Thomas D. Marcotte
University of California, San Diego
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Featured researches published by Thomas D. Marcotte.
Neurology | 2010
Robert K. Heaton; David B. Clifford; Donald R. Franklin; Steven Paul Woods; Christopher F. Ake; Florin Vaida; Ronald J. Ellis; S. Letendre; Thomas D. Marcotte; Atkinson Jh; M. Rivera-Mindt; Ofilio Vigil; Michael J. Taylor; Ann C. Collier; C. M. Marra; Benjamin B. Gelman; Justin C. McArthur; Susan Morgello; David M. Simpson; McCutchan Ja; Ian Abramson; Anthony Gamst; Christine Fennema-Notestine; Terry L. Jernigan; Joseph K. Wong; Igor Grant
Objectives: This is a cross-sectional, observational study to determine the frequency and associated features of HIV-associated neurocognitive disorders (HAND) in a large, diverse sample of infected individuals in the era of combination antiretroviral therapy (CART). Methods: A total of 1,555 HIV-infected adults were recruited from 6 university clinics across the United States, with minimal exclusions. We used standardized neuromedical, psychiatric, and neuropsychological (NP) examinations, and recently published criteria for diagnosing HAND and classifying 3 levels of comorbidity (minimal to severe non-HIV risks for NP impairment). Results: Fifty-two percent of the total sample had NP impairment, with higher rates in groups with greater comorbidity burden (40%, 59%, and 83%). Prevalence estimates for specific HAND diagnoses (excluding severely confounded cases) were 33% for asymptomatic neurocognitive impairment, 12% for mild neurocognitive disorder, and only 2% for HIV-associated dementia (HAD). Among participants with minimal comorbidities (n = 843), history of low nadir CD4 was a strong predictor of impairment, and the lowest impairment rate on CART occurred in the subset with suppressed plasma viral loads and nadir CD4 ≥200 cells/mm3 (30% vs 47% in remaining subgroups). Conclusions: The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.
Journal of NeuroVirology | 2011
Robert K. Heaton; Donald R. Franklin; Ronald J. Ellis; J. Allen McCutchan; Scott Letendre; Shannon LeBlanc; Stephanie H. Corkran; Nichole A. Duarte; David B. Clifford; Steven Paul Woods; Ann C. Collier; Christina M. Marra; Susan Morgello; Monica Rivera Mindt; Michael J. Taylor; Thomas D. Marcotte; J. Hampton Atkinson; Tanya Wolfson; Benjamin B. Gelman; Justin C. McArthur; David M. Simpson; Ian Abramson; Anthony Gamst; Christine Fennema-Notestine; Terry L. Jernigan; Joseph K. Wong; Igor Grant
Combination antiretroviral therapy (CART) has greatly reduced medical morbidity and mortality with HIV infection, but high rates of HIV-associated neurocognitive disorders (HAND) continue to be reported. Because large HIV-infected (HIV+) and uninfected (HIV−) groups have not been studied with similar methods in the pre-CART and CART eras, it is unclear whether CART has changed the prevalence, nature, and clinical correlates of HAND. We used comparable methods of subject screening and assessments to classify neurocognitive impairment (NCI) in large groups of HIV + and HIV − participants from the pre-CART era (1988–1995; N = 857) and CART era (2000–2007; N = 937). Impairment rate increased with successive disease stages (CDC stages A, B, and C) in both eras: 25%, 42%, and 52% in pre-CART era and 36%, 40%, and 45% in CART era. In the medically asymptomatic stage (CDC-A), NCI was significantly more common in the CART era. Low nadir CD4 predicted NCI in both eras, whereas degree of current immunosuppression, estimated duration of infection, and viral suppression in CSF (on treatment) were related to impairment only pre-CART. Pattern of NCI also differed: pre-CART had more impairment in motor skills, cognitive speed, and verbal fluency, whereas CART era involved more memory (learning) and executive function impairment. High rates of mild NCI persist at all stages of HIV infection, despite improved viral suppression and immune reconstitution with CART. The consistent association of NCI with nadir CD4 across eras suggests that earlier treatment to prevent severe immunosuppression may also help prevent HAND. Clinical trials targeting HAND prevention should specifically examine timing of ART initiation.
