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Neurodegeneration and Ageing in the HAART Era.......
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"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.......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"
J Neuroimmune Pharmacol (2009)
Bruce J. Brew & S. M. Crowe & A. Landay &
Lucette A. Cysique & Gilles Guillemin
(1) 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.
(2) 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. 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.
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.
(3) "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
(4) 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."
(5) 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".
From this brief review, it is plausible that aging 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.
(6) 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
(7) 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).
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).
(8) Potential therapeutic interventions
.....two broad approaches: optimization of HAART to enhance central nervous system (CNS) penetration and risk factor reduction......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.
.......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.
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Neurodegeneration and Ageing in the HAART Era
J Neuroimmune Pharmacol (2009)
Bruce J. Brew & S. M. Crowe & A. Landay &
Lucette A. Cysique & Gilles Guillemin
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.
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, Ithere 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.I 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.
EXCERPTS
In CSF, IAlzheimer disease (AD)I 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 frontotemporal 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 frontotemporal 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.
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.
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
Normal ageing and HIV
Neuropsychology
There is now converging evidence that with normal aging, 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).
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.
From this brief review, it is plausible that aging 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.
IHIV 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.
IInflammation
Activated microglia and astrocytes are important and common to both HIV and neurodegenerative diseases
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 substantial 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).
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).
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. 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.
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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