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1.  An Eye on Brain Integrity: Acute Optic Neuritis Affects Resting State Functional Connectivity 
Currently, the ability for imaging to capture brain adaptations to injury that occurs in multiple sclerosis (MS) is limited. In particular, how the brain initially contends with the earliest clinical manifestations of white matter injury has yet to be defined. The purpose of this study was to determine the impact of acute optic neuritis (ON) on resting state functional connectivity magnetic resonance imaging (rs-fcMRI).
Fifteen patients with a clinically isolated syndrome of acute ON were evaluated at an academic center in a prospective study. Subjects were assessed with structural and functional vision measures, including optical coherence tomography (OCT), high- and low-contrast letter acuity testing, and visual fields and quality-of-life measures (VFQ-25). The rs-fcMRI was compared with age- and sex-matched healthy controls.
We observed reduced functional connectivity within the visual system and a loss of anticorrelations between the visual system and nonvisual networks. Stronger functional connectivity between visual regions correlated with better quality of life, as measured by the VFQ-25, and better acuity scores for both high- and low-contrast testing in the affected eye.
The rs-fcMRI functional connectivity changes within (intranetwork) and between (internetwork) resting state networks occur after acute ON, indicating immediate cortical responses to focal inflammatory demyelination. Thus, focal white matter injury in the central nervous system acutely results in widespread network alterations that may lead to functional neurologic changes seen in MS.
Focal white matter injury in the central nervous system acutely results in widespread network alterations that may lead to functional neurologic changes seen in MS.
PMCID: PMC4416526  PMID: 25813992
optic neuritis; multiple sclerosis; fcMRI; connectivity
3.  Network Dysfunction in Alzheimer's Disease: Refining the Disconnection Hypothesis 
Brain Connectivity  2014;4(5):299-311.
Much effort in recent years has focused on understanding the effects of Alzheimer's disease (AD) on neural function. This effort has resulted in an enormous number of papers describing different facets of the functional derangement seen in AD. A particularly important tool for these investigations has been resting-state functional connectivity. Attempts to comprehensively synthesize resting-state functional connectivity results have focused on the potential utility of functional connectivity as a biomarker for disease risk, disease staging, or prognosis. While these are all appropriate uses of this technique, the purpose of this review is to examine how functional connectivity disruptions inform our understanding of AD pathophysiology. Here, we examine the rationale and methodological considerations behind functional connectivity studies and then provide a critical review of the existing literature. In conclusion, we propose a hypothesis regarding the development and spread of functional connectivity deficits seen in AD.
PMCID: PMC4064730  PMID: 24796856
Alzheimer's disease; brain networks; resting-state functional connectivity
4.  A better screening tool for HIV-associated neurocognitive disorders: is it what clinicians need? 
AIDS (London, England)  2015;29(8):895-902.
Existing screening tools for HIV-Associated Neurocognitive Disorders (HAND) may lack the accuracy required for clinical use. We hypothesized that the diagnostic accuracy of the Montreal Cognitive Assessment (MoCA) as a screening tool for HAND might be improved with a stronger scoring methodology.
Two hundred HIV-positive participants aged 18–65 years completed the MoCA and a battery of neuropsychological tests.
HAND diagnosis was established according to the Frascati criteria, and an NPZ-8 score was also calculated. Rasch analysis was applied to the MoCA items to create a quantitative score.
The optimal cut-off on the quantitative MoCA for detecting impairment as per Frascati criteria yielded a sensitivity of 0.74 and a specificity of 0.68. Overall accuracy was 0.79 (95% CI: 0.73–0.85), an improvement over standard scoring methods. However, whether cognition was quantified with the quantitative MoCA or with NPZ-8, there was substantial overlap between diagnostic categories; several individuals categorized as impaired had better overall cognitive function as assessed by NPZ-8 or quantitative MoCA than those classified as normal using standard criteria.
Quantifying performance on MoCA items through Rasch analysis improves its accuracy as a screening tool for HAND, and demonstrates that cognition can be measured as a unidimensional construct in HIV, at least at the level of precision of bedside testing. However, the current categorical diagnostic approach to HAND is poorly aligned with summary measures of cognitive ability. Measuring cognition as a quasi-continuous construct may be more relevant than conventional HAND diagnostic categories for many clinical purposes.
