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Alzheimer disease and HIV A tangled story - Editorial
 
 
  Published online before print June 9, 2010 NEUROLOGY 2010
 
Bruce J. Brew, MBBS, MD and Lucette A. Cysique, PhD
 
From the St. Vincent's Centre for Applied Medical Research (B.J.B., L.A.C.), Department of Neurology and HIV Medicine, St. Vincent's Hospital, Darlinghurst; and Brain Sciences (L.A.C.), University of New South Wales, Sydney, Australia.
 
Address correspondence and reprint requests to Professor B.J. Brew, Department of Neurology, St. Vincent's Hospital, Darlinghurst, NSW 2010, Australia B.Brew@UNSW.edu.au
 
HIV-associated neurocognitive disorders (HAND)1 remain common despite highly active antiretroviral therapy (HAART) that is effective both in the blood and the CSF.2,3 There are several potential reasons, each of which may be relevant in individual patients, but at present it is not clear what the dominant reason is at a population level. Moreover, we should recognize that what may be important in the next year or so may not be so in another 5 years as patients age and antiretroviral agents change. Additionally, some of the current study cohorts could be affected by a significant survivor bias, having remained alive despite suboptimal therapies in the past.
 
Some patients may have HAND as a consequence of an incomplete response to HAART, a so-called "legacy effect." However, the relatively frequent development of HAND on HAART argues against this as a major explanation (reviewed in reference 2). Some patients with subclinical HAND may develop impairment as a consequence of an immune restoration disorder (IRD). This is an intriguing condition in which antiretroviral-induced improvement in immune function leads to an exacerbation of disease that was previously minor or subclinical: HAART may paradoxically "convert" asymptomatic impairment to dementia through enhancement of immunopathology. However, in relation to HAND, further data are required. Nonetheless, at this stage it appears to be very uncommon, mild, and usually occurs shortly after HAART commencement. Another potential reason is that patients with mild HAND symptoms may delay seeking medical attention in the belief that the mild symptoms are not of any consequence. But by the time medical intervention occurs, there may already be a sizeable degree of accumulated fixed damage; this stands in contradistinction to more severe disease, where medical intervention occurs more acutely. We have termed this delay in seeking medical help "symptom minimization effect." Other patients may develop HAND as a result of inadequate brain levels of HAART,4 while some may develop impairment as a consequence of HAART CNS toxicity,5,6 though further data are needed.
 
Perhaps most interesting and important is the possibility that some patients develop HAND as a consequence of accelerated aging and accelerated expression of neurodegenerative diseases.2,7 Among these is the possibility of increased risk for Alzheimer disease (AD) or at least something akin to it. There are several lines of evidence, albeit controversial, in support of this possibility: common risk factors (insulin resistance, midlife raised lipids, lowered leptin levels, APOE4 status, elevated CD69+ monocytes), abnormal CSF levels of AD biomarkers in HIV, neuropathologic evidence of amyloid plaques as well as neurofibrillary tangles in some HIV brains, an overlapping anatomic substrate (the hippocampus), common pathogenetic pathways (inflammation, disturbed ubiquitin-proteosomal function, inhibition of autophagy), and in vitro mechanisms for HIV intersecting with AD (Tat, the regulatory protein of HIV, inhibits neprilysin, the chief amyloid-β degrading enzyme; ritonavir inhibits amyloid clearance from the brain).2,7-9
 
