Lithium therapy for human immunodeficiency virus type 1–associated neurocognitive impairment

Schifitto, Giovanni; Zhong, Jianhui; Gill, David; Peterson, Derick R.; Gaugh, Michelle; Zhu, Tong; Tivarus, Madalina E.; Cruttenden, Kim; Maggirwar, Sanjay B.; Gendelman, Howard Eliot; Dewhurst, Stephen; Gelbard, Harris A.

doi:10.1080/13550280902758973

Cited by 69 publications

(55 citation statements)

References 44 publications

(50 reference statements)

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“…This is consistent with recent studies showing that aberrant activation of the CDK5 7,36 and GSK3␤ 7,[33][34][35]58 signaling pathways contribute to the neurodegenerative pathology in patients with HIV-associated neurocognitive impairment. Although a previous study focused on the role of p35 and CDK5 activation via the N-methyl-D-aspartate receptor (NMDAR), 36 the present study investigated the contribution of abnormal activation of this pathway to tau hyperphosphorylation in patients with HIVE.…”

Section: Discussionsupporting

confidence: 81%

Increased CDK5 Expression in HIV Encephalitis Contributes to Neurodegeneration via Tau Phosphorylation and Is Reversed with Roscovitine

Patrick

Crews

Desplats

et al. 2011

The American Journal of Pathology

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Recent treatments with highly active antiretroviral therapy (HAART) regimens have been shown to improve general clinical status in patients with human immunodeficiency virus (HIV) infection; however, the prevalence of cognitive alterations and neurodegeneration has remained the same or has increased. These deficits are more pronounced in the subset of HIV patients with the inflammatory condition known as HIV encephalitis (HIVE). Activation of signaling pathways such as GSK3␤ and CDK5 has been implicated in the mechanisms of HIV neurotoxicity; however, the downstream mediators of these effects are unclear. The present study investigated the involvement of CDK5 and tau phosphorylation in the mechanisms of neurodegeneration in HIVE. In the frontal cortex of patients with HIVE, increased levels of CDK5 and p35 expression were associated with abnormal tau phosphorylation. Similarly, transgenic mice engineered to express the HIV protein gp120 exhibited increased brain levels of CDK5 and p35, alterations in tau phosphorylation, and dendritic degeneration. In contrast, genetic knockdown of CDK5 or treatment with the CDK5 inhibitor roscovitine improved behavioral performance in the water maze test and reduced neurodegeneration, abnormal tau phosphorylation, and astrogliosis in gp120 transgenic mice. These findings indicate that abnormal CDK5 activation contributes to the neurodegenerative process in HIVE via abnormal tau phosphorylation; thus, reducing CDK5 might ameliorate the cognitive impairments associated with HIVE. The human immunodeficiency virus (HIV) enters the central nervous system (CNS) early in the progression of the disease, resulting in a spectrum of behavioral and motor alterations that range from mild cognitive deficits to dementia.

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Section: Discussionsupporting

confidence: 81%

Increased CDK5 Expression in HIV Encephalitis Contributes to Neurodegeneration via Tau Phosphorylation and Is Reversed with Roscovitine

Patrick

Crews

Desplats

et al. 2011

The American Journal of Pathology

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“…In HIV, human and animal models have shown decreased levels of cerebral Glx Ratai et al, 2009;Chang et al, 1997), including patients with progressive multifocal leukoencephalopathy. Another study showed decreased frontal Glx concentrations, along with increased white matter integrity on diffusion tensor imaging among patients treated with lithium for HIV-associated cognitive impairment (Schifitto et al, 2009b). Accordingly, although alteration of cerebral Glx level appears to be common in brain disorders, whether increased or decreased levels are observed seems to depend on the nature of the underlying disturbance.…”

Section: Discussionmentioning

confidence: 99%

Cerebral metabolite abnormalities in human immunodeficiency virus are associated with cortical and subcortical volumes

