HIV-associated dementia will eventually develop in 15-20% of individuals with advanced HIV disease. It has become one of the leading causes of dementia in the young, with 10,000 new cases annually in the USA (Semin Neurol. 1999; 19(2): 129-50). With HAART treatment, AIDS related dementia (ARD) has become a chronic disease in some. Very little controlled research is available and none showing any effective treatment. However, it is clear from epidemiological studies that the HAART treatment itself appears the most important element in preventing ARD. ARD is characterized by high CNS viral loads and which appears to be caused in part by the viral coat gp120.
There is suggestive evidence of neuroprotective effects from lithium, estrogen, B-12, nimodipine, and valproic acid. Since lithium is a good treatment for depression in HIV negative patients, it might be the best first choice for HIV positive patients with both depression and other symptoms of cognitive impairment. Folic acid, B-12, and fish oil would appear useful supplements. Estrogen might be added for women. Research on acetyl-L-carnitine and carnitine has primarily been on HIV neuropathy and is small and uncontrolled.
Both HIV-Positive and Hepatitis-C-Positive Show Psychomotor Slowing: In a study of 43 HIV positive, 43 hepatitis C positive, 43 dual positive, and 43 control patients, all three groups of infected patients showed slowing on rapid alternating movement testing of both right and left hands. Affective disturbances were also present, especially in the HIV patients. Dusseldorf. Psychomotor Slowing in Hepatitis C and HIV Infection. Von Giesen HJ, Heintges T, Abbasi-Boroudjeni N, Kucukkoylu S, Koller H, Haslinger BA, Oette M, Arendt G. J Acquir Immune Defic Syndr. 2004 Feb 1; 35(2): 131-7
HIV Direct Effect on Brain: Although highly active antiretroviral therapy (HAART) dramatically decreased the incidence of opportunistic infections and malignancies in the central nervous system, it has reduced but not eliminated HIV encephalopathy. This suggests a direct cytopathic effect of HIV on neuronal tissue. Mt. Sinai NYU. Neurologic consequences of HIV infection in the era of HAART. Sperber K, Shao L. AIDS Patient Care STDS. 2003 Oct; 17(10): 509-18
Neprilysin, Which Degrades Abeta, Inhibited by HIV: HIV-1 Tat, a viral transactivating transcription factor inhibited neprilysin (NEP), a neuronal endopeptidase important for Abeta degradation, by 80%. Patients with HIV-1 infection (n = 14) had a significant increase in Abeta, compared to controls. Correlative analysis linked Abeta load to the duration of HIV-1 seropositive status. HIV-1 Tat inhibits neprilysin and elevates amyloid beta. Rempel HC, Pulliam L. University of California, San Francisco. AIDS. 2005 Jan 28;19(2):127-35.
General Review: Based on mouse research, valproic acid is being researched for neuroprotective effects in HIV infected individuals. J Neurosci. 2003 Oct 8; 23(27): 9162-70; HIV-1 encephalopathy (HIVE) is associated with high levels of viral RNA in the central nervous system (CNS). Highly active antiretroviral therapy (HAART) effectively reduces HIV replication in both plasma and cerebrospinal fluid (CSF). Some individuals, however, exhibit delayed CSF HIV RNA suppression in the presence of rapid plasma responses. HIVE was found associated with delayed virus elimination during HAART in the CSF. This suggests a distinct pattern of viral replication in the CNS in HIVE. AIDS. 2003 Sep 5; 17(13): 1897-906
Lithium Might Protect Against HIV Dementia: Mice were exposed to lithium and gp120, the viral coat. Levels of the neuronal markers, microtubule-associated protein-2 and NeuN, and the astrocyte marker, glial fibrillary acidic protein, were determined. In addition, SH-SY5Y neuronal cells exposed to gp120 and lithium were assessed for cell viability. Lithium pretreatment protected the hippocampus of mice from gp120-mediated toxicity. Preexposure of neuronal cultures to lithium significantly reduced gp120-associated neurotoxicity. However, posttreatment with lithium had minimal neuroprotective effects against gp120, both in vivo and in vitro. The protective effects of lithium in vitro were blocked by LY294002, an inhibitor of the phosphatidylinositol 3-kinase/Akt pathway. These results demonstrate that lithium might be neuroprotective against gp120-mediated toxicity and suggest that prophylactic treatment with lithium may prevent the onset/progression of HIV-associated cognitive impairments. Lithium ameliorates HIV-gp120-mediated neurotoxicity. Everall IP, Bell C, Mallory M, Langford D, Adame A, Rockestein E, Masliah E. Mol Cell Neurosci. 2002 Nov; 21(3): 493-501; Case reports in AIDS patients, as well as animal studies using related immunodeficiency viruses, provide support for a novel therapeutic role for lithium salts in the treatment of HIV infection. In both in vitro and human studies, lithium has been found to increase the synthesis of neuroprotective proteins and to exert possible neurotrophic effects in the human brain. Psychopharmacol Bull. 2002 Winter; 36(1): 5-26
