Increased glial metabolites predict increased working memory network activation in HIV brain injury

Deficits in attention and working memory are common in human immuno deficiency virus type 1 (HIV-1)-infected patients, but the pathophysiology of these deficits is poorly understood. Modern neuroimaging techniques, such as proton magnetic resonance spectroscopy ((1)H MRS) and functional MRI (fMRI), can assess some of the processes underlying HIV brain injury. To evaluate the model that attentional deficits in early HIV brain disease are related to brain inflammation, (1)H MRS and fMRI were performed in 14 HIV-positive subjects [acquired immunodeficiency syndrome (AIDS) dementia complex stage 1 or less]. Increasing attentional load on three working memory tasks was assessed with fMRI, and the concentrations of brain metabolites were measured with (1)H MRS in the frontal gray and white matter, and basal ganglia. Metabolite concentrations were correlated with fMRI blood oxygenation level-dependent (BOLD) signals, using a random-effects linear regression model in SPM99. Several positive correlations were observed between the BOLD signal strength in the working memory network (posterior parietal cortex and lateral prefrontal cortex) and the concentrations of frontal white matter and basal ganglia metabolites that are predominant in glial cells (choline-containing compounds, myo-inositol, and total creatine). In contrast, BOLD signals in the working memory network were not correlated with the concentration of N-acetyl compounds, which are markers of neuronal viability, or with metabolite concentrations in the frontal gray matter. These findings are consistent with previous results that mild HIV brain injury is associated with increased glial activation without major involvement of neuronal abnormalities. We propose that the inflammatory glial abnormalities reduce the efficiency of neural processing, and necessitate compensatory increases in attention in patients, and associated BOLD signals, to perform a given task. The same mechanism may also contribute to cognitive dysfunction in other brain diseases that involve inflammation.

[1]  I. Wilkinson,et al.  A multicenter proton magnetic resonance spectroscopy study of neurological complications of AIDS. , 1996, AIDS research and human retroviruses.

[2]  Stuart A. Lipton,et al.  Pathways to neuronal injury and apoptosis in HIV-associated dementia , 2001, Nature.

[3]  R. Kast.  Feedback between Glial Tumor Necrosis Factor-α and gp120 from HIV-Infected Cells Helps Maintain Infection and Destroy Neurons , 2002, Neuroimmunomodulation.

[4]  H. Hefter,et al.  Potential time course of human immunodeficiency virus type 1-associated minor motor deficits: electrophysiologic and positron emission tomography findings. , 2000, Archives of neurology.

[5]  I. Grant,et al.  Neuropsychology of HIV infection , 1994 .

[6]  Wade Morishita,et al.  Control of Synaptic Strength by Glial TNFα , 2002, Science.

[7]  C. Hardy,et al.  AIDS dementia complex: brain high-energy phosphate metabolite deficits. , 1990, Radiology.

[8]  P. Bottomley.  Spatial Localization in NMR Spectroscopy in Vivo , 1987, Annals of the New York Academy of Sciences.

[9]  H. Budka,et al.  Loss of neurons in the frontal cortex in AIDS brains , 2004, Acta Neuropathologica.

[10]  Bruce J. Brew,et al.  The management of the neurological complications of HIV infection and AIDS. , 1988, AIDS.

[11]  L. Campbell,et al.  Actual versus self-reported cognitive dysfunction in HIV-1 infection: memory-metamemory dissociations. , 1996, Journal of clinical and experimental neuropsychology.

[12]  G. Fein,et al.  Elevated subcortical choline metabolites in cognitively and clinically asymptomatic HIV patients , 1999, Neurology.

[13]  F. Hyder,et al.  Cerebral energetics and spiking frequency: The neurophysiological basis of fMRI , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[14]  P. Lantos,et al.  Neuronal loss in the frontal cortex in HIV infection , 1991, The Lancet.

[15]  C. Duyckaerts,et al.  HIV‐1‐associated cognitive/motor complex , 1993, Neurology.

[16]  B D Ross,et al.  Absolute Quantitation of Water and Metabolites in the Human Brain. I. Compartments and Water , 1993 .

[17]  P. Barker,et al.  AIDS dementia complex: evaluation with proton MR spectroscopic imaging. , 1995, Radiology.

[18]  C. Power,et al.  HIV-1 Associated Dementia: Clinical Features and Pathogenesis , 1995, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[19]  P. Simmonds,et al.  HIV encephalitis, proviral load and dementia in drug users and homosexuals with AIDS. Effect of neocortical involvement. , 1998, Brain : a journal of neurology.

[20]  P. Cinque,et al.  Spatial working memory in asymptomatic HIV-infected subjects. , 1999, The Journal of neuropsychiatry and clinical neurosciences.

[21]  L. Sharer,et al.  Pathology of HIV‐1 Infection of the Central Nervous System. A review , 1992, Journal of neuropathology and experimental neurology.

