaneously, investigators also accepted the existence of a minor cognitive disorder. The syndrome was understood as a mild dementia, which presumably could coexist with frank dementia. At that time, despite significant variation in ADC prevalence rates (10%-70%), mild dementia was concretely estimated in 33% of patients with AIDS [6].

Neurocognitive and Motor Disorders in HIV Infection…

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Hence, the existence of mild cognitive impairment has been accepted since the onset of research in HIV-related neurocognitive functioning. However, this was in the context of patients with AIDS, because the presence of disruption on neurocognitive functioning in asymptomatic HIV-infected patients has remained more controversial. Different causes have determined the lack of a definitive response, among them, variable neuropsychological testing, different compositions of study samples, uncertain statistical approach, low agreement in cognitive disorder diagnosis, and other relevant variables in this research setting. Table 1. Neurological complications of HIV-1 infection Primary neurological complications HIV-1 neurocognitive disorders HIV-related mild neurocognitive disorder HIV-related dementia Other HIV-1 neurological complications HIV-1 meningitis HIV-1 vacuolar myelopathy HIV-1 neuropathies Distal sensory polyneuropathy Asceding neuromuscular syndrome Mononeuritis multiplex Inflammatory demyelinating polyneuropathies HIV-related polymyositis Secondary neurological complications Infections Cerebral toxoplasmosis Cryptococcal meningitis Cytomegalovirus retinitis/encephalitis/polyradiculitis Progressive multifocal leukoencephalopathy Other infections of the CNS Neoplasms Primary or secundary CNS lymphomas Karposi sarcoma Other neoplasms Cerebrovascular disease related to HIV infection Other delirium Hypoxemia, hypercapnia Other metabolic and nutritional disorders Nowadays it is assumed that cognitive impairment may be present even during early HIV infection. According to a report of UNAIDS, there is accumulating evidence confirming cognitive impairment in HIV-infected persons, even before the onset of AIDS [7]. Moreover,

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neuropsychological studies have largely demonstrated this reality, as well as neuroimaging, neuropathological and electrophysiological studies, which have also showed evidence of neurobiological changes in the brains of individuals with early HIV disease [7]. According to the existence of mild neurocognitive impairment, a systematic review compared 30 studies during the pre-HAART era and estimated that 35% of HIV-asymptomatic seropositive individuals were impaired, versus an impairment rate of 12% in non-infected people [8]. On the other hand, ADC has showed a pre-HAART prevalence between 20% and 30% [9]. HIV-related neurocognitive disorders may be well understood from the classification of the neurobiological complications associated with HIV-1 infection [10], as displayed in Table 1. At the present time, three forms of neurocognitive disorders may be considered within HIV-infected persons: asymptomatic neuropsychological impairment (ANI), mild neurocognitive disorder, and HIV-D. Table 2. Diagnosis criteria for HIV-related Asymptomatic Neurocognitive Impairment HIV-related Asymptomatic Neurocognitive Impairment 1. Acquired impairment in cognitive functioning, involving at least 2 ability domains, documented by performance of at least 1.0 standard deviation below the mean for ageeducation-appropriate norms on standardized neuropsychological tests, assessing the following abilities: attention/working memory, processing speed, fluency, executive functioning, learning, delayed recall, and motor skills 2. The cognitive impairment does not produce interference in daily functioning, including work, home life, and social activities, assessed by (a) self-report or knowledgeable others, or (b) objective standardized measures 3. The cognitive impairment has been present for at least 1 month 4. The cognitive impairment does not meet criteria for HIV dementia or delirium 5. There is no evidence of another pre-existing cause for the disorder (e.g. CNS infection or neoplasm, cerebrovascular disease, pre-existing neurological disease, psychiatric disorder, or severe substance abuse)

Asymptomatic Neuropsychological Impairment This is presented when mild neurocognitive impairment is detected in two or more different cognitive areas on comprehensive neuropsychological testing, but when the assessment of everyday functioning does not indicate functional decline. This mildest form of neurocognitive complication is characterized by subtle changes in cognitive functioning, which appear not to interfere in the activities of daily functioning. Nevertheless, self-report is not sufficient for its diagnosis, and neuropsychological testing is required due to the possible influence of other interfering variables, such as emotional status or educational level. Table 2 describes criteria for diagnosing ANI.