PMCID: PMC4444425  PMID: 25291105
cognition; cognition disorders; HIV; HIV-associated neurocognitive disorder; Montreal Cognitive Assessment; neuropsychological tests
5.  Functional connectivity and graph theory in preclinical Alzheimer’s disease 
Neurobiology of aging  2013;35(4):10.1016/j.neurobiolaging.2013.10.081.
Alzheimer’s disease (AD) has a long preclinical phase in which amyloid and tau cerebral pathology accumulate without producing cognitive symptoms. Resting state functional connectivity MRI (rs-fcMRI) has demonstrated that brain networks degrade during symptomatic AD. It is unclear to what extent these degradations exist prior to symptomatic onset. In this study, we investigated graph theory metrics of functional integration (path length), functional segregation (clustering coefficient), and functional distinctness (modularity) as a function of disease severity. Further, we assessed whether these graph metrics were affected in cognitively normal participants with cerebrospinal fluid evidence of preclinical AD. Clustering coefficient and modularity, but not path length, were reduced in AD. Cognitively normal participants who harbored AD biomarker pathology also showed reduced values in these graph measures, demonstrating brain changes similar to, but smaller than, symptomatic AD. Only modularity was significantly affected by age. We also demonstrate that AD has a particular effect on hub-like regions in the brain. We conclude that AD causes large-scale disconnection that is present before onset of symptoms.
PMCID: PMC3880636  PMID: 24216223
Alzheimer’s disease; biomarker; functional connectivity; graph theory; resting-state
6.  The effect of APOE ε4 allele on cholinesterase inhibitors in patients with Alzheimer’s disease: Evaluation of the feasibility of resting state functional connectivity magnetic resonance imaging 
This work is to determine whether apolipoprotein E (APOE) genotype modulates the effect of cholinesterase inhibitor (ChEI) treatment on resting state functional connectivity magnetic resonance imaging (rs-fcMRI) in patients with Alzheimer’s disease (AD). We retrospectively studied very mild and mild AD participants who were treated (N=25) or untreated (N=19) with ChEIs with respect to rs-fcMRI measure of 5 resting state networks (RSNs): default mode, dorsal attention (DAN), control (CON), salience (SAL), and sensory-motor. For each network, a composite score was computed as the mean of Pearson’s correlations between pairwise time courses extracted from areas comprising this network. The composite scores were analyzed as a function of ChEI treatment and APOE ε4 allele. Across all participants, significant interactions between ChEI treatment and APOE ε4 allele were observed for all 5 RSNs. Within APOE ε4 carriers, significantly greater composite scores were observed in the DAN, CON and SAL for treated compared to untreated participants. Within APOE ε4 non-carriers, treated and untreated participants did not have significantly different composite scores for all RSNs. These data suggest that APOE genotype affects the response to ChEI using rs-fcMRI. Rs-fcMRI may be useful for assessing the therapeutic effect of medications in AD clinical trials.
PMCID: PMC4024181  PMID: 24830360
Alzheimer’s disease (AD); functional magnetic resonance imaging (fMRI); Cholinesterase inhibitor; Apolipoprotein E (APOE); resting state functional connectivity
7.  Impact of human immunodeficiency virus on neurocognition and risky behaviors in young adults 
Journal of neurovirology  2014;20(5):466-473.
Previous studies have identified cognitive impairments due to human immunodeficiency virus (HIV) in adults. However, few studies have examined the impact of HIV on cognition in young adults (18-24 years old). Yet, this group is one of the largest populations of individuals with new HIV infection. Young adulthood is also an important developmental window as the brain has not fully matured and individuals are prone to engage in risky behavior. The purpose of the present study was to examine the impact of HIV on neurocognition and risky behaviors. We hypothesized that HIV+ young adults (n=23) would exhibit greater cognitive impairment and risky behaviors compared to seronegative controls (n=21). In addition, we predicted that self-reported risky behavior as assessed by the Risk Assessment Battery (RAB) would covary with cognitive performances. Results revealed poorer executive function in HIV+ young adults compared to seronegative controls. HIV+ young adults also exhibited significantly greater risk scores on the RAB (p < 0.01) compared to HIV- young adults. However, there were no relationships between risky behavior and cognitive performance. Overall, our results suggest that HIV is associated with poorer cognition and increased risky behaviors in young adults.
