. CSF biomarkers of Alzheimer disease in HIV-associated neurologic disease. Neurology. 2009 Dec 8;73(23):1982-7. PubMed.


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  1. The recent article by Clifford et al. (1) highlights the potential overlap between Alzheimer disease (AD) and HIV-associated neurocognitive impairment (HAND). The data confirm findings from our earlier study (2), where CSF Aβ1-42 levels were low in HAND patients just as they are in AD. Clifford et al. did not, however, confirm that CSF total tau levels were abnormal in HAND, unlike the earlier study. This is possibly the consequence of the antiretroviral therapy in the study population described by Clifford et al. The lack of verification of CSF p-tau elevation is harder to explain: it may be related to the different study populations used or to smaller numbers with more severe HAND in the Clifford et al. manuscript.

    Nonetheless, the findings highlight an important issue, namely the distinct possibility of convergent pathogenic processes in AD and HAND, and possibly the accelerated expression of AD, or an AD-like illness, in HAND. There are data from other sources, in particular, neuropathology and basic science, that have largely but not conclusively confirmed the overlap between AD and HAND. At present this has not translated into a clinically significant overlap, except for one report of an HIV patient with AD, which may have only been coincidental (3). It could be predicted that as HIV patients live longer, they may be more likely to develop AD, which in some cases may be a “hybrid” of AD deficits and HAND. There are numerous potential mechanisms: markedly elevated mid-life lipids in HIV patients, inhibition of physiological amyloid clearance from the brain by certain HIV drugs such as ritonavir, and by the HIV protein tat disturbing the function of neprilysin, to name a few (see reference 4 for review).


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  2. The similarity, or otherwise, of HIV-associated neurologic disease to dementia of the Alzheimer’s type (DAT) seems as vexed a topic as that of an ApoE-ε4 association (or not) with HIV dementia or HIV encephalitis. In this paper, Clifford et al. (1), like several predecessors, describe levels of β amyloid and/or phosphorylated tau (p-tau) in the CSF of HIV subjects with or without normal cognition, subjects with mild DAT, and subjects from the general population with normal cognition. The authors found that CSF Aβ42 levels in cognitively impaired HIV patients were similar to those of patients with mild DAT, both being lower than in unaffected normal subjects, but tau and p-tau levels were similar to those of the controls, in contrast to the data of Brew et al. (2) but consistent with certain other studies. They suggest that the discrepancy might be because most of their subjects were taking antiretroviral therapy, whereas those of Brew et al. (2) were untreated. Age differences between HIV patients and those with DAT were dealt with by including age as a covariate, but they stress the need to examine CSF tau values of HIV patients on reaching older age, and the need to elucidate changes in amyloid metabolism in cognitively impaired HIV patients, especially as CSF HIV viral load and CD4 counts do not correlate with the development of neurocognitive disorder.

    Each set of data for each of the groups showed a wide scatter—not surprisingly (although the mean differences were statistically significant)—so it would be interesting to know if there is any correlation with ApoE genotype—if, say, the average CSF Aβ42 level is lower in those carrying an ApoE-ε4 allele, or if there is any correlation with duration of infection or of treatment.

    HIV subjects with neurological disease are an example of a microbial cause of a chronic CNS disease. Another example is H5N1 influenza virus infection which, in mice, causes long-term consequences after virus entry into the CNS (from the PNS), including neuroinflammation and neurodegeneration, α-synuclein phosphorylation and aggregation (3). These phenomena, like the HIV-induced production of Aβ in the brain, resemble in several ways the events that we suggest occur (particularly severely in ApoE-ε4 carriers) in elderly brains that harbor HSV1 (4), and recur on reactivation due to immunosuppression, stress, or peripheral infection, leading eventually to DAT: HSV1-induced Aβ accumulation (5,6) and formation of plaques (as revealed in DAT brains by the presence within plaques of much of the HSV1 DNA (7), perhaps entombed by the amyloid). These concepts are consistent with the idea that in HIV subjects, at least part of the CNS damage might be due to HSV1 which, because of the subjects’ state of immunosuppression, has reached the brain prematurely, and reactivates often.