Journal of The International Neuropsychological Society | 1995
Robert K. Heaton; Igor Grant; Nelson Butters; Desiree A. White; Kirson D; J. Hampton Atkinson; J. Allen McCutchan; Michael J. Taylor; Mark D. Kelly; Ronald J. Ellis; Tanya Wolfson; Robert A. Velin; Thomas D. Marcotte; John R. Hesselink; Terry L. Jernigan; James L. Chandler; Mark S. Wallace; Ian Abramson
The present study examined neuropsychological (NP) functioning and associated medical, neurological, brain magnetic resonance imaging (MRI), and psychiatric findings in 389 nondemented males infected with Human Immunodeficiency Virus-Type 1 (HIV-1), and in 111 uninfected controls. Using a comprehensive NP test battery, we found increased rates of impairment at each successive stage of HIV infection. HIV-related NP impairment was generally mild, especially in the medically asymptomatic stage of infection, and most often affected attention, speed of information processing, and learning efficiency; this pattern is consistent with earliest involvement of subcortical or frontostriatal brain systems. NP impairment could not be explained on the bases of mood disturbance, recreational drug or alcohol use, or constitutional symptoms; by contrast, impairment in HIV-infected subjects was related to central brain atrophy on MRI, as well as to evidence of cellular immune activation and neurological abnormalities linked to the central nervous system.
Journal of The International Neuropsychological Society | 2004
Julie D. Rippeth; Robert K. Heaton; Catherine L. Carey; Thomas D. Marcotte; David Moore; Raul Gonzalez; Tanya Wolfson; Igor Grant
Both HIV infection and methamphetamine dependence can be associated with brain dysfunction. Little is known, however, about the cognitive effects of concurrent HIV infection and methamphetamine dependence. The present study included 200 participants in 4 groups: HIV infected/methamphetamine dependent (HIV+/METH+), HIV negative/methamphetamine dependent (HIV-/METH+), HIV infected/methamphetamine nondependent (HIV+/METH-), and HIV negative/methamphetamine nondependent (HIV-/METH-). Study groups were comparable for age, education, and ethnicity, although the HIV-/METH- group had significantly more females. A comprehensive, demographically corrected neuropsychological battery was administered yielding a global performance score and scores for seven neurobehavioral domains. Rates of neuropsychological impairment were determined by cutoff scores derived from performances of a separate control group and validated with larger samples of HIV+ and HIV- participants from an independent cohort. Rates of global neuropsychological impairment were higher in the HIV+/METH+ (58%), HIV-/METH+ (40%) and HIV+/METH- (38%) groups compared to the HIV-/METH- (18%) group. Nonparametric analyses revealed a significant monotonic trend for global cognitive status across groups, with least impairment in the control group and highest prevalence of impairment in the group with concurrent HIV infection and methamphetamine dependence. The results indicate that HIV infection and methamphetamine dependence are each associated with neuropsychological deficits, and suggest that these factors in combination are associated with additive deleterious cognitive effects. This additivity may reflect common pathways to neural injury involving both cytotoxic and apoptotic mechanisms.
Brain Pathology | 2006
Ian Everall; Robert K. Heaton; Thomas D. Marcotte; Ronald J. Ellis; McCutchan Ja; Atkinson Jh; Igor Grant; Margaret Mallory; Eliezer Masliah
Dendritic and synaptic damage (without frank neuronal loss) may be seen in milder human immunodeficiency virus (HIV)‐related cognitive disorders. Synapse volume estimates, performed by stereological methods, could enhance the ability to detect subtle neuronal changes that may accompany cognitive impairment in HIV infection. For the present study, synaptic density and neuronal number were assessed by combined stereology/confocal microscopy and these measures were then correlated with ante‐mortem levels of cognitive performance in AIDS patients. Three‐dimensional stereological measures showed a significant correlation between reduced synaptic density and poor neuropsychological performance. To evaluate the specificity of any observed associations, additional variables including viral burden, astrogliosis and number of calbindin‐immunoreactive neurons were measured. Factor analysis of a set of neuropathological variables revealed two factors; one defined by synaptic density and volume fraction, calbindin pyramidal neuronal densities and viral burden; the second by astrocytosis and calbindin interneuron density. Only the first factor correlated significantly with neuropsychological functioning during life.
