Journal of Neuroimmune Pharmacology

, 4:163

Neurodegeneration and Ageing in the HAART Era

Authors

    • Department of NeurologySt Vincent’s Hospital
    • Applied Medical Research CentreSt Vincent’s Hospital
  • S. M. Crowe
    • Department of MedicineMonash University
    • Centre for VirologyBurnet Institute
  • A. Landay
    • Department of Immunology and MicrobiologyRush University
  • Lucette A. Cysique
    • Department of NeurologySt Vincent’s Hospital
    • Brain Sciences InstituteUniversity of New South Wales
  • Gilles Guillemin
    • Department of NeurologySt Vincent’s Hospital
    • Applied Medical Research CentreSt Vincent’s Hospital
    • Department of PharmacologyUniversity of New South Wales
Invited Review

DOI: 10.1007/s11481-008-9143-1

Cite this article as:
Brew, B.J., Crowe, S.M., Landay, A. et al. J Neuroimmune Pharmacol (2009) 4: 163. doi:10.1007/s11481-008-9143-1

Abstract

Cognitive impairment and neurodegeneration still occur despite highly active antiretroviral therapy (HAART). While there are many potential reasons for this, there is increasing evidence that such impairment occurs in the absence of a clear cause. Furthermore, there are data that some neurodegenerative diseases, especially Alzheimer’s or an Alzheimer-like illness, are becoming more common in the context of HAART-treated human immunodeficiency virus (HIV) disease. This review will critically examine the evidence underpinning these observations. Potential mechanisms will be discussed with particular emphasis on the effect of ageing and how it overlaps with the effects of HIV disease itself thereby leading to neurodegeneration. The nature of this overlap will then be explored for its potential role in the facilitated expression and development of neurodegenerative diseases. Lastly, there will be a brief discussion of interventions to minimize such neurodegeneration including optimization of HAART for brain entry.

Keywords

HIVHAARTneurodegenerative diseasesdementiaAlzheimer’s

Introduction

The introduction of highly active antiretroviral therapy (HAART) in 1996–1997 has led to dramatic changes in human immunodeficiency virus (HIV) disease. Patients are now living for a significantly longer time; indeed the number of patients aged over 50 and even 60 years is increasing. Most of these have been living with HIV disease for many years, some in excess of 20 years. Furthermore, the number of patients over 50 years who have recently acquired HIV infection is increasing. Despite the benefits of HAART, cognitive impairment remains. While the incidence of HIV-associated dementia (HAD) has significantly fallen with HAART, its prevalence is increasing as patients live longer with fixed deficits (Cysique et al. 2005; Dore et al. 2003; Brew et al. 2007). Furthermore, the prevalence of milder cognitive impairment, now termed minor neurocognitive disorder and included under the broader term HIV-associated neurocognitive disorder (HAND; Antinori et al. 2007), has not changed despite the introduction of HAART (Cysique et al. 2004a; Antinori et al. 2007). While there are many potential reasons for this, there is concern that the longer duration of HIV disease, as a consequence of HAART, together with the increasing age of infected persons may have a compounding detrimental effect on cognitive function. Additionally, these two factors may facilitate and perhaps enhance the expression of a variety of neurodegenerative diseases as HIV-infected patients approach the age where such disorders become increasingly common.

This manuscript will first review the evidence for the potential compounding effect of age on cognition in HIV disease by examining the evidence for persistent and developing neurodegeneration in HAART-treated patients. This is best done by focusing on those who have persistent and developing cognitive impairment in the absence of any other explanation most particularly in the context of maximal suppression of HIV viral load in the blood and cerebrospinal fluid (CSF). In relation to the second issue, namely the facilitation of neurodegenerative diseases by HIV and age, data from CSF and neuropathological studies will be reviewed.

After discussion of the evidence, a delineation of the potential mechanisms will be presented. This will be approached firstly by a review of the general aspects of the pathogenesis of neurodegenerative diseases. Then the effects of normal ageing and how they intersect with HAND will be discussed, followed by a review of the overlapping features and mechanisms in HIV and neurodegenerative diseases.

