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Lithium improves HIV-associated neurocognitive impairment
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AIDS: Volume 20(14) 11 September 2006 p 1885-1888
Letendre, Scott La; Woods, Steven Pb; Ellis, Ronald Jc; Atkinson, J Hamptonb; Masliah, Eliezerc; van den Brande, Geoffreyc; Durelle, Janisc; Grant, Igorb; Everall, Ianb; the HNRC Group
From the aDepartments of Medicine, USA
bPsychiatry, USA
cNeurosciences, University of California, San Diego, California, USA.
Note from Jules Levin: many HIV+ individuals are aging and in there 50s and 60s or soon will be 60+ and hopefully approaching 70 to 80+. Having HIV and the complications associated with HIV such as elevated lipids, diabetes/insulin resistance, renal insufficiency worsens with age, and normal mental/emotional cognitive issues associated with aging. Studies show diabetes and insulin resistance and elevated lipids are associated with cognitive impairment and can worsen with aging. Therefore, older HIV+ individuals are at greater risk for increased cognitive impairment and perhaps at greater risk for mental illnesses such as Alhzeimers. It is important that HIV researchers begin to address these concerns.
Author Discussion
In this study of eight individuals with HNCI, treatment with lithium resulted in statistically significant improvements in neuropsychological performance when administered as an adjunct to stable ART. The improvements were noted in the domains of executive functions and information processing speed, functions that are often impaired by HIV infection [11] and associated with deficits in daily functioning [15], such as medication management. Six of the eight individuals improved sufficiently to reduce their GDS from the impaired (value of 0.49 or greater) to the normal range. These improvements were statistically significant even though the sample size was small and the lithium dosage was low. These findings are mitigated by the uncontrolled study design, which does not exclude the possibility that practice effects, spontaneous remission, or test error might have accounted for them. Improvements in mood did not account for neuropsychological improvements, a finding that is supported by prior studies by our group [16]. Finally, lithium was well tolerated and was not associated with changes in HIV RNA or CD4 cell counts.
These clinical observations support in-vitro investigations that demonstrated that lithium can limit the neuronal injury induced by gp120 [6] or Tat [9]. Lithium may protect neurons by potently inhibiting GSK-3β, which is associated with protection against HIV neurodegeneration [7]. The observed improvements probably did not result from increased expression of soluble TNF receptors, which can bind TNFα, a neurotoxic protein, since lithium did not seem to alter their concentrations.
Combining the observations from the current clinical study and previous in-vitro studies indicate that lithium may be a useful therapeutic adjunct to ART in individuals suffering from HNCI. These preliminary results support the performance of a larger, randomized, placebo-controlled clinical trial of lithium or another GSK-3β inhibitor in development [17].
Abstract
Objective: To determine the effects of low-dose oral lithium on the neuropsychological performance of individuals diagnosed with HIV-associated neurocognitive impairment.
Design and methods: The project was a single-arm, open-label, 12-week pilot study at a university-based tertiary care center. The participants were adults who had been diagnosed with HIV-associated neurocognitive impairment and had been on stable antiretroviral therapy for at least 12 weeks. Conditions that could affect cognition, worsen adherence to study procedures, or increase the risk of lithium adverse reactions were excluded. Twenty-one individuals were screened and eight were enrolled, all of whom completed the study. Oral lithium was initiated at 300 mg daily and was titrated to maintain 12-h trough concentrations between 0.4 and 0.8 mEq/l. Global neuropsychological performance was assessed by the global deficit score.
Results:
At baseline, all participants had impaired neuropsychological performance and most had reduced CD4 cell counts (median 292 cells/μl), and HIV RNA levels in plasma below 400 copies/mL (seven of eight).
Titrated lithium doses ranged between 600 and 1200 mg/day. Performance improved in all eight individuals after 12 weeks, and became unimpaired in six.
The study treatment was well tolerated with no grade 3 or 4 adverse events and no premature discontinuations.
Conclusions: Lithium resulted in improved neuropsychological performance in antiretroviral-treated, impaired individuals in this small, open-label study. Based on published in vitro data, lithium may exert this effect by inhibiting neuronal glycogen synthase kinase-3β.
lithium levels were titrated to maintain 12-h trough concentrations between 0.4 and 0.8 mEq/l.
Study assessments included neuromedical examinations, phlebotomy, lumbar puncture, and comprehensive, standardized neuropsychological testing.
Neuropsychological test results were summarized using the global deficit score (GDS), a validated measure that accounts for performance in seven cognitive domains and adjusts for age, education, and ethnicity [13]. Trained, blinded neuropsychologists then assigned clinical ratings of neuropsychological status using a reliable and validated rating system, which was based on participants' demographically-adjusted T-scores on standardized neuropsychological tests and ranged from 1 (above average) to 9 (severely impaired) [14]. Scores greater than four denoted definite cognitive impairment. The Beck Depression Inventory (BDI) was used to assess mood. HIV RNA levels were measured by reverse transcriptase-polymerase chain reaction and CD4+ lymphocytes were counted by flow cytometry. Soluble TNF receptor (p75) levels were measured by enzyme-linked immunosorbent assay. Baseline and week 12 values of continuous variables were compared with paired t-tests. Statistical analyses of data collected at baseline and at 12 weeks were performed using paired t-tests. Data were transformed as indicated by their distributions.