Journal of Clinical and Experimental Neuropsychology | 2004
Steven Paul Woods; Julie D. Rippeth; Alan B. Frol; Joel K. Levy; Elizabeth Ryan; Vicki M. Soukup; Charles H. Hinkin; Deborah Lazzaretto; Mariana Cherner; Thomas D. Marcotte; Benjamin B. Gelman; Susan Morgello; Elyse J. Singer; Igor Grant; Robert K. Heaton
We examined the interrater reliability (IRR) of clinical ratings of neuropsychological (NP) impairment and neurocognitive diagnoses in HIV. Thirty participants with advanced HIV-infection who were enrolled in a multicenter HIV brain banking research project underwent comprehensive NP and neuromedical evaluations. Using a standardized system of guidelines, neuropsychologists from six participating sites independently assigned clinical ratings of NP impairment, as well as multilevel diagnoses reflecting the inferred etiology of the impairments and their effects on everyday functioning. Findings indicated excellent IRR in rating the presence and severity of NP impairment, but overall modest IRR for neurocognitive diagnoses. Not surprisingly, most diagnostic disagreements concerned the etiology of impairments in persons with medical and neuropsychiatric risk factors in addition to HIV.
Neurology | 2002
Mariana Cherner; Eliezer Masliah; Ronald J. Ellis; Thomas D. Marcotte; David Moore; Igor Grant; Robert K. Heaton
Objective: To investigate the value of antemortem cognitive functioning in predicting postmortem evidence of HIV encephalitis (HIVE). Methods: Thirty-nine subjects were assessed during life with a comprehensive neuropsychological battery and went on to autopsy within 18 months of testing. Cognitive impairment was determined by blind clinical ratings, based on demographically corrected test scores. Presence of HIVE was based on postmortem immunocytochemical detection of the viral protein gp41 or by measurement of HIV RNA by PCR in multiple brain areas as well as by histopathologic evidence such as microgliosis, presence of multinucleated giant cells, and myelin pallor in several brain regions. Results: The sensitivity and specificity of neurocognitive impairment in detecting the occurrence of HIVE were 67 and 92%. Eighteen of 19 subjects with antemortem neurocognitive impairment had evidence of HIV-related brain disease (positive predictive value = 95%). Conclusion: Neuropsychological assessment can help select HIV-positive patients for treatment of CNS disease.
AIDS | 2006
David Moore; Eliezer Masliah; Julie D. Rippeth; Raul Gonzalez; Catherine L. Carey; Mariana Cherner; Ronald J. Ellis; Cristian L. Achim; Thomas D. Marcotte; Robert K. Heaton; Igor Grant
Objective:To determine the association of markers of regional neurodegeneration (ND) at autopsy to degree of neurocognitive impairment in persons with HIV. Design:In a prospectively followed cohort of HIV-infected individuals we examined the relationship between antemortem neuropsychological (NP) abilities and postmortem neuropathological data. Methods:Twenty-seven HIV-infected individuals with both neuropsychological and neuropathological data were identified. Laser confocal scanning microscopy was used to determine the degree of ND based on: (1) microtubule-associated protein (MAP2; reflecting neuronal cell bodies and dendrites) and (2) synaptophysin (SYN; a measure of presynaptic terminals). A regional combined score, based on the distribution of percentage neuropil occupied by MAP2 and SYN and emphasizing severity of ND, was created for each brain region: midfrontal cortex, hippocampus, and putamen. Results:The regional combined scores from each brain region studied were better correlated with level of global NP impairment than measures of SYN and MAP2 individually. In a regression, hippocampal and putamen regional combined scores were independent predictors of degree of antemortem NP impairment (F3,23 = 6.17; P < 0.01; R2 = 0.45). The correlations among regional ND measures demonstrated that ND is unevenly distributed across multiple brain regions. Conclusions:As the anatomic distribution and temporal progression of neuropathologic changes appears to differ across individuals, it is important to consider both cortical and subcortical brain regions in studies of neuropathogenesis and treatment of HIV-related brain disease. Furthermore, combining information from several markers of neural injury provided the strongest association with degree of neurocognitive impairment during life.