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  3. Cerebral β Amyloid Deposition and HIV-associated Neurocognitive Impairment
    HIV-1 infected (HIV+) patients who benefit from highly active antiretroviral therapy (HAART) have plasma viral loads below detectable levels, maintain good immune function without serious opportunistic diseases, and potentially live to old age. Nonetheless, HIV-associated neurocognitive disorders (HAND) continue to impact the clinical outcome of HIV infection in the HAART era, even in the context of systemic viral suppression (1). Also, the use of antiretroviral drug regimens with effective CNS penetration may be important in achieving viral suppression in the cerebrospinal fluid (CSF) (2). Reports on the effects of aging and HIV disease duration on the development of HAND remain inconsistent across different cohorts (1,3). When HIV+ patients develop neurocognitive decline in their old age, it is important to distinguish between HAND (potentially with a brain aging component) and neurodegenerative diseases, such as dementia of the Alzheimer type (DAT), vascular dementia, and diffuse Lewy body disease.

    In a recent article by Clifford et al. (4), in agreement with an earlier report by Brew et al. (5), β amyloid (Aβ) 42 levels in CSF were decreased in patients with HAND, similar to those in patients with mild DAT (Clinical Dementia Rating of 0.5), when compared to the levels in subjects with normal cognition. In contrast, tau and p-tau181 levels in CSF were increased only in the mild DAT group. These findings suggest that CSF tau and p-tau181 measurements may be useful in distinguishing between HAND and DAT in HIV+ patients who develop cognitive decline in old age. Reductions in CSF Aβ42 levels were shown earlier to correlate with cerebral Aβ deposition measured by Pittsburgh Compound B (PIB) PET in DAT patients, as well as elderly individuals with normal cognition (6). Accordingly, the findings in the study by Clifford et al. suggest the presence of cerebral Aβ accumulation in patients affected by HAND. However, in a recent report by Gisslen et al. (7), Aβ42 levels in CSF were decreased in HIV+ patients with opportunistic CNS infections, but not in those affected by HIV-1-associated dementia (HAD), as compared to the levels in those without neurological symptoms and signs. The mean age in the HAND group in the study by Clifford et al. (48 years) was much higher than that in the HAD or opportunistic-infection group in the study by Gisslen et al. (38 years). Moreover, most HIV+ patients in the former study were receiving antiretroviral therapy, while those in the latter study were untreated. Both brain aging and selected antiretroviral agents may play a role in cerebral Aβ accumulation (discussed below). Also, the difference in assay methods used may partly explain the result discrepancies.

    Previous autopsy studies showed “early” signs of cerebral Aβ deposition (8,9) and tau pathology (10) in the setting of HIV infection compared to the age-matched non-HIV controls, although the former was not confirmed in other studies (10,11). Both cerebral Aβ deposition (12) and tau pathology (10) seemed to be more prevalent in HAART-treated patients. Still, most of these studies lacked in-depth analyses exploring potential associations between the histological findings and markers that could readily be assessed during life, such as neurocognitive performances, PET imaging findings, and CSF levels of Aβ and tau proteins. Apolipoprotein E (ApoE) genotypes, which are important in cerebral Aβ metabolism, have not been assessed in these studies.

    The ApoE ε4 allele was shown to correlate in elderly subjects with cerebral neocortical Aβ burden measured by PIB-PET (13) and in Alzheimer disease (AD) brains with Aβ40 accumulation in senile plaques (14,15) and vessel walls (16) previously seeded with Aβ42. Whether the ApoE ε4 allele predicts the presence and degree of cerebral Aβ deposition in HIV+ patients is currently unknown. The relationship between the ApoE genotypes and HAD remains controversial (17-19).