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Mild Neurocognitive Disorder Also known as MCMD, this exists when there is a mild deficient performance in two or more areas of neurocognitive functioning, and moreover, accompanied by disturbances in daily functioning. As in the case of ANI, comprehensive neuropsychological testing is necessary for its diagnosis, but in this case, daily functioning must also be assessed to determine whether it is influenced by the presence of altered cognitive performance. Table 3 describes criteria for diagnosing MCMD. Table 3. Diagnosis criteria for HIV-related Mild Neurocognitive Impairment HIV-related Mild Neurocognitive Impairment 1. Acquired impairment in cognitive functioning, involving at least 2 ability domains, documented by performance of at least 1.0 standard deviation below the mean for ageeducation-appropriate norms on standardized neuropsychological tests, assessing the following abilities: attention/working memory, processing speed, fluency, executive functioning, learning, delayed recall, and motor skills 2. The cognitive impairment produces mild interference in daily functioning, including work, home life, and social activities, assessed by (a) self-report or knowledgeable others, or (b) objective standardized measures 3. The cognitive impairment has been present for at least 1 month 4. The cognitive impairment does not meet criteria for HIV dementia or delirium 5. There is no evidence of another pre-existing cause for the disorder (e.g. CNS infection or neoplasm, cerebrovascular disease, pre-existing neurological disease, psychiatric disorder, or severe substance abuse)

HIV-related Dementia Characterized by the presence of ADC, this is presented when marked acquired impairment in cognitive functioning is observed, involving two or more ability domains, and followed by a marked interference in daily functioning. Like both of the disorders mentioned above, dementia must be rigorously diagnosed, applying in this case neuropsychological testing that is more focused on dementia assessment. Table 4 describes criteria for diagnosing HIV-D. The profile of HIV-related neuropsychological deficits is currently well-known, involving attention/working memory, executive functions, information processing speed, learning, motor skills, verbal memory and verbal fluency. In addition, neurocognitive effects have been supported by neuroimaging and neuropathological studies, which have confirmed a disruption of fronto-subcortical systems [11]. HIV neuropsychological complications are usually associated with subcortical causes in the brain, observing a pattern of impairment that affects primarily the subcortical structures or white matter, and involving frontostriatal circuits. Indeed, it has been found that HIV is not uniformly distributed throughout the brain, and selective regions, including basal ganglia and hippocampus, show the highest levels of

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virus [12]. Accordingly, people with this neuropathological pattern tend to manifest difficulties in the functions mentioned above, which are motor function, information processing speed, initiation, divided attention, learning, information retrieval, some executive functions and verbal fluency. By contrast, this appears to differ from a cortical pattern, where other features, such as difficulties with new information learning, severe memory impairment, rapid forgetting, problems in naming and comprehension or disturbances in praxis, are more commonly observed [13]. Thus, the deterioration of neurocognitive functioning appears to be progressive, although variable. First, a subtle disruption is initiated in concrete ability domains, but over time, the person may become seriously deteriorated. In these advanced stages, symptoms usually include psychomotor slowing, reduced coordination, marked inattention, severe slowness in information processing, difficulty in learning new information, and significantly affected verbal fluency, which may be accompanied by psychosis or delirium. For these reasons, the diagnosis of HIV-D frequently indicates a poor prognostic sign in HIV disease, with a relevant probability of developing a serious complication, or progressing to a fatal outcome. Table 4. Diagnosis criteria for HIV-related Dementia HIV-related Dementia 1. Marked acquired impairment in cognitive functioning, involving at least 2 ability domains, assessing the following abilities: attention/working memory, processing speed, fluency, executive functioning, learning, delayed recall, and motor skills 2. The cognitive impairment produces marked interference in daily functioning, including work, home life, and social activities, assessed by (a) self-report or knowledgeable others, or (b) objective standardized measures 3. The cognitive impairment has been present for at least 1 month 4. The cognitive impairment does not meet criteria for delirium (e.g. clouding of consciousness) 5. There is no evidence of another pre-existing cause for the disorder (e.g. CNS infection or neoplasm, cerebrovascular disease, pre-existing neurological disease, psychiatric disorder, or severe substance abuse)

3. NEUROCOGNITIVE PERFORMANCE ASSESSMENT The observation of cognitive and motor deficits is, in the case of HV infection, closely linked to the tool used during patients' assessment. When the deterioration is moderately evident, the tests for its evaluation usually are largely accurate. However, when deficits are mild, the necessity of sensitivity and specificity becomes particularly significant. Although numerous studies assessing neurocognitive impairment associated with HIV infection have been published, there is still no standard approach to optimally evaluate neuropsychological deficits [14]. Furthermore, when patients present an appropriate immunologic status, neuropsychological changes are usually subtle and affect few