AIDS | 2002
T. Dianne Langford; Scott Letendre; Thomas D. Marcotte; Ronald J. Ellis; J. Allen McCutchan; Igor Grant; Margaret Mallory; Lawrence A. Hansen; Sarah L. Archibald; Terry L. Jernigan; Eliezer Masliah
Objectives To describe a severe form of demyelinating HIV-associated leukoencephalopathy in AIDS patients failing highly active antiretroviral therapy (HAART), its relationship to clinical and neuroimaging findings, and suggest hypotheses regarding pathogenesis. Design and methods AIDS patients who failed HAART and displayed severe leukoencephalopathy were included. All cases had detailed neuromedical, neuropsychological, neuroimaging and postmortem neuropathological examination. Immunocytochemical and PCR analyses were performed to determine brain HIV levels and to exclude other viruses. Results Seven recent autopsy cases of leukoencephalopathy in antiretroviral-experienced patients with AIDS were identified. Clinically, all were severely immunosuppressed, six (86%) had poorly controlled HIV replication despite combination antiretroviral therapy, and five (71%) had HIV-associated dementia. Neuropathologically, all seven had intense perivascular infiltration by HIV-gp41 immunoreactive monocytes/macrophages and lymphocytes, widespread myelin loss, axonal injury, microgliosis and astrogliosis. The extent of damage exceeds that described prior to the use of HAART. Brain tissue demonstrated high levels of HIV RNA but evidence of other pathogens, such as JC virus, Epstein–Barr virus, cytomegalovirus, human herpes virus type-8, and herpes simplex virus types 1 and 2, was absent. Comparison of the stages of pathology suggests a temporal sequence of events. In this model, white matter damage begins with perivascular infiltration by HIV-infected monocytes, which may occur as a consequence of antiretroviral-associated immune restoration. Intense infiltration by immune cells injures brain endothelial cells and is followed by myelin loss, axonal damage, and finally, astrogliosis. Conclusions Taken together, our findings provide evidence for the emergence of a severe form of HIV-associated leukoencephalopathy. This condition warrants further study and increased vigilance among those who provide care for HIV-infected individuals.
Clinical Neuropsychologist | 2004
Catherine L. Carey; Steven Paul Woods; Julie D. Rippeth; Raul Gonzalez; David Moore; Thomas D. Marcotte; Igor Grant; Robert K. Heaton
This study sought to develop and validate a screening battery for detecting HIV-related neuropsychological(NP)impairment. Six NP measures representing the ability areas most likely affected by HIV infection were paired in 14 combinations and their diagnostic accuracy rates compared. The measures were selected from a larger NP battery administered to 190 HIV-seropositive(HIV + )participants. Screening battery performance was classified as NP impaired if demographically correctedT-scores fell below 40 on both tests, or below 35 on one test. Using blind clinical ratings of NP test results from the larger battery as the“gold standard”for global NP status(impaired or unimpaired), we found that several test combinations demonstrated adequate diagnostic accuracy in detecting NP impairment. The most sensitive test combinations were the Hopkins Verbal Learning Test–Revised(HVLT–R; Total Recall)and the Grooved Pegboard Test nondominant hand(PND)pair and the HVLT–R and WAIS-III Digit Symbol(DS)subtest pair(sensitivity = 78%and 75%, respectively). Both test combinations(HVLT–R/PND, HVLT–R/DS)were more accurate than the HIV Dementia Scale(HDS)in classifying HIV + participants as NP impaired or unimpaired. Results suggest that demographically correctedT-scores from pairs of common NP measures may serve as valid screening instruments to identify subjects with HIV-related neurocognitive impairment who could benefit from more extensive NP examination.