Dendritic injury is a pathological substrate for human immunodeficiency virus—related cognitive disorders

Masliah, Eliezer; Heaton, Robert K.; Marcotte, Thomas D.; Ellis, Ronald J.; Wiley, Clayton A.; Mallory, Margaret; Achim, Cristian L.; McCutchan, J. Allen; Nelson, Jay A.; Atkinson, J. H.; Grant, Igor

doi:10.1002/ana.410420618

Cited by 452 publications

(371 citation statements)

References 45 publications

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“…The sensitivity of NP testing to brain disorders of diverse etiologies is well established (Lezak et al, 2004). Within the context of HIV infection, results of NP testing have shown robust associations with structural and functional brain imaging (Jernigan et al, 1993;Stout et al, 1998), as well as with postmortem neuropathology findings (Cherner et al, 2002;Everall et al, 1999;Masliah et al, 1997;Moore et al, 2006). Moreover, NP impairment in HIV-infected persons has been shown to be an independent predictor of early mortality Mayeux et al, 1993) and to be strongly predictive of a wide variety of difficulties in activities of daily living (Heaton et al, 2004a).…”

Section: Introductionmentioning

confidence: 99%

Neurobehavioral effects of HIV-1 infection in China and the United States: A pilot study

Cysique

Jin

Franklin

et al. 2007

J. Inter. Neuropsych. Soc.

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The HIV epidemic in China has been increasing exponentially, yet there have been no studies of the neurobehavioral effects of HIV infection in that country. Most neuroAIDS research has been conducted in Western countries using Western neuropsychological (NP) methods, and it is unclear whether these testing methods are appropriate for use in China. Twenty-eight HIV seropositive (HIV+) and twenty-three HIV seronegative (HIV−) individuals with comparable gender, age, and education distributions were recruited in Beijing and the rural Anhui province in China. Thirtynine HIV+ and thirty-one HIV− individuals were selected from a larger U.S. cohort recruited at the HIV Neurobehavioral Research Center, in San Diego, to be matched to the Chinese sample for age, disease status, and treatment variables. The NP test battery used with the U.S. and China cohorts included instruments widely used to study HIV infection in the United States. It consisted of 14 individual test measures, each assigned to one of seven ability areas thought to be especially vulnerable to effects of HIV on the brain (i.e., verbal fluency, abstraction/executive function, speed of information processing, working memory, learning, delayed recall, and motor function). To explore the cross-cultural equivalence and validity of the NP measures, we compared our Chinese and U.S. samples on the individual tests, as well as mean scaled scores for the total battery and seven ability domains. On each NP test measure, the mean of the Chinese HIV+ group was worse than that of the HIV−group. A series of 2 × 2 analyses of variance involving HIV+ and HIV− groups from both countries revealed highly significant HIV effects on the Global and all Domain mean scaled scores. Country effects appeared on two of the individual ability areas, at least partly due to education differences between the two countries. Importantly, the absence of HIV-by-Country interactions suggests that the NP effects of HIV are similar in the two countries. The NP test battery that was chosen and adapted for use in this study of HIV in China appears to have good cross-cultural equivalence, but appropriate Chinese norms will be needed to identify disease-related impairment in individual Chinese people. To inform the development of such norms, a much larger study of demographic effects will be needed, especially considering the wide range of education in that country.

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Section: Introductionmentioning

confidence: 99%

Neurobehavioral effects of HIV-1 infection in China and the United States: A pilot study

Cysique

Jin

Franklin

et al. 2007

J. Inter. Neuropsych. Soc.

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“…Synaptodendritic simplification in the frontal cortex has been shown to be associated with HIV-associated NP impairment [20, 21]. Furthermore, subtle motor impairments can develop as a result of damage to basal ganglia structures, which have also been documented to undergo HIV-associated synaptodendritic simplification and be associated with NP performance [23].…”

Section: Discussionmentioning

confidence: 99%

Family History of Dementia Predicts Worse Neuropsychological Functioning Among HIV-Infected Persons

Moore

Arce

Moseley

et al. 2011

Journal of Neuropsychiatry

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HIV-negative individuals with a family history of dementia (FHD) are more likely to develop dementia than those without a FHD. Whether FHD increases risk for neuropsychological (NP) impairment in HIV+ persons is unknown. As part of a multi-site study into HIV-Associated Neurocognitive Disorders (HAND), we captured FHD with a free-response, self-report question, and assessed NP performance with a comprehensive battery of tests. We examined HIV+ persons with (n=190) and without (n=916) self-reported FHD. Despite the fact that the FHD group had factors typically associated with better NP performance (e.g., higher CD4 counts and estimated verbal IQ [VIQ]), persons with FHD had significantly worse NP ability than those without FHD as measured by a Global Deficit Score (GDS) (FHD mean=0.66; No FHD mean=0.55; p<0.05). Thus, FHD appears to be a risk factor for HAND; the mechanism(s) underlying how FHD contributes to NP impairment among HIV+ persons warrants study.