The last section will deal with a discussion of two potential therapeutic interventions. First, the rationale for optimizing HAART to ensure adequate brain penetration of antiretroviral drugs will be presented. Second, evidence supporting the clinical value of risk factor reduction for neurodegenerative diseases will be reviewed.

The evidence for persistent neurodegeneration in HAART-treated patients

There are data from several investigators that have pointed to the existence of persistent neurodegeneration in the context of successful viral suppression in HAART-treated patients though there has not been a study specifically designed to address the issue. Cysique et al. (2006a) prospectively assessed 101 clinically stable subjects who had been on HAART for at least 5 years and who had had an AIDS defining illness in the past. All subjects were then followed every 12 months for the next 27 months. Changes to HAART were made by their HIV physician independent of the assessments. Patients who were impaired neuropsychologically were evaluated medically to exclude treatable causes. Between 8% and 34% (depending on the time point of the assessment) showed significant cognitive decline over the study period despite an undetectable plasma viral load. Increased age (mean 48 years) was not associated with impairment, but this was thought to reflect regression towards the mean. The nadir CD4 cell count (mean 73 cells/μl), a surrogate measure for disease duration, was significantly associated with cognitive decline. Similar results were recently published by Robertson et al. (2007) from the ALLRT study, a prospective observational cohort consisting of 1,160 subjects participating in ACTG clinical trials of HAART. The median age was 41 years. At baseline, 39% had mild cognitive impairment while 26% had moderate impairment. This was sustained in 22% and a further 21% developed impairment while on study independent of viral load suppression. Age was associated with impairment but duration of HIV infection was not assessed except for a relationship with the nadir CD4 cell count. Another study by Sevigny et al. (2004) reported on 203 non-demented subjects with CD4 lymphocyte counts less than 200/μl, or less than 300/μl but with cognitive impairment who were followed for a median time of 20.7 months. Seventy-four (36%) subjects developed dementia during the study period despite an undetectable plasma viral load in 21% and an undetectable CSF viral load in 43%. The incidence of dementia increased over time: 20% at 1 year and 33% at 2 years but was not related to the age of the patients or the duration of HIV disease. This may have been a consequence of the patients being younger (mean age 41 years) and the duration of HIV infection being shorter (mean 7 years approximately) than in other studies. Valcour et al. (2004), however, did observe the effect of age on cognitive impairment. In a prospective study of two cohorts one aged over 50 years and the other aged between 20 and 39 years, there was a significantly higher prevalence of dementia in the older group (25% vs 13%). Impairment was not related to plasma viral load as approximately half had undetectable levels but the exact number with cognitive impairment with a concomitant undetectable plasma viral load is not clear from the published data. Bhaskaran et al. (2008) in the largest cohort thus far published (15,380 patients) noted 222 that had developed HAD. This was an observational cohort across a large number of countries. Older age at seroconversion and the duration of infection, both significantly increased the risk of HAD. While HAD was noted to be associated with a detectable plasma viral load, no data were presented on the occurrence of HAD in patients with an undetectable viral load.

Thus, there is a consistent theme that cognitive impairment in HIV-infected individuals can occur in the context of maximal viral suppression with just over half the studies showing a relationship to increased age. The lack of a consistent relationship to age and duration of HIV disease across studies may relate to issues specific to the study populations but there is also the possibility that a more general issue is at play. The effects of age and disease duration on cognitive impairment are probably interlinked: the risk of cognitive impairment in a 40 year old with 20 years of HIV infection is likely to be different to that of a 60 year old with 20 years of HIV infection. Future studies should perhaps examine this effect more thoroughly, an effect that we have tentatively termed “the age-duration effect”. It may be more accurate to add the two together to arrive at a single score, “the age-duration index”.