In this issue of Neurology, Ances et al.10 address the possibility of HIV-related AD from a different perspective by using in vivo amyloid imaging with 11C-PiB PET technology. Ances et al. found that patients with HIV did not have amyloid deposition. This is a useful contribution to the field and adds to understanding of the issue in the population studied. However, the results may not extend to other HIV patient groups. First, the duration of HIV disease is not clear, though some may have been infected for long periods given the low nadir CD4 cell count. Additionally, there is likely to be a complex interplay between duration of HIV disease and age given that chronic inflammation is considered by most to be important in AD pathogenesis: 20 years of HIV disease in a 40-year-old patient is likely to be quite different from that in a 60-year-old patient.2 Second, the sample size was small-an obstacle that will be an issue for many studies given the complexity and expense of 11C-PiB PET studies. Third, 11C-PiB PET only identifies extraneuronal amyloid and so may not be the most sensitive tool as most investigators consider intraneuronal amyloid the forerunner to extraneuronal deposition. Furthermore, as the authors point out, diffuse soluble amyloid is not detected by 11C-PiB PET, yet it is the soluble oligomeric complexes of amyloid that are now considered to be the chief drivers of neurotoxicity in AD. Finally, in AD it is not presently known whether CSF amyloid-β 1-42 reductions accompany, precede, or succeed 11C-PiB PET changes: the negative result in this study may be explained by the CSF changes antedating the PET abnormalities.
 
Further studies of amyloid metabolism and indeed accelerated aging as well as neurodegenerative diseases in HIV disease are clearly needed. Meanwhile, what is the clinician to do? In most cases, identification of the legacy effect should be possible by careful analysis of the history. In other less clear situations, consideration can be given to more intensive neurologically targeted antiretroviral and adjunctive therapies, though it must be understood that at present there is no supporting Class I evidence. Such decisions must be carefully made balancing potential benefit against toxicity-not just that related to the CNS but also the cardiovascular and cerebrovascular systems.
 
Hopefully, the future will provide tools by which the causes of HAND in the context of successful HAART can be identified. This combined with more brain-efficacious, less-toxic antiretroviral agents will afford optimal patient management.
 
DISCLOSURE
 
Professor Brew serves/has served on the scientific advisory boards for GlaxoSmithKline, ViiV Healthcare, Biogen Idec, and Merck Serono; receives royalties from the publication of HIV Neurology (Oxford University Press, 2001) and Palliative Neurology (Cambridge University Press, 2006); has received speaker honoraria from GlaxoSmithKline, ViiV Healthcare, Boehringer Ingelheim, Abbott, and Biogen Idec; and has received research support from GlaxoSmithKline, ViiV Healthcare, Merck Serono, the National Health and Medical Research Council (NHMRC) of Australia, and the NIH (R01 NS43103, Co-PI). Dr. Cysique has received speaker honoraria from ViiV Healthcare and receives research support from the NHMRC of Australia.
 
REFERENCES
 
1. Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders (HAND). Neurology 2007;69:1789-1799
 
2. Simioni S, Cavassini M, Annoni JM, et al. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS Epub 2009 Dec 7.
 
3. Brew BJ, Crowe SM, Landay A, Cysique LA, Guillemin G. Neurodegeneration and ageing in the HAART era. J Neuroimmune Pharmacol 2009;4:163-174
 
4. Letendre S, Marquie-Beck J, Capparelli E, et al. Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol 2008;65:65-70.
 
5. Robertson KR, Su Z, Margolis DM, et al, for the A5170 Study Team. Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology 2010;74:1260-1266.
 
6. Brew BJ. Benefit or toxicity from neurologically targeted antiretroviral therapy? Clin Infect Dis 2010;50:930-932.
 
7. Brew BJ, Pemberton L, Blennow K, Wallin A, Hagberg L. Cerebrospinal fluid amyloid β42 and tau levels correlate with AIDS dementia complex. Neurology 2005;65:1490-1492.
 
8. Clifford DB, Fagan AM, Holtzman DM, et al. CSF biomarkers of Alzheimer disease in HIV-associated neurologic disease. Neurology 2009;73:1982-1987.
 
9. Gisslén M, Krut J, Andreasson U, et al. Amyloid and tau cerebrospinal fluid biomarkers in HIV infection. BMC Neurol 2009;9:63.
 
10. Ances BM, Christensen JJ, Teshome M, et al. Cognitively unimpaired HIV-positive subjects do not have increased 11C-PiB: a case-control study. Neurology 2010;75:111-115.
 
 
 
 
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