    Brains of HIV+ patients exhibiting cerebral Aβ deposits contain Aβ plaques mostly of the diffuse type (and rarely of neuritic type) (8,9,20), similar to those seen in non-HIV elderly individuals with normal cognition (21). These findings suggest that the overall Aβ plaque burden is unlikely to predict neurocognitive impairment. In AD, where neuritic Aβ plaques and tau pathology are the histological hallmarks, an increase in soluble Aβ40 in brain tissue was shown to correlate with cognitive decline (22). Recent studies implicated soluble Aβ oligomers in amyloid neurotoxicity in AD (23,24). In this context it would be of interest to assess tissue levels of different soluble Aβ isoforms, including intraneuronal Aβ42 oligomers (25), in brains of HIV+ patients in relation to other histological parameters and premortem data.

    It has been postulated that in HIV+ subjects there are factors (e.g., antiretroviral agents, viral proteins, neuroinflammation) that alter the metabolism of Aβ and tau proteins in the brain, leading to Aβ accumulation and tau hyperphosphorylation earlier than expected by age. These factors may prematurely trigger or promote a cascade of metabolic disturbances that would otherwise only occur in the aging brain. In HIV autopsy studies, the prevalence of cerebral Aβ plaques was clearly shown to increase with age (8). Also, the severity of tau pathology displayed a tendency to increase with age (10). The HIV-1 protease inhibitor Nelfinavir was shown in vitro to inhibit insulin-degrading enzyme, an Aβ degrading enzyme in the CNS (26). In an autopsy study, cerebral Aβ deposition appeared to be more prevalent in HAART-treated patients (12). In vitro studies showed that HIV-1 Tat peptides inhibited neprilysin activity, another Aβ degrading enzyme (9,27). HIV-1 Tat was also shown to inhibit microglial phagocytosis of Aβ42 in cell cultures, and this inhibition was enhanced by γ-interferon (28). Neuronal uptake of HIV-1 Tat through binding to the heparan sulfate proteoglycan and via low-density lipoprotein receptor-related protein (LRP)-mediated endocytosis inhibited neuronal clearance of physiological ligands for LRP, including ApoE4, amyloid precursor protein, and Aβ (29). Even in the absence of productive HIV infection in the brain, HIV-1 tat may be able to disturb cerebral Aβ metabolism as long as the virus is sequestered in perivascular microglia/macrophages (30). In agreement with this argument, Esiri et al. reported that the prevalence of Aβ plaques was not correlated with the presence of HIV encephalitis or CNS opportunistic diseases in the pre-HAART era (8). Green et al. found no clear association between cerebral Aβ accumulation and HIV-related neuropathology (12). With regard to tau pathology, no association of the degree of tau pathology with the presence of HIV encephalitis or history of cognitive impairment was observed (10).

    In summary, how and to what extent the cerebral Aβ accumulation contributes to neurocognitive impairment in the setting of HIV infection remain to be determined in large prospective cohort studies that allow systematic analysis of potential associations between the histological findings and premortem parameters. A paramount goal is to identify accurate and practical biomarkers for detecting HIV-associated neural injury at stages earlier than the onset of clinical manifestation or abnormal neuropsychological testing, in order to allow disease-modifying therapeutic interventions, as well as evaluation of response to treatment.

    Proteins measurable in CSF may be good biomarker candidates. In the non-HIV setting, high CSF tau/Aβ42 ratios have predicted cognitive decline in non-demented older individuals (31,32), progression to DAT in patients with mild cognitive impairment (33), and more rapid progression of cognitive decline in mild DAT patients (34). On the other hand, PIB-PET might not be sensitive enough to detect the non-fibrillar form of Aβ (35), which comprises the vast majority of Aβ plaques in early stages of cerebral Aβ deposition. Nonetheless, a multimodal approach, rather than a single test, may be needed for screening and confirming the early development of HIV-associated neural injury, as it has been attempted in DAT (36).


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