[22]  R. Janssen,et al.  Estimation of the temporal probability of human immunodeficiency virus (HIV) dementia after risk stratification for HIV‐infected persons , 1998, Neurology.

[23]  D. Gadian,et al.  Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[24]  D. Benos,et al.  Alkaline pH changes in the cerebellum of asymptomatic HIV‐infected individuals , 2001, NMR in biomedicine.

[25]  R. Fields,et al.  New insights into neuron-glia communication. , 2002, Science.

[26]  S C Strother,et al.  Abnormal cerebral glucose metabolism in HIV-1 seropositive subjects with and without dementia. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[27]  Linda Chang,et al.  Relationships among Brain Metabolites, Cognitive Function, and Viral Loads in Antiretroviral-Naı̈ve HIV Patients , 2002, NeuroImage.

[28]  B D Ross,et al.  Absolute Quantitation of Water and Metabolites in the Human Brain. II. Metabolite Concentrations , 1993 .

[29]  B D Ross,et al.  Localized 1H NMR spectroscopy in patients with chronic hepatic encephalopathy. Analysis of changes in cerebral glutamine, choline and inositols , 1991, NMR in biomedicine.

[30]  M W Weiner,et al.  Effects of chronic alcohol abuse and HIV infection on brain phosphorus metabolites. , 1995, Alcoholism, clinical and experimental research.

[31]  J. Becker,et al.  Neuropsychological performance in HIV‐1‐infected homosexual men , 1990, Neurology.

[32]  L. Chang,et al.  Cerebral metabolite abnormalities correlate with clinical severity of HIV-1 cognitive motor complex , 1999, Neurology.

[33]  G. Fein,et al.  Alterations in brain phosphate metabolite concentrations in patients with human immunodeficiency virus infection. , 1991, Archives of neurology.

[34]  Adelbert Ames,et al.  CNS energy metabolism as related to function , 2000, Brain Research Reviews.

[35]  J. Hennig,et al.  HIV-related metabolic abnormalities in the brain: depiction with proton MR spectroscopy with short echo times. , 1996, Radiology.

[36]  J. Jovicich,et al.  Abnormal brain activation on functional MRI in cognitively asymptomatic HIV patients , 2002, Neurology.

[37]  L. Wilkins.  Clinical confirmation of the American Academy of Neurology algorithm for HIV-1-associated cognitive/motor disorder , 1996, Neurology.

[38]  D. Leibfritz,et al.  Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. , 1993, Developmental neuroscience.

[39]  T. Ernst,et al.  Elimination of artifacts in short echo time 1H MR spectroscopy of the frontal lobe , 1996, Magnetic resonance in medicine.

[40]  Herbert Budka,et al.  Neuropathology of Human Immunodeficiency Virus Infection , 1991, Brain pathology.

[41]  A. Guimarães,et al.  Brain choline-containing compounds are elevated in HIV-positive patients before the onset of AIDS dementia complex , 1996, Neurology.

[42]  S. De,et al.  Elevated Levels of Tumor Necrosis Factor Alpha (TNF-α) in Human Immunodeficiency Virus Type 1-Transgenic Mice: Prevention of Death by Antibody to TNF-α , 2002, Journal of Virology.

[43]  Karl J. Friston,et al.  Statistical parametric maps in functional imaging: A general linear approach , 1994 .

[44]  E. Hansson,et al.  Glial neuronal signaling in the central nervous system , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[45]  R. Lenkinski,et al.  Proton MR spectroscopy of HIV-infected patients: characterization of abnormalities with imaging and clinical correlation. , 1993, Radiology.

[46]  I. Wilkinson,et al.  Proton spectroscopy of the brain in HIV infection: correlation with clinical, immunologic, and MR imaging findings. , 1993, Radiology.

[47]  G. Fein,et al.  Reduced brain N‐acetylaspartate suggests neuronal loss in cognitively impaired human immunodeficiency virus‐seropositive individuals , 1993, Neurology.

[48]  G. Radda,et al.  Role of phosphocreatine in energy transport in skeletal muscle of bullfrog studied by 31P-NMR. , 1990, Biochimica et biophysica acta.

[49]  A. Salazar,et al.  Working memory in individuals with HIV infection. , 1994, Journal of clinical and experimental neuropsychology.

[50]  E. Martin,et al.  Delayed recognition memory span in HIV-1 infection , 1995, Journal of the International Neuropsychological Society.

[51]  J. Callicott,et al.  The Relationship between Dorsolateral Prefrontal Neuronal N-Acetylaspartate and Evoked Release of Striatal Dopamine in Schizophrenia , 2000, Neuropsychopharmacology.

[52]  J. Becker,et al.  Dementia in AIDS patients , 1993, Neurology.

[53]  T. Ernst,et al.  Neural correlates of attention and working memory deficits in HIV patients , 2001, Neurology.