Estrogen Neuroprotective: Stanford researchers found estrogen 17beta-estradiol, in concentrations of 100 nM or higher, lessens the neurotoxicity of gp120 in hippocampal and cortical cultures, blunts gp120-induced calcium mobilization, and lessens the oxidative consequences. Protection against gp120-induced neurotoxicity by an array of estrogenic steroids. Zemlyak I, Brooke SM, Sapolsky RM. Brain Res. 2002 Dec 27; 958(2): 272-6
Viral Coat Causes Memory Defect: Researchers injected into the lateral cerebral ventricle of mice HIV-1 pseudoviruses expressing the full viral genome with or without the viral coat glycoproteins, gp120/gp41. Only virus possessing gp120/gp41 induced defects in memory. By itself, gp120 also induced impairments that were reversed by hippocampal cholinergic stimulation. Mechanisms of HIV type 1-induced cognitive impairment: evidence for hippocampal cholinergic involvement with overstimulation of the VIPergic system by the viral coat protein core. Farr SA, Banks WA, Uezu K, Freed EO, Kumar VB, Morley JE. AIDS Res Hum Retroviruses. 2002 Nov 1; 18(16): 1189-95
HAART Treatment of CNS Involvement: To be effective in the CNS, HAART should contain either zidovudine or stavudine and NNRTI should be added if there is dinical or preclinical evidence of CNS involvement. Protease inhibitors may be sufficient to lower high systemic viral burden and thus protect the CNS from HIV-1 invasion. Univ. Dusseldorf. Drug treatment for HIV-1-associated dementia. von Giesen HJ, Arendt G. Curr Opin Investig Drugs. 2002 Nov; 3(11): 1643-6
Risk Factors for CNS Involvement: Low Education, Homosexual, Lack of HAART: A Univ of Bologna study of 90 HIV negative, 88 HIV positive, and 94 HIV positive with cognitive impairment found that compared with individuals with higher levels of education, those with less than 6 years of schooling had an odds ratio (OR) of 17.2 for cognitive impairment, independent of age, sex, disease stage, antiretroviral therapy, and risk behavior. Compared with injecting drug users, homosexual/bisexual and heterosexual participants had ORs of 9.6 and 6.3 for cognitive impairment. Use of antiretroviral treatment (any vs. none) was associated with lower prevalence of cognitive impairment (OR, 0.1). Compared with persons with high CD4+ cell counts (> or =500/microL), those with low (<200/microL) and moderate (200-499/microL) CD4+ cell counts had adjusted ORs of 8.6 and 6.9. The presence of prominent depressive symptoms did not change the results. Arch Neurol. 2002 May; 59(5): 812-8; Testing for early psychomotor slowing may be used to identify patients at risk of HIV dementia and HIV encephalitis. Acta Neurol Scand. 2002 Apr; 105(4): 270-5
B-12 Used: The FDA approved Nascobal, a gel formulation of Vitamin B-12 that is pumped inside the nose. The drug costs about $60 for 8 treatments and is used to prevent or reverse nerve damage and prevent memory problems and dementia. Johns Hopkins uses the drug as standard treatment for HIV cognitive dysfunction. Posit Aware. 1998 Jan-Feb; 9(1): 17
Nimodipine Used: The AIDS Clinical Trials Group has completed a study showing that nimodipine, a calcium-channel blocker, can lessen damage to the brain, and is safe and generally well tolerated. Johns Hopkins. Posit Aware. 1996 Mar-Apr; 7(2): 10-1
Nimodipine High Dose Might Help a Little: A DB PC study of nimodipine 60 mg five times a day vs. nimodipine 30 mg. three times a day vs. placebo with 41 patients with mild to severe AIDS Dementia Complex for 16 weeks showed a trend in favor of the high dose nimodipine. A phase I/II trial of nimodipine for HIV-related neurologic complications. Navia BA, Dafni U, Simpson D, Tucker T, Singer E, McArthur JC, Yiannoutsos C, Zaborski L, Lipton SA. Neurology. 1998 Jul; 51(1): 221-8
Peptide T Not Effective for Cognitive Impairment: A DB PC study of 216 AIDS patients with cognitive impairment. Posit Aware. 1996 Jan-Feb; 7(1): 5