The evidence for facilitated expression of neurodegenerative diseases

Introduction

Before reviewing this evidence, it is important to briefly revise the markers that are used in the identification of such diseases. In CSF, Alzheimer disease (AD) is characterized by the finding of low concentrations of amyloid beta (AB) 1-42 and elevated total tau (t-tau) as well as phosphorylated tau (p-tau). In brain tissue, AD is notable for the presence of amyloid plaques (containing amyloid fragments) and neurofibrillary tangles (containing hyperphosphorylated tau). Amyloid plaques are often categorized as either diffuse or neuritic, the latter being directly associated with abnormal neuronal and glial processes. Parkinson’s disease is associated with the presence of Lewy bodies (containing alpha synuclein, ubiquitin, lipids, proteasomal subunits, parkin, and synphilin-1) and tau deposition, while fronto-temporal dementia has neurofibrillary tangles, ubiquitin deposits, and TAR DNA binding protein-43; progressive supranuclear palsy is associated with tau deposition, and multisystem atrophy with alpha synuclein inclusions and tau deposits. There is evidence for the increased expression in HIV-infected individuals (presumably facilitated by HIV) of each of the latter diseases with the exception of fronto-temporal dementia, progressive supranuclear palsy, and multisystem atrophy. However, some of the data that have been published showing abnormal expression of the aforementioned markers may have relevance to these diseases.

CSF studies

In the CSF, Brew et al. (2005) found markedly low concentrations of amyloid beta 1-42 and raised t-tau as well as p-tau in patients with HAD. The levels were comparable to those of the group of AD patients. These data have been replicated in a larger data set with the exception that the p-tau values were normal (Brew et al. 2008). Clifford et al. (2008) have also noted the same findings including the normal p-tau. The unreplicated finding of elevated p-tau concentrations in the earlier study is unexplained. It is not likely related to sample size but it maybe an infrequent finding in a subgroup of patients who are in the process of developing an AD-like illness. Raised p-tau levels thus far seem to be specific for AD (Andreasen et al. 2003).

Neuropathological studies

Neuropathologically, there have been several publications establishing a link between HIV infection and AD. Esiri et al. (1998) were the first to observe significant amyloid deposition in the brains of HIV-infected patients, while Green et al. (2005) had the largest number of patients. Several other groups have made similar observations (see Table 1 for full description of the studies). There is usually a consistent relationship with increased age as best detailed by Esiri et al.: a prevalence of 18% in the fourth decade rising to 50% in the seventh decade in AIDS cases. In controls, the equivalent figures were none in the fourth decade and 36% in the seventh decade. The differences between AIDS and controls in the fourth decade and in the series as a whole were significant (p 0.014 and 0.004, respectively). Rempel and Pulliam (2005) on the other hand found a correlation with years of infection rather than age. This may reflect the smaller number of subjects studied or the interaction between age and years of infection—the age-duration effect as previously mentioned. Not all studies have rigorously examined all parts of the brain but there does seem to be a preponderance of deposition in the hippocampus and frontal lobe, the latter being unusual for AD. Another consistent theme is the lack of a clear relationship to the presence of any other pathology most especially HIV encephalitis. The latter finding is curious but it may reflect the small numbers of patients examined who had HIV encephalitis. Most studies found diffuse plaques, only occasionally were there “neuritic” plaques which are directly associated with AD. These observations do not mitigate the significance of diffuse plaques. They are consistently seen in patients with Down’s syndrome who invariably develop AD if they live long enough and are the only type of plaque seen in particular areas of AD brains. Finally, most investigators consider the diffuse plaque to be the forerunner of the neuritic plaque. Not all studies have found amyloid deposition, however. Giometto et al. (1997) did not find any evidence of amyloid plaques but the ages of the patients are not stated, the number of patients was relatively small, and the sections examined were not optimal. Gelman and Schuenke (2004) were unable to find any significant increase in amyloid plaques in HIV-infected patients when compared to an age-matched control population. There may be three explanations: the sample size is smaller than other studies, the patients may have had a shorter duration of HIV disease, and the whole brain was not assessed—only the hippocampus, entorhinal cortex, and parahippocampal gyrus.
Table 1

Summary of neuropathological studies of amyloid deposition in HIV disease

Study

Number of patients

Age

HIV stage

Number of patients with plaques

Distribution of amyloid deposits

Diffuse or neuritic plaques

Esiri et al. (1998)

97

47 ± 10.2

87 AIDS 10 pre-AIDS

28 (significantly greater than controls)