Cohen

Harezlak

Gongvatana

et al. 2010

Journal of NeuroVirology

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Cerebral metabolite disturbances occur among human immunodeficiency virus (HIV)-infected people, and are thought to reflect neuropathology, including proinflammatory processes, and neuronal loss. HIV-associated cortical atrophy continues to occur, though its basis is not well understood, and the relationship of cerebral metabolic disturbance to structural brain abnormalities in HIV has not been well delineated. We hypothesized that metabolite disturbances would be associated with reduced cortical and subcortical volumes. Cerebral volumes were measured in 67 HIV-infected people, including 10 people with mild dementia (acquired immunodeficiency syndrome [AIDS] Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript cerebral metabolites N-acetylaspartate (NAA), myo-inositol (MI), choline-containing compounds (Cho), glutamate/glutamine (Glx), and creatine (Cr) from three brain regions (frontal gray matter, frontal white matter, basal ganglia). Analyses were conducted to examine the associations between MRS and cerebral volumetric measures using both absolute and relative metabolite concentrations. NAA in the mid-frontal gray matter was most consistently associated with cortical (global, frontal, and parietal), ventricular, and caudate volumes based on analysis of absolute metabolite levels, whereas temporal lobe volume was associated with basal ganglia NAA and Glx, and Cho concentrations in the frontal cortex and basal ganglia. Hippocampal volume was associated with frontal white matter NAA, whereas thalamic volume was associated with both frontal white matter NAA and basal ganglia Glx. Analyses of relative metabolite concentrations (referenced to Cr) yielded weaker effects, although more metabolites were retained as significant predictors in the models than the analysis of absolute concentrations. These findings demonstrate that reduced cortical and subcortical volumes, which have been previously found to be linked to HIV status and history, are also strongly associated with the degree of cerebral metabolite disturbance observed via MRS. Reduced cortical and hippocampal volumes were most strongly associated with decreased NAA, though reduced Glx also tended to be associated with reduced cortical and subcortical volumes (caudate and thalamus) as well, suggesting both neuronal and glial disturbances. Interestingly, metabolite-volumetric relationships were not limited to the cortical region from which MRS was measured, possibly reflecting shared pathophysiological processes. The relationships between Cho and volumetric measures suggest a complicated relationship possibly related to the effects of inflammatory processes on brain volume. The findings demonstrate the relationship between MRI-derived measures of cerebral metabolite disturbances and structural brain integrity, which has implication in understanding HIV-associated neuropathological mechanisms.

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“…Trials on rivastigmine failed to show benefit in terms of cognitive performance, but there were some secondary improvements in processing speed and executive function. To date, the therapeutic options for HAND appear limited to none [27,[30][31][32] .…”

Section: Updates In Human Immunodeficiency Virusassociated Cognitive mentioning

confidence: 99%

Then and Now … HIV Consultation Psychiatry Update

Goforth

Bader²,

Fernandez³

2015

Clinical Challenges in the Biopsychosocial Interface

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Over the last 2 decades, human immunodeficiency virus (HIV) illness has transformed to a chronic disease model. However, challenges, including the effects of co-morbid illnesses and the challenge of preventing future spread of the disease, continue to confront those infected with HIV. Addictions remain an important problem and a serious contributor to overall morbidity and mortality in this population. This book chapter seeks to illustrate the new developments in the treatment of these addictions as well as provide an overview of the medical updates regarding HIV and hepatitis C virus exposure prophylaxis and how they relate to the consultant psychiatrist.

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Lithium therapy for human immunodeficiency virus type 1–associated neurocognitive impairment

Cited by 69 publications

References 44 publications

Increased CDK5 Expression in HIV Encephalitis Contributes to Neurodegeneration via Tau Phosphorylation and Is Reversed with Roscovitine

Increased CDK5 Expression in HIV Encephalitis Contributes to Neurodegeneration via Tau Phosphorylation and Is Reversed with Roscovitine

Cerebral metabolite abnormalities in human immunodeficiency virus are associated with cortical and subcortical volumes

Then and Now … HIV Consultation Psychiatry Update

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