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“…Human immunodeficiency virus (HIV) is a neurotropic virus that results in a spectrum of inflammatory related brain changes, including HIV encephalitis and HIV leukoencephalopathy (Budka et al , 1991), accompanied by reductions in synaptodendritic markers and neuronal loss (Everall et al , 1991, 1993, 1999; Masliah et al , 1997). Clinically, both inflammatory and synaptodendritic degeneration seen postmortem correlate with the severity of HIV-associated neurocognitive disorder (HAND) seen prior to death (Cherner et al , 2002; Everall et al , 1999; Masliah et al , 1997).…”

Section: Introductionmentioning

confidence: 99%

“…Clinically, both inflammatory and synaptodendritic degeneration seen postmortem correlate with the severity of HIV-associated neurocognitive disorder (HAND) seen prior to death (Cherner et al , 2002; Everall et al , 1999; Masliah et al , 1997). Despite the introduction of highly active retroviral treatment (HAART), HAND still remains prominent within the HIV-infected community (Clifford, 2008; Nath et al , 2008).…”

Section: Introductionmentioning

confidence: 99%

“…The pathophysiological process that results in HIV neurodegeneration is complex and mediated by both direct toxic effects of HIV viral proteins as well as indirect toxic effects via release of proinflammatory cytokines and dysregulation of other processes, including trophic factors. Previously, we have noted that synaptodendritic damage is related to brain viral burden (Everall et al , 1999; Masliah et al , 1997) and that the severity of neurodegeneration can be ameliorated when the host brain neurons can maintain expression of the neurotrophic agent fibroblast growth factor-1 (FGF1) (Everall et al , 2001). In further experiments, we noted that the intracellular signaling pathway by which FGF1 mediates this neuroprotection involved the inhibition of glycogen synthase kinase-3β (GSK3β).…”

Section: Introductionmentioning

confidence: 99%

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Glycogen synthase kinase-3β (GSK-3β) inhibitors AR-A014418 and B6B3O prevent human immunodeficiency virus-mediated neurotoxicity in primary human neurons

Nguyễn

Lucero

Chana

et al. 2009

J. of Neurovirology

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Glycogen synthase kinase-3β (GSK3β) role in human immunodeficiency virus (HIV)-associated neurodegeneration has been evidenced by previous investigations. In this study, we investigated the specificity of two GSK3β-specific inhibitors, AR-A014418 (A) and B6B30 (B) to prevent direct neurotoxicity in primary human neurons exposed to HIV (BaL). Neurons were exposed to HIV (500 pg/ml) for 12-h and 6-day periods in the presence and absence of A (1 µM, 100 nM, 10 nM) and B (50 nM, 5 nM, 500 pM) to investigate acute and ongoing mechanisms of HIV neurotoxicity. Using an lactate dehydrogenase (LDH) assay to assess cytotoxicity, we observed a significant neurotoxic effect of HIV from control values (P < .01) that was not restored via coexposures of all concentrations of A and B. Additionally, no change in LDH levels were observed after 6 days. However, activity of the acute proapoptotic markers caspases 3 and 7 using a luminescence assay were measured and found to be increased by exposure to HIV (BaL) compared to controls (P = .022). This effect was ameliorated via coexposure to all concentrations of A and 50 nM B after 12 h (P < .01) and to all concentrations of A and B after 6 days (P < .01). Overall, the results from this study provide further evidence for the ability of GSK3β inhibition to be neuroprotective against HIV-associated neurotoxicity by reducing HIV associated procaspase induction. These data support a role for GSK3β as a potential therapeutic target and may have important clinical implications for treatment of HIV-associated neurocognitive disorder.

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Dendritic injury is a pathological substrate for human immunodeficiency virus—related cognitive disorders

Cited by 452 publications

References 45 publications

Neurobehavioral effects of HIV-1 infection in China and the United States: A pilot study

Neurobehavioral effects of HIV-1 infection in China and the United States: A pilot study

Family History of Dementia Predicts Worse Neuropsychological Functioning Among HIV-Infected Persons

Glycogen synthase kinase-3β (GSK-3β) inhibitors AR-A014418 and B6B3O prevent human immunodeficiency virus-mediated neurotoxicity in primary human neurons

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