Temporal > frontal

Both (only 6 had neuritic)

Izycka-Swieszewska et al. (2000)

15

34 (24–48)

AIDS

3

Neocortex more than hippocampus

Diffuse

Green et al. (2005)

162

44 (24–75)

103 had AIDS

50% of AIDS (no controls)

Frontal especially (from frontal cortex, hippocampus, caudate, putamen, and globus pallidus)

Diffuse

Rempel and Pulliam (2005)

14

44 (31–58)

HAD in 6

14

Frontal examined only

Diffuse

Khanlou et al. (2008)

36 (frontal and temporal)

55(50–76)

HAD in 11, 38 of 49: CD4<200

35

Frontal and temporal

Neither: intraneuronal or within vessel walls

Anthony et al. (2006)

29

40 (33–46)

9 presymptomatic, 11 AIDS, 9 HAART

13 (of borderline significance)

Medial temporal lobe (from hippocampus and pons)

Diffuse

Giometto et al. (1997)

27

Not stated

AIDS

0

Anterior frontal and parietal lobes

 

Gelman and Schuenke (2004)

25

53 (22–75)

AIDS

7 (not different from controls)

Medial temporal lobe (from hippocampus, entorhinal cortex and parahippocampal gyrus)

 

There are emerging studies of other neurodegenerative disorders in the setting of HIV infection. Gelman and Schuenke (2004) noted the significantly greater presence (in 48% of AIDS patients with 100% in those aged between 62 and 75 years) of ubiquitinylated deposits in all age groups predominantly in the temporal lobe white matter compared to controls. The nature of the deposits was unable to be determined precisely but thought to be related to synaptic components. Similar ubiquitinylated deposits have been noted by others in HIV-infected patients (An et al. 1997; Adle-Biassette et al. 1999; Izycka-Swieszewska et al. 2000). Khanlou et al. (2008) have observed increased α-synuclein expression in the substantia nigra in 16% of HIV-infected patients aged between 50 and 76 years while there was no α-synuclein expression in the controls.

Thus, the evidence is compelling for the existence of persistent and evolving neurodegeneration even in the presence of well-controlled HIV disease at least systemically. Furthermore, the neurodegeneration does not appear to be closely linked to HAD. While there is the possibility that the neurodegeneration could be related to antiretroviral drug toxicity, this seems unlikely given the nature of the neuropathological changes and the fact that these changes were seen even before the introduction of HAART. The fact that they are now more common in HAART-treated patients more likely reflects the longer life span of such patients thereby providing the setting in which neurodegeneration can occur.

Potential mechanisms

To understand how neurodegeneration may be occurring despite maximal HIV suppression, one first has to review the most generally accepted framework for the pathogenesis of neurodegenerative diseases. With this background, how the effects of normal ageing overlap with the effects of HIV will be discussed. This will be followed by a review of how in general these neurodegenerative diseases intersect with HIV, and a discussion related to specific neurodegenerative diseases. The last section will integrate the intersection of ageing, neurodegenerative diseases, and HIV.

General pathogenetic framework for neurodegenerative diseases

While there are many aspects of neurodegenerative diseases that are specific to the disease in question, there are mechanisms that are common to most if not all of the neurodegenerative diseases. A frequently articulated model is that there is a breakdown of cellular defense mechanisms which then leads to a cascade of damage. From the available literature, a model of the pathogenesis of neurodegenerative diseases can be advanced, as detailed in Fig. 1. In broad terms, a pathogenic insult, in the case of most neurodegenerative diseases, seems to be a misfolded protein that leads to activation of cellular defense pathways. These include heat shock proteins, endoplasmic reticulum chaperones, the ubiquitin–proteasome complex, autophagy, the kynurenine pathway through production of picolinic acid, and the P-glycoprotein system. Most of these defenses are well known and documented but the importance of picolinic acid is only emerging. It is one of the near-final products of the kynurenine pathway that is upregulated in a variety of disease states (Guillemin et al. 2007). Picolinic acid itself is the most potent endogenous metal chelator and therefore may be important in cellular defense against the effects of protein misfolding (Cherny et al. 1999). The pathogenic insult and the defense mechanisms are in a dynamic equilibrium until the burden of the insult exceeds the defense capacity or the defense pathways become exhausted. The consequences then are the activation of further inflammation, excitotoxicity, oxidative and nitrosative stress, mitochondrial dysfunction, and transcription dysregulation. The inter-relationships among these are complex and often bi-directional. Nonetheless, the end result is cell dysfunction and death.
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Fig. 1