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neurocognitive domains. For these reasons, to assess adequately impaired neurocognitive functioning has become a challenge in research, as well as in the clinical setting. There are accumulating recommendations for covering different neurocognitive areas when HIV-related neuropsychological functioning is assessed. In this sense, the National Institute of Mental Health (NIMH) proposed the use of neuropsychological assessment by test batteries that included the following domains: premorbid intelligence, attention, speed of processing, memory, abstraction, language, visuoperception, constructional abilities, motor abilities, and psychiatric evaluation [15]. With this purpose, the NIMH suggested the use of large neuropsychological batteries (79 hours of duration). Nevertheless, it is evident that the application of these batteries in clinical practice may be complex or even unfeasible. For this reason, the use of briefer batteries examining the same recommended ability domains has also been proposed [15]. Table 5 shows the ability domains most recommended to explore neurocognitive performance, including examples of the most frequently used or representative neuropsychological tests in HIV infection. As described in the previous section, there is a body of evidence that indicates that neurocognitive changes in early HIV infection reflect more of a subcortical pattern of impairment [7]. In addition, more advanced manifestations of HIV-associated brain disease tend to involve impairment in more cortical areas [13]. This observation should be specifically taken into consideration to assess neurocognitive functioning with HIV infection. As indicated by expert consultants for UNAIDS, this may be the reason why studies only including tests of "higher" cognitive functioning (such as abstraction or naming) have tended to find fewer differences between HIV-infected and seronegative individuals, while those studies that have included a broader range of tests, particularly tests of reaction time, attention and information processing speed, have found more differences [7]. Although it has been suggested that the application of computerized neuropsychological batteries may be important to examine neuropsychological functioning in HIV infected patients, it has also been revealed that they do not measure the same thing as traditional batteries, and that they are not interchangeable assessment methods [14]. For this reason, it is more recommendable the use of both, integrating comprehensive tests that actually study the ability domains previously cited. The type of tests used is strongly associated with the importance of test battery size. It is relevant to note that small batteries may be likely to find fewer deficits than more extensive batteries, especially when differences tend to be slight [8]. However, at the present time, and after the publication of many studies assessing HIV-related neuropsychological functioning, the batteries used appear to be briefer than years ago, though they have a high level of accuracy. The diagnosis of a neurocognitive complication associated with HIV-1 infection requires evidence that the change in cognitive performance has been acquired since the person became HIV infected, which cannot be explained by other causes. Therefore, the diagnosis must be extremely precise in determining neuropsychological impairment, while avoiding the existence of other inducing pathologies.

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Table 5. Ability domains recommended for HIV-related neuropsychological assessment and examples of most common neuropsychological tests Ability Domain / Tests Premorbid Intelligence Wechsler Adult Intelligence Scale – Third Edition (WAIS-III) Vocabulary Test [16] National Adult Reading Test (NART) Full IQ Scale (FIQS) [17] Attention/Working Memory California Computerized Assessment Package (CalCAP) [18] Paced Auditory Serial Addition Task (PASAT) [19] WAIS-III Digits Test [16] WAIS-III Letter-Numbers Test [16] Continuous Performance Tests - Second Edition (CPT-II) [20] Information Processing Speed Trail Making Tests (TMT) - Part A [21] Symbol Digit Modalities Test (SDMT) [22] CalCAP [18] Motor Function Grooved Pegboard Test (GPT) [23] Electronic Tapping Test (ETT) [24] Learning/Memory California Verbal Learning Test - Second Edition (CVLT-II) [25] Rey Auditory Verbal Learning Test [26] Wechsler Memory Scale - Revised (WMS-R) [27] Visual Memory Rey Complex Figure Test [28] Modified Visual Reproduction Test [29] WMS-R [27] Visuoconstruction Rey Complex Figure Test [28] WAIS-III Block Design Test [16] Executive Functions Stroop Test [30] TMT - Part B [21] Wisconsin Card Sorting Test (WCST) [31] Category Test [21] Verbal Fluency Controllled Oral Word Association (COWAT) [32] Animals Test [33] Boston Naming Test [34] Emotional Status (Depression, Anxiety) Beck Depression Inventory - Second Edition (BDI-II) [35] State-Trait Anxiety Inventory (STAI) [36] Hamilton Depression Scale (HDS) [37] Hospital Anxiety Depression Scale (HADS) [38] Depression Anxiety Stress Scale (DASS) [39]

The differential diagnosis should be specifically focused on differentiating the neuropsychological condition from an opportunistic infection, such as primary cerebral