Baseline Characteristics
The average age of the 8 study patients was 44 with ages ranging from 37 to 61. Most patients were in their 40s. 7 of the 8 were men. 4 patients were Caucasian, 1 African-American, and 3 hispanic. Blood CD4 were in each of the 8 patients: 619, 185, 213, 230, 383, 1023, 280, 303, with an average of 292. Plasma HIV-RNA was <400 in 7 of 8 patients and 9244 in 1 patient. CSF HIV-RNA was <50 copies/ml in 8/8 patients. Education in years for the patients ranged from 11 to 17 with an average of 14.
Results
The participants were mostly middle-aged, well-educated, white men.
Neuropsychological performance improved in all participants after 12 weeks of lithium (Fig. 1a; median improvement 0.29, P = 0.008, two-way paired t-test). Clinical ratings indicated improvements specifically in executive functions and information processing speed (both P < 0.05). In contrast, mood did not change (Fig. 1b; median BDI reduction -6, P = 0.11, two-way paired t-test) and changes in BDI scores did not correlate with changes in GDS (P = 0.22).
Fig. 1. (a) Changes in global deficit score. Global deficit scores improved in all participants between baseline and 12 weeks (P = 0.008). (b) Changes in Beck Depression Score. Beck Depression Scores did not improve between baseline and 12 weeks (P = 0.11); (c) Changes in soluble tumor necrosis factor (TNF) receptors-II in plasma. Soluble TNF receptors (p75) did not change between baseline and 12 weeks (P = 0.09).
HIV RNA levels in plasma and cerebrospinal fluid remained stable between baseline and week 12 (both P > 0.10). CD4 cell counts did not vary (P = 0.20) except for one participant who was failing antiretroviral therapy at baseline. Soluble TNF receptor levels in plasma did not change significantly during the study (Fig. 1c, P = 0.09, one-way paired t-test). None of the participants experienced serious and unexpected reactions due to lithium. Three individuals complained of reversible erectile dysfunction, one developed a mild worsening of a pre-existing acneiform rash, and one sustained an ankle fracture during trauma.
Introduction
HIV-1 infects the central nervous system (CNS) shortly after acquisition and can cause progressive neurologic disease. HIV-associated neurocognitive impairment (HNCI), which includes subsyndromic neuropsychological impairment, minor cognitive motor disorder (MCMD) and HIV-associated dementia (HAD), profoundly affects the quality of life of people living with HIV [1]. Antiretroviral therapy (ART) has reduced the incidence of more severe forms of HNCI, probably by decreasing HIV replication in the CNS. Despite this, the prevalence of HNCI remains high [2], indicating that ART does not completely protect the brain from HIV-associated injury or fully reverse pre-treatment injury. This may be because the neuroprotective effects of ART are indirect, occurring via inhibition of HIV replication and reduction of neurotoxins [3]. As such, neuroprotectants may become important adjuncts to ART as the epidemic continues to evolve.
Lithium has been used therapeutically since the 1800s and is approved for the prophylaxis and treatment of bipolar disorder. Lithium may prevent or delay neuronal injury via several mechanisms, including: (1) stabilization of neuronal Na+/K+ ion channels; (2) reduction of inflammation; and (3) modulation of anti- and pro-apoptotic protein expression. Gallicchio and colleagues identified that lithium may have benefits in murine immunodeficiency models [4] and suggested that it might be beneficial in humans with HAD [5]. The present authors have demonstrated that lithium prevents gp120-induced HIV neurodegeneration in vitro [6] and that this was mediated via inhibition of GSK-3β [7,8]. Maggiwar et al. have reported similar findings for Tat-induced neuronal injury [9]. In the setting of neuro-AIDS, lithium's neuroprotection may also be mediated by increasing expression of soluble tumor necrosis factor (TNF) receptors [10] that bind the neurotoxic cytokine, TNFα, the expression of which is increased by HIV infection. In the setting of these observations, we hypothesized that lithium would improve neuropsychological performance in individuals with symptomatic HNCI.
Methods
This was a single-arm, open-label, 12-week study of low-dose oral lithium that was funded by the Center for AIDS Research and approved by the Human Research Protections Program of the University of California, San Diego (Project 001037). Inclusion criteria included age between 18 and 65 years; diagnosis of MCMD or HAD; Karnofsky score ≥ 50; stable ART for at least 12 weeks; and English fluency. HAD and MCMD are more common in individuals who have blood CD4+ cell counts below 500 cells/μl so this condition was preferred but was not required. HIV RNA levels below 400 copies/ml in plasma and cerebrospinal fluid were also preferred as putative indicators of the cognitive benefits of ART. Exclusion criteria included: history of bipolar disorder; creatinine > 1.5 mg/dl; clinically significant cardiovascular or thyroid disease; neurologic diseases other than HNCI that are known to affect cognition; pregnant or nursing women; untreated or unstable psychiatric illness; severe pre-morbid psychiatric illness; active alcohol or psychoactive drug abuse; active, symptomatic, opportunistic infections; and baseline absolute neutrophil count < 500 cells/μl. Twenty-one patients were screened but 13 were excluded due to normal neuropsychological performance, active psychoactive drug use, cognitive impairment due to a cause other than HIV, and/or self-elimination.
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