PMCID: PMC4305333  PMID: 24970235
HIV; Cognition; Risky Behavior; Neuropsychology; Executive Function
8.  Allodynia and Descending Pain Modulation in Migraine: A Resting State Functional Connectivity Analysis 
Pain medicine (Malden, Mass.)  2013;15(1):154-165.
Most migraineurs develop cutaneous allodynia during migraines and many have cutaneous sensitization between attacks. Atypical pain modulation via the descending pain system may contribute to this sensitization and allodynia. The objective of this study was to test the hypothesis that compared to non-allodynic migraineurs, allodynic migraineurs have atypical periaqueductal gray (PAG) and nucleus cuneiformis (NCF) resting state functional connectivity (rs-fc) with other pain processing regions.
Ten minutes resting-state BOLD data were collected from 38 adult migraineurs and 20 controls. Seed-based analyses compared whole-brain rs-fc with PAG and with NCF in migraineurs with severe ictal allodynia (n=8) to migraineurs with no ictal allodynia (n=8). Correlations between the strength of functional connections that differed between severely allodynic and non-allodynic migraineurs with allodynia severity were determined for all migraineurs (n=38). PAG and NCF rs-fc in all migraineurs was compared to rs-fc in controls.
Migraineurs with severe allodynia had stronger PAG and NCF rs-fc to other brainstem, thalamic, insula and cerebellar regions that participate in discriminative pain processing, as well as to frontal and temporal regions implicated in higher-order pain modulation. Evidence that these rs-fc differences were specific for allodynia included: 1) strong correlations between some rs-fc strengths and allodynia severity among all migraineurs; 2) absence of overlap when comparing rs-fc differences in severely allodynic vs. non-allodynic migraineurs with those in all migraineurs vs. controls.
Atypical rs-fc of brainstem descending modulatory pain regions with other brainstem and higher-order pain modulating regions is associated with migraine-related allodynia.
PMCID: PMC4188437  PMID: 24165094
Migraine; Functional Connectivity; Functional Magnetic Resonance Imaging; Allodynia; Central Sensitization
9.  Functional Connectivity in Autosomal Dominant and Late-Onset Alzheimer Disease 
JAMA neurology  2014;71(9):1111-1122.
Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in three specific genes, in contrast to late-onset Alzheimer Disease (LOAD), which has a more polygenetic risk profile.
Design, Setting, and Participants
We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of ADAD (N=79) and LOAD (N=444) human participants using resting state functional connectivity MRI (rs-fcMRI) at multiple international academic sites.
Main Outcomes and Measures
For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity as measured by clinical dementia rating (CDR). In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within five RSNs.
Functional connectivity decreases with increasing CDR were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in each type of AD accurately predicted CDR stage in the other, further demonstrating similarity of functional connectivity loss in each disease type. Among ADAD participants, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared to asymptomatic mutation non-carriers.
Conclusions and Relevance
rs-fcMRI changes with progressing AD severity are similar between ADAD and LOAD. Rs-fcMRI may be a useful endpoint for LOAD and ADAD therapy trials. ADAD disease process may be an effective model for LOAD disease process.
PMCID: PMC4240274  PMID: 25069482
Resting-state functional connectivity; autosomal dominant Alzheimer's disease; late-onset Alzheimer's disease; default mode network; apolipoprotein E (APOE)
10.  Diagnosis and Evaluation of a Patient with Rapidly Progressive Dementia 
Missouri medicine  2013;110(5):422-428.
While the most common dementia is Alzheimer’s disease (AD), a detailed history is needed to rule out rapidly progressive dementias (RPDs). RPDs are less than two years in duration and have a rate of progression faster typical neurodegenerative diseases. Identification of RPDs is important as some are treatable. This review focuses on the spectrum of RPDs, with special emphasis on paraneoplastic disorders and Creutzfeldt-Jakob disease (CJD).
PMCID: PMC4217278  PMID: 24279195
11.  Role of Neuroimaging in HIV Associated Neurocognitive Disorders (HAND) 
Seminars in neurology  2014;34(1):89-102.