Hypothetical model of the general aspects of the pathogenesis of neurodegenerative diseases. Hsps hear shock proteins, ER endoplasmic reticulum, Pic picolinic acid, PgP P-glycoprotein system

Normal ageing and HIV

Neuropsychology

There is now converging evidence that with normal ageing, particular cognitive abilities are affected. Interestingly, this neuropsychological pattern of impairment shares many similarities with HAND. This was empirically demonstrated in a study comparing young adults with HAND and older healthy individuals (Hinkin et al. 1990).

Specifically, attentional processes inclusive of complex attention, speed of information processing, and working memory are primarily affected by ageing (Glisky 2007; Kramer and Madden 2008) as well as HAND (Cysique et al. 2006b; Reger et al. 2002; Woods et al. 2008b). Neuropsychological findings for attentional deficits in ageing show a decreased capacity for dividing and switching between tasks. These difficulties have also been interpreted as being related to working memory impairment, in the sense that working memory involves the ability to manipulate information on which attentional resources are currently focused. Several mechanisms have been implicated but the most likely is that older persons are slower to process information (Salthouse 1996). Indeed, a large part of the variance in working memory is due to a general slowing of information processing. A non-exclusive alternative explanation is a failure to inhibit irrelevant information (Harsher et al. 1999). Interestingly, the same interpretative framework has been proposed in HAND (Hardy and Hinkin 2002). In addition, psychomotor slowing has been shown to be predictive of further deterioration (Sacktor et al. 1996).

Memory function is also commonly affected by ageing, particularly episodic memory—the memory for particular events at a specific time and place. While encoding and storage capacities may be affected, it is mostly effortful retrieval that is primarily impaired in normal ageing. Interestingly, this pattern of impaired retrieval and preserved long-term storage (when aided with cues) is also predominant in HAND in addition to learning deficits. In both conditions, the pattern of effortful learning/recall disturbances has been interpreted as being partially dependent on working memory deficits and slowing of cognitive processes (Peavy et al. 1994; Hartley 2006). Another interpretative framework that has been proposed in ageing research is that of a deficiency of executive control (West 1996). This involves a range of processes such as planning, organizing, coordinating, implementing, and evaluating mental activities and actions. In HAND, executive dysfunctions in the form of alteration of abstract reasoning and problem solving are also common findings especially in the moderate and more advanced stages of the disease (Cysique et al. 2006b). Lastly, there is accumulating evidence for prospective memory alteration in both HAND (Woods et al. 2008a) and normal ageing (Henry et al. 2004). Prospective memory represents the ability to remember things that are to happen in the future. In both ageing and HAND, prospective memory deficits are more obvious in tasks with high strategic load. These difficulties have also been interpreted as partially dependent on working memory abilities.

Finally, as in ageing, the milder stages of HAND are characterized by a relative preservation of language abilities (when no speed-based test is involved), semantic knowledge, and visuo-spatial abilities (Cysique et al. 2006b; Glisky 2007).

Putative brain macro-structural changes associated with the neuropsychological pattern detailed above also share similarities with normal ageing (Raz and Rodrigue 2006) and HAND (Tucker et al. 2004). Macrostructural changes mainly in the form of atrophy and white matter lesions have been shown to preferentially involve striato-frontal networks. From this brief review, it is plausible that ageing and HAND may act in concert to increase the cognitive difficulties that are common to both (processing speed, working memory, and effortful learning/retrieval), thus favoring an earlier onset of this type of difficulties. Further, there maybe acceleration of cognitive decline potentially leading to severe cognitive deficits in these same cognitive domains. Lastly, the overlap between the two may lead to an altered neuropsychological profile reflecting the partly hybrid nature of the interaction.