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lymphoma, other HIV-related neoplasms, HAART-related toxic effects, malnutrition and, obviously, any mental illness or brain injury with a different origin. Other instruments may be considered to complete an accurate diagnosis, such as brain scans (magnetic resonance imaging or computerized tomography), a lumbar puncture to make an evaluation of the Cerebrospinal Fluid (CSF), or any tool for assessment based on other clinical manifestations, such as, medical history or other laboratory findings. The assessment of everyday functioning is a transcendental point for the diagnosis of neurocognitive disorders. And, although this does not mean that all cognitive deficits have implications for real-life performance [7], different studies regarding the relationship between neurocognitive impairment and daily-living performance have strongly linked difficulties in neuropsychological domains to functional decline [1]. For this reason, functional batteries including measurements with respect to the activities of daily living, such as shopping, cooking, financial management, medication management or vocational abilities, have been proposed [1]. This influence on daily living may be assessed by different methods, including selfreported everyday functioning, caregiver's report, or some other objective assessment method that pertains to everyday activities. Finally, similarly to clinical criteria for neurocognitive impairment, the assessment of functional decline is required to be based on standardized self-report instruments, or objective performance-based instruments. Reasonably, measurements in both cases should be correctly classified by established norms, which define normality and abnormality in performance. Furthermore, also as in the case of neurocognitive impairment, the assessment of decline in everyday functioning should not be confounded by the presence of other disorders, which frequently include drug use, infectious disease, or psychiatric pathology.

4. INTERVENTIONS Up to the present, the strategy that has demonstrated the most considerable benefits on HIV-related neuropsychological impairment has been the use of HAART regimens [3,40-43]. They have achieved neurocognitive improvement, particularly when patients have been assessed in the short term, and when a reduction of HIV presence in CNS has been associated with that improvement. However, the concrete mechanisms involved in this neurocognitive recovery are not yet well known. There is doubt concerning the clear benefits on neuropsychological functioning, particularly because of the low improvement in a significant proportion of HAART-treated HIV-infected patients [4,43]. Additionally, HAART regimens have demonstrated a variable ability to penetrate the Blood-Brain Barrier (BBB), and therefore have a limited ability to enter into the CNS [44]. In this respect, there is currently a body of support confirming that neuropsychological deficits remain common in the post-HAART era [45]. It has been suggested that the prevalence of both HIV-related neurocognitive impairment and HIV-D remain unchanged independently of pre- and post-HAART eras, and, in fact, it is important to note that the

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improvement mediated by HAART has been estimated to occur in only one third of neurocognitively impaired patients [4]. In addition, evidences of changes in the pattern of the deficits observed have been recently found. Ability domains affected at the present time seem not to be exactly the same as deteriorated domains during the pre-HAART era [46]. The well-known fronto-subcortical pattern nowadays may be changing towards a more cortical pattern, and may be comparable, for instance, to pathologies like Alzheimer's disease. Hence, all of these data indicate that cognitive and motor problems still remain a concern in people living with HIV despite HAART. There is a current need for additional knowledge about the course of such disorders. Understanding the factors associated with neuropsychological impairment will allow clinicians and researchers not only to clarify the effect of HIV on neurocognitive functioning, but also to establish new clinical strategies in order to provide a greater CNS protection, or even to achieve a major neurocognitive recovery. Different risk factors have been traditionally associated with neurocognitive impairment with HIV infection. First, age, education and drug abuse were found as risk conditions [10]. For instance, it has been seen that cerebral cognitive reserve might be reduced in drug users, as a consequence of chronic exposure to the abused substance producing more vulnerability to the effects of HIV [47]. In a similar manner, it has been determined that alcohol consumption may have future and permanent consequences on performance [47]. Thus, this situation may occur in similar cases of people under the exposure of other risk factors. At the present time, based on the continued prevalence of deficits and the changes in the neuropsychological pattern, new potential risk factors are being proposed as possible influencing conditions for HIV-related impairment. Among them may be included the number of years with HIV infection, years on treatment, nadir CD4 cell count, coinfection with the hepatitis C virus, or HAART regimen [48]. Monitoring these factors, or controlling changes related to these conditions, currently appears to be an essential intervention for better understanding the course of cognitive disorders. Likewise, preventing as many of these conditions as possible would help to preserve neurocognitive functioning, at least more than at the present. On the other hand, the benefits of HAART might differ depending on the antiretroviral regimen. To find the most optimal regimen is one of the existing research fields in development. One main question for this intervention is to differentiate between drugs manifesting good penetration of the BBB, and those that do not. However, the drugs with highest facility to enter the CNS, the neuroactive drugs, have still not demonstrated a better action on HIV-related functioning in comparison with non-neuroactive drugs [49]. In any case, this is under investigation today, and it is likely that the total number of neuroactive drugs composing the HAART regimen could determine this response. In contrast, some individuals fail to respond to HAART. This reality may be a result of irreversible changes, with prominent neuronal loss or "burn out" inflammation. In this sense, although the prevention of risk factors probably would not achieve a better response, a major protection of the CNS would be sought. Changing the focus of intervention, cognitive rehabilitation has been proposed as a useful and recommended strategy for neurological diseases in which progression induces an


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impairment of neurocognitive functioning [50]. While the benefits of this intervention have been demonstrated especially in those cases in which deterioration of neurocognitive functioning is clearer, cognitive rehabilitation might be a possible intervention for patients with HIV infection. Different programs may be designed and developed, based on the theoretical pattern of impairment observed, as well as focusing the intervention keys on the stimulation of the affected ability domains, according to prior assessment. Although studies developing this strategy do not presently exist, its efficacy certainly might be ascertained.

5. CONCLUSIONS Neurocognitive and motor functioning may be affected in HIV-infected patients. This disruption may start with subtle impairment on neurocognitive and motor performance, but certainly may lead to severe neurocognitive complications. It is known that cognitive problems are associated with a significant interference with daily living [1], and even with an increased risk of death [51]. Thus, HIV-related cognitive and motor disorders continue to be a transcendental issue in HIV infection. There is a particular need for an accurate assessment, but also for interventions that help to protect or recover affected neuropsychological functioning. As the deterioration of neuropsychological performance may appear in a slight manner, the selection of assessment tests must be a priority decision. Neuropsychological test batteries are the main methods used to measure neurocognitive and motor functioning. Scores on these batteries have been the primary outcomes used to observe changes in deficits. For this reason, rigorous assessment is required to be developed when neurocognitive performance is evaluated in patients with HIV infection. Similarly, neuropsychological assessment must cover different ability domains, but also relevant confounding variables. Demographic characteristics, and current substance dependence, or emotional status, for instance, may have an influence on neuropsychological performance. Hence, the evaluations of neurocognitive functioning must be not only based on possible changes produced by the effect of HIV, but also on emotional status, as well as other significant demographic and clinical variables. The assessment of functional decline is also required to diagnose cognitive disorders. As a consequence, when neurocognitive performance is studied, both the measurement of neuropsychological impairment and the interference in activities of daily living should be evaluated. Moreover, seropositive people are often aware of certain limitations induced by cognitive problems in their activities of daily living, but in other occasions this is not so. The use of HAART helps to improve neuropsychological disorders, though currently it is known that a total recovery most likely cannot be achieved. In fact, this reversal appears to occur in less than half of the neurocognitively impaired HIV-infected patients [4]. Confirming this, in clinical practice, HIV-infected patients still continue to frequently report problems with their cognitive functioning. In addition, it has been observed that the prevalence of cognitive deficits have not changed across pre-HAART and post-HAART eras [45], and that the pattern of impairment is changing to a more cortical pattern [46].

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Therefore, this changing face of the reality associated with HIV-related impairment indicates that HAART is not sufficiently capable of improving the present situation, and that new potential risk factors for deterioration of neuropsychological functioning exist. The identification of predictive factors for current treatment response will be of great importance for better understanding the course of impairment, as well as for understanding its pathogenetic mechanisms. As a consequence, a strategy of preventing risk factors might permit the design of different interventions to protect neuropsychological functioning in the HIV-infected population. Factors such as drug abuse, HAART interruptions, or even the time to start the antiretroviral treatment, may need to be adapted in order to minimize the risk of neurological damage. The concrete HAART regimen is also a field of intervention that surely will collaborate with such purpose. The nature of the drugs used in HAART regimens, and differentiating between more neuroactive drugs and less neuroactive drugs, will also determine the efficacy of this approach. Hence, in consideration of all of the abovementioned reasons, it is important to conclude that there is a clear need for additional research of the course of cognitive and motor disorders. The reality involving HIV-related neuropsychological performance is changing associated with the use of HAART and the long-lasting progression of HIV infection. Therefore, the major knowledge of current factors associated with neuropsychological impairment will allow researchers and clinicians not only to clarify the effects of HIV on neuropsychological functioning, but also to establish new strategies to achieve neurocognitive recovery, or at least, to provide the greatest level of protection against cognitive and motor decline.

6. ACKNOWLEDGEMENTS I want to thank especially the support and collaboration given for the elaboration of this manuscript by Carmina R. Fumaz, Maria J. Ferrer, Denise Cinquegrana, Eugènia Negredo, Anna Prats, Maite Garolera and Bonaventura Clotet.

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