HIV enters the brain soon after seroconversion and can cause HIV associated neurocognitive disorders (HAND). While the more severe and progressive forms of HAND are less prevalent due to combination antiretroviral therapy (cART), ~ 40% of HIV-infected (HIV+) patients continue to have cognitive impairment. Some HIV+ individuals who have effective plasma HIV-1 RNA suppression with cART still develop HAND. It is often difficult to diagnose HAND in the outpatient setting as detailed neuropsychological performance testing is required.
Additional biomarkers that are relatively easy to obtain and clinically relevant are needed for assessing HIV associated neuropathologic changes. Recently developed non-invasive magnetic resonance imaging (MRI) techniques have great potential to serve as biomarkers. We review the application of some of these neuroimaging techniques [magnetic resonance spectroscopy (MRS), volumetric MRI, diffusion tensor imaging (DTI), functional MRI (fMRI)] in HIV+ individuals. Each of the neuroimaging methods offers unique insight into mechanisms underlying neuroHIV, could monitor disease progression, and may assist in evaluating the efficacy of particular cART regimens. It is hoped that considerable progress will continue to occur such that some of these neuroimaging methods will be incorporated across multiple sites and included in future HAND guidelines.
PMCID: PMC4217280  PMID: 24715492
HIV; neuroimaging; magnetic resonance spectroscopy; volumetrics; diffusion tensor imaging; functional MRI
12.  HIV-Associated Neurocognitive Disorder (HAND) 
The Lancet infectious diseases  2013;13(11):976-986.
Neurological involvement in HIV is commonly associated with cognitive impairment. While severe and progressive neurocognitive impairment has become rare in HIV clinics in the era of potent antiretroviral therapy, a majority of HIV patients worldwide perform below expectations on formal neurocognitive tests. Co-morbid conditions contribute to impairment, but they are insufficient to explain the frequency of impairment encountered. HIV disease markers like current viral load and CD4 counts are no longer strongly associated with ongoing impairment on therapy, while cardiovascular disease markers and inflammatory markers appear more closely associated. Novel cerebrospinal fluid and neuroimaging biomarkers are needed to detect and follow impairment. Ongoing research to optimize HIV therapy within the central nervous system, and potentially to intervene in downstream mechanisms of neurotoxicity remain important avenues of future investigation. Ultimately, the full control of virus in the brain is a necessary step in the goal of HIV eradication. Weekly searches of English language publications referring to HIV neurocognitive impairment, HIV neuropathy, HIV myelopathy, HIV dementia, and HIV from 1988 to August 2013 were performed. In addition, the authors’ own files were manually searched.
PMCID: PMC4108270  PMID: 24156898
HAND; HAD; dementia; HIV; imaging; HIV therapy; biomarkers
13.  HIV Clades B and C are Associated With Reduced Brain Volumetrics 
Journal of neurovirology  2013;19(5):10.1007/s13365-013-0202-x.
HIV has multiple genetic clades with varying prevalence throughout the world. Both HIV-clade C (HIV-C) and HIV-clade B (HIV-B) can cause cognitive impairment but it is unclear if these clades are characterized by similar patterns of brain dysfunction. We examined brain volumetrics and neuropsychological performance among highly active anti-retroviral therapy (HAART) naïve HIV-B and HIV-C participants.
Thirty-four HAART-naïve HIV-infected (HIV+) participants [(17 HIV-B (United States); 17 HIV-C (South Africa)] and 34 age and education-matched HIV-uninfected (HIV−) participants were evaluated.
All participants underwent similar laboratory, neuropsychological, and neuroimaging studies. Brain volume measures were assessed within the caudate, putamen, amygdala, thalamus, hippocampus, corpus callosum and cortical (grey and white matter) structures. A linear model that included HIV status, region, and their interaction assessed the effects of the virus on brain volumetrics.
HIV− and HIV+ individuals were similar in age. On laboratory examination, HIV-C participants had lower CD4 cell counts and higher plasma HIV viral loads than HIV-B individuals. In general, HIV+ participants performed significantly worse on neuropsychological measures of processing speed and memory and had significantly smaller relative volumetrics within the thalamus, hippocampus, and corpus callosum and cortical grey and white matter compared to respective HIV− controls. Both HIV-clades B and C are associated with similar volumetric declines when compared to matched HIV− controls.
HIV-B and C were associated with significant reductions in brain volumetrics and poorer neuropsychological performance; however, no specific effect of HIV clade subtype was evident. These findings suggest that HIV-B and HIV-C both detrimentally affect brain integrity.
PMCID: PMC3845807  PMID: 24078556
HIV clade; brain volumetrics; magnetic resonance imaging; neuropsychological performance
14.  Role of HIV in Amyloid Metabolism 
HIV infection has changed from an acute devastating disease to a more chronic illness due to combination anti-retroviral treatment (cART). In the cART era, the life expectancy of HIV-infected (HIV+) individuals has increased. More HIV+ individuals are aging with current projections suggesting that 50% of HIV+ individuals will be over 50 years old by 2015. With advancing age, HIV+ individuals may be at increased risk of developing other potential neurodegenerative disorders [especially Alzheimer’s disease (AD)]. Pathology studies have shown that HIV increases intra and possibly extracellular amyloid beta (Aβ42), a hallmark of AD. We review the synthesis and clearance of Aβ42 and the effects of HIV on the amyloid pathway, and contrast the impact of AD and HIV on Aβ42 metabolism. Biomarker studies (cerebrospinal fluid AB and amyloid imaging) in HIV+ have shown mixed results. CSF Aβ42 has been shown to be either normal or diminished in HIV+ patients with HIV associated neurocognitive disorders (HAND). Amyloid imaging using [11C] PiB has also not demonstrated increased extracellular amyloid fibrillar deposits in HAND patients. We further demonstrate that Aβ42 deposition is not increased in older HIV+ patients using [11C] PiB amyloid imaging. Together, these results suggest that HIV and aging each independently affect Aβ42 deposition with no significant interaction present. Older HIV+ patients are probably not at increased risk for developing AD. However, future longitudinal studies of older HIV+ patients using multiple modalities (including the combination of CSF markers and amyloid imaging) are necessary for investigating the effects of HIV on Aβ42 metabolism.
PMCID: PMC4157652  PMID: 24816714
HIV; CNS; Amyloid; cerebrospinal fluid (CSF); amyloid imaging; combination anti-retroviral therapy (cART); HIV associated neurocognitive disorders (HAND)
15.  Relationship Between Stroop Performance and Resting State Functional Connectivity in Cognitively Normal Older Adults 
Neuropsychology  2013;27(5):10.1037/a0033402.
Early biomarkers of Alzheimer’s disease (AD) are needed for developing therapeutic interventions. Measures of attentional control in Stroop-type tasks discriminate healthy aging from early stage AD (Hutchison et al., 2010) and predict future development of AD (Balota et al., 2010) in cognitively normal individuals. Disruption in resting state functional connectivity magnetic resonance imaging (rs-fcMRI) has been reported in AD (Greicius et al., 2004), and in healthy controls at risk for AD (Sheline et al, 2010a). We explored the relationship among Stroop performance, rs-fcMRI, and CSF Aβ42 levels in cognitively normal older adults.
A computerized Stroop task (along with standard neuropsychological measures), rs-fcMRI, and CSF were obtained in 237 cognitively normal older adults. We compared the relationship between Stroop performance, including measures from reaction distributional analyses, and composite scores from four resting state networks (RSNs) [default mode (DMN), salience (SAL), dorsal attention (DAN), and sensory motor (SMN)], and the modulatory influence of CSF Aβ42 levels.
A larger Stroop effect in errors was associated with reduced rs-fcMRI within the DMN and SAL. Reaction time distributional analyses indicated the slow tail of the reaction time distribution was related to reduced rs-fcMRI functional connectivity within the SAL. Standard psychometric measures were not related to RSN composite scores. A relationship between Stroop performance and DMN (but not SAL) functional connectivity was stronger in CSF Aβ42 positive individuals.
A link exists between RSN composite scores and specific attentional performance measures. Both measures may be sensitive biomarkers for AD.
PMCID: PMC3837537  PMID: 24040929
resting state functional connectivity; Stroop; Alzheimer’s disease
16.  Tumefactive demyelination in a patient with human immunodeficiency virus 
Journal of neurovirology  2013;19(3):265-269.