Neuropathology

There is intersection between ageing and HIV particularly in relation to the frontal lobe and hippocampus. Increasing age eventually leads to approximately a 50% neuronal loss in the basal forebrain and locus coeruleus (Rosene 1993; Kemper 1993). With age, there is less efficient myelination by oligodendrocytes—especially in the frontal lobes (Nielsen and Peters 2000). Microscopically, there is loss of synaptic integrity especially in the CA3 region of hippocampus (Rosenzweig and Barnes 2003), an area also affected by HIV (Torres-Munoz et al. 2001). Both are also characterized by dopamine deficiency (Berger et al. 1994; Arnsten et al. 1995; Berger and Arendt 2000). Lastly, impairment of the blood–brain barrier (Buckner et al. 2006; Young et al. 2008) is common to both.

Physiology

Ageing is notable for disturbances in the cellular disposal of toxins. An abnormal form of ubiquitin, UBB+, is increased intracellularly leading to inhibition of protein degradation (van Leeuwen et al. 1998, 2002). Additionally, heat shock proteins (Hsps) are decreased intracellularly due to defective activation of transcription factor HSF1 (Heydari et al. 1994, 2000) and the lysosomal pathway is impaired (Cuervo and Dice 1998). HIV, particularly tat, and some of the protease inhibitors used to treat HIV disease also disturb the ubiquitin–proteasome complex as well as autophagy, thereby impairing the cellular disposal of toxins (Apcher et al. 2003; Gelman and Schuenke 2004; Haorah et al. 2004; Piccinini et al. 2005; Goila-Gaur and Strebel 2008; Alirezaei et al. 2008a, b). Similarly, ageing is characterized by impaired autophagy (Rajawat and Bossis 2008).

Immunology

Inflammation-associated genes are increased with ageing (Blalock et al. 2005) and perhaps more importantly there is evidence, albeit preliminary, of raised serum levels of lipopolysaccharide (Landay, personal communication) which is pro-inflammatory. HAND is also associated with inflammation as well as elevated lipopolysaccharide concentrations (Ancuta et al. 2008).

HIV and neurodegenerative diseases

There are several areas of commonality in the pathogenesis of HAND and neurodegenerative diseases in general as well as in specific diseases which will be discussed later.

Common general mechanisms

Inflammation

Intersecting pathogenesis pathways relate to both particular cells and their products. Activated microglia and astrocytes are important and common to both HIV and neurodegenerative diseases (Minagar et al. 2002; Kadiu et al. 2005; Ting et al. 2007). TNFa, IL6, MCP-1, and quinolinic acid and other kynurenine pathway products are elevated in HAND both in the serum and CSF and many neurodegenerative diseases (Stone 2001; Guillemin et al. 2005; Town et al. 2008; Björkqvist et al. 2008; Sokolova et al. 2008). In the context of immune activation, it is always a concern as to whether the inflammation is “beneficial” or truly detrimental. However, as pointed out by Wyss-Coray (2006) chronic exposure of microglia to MCP-1, and lipopolysaccharide for that matter, is associated with a more neurotoxic microglial phenotype while acute exposure is linked to a more phagocytic phenotype. The increase in such immune activation products especially MCP-1 is therefore likely to render a more neurotoxic microglial environment. Toll-like receptor-4 (Walter et al. 2007) and decreased immune surveillance are common themes in HAND and neurodegenerative diseases (Richartz-Salzburger et al. 2007; Salaria et al. 2007; Tahara et al. 2006). Lastly, the blood–brain barrier is frequently impaired in both HAND and neurodegenerative diseases (Banks 1999; Bowman et al. 2007).

Degradation pathways

Perhaps of most significance is the intersection of cellular degradation pathways in HAND and neurodegenerative diseases. Evidence from several investigators points to HIV inhibiting the ubiquitin–proteasome complex as previously mentioned (Gelman and Schuenke 2004; Haorah et al. 2004; Goila-Gaur and Strebel 2008). In AD, Parkinson’s, and motor neuron disease similar inhibition occurs (Chung et al. 2001; McNaught et al. 2001). Moreover, autophagy is inhibited by HIV (Alirezaei et al. 2008a, b) and in neurodegenerative diseases (Zatloukal et al. 2002; Nagaoka et al. 2004). Lastly, P-glycoprotein expression is deliberately inhibited in HIV therapy to enhance the efficacy of particular antiretroviral agents, the protease inhibitors. Other antiretroviral drugs such as efavirenz may also inhibit its expression. However, there is some evidence that the P-glycoprotein system is important in the normal clearance of amyloid from the brain (Lam et al. 2001). If the clearance is impeded by P-glycoprotein inhibition, then, it is likely that there will be accumulation of amyloid in the brain with consequent tissue damage. The P-glycoprotein system is thought to have a role in the pathogenesis of some neurodegenerative diseases, most particularly Parkinson’s disease and in the removal of potential toxins (Christensen et al. 1998; Lee and Bendayan 2004).

Oxidative and nitrosative stress

Oxidative stress is increasingly thought to be a final common pathway for HAND (Nath et al. 2008) as well as some neurodegenerative diseases such as Alzheimer’s disease (Lovell et al. 2007). Furthermore, nitrosative stress with peroxynitrite formation leading to modification of tyrosines in proteins is considered to enhance the aggregation of α-synuclein which in turn is pathogenetically significant in Parkinson’s, Lewy body dementia, progressive supranuclear palsy, multisystem atrophy, as well as HAND (Haughey et al. 2008; Li et al. 2008).

Mechanisms common to specific diseases

Specific characteristics of several neurodegenerative diseases intersect with HIV in unique ways. Each of these will now be discussed in detail.

Parkinson’s disease

Both Parkinson’s disease and HIV have a common anatomical substrate namely the substantia nigra (Brew et al. 1995) and a common neurochemical disturbance namely dopamine deficiency (Berger and Arendt 2000). Furthermore, both diseases are associated with testosterone deficiency (Okun et al. 2004).

Alzheimer’s disease

AD and HIV also share a common anatomical substrate namely the hippocampus (Torres-Muñoz et al. 2001). Furthermore, there are risk factors for AD that are common in HAART-treated patients, including insulin resistance, raised cholesterol especially in mid-life, and testosterone deficiency, which occurs in approximately 30% of patients with advanced HIV disease (Brew 2004; Mylonakis et al. 2001; Okun et al. 2004). Additionally, apoE4 is a risk factor for HAND in some studies especially those who are older (Pemberton et al. 2008; Valcour et al. 2008). There is also commonality in the cytokines that are elevated: S100b, TNFa, IL1b, and IL6 (Pemberton et al. 2001; Brew 2001). Furthermore, elevations in lipopolysaccharide concentrations in the blood are associated with HAND (Ancuta et al. 2008) and with AD (Kitazawa et al. 2005; Herber et al. 2006; Landay, personal communication). The significance of raised lipopolysaccharide concentrations in AD is still open: acute elevation may be beneficial while chronic elevation may be detrimental (Wyss-Coray 2006). It remains to be determined whether AD patients have chronically elevated concentrations although the preliminary data from Landay et al. (personal communication) are suggestive. CD69+ monocytes in blood are also increased in both (Kusdra et al. 2000) as are elevated concentrations of QUIN (Guillemin and Brew 2007). Furthermore, AB1-42, the neurotoxic fragment of amyloid beta, can lead to QUIN production by macrophages and microglia (Guillemin et al. 2003). Lastly, Tat, the regulatory protein of HIV, inhibits neprilysin the chief amyloid β degrading enzyme (Rempel and Pulliam 2005).

Integration of the effects of ageing, HIV, and neurodegenerative diseases

As can be seen from the discussion detailed above, there are many areas where all three effects, ageing, HIV, and neurodegenerative diseases, intersect. As hypothetically conceptualized in Fig. 2, the risk of developing a neurodegenerative disease is progressively increased according to host susceptibility factors, age, HIV infection, and certain medications, particularly ritonavir and probably other protease inhibitor drugs. This proposed model can be tested for validity and for definition as to the nature of the incremental risk when there is more than one factor.
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Fig. 2

Diagrammatic representation of the interplay of the key factors in the expression of neurodegenerative diseases in the context of HIV disease

At the subcellular level, from the data discussed previously, there appear to be more specific intersections in the pathophysiology of HAND, ageing, and neurodegenerative diseases. This is diagrammatically represented in Fig. 3 and affords a testable model.
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Fig. 3

Intersection between HIV, ageing, and neurodegenerative diseases at the subcellular level

If these models are correct then HAND, especially in HAART treated patients, can be seen as a form of premature ageing sometimes facilitating the expression of the diseases of ageing, namely the neurodegenerative diseases.

Potential therapeutic interventions

The validation of the latter hypothetical models will clearly take several years. What can be done now to minimize the risk of persistent neurodegeneration and the facilitation of neurodegenerative diseases? There are two broad approaches: optimization of HAART to enhance central nervous system (CNS) penetration and risk factor reduction.

Optimization of HAART

The use of antiretroviral drugs in a regimen to specifically enhance CNS penetration is still controversial. There is a body of clinicians and researchers who consider that antiretroviral drugs do not need to penetrate the CNS to have CNS efficacy. This view until recently has been given credence by past studies that have tried to examine the issue and found no benefit. However, mainly, these studies had significant methodological flaws. Some were predicated on all HIV patients developing HAND, which is now known not to be the case. Some only studied the effect of adding one or two CNS penetrant drugs to a background regimen. As it is known that the brain and systemic compartments can behave quite independently especially in HAND patients, it seems illogical to treat with so few drugs. Systemic disease is by and large not treated with one or two drugs so why should it be different for the brain? The next common methodological flaw is to not assess the blood–brain barrier. It is known that some HAND patients have an impaired blood–brain barrier. If these patients are included in a study to assess the benefit of CNS penetrating drugs vs non-penetrating drugs then the study will be uninterpretable. Fourthly, some studies may not have included patients with active HAND—some may have had an inactive or at least indolent form of the disorder where the study time period may have been too short.

Recently though, there has been an increasing number of studies showing the benefit of a CNS penetrating regimen (Cysique et al. 2004b; Letendre et al. 2004) in achieving a more favorable clinical outcome. The nature of a CNS penetrant regimen is the subject of ongoing studies but according to one group a central nervous system penetration effectiveness score of 3 or more is associated with a better outcome (Letendre et al. 2008). While it seems likely that the adoption of such a regimen will be beneficial, there is the possibility that it will not be as effective as hoped, chiefly because drugs do vary in the ability to suppress chronic infection. Furthermore, there is increasing evidence of the importance of astrocytic infection in HAD (Clarke et al. 2006; Churchill et al., personal communication). The efficacy of antiretroviral drugs in astrocytes remains largely unexplored, but as it is not a productive infection, it is unlikely that antiretroviral drugs would have much benefit.

Risk factor reduction

At present, there are no rigorously proven measures that can reduce the risk of developing neurodegenerative diseases in general. Nonetheless, regular exercise both physical and mental appears to be helpful in minimizing the effects of ageing as well as perhaps delaying the onset of AD (Lautenschlager et al. 2008). Secondly, improvement in glucose control seems to be beneficial (Stranahan et al. 2008; van Harten et al. 2007; Whitmer 2007). Thirdly, better control of hypertension appears to be helpful although the recent HYVET trial did not show a benefit (Peters et al. 2007). The explanation is purely speculative but the length of follow-up of the study participants may have been too short. Lastly, control of hypercholesterolemia is becoming accepted as important (Cramer et al. 2008). The more controversial issues, however, are whether statin therapy carries benefit independent of cholesterol reduction and whether a statin that has good brain penetration is superior or even necessary.

Conclusion

HAART has led to dramatic improvements in HIV patients but the neurological complications remain problematic in some. Moreover, there is increasing evidence that the expression and progression of neurodegenerative diseases may be facilitated by HIV. Future studies will need to address the mechanisms by which these occur to allow the development of effective therapies.

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© Springer Science+Business Media, LLC 2008