PMCID: PMC3700605  PMID: 23645348
tumefaction; demyelination; HIV; viral inclusion; leukoencephalopathy
17.  Identifying Risk Factors for HIV-Associated Neurocognitive Disorders Using the International HIV Dementia Scale 
HIV-associated neurocognitive disorders (HAND) persist despite great advancements in combination antiretroviral therapy (cART). The gold standard for diagnosing cognitive impairment consists of a time-consuming neuropsychological battery of tests given by a trained neuropsychologist, however in the outpatient HIV clinic this is not feasible. The International HIV Dementia Scale (IHDS) was developed to help identify individuals with cognitive impairment in the outpatient setting. The IHDS is moderately sensitive for detecting more symptomatic forms of HAND but sensitivity has been shown to be poor in mild impairment. The IHDS has not been evaluated in developed countries in large cohort populations. We conducted a prospective cross-sectional study of only HIV+ individuals in an urban clinic and evaluated the prevalence of HAND and associated risk factors for cognitive impairment using the IHDS. A total of 507 HIV+ individuals participated in the study of which the majority were male (65%) and African American (68%); and 41% had cognitive impairment. On multivariate analysis, African American race (p=2.21), older age (p=1.03), high school education or less (p=2.03) and depression (p=1.05) were associated with cognitive impairment. The high prevalence of HAND in this group suggests that more severe forms of HAND persist despite cART. Identified risk factors were non-HIV-related and suggest that environmental and sociodemographic factors have a significant impact on cognitive functioning and should be given more attention. The IHDS should be further evaluated in large cohort HIV+ and HIV− populations in the United States, as there remains a significant need to identify an effective brief screening tool for cognitive impairment.
PMCID: PMC4039628  PMID: 24114509
HIV; International HIV Dementia Scale (IHDS); HIV associated neurocognitive disorders (HAND)
18.  Cerebrospinal fluid amyloid β42, phosphorylated tau181, and resting state functional connectivity 
JAMA neurology  2013;70(10):1242-1248.
Resting state functional connectivity magnetic resonance imaging (rs-fcMRI) has great potential for characterizing pathophysiological changes during the preclinical phase of Alzheimer’s disease (AD).
To assess the relationship between default mode network (DMN) integrity and cerebrospinal fluid (CSF) biomarkers of AD pathology in cognitively normal older individuals
Cross-sectional cohort study
Knight Alzheimer’s Disease Research Center at Washington University in St Louis, Missouri.
207 older adults with normal cognition (Clinical Dementia Rating of 0).
Main Outcome measures
rs-fcMRI measures of DMN integrity.
Decreased CSF Aβ42 or increased CSF phosphorylated tau181 (ptau181) were independently associated with reduced DMN integrity, with the most prominent decreases in functional connectivity observed between the posterior cingulate and medial temporal regions. Observed reductions in functional connectivity were not attributable to age or structural atrophy in the posterior cingulate and medial temporal areas. Similar rs-fcMRI findings in relation to CSF biomarkers were obtained using region-of-interest analyses and voxel-wise correlation mapping.
Both Aβ and tau pathology affect DMN integrity prior to clinical onset of AD.
PMCID: PMC3836828  PMID: 23959173
19.  Pathways to neurodegeneration 
Neurology  2013;80(13):1186-1193.
Resting-state functional connectivity MRI (rs-fcMRI) may provide insight into the neurophysiology of HIV and aging.
In this cross-sectional study, we used rs-fcMRI to investigate intra- and internetwork connectivity among 5 functional brain networks in 58 HIV-infected (HIV+) participants (44% receiving highly active antiretroviral therapy) and 53 HIV-uninfected (HIV−) controls. An analysis of covariance assessed the relationship among age, HIV laboratory markers, or degree of cognitive impairment and brain networks.
Individuals who were HIV+ had decreased rs-fcMRI intranetwork correlations in the default mode (DMN, p = 0.01), control (CON, p = 0.02), and salience (SAL, p = 0.02) networks, but showed no changes in the sensorimotor (SMN) or dorsal attention (DAN) network. Compared with HIV− controls, participants who were HIV+ had a significant loss of internetwork correlations between the DMN-DAN (p = 0.02), trending loss in DMN-SAL (p = 0.1) and CON-SMN (p = 0.1), and trending increase in CON-SAL (p = 0.1). Neither HIV markers (plasma HIV viral load or CD4+ cell count) nor degree of cognitive impairment correlated with rs-fcMRI measures. Aging correlated with a decrease in the magnitude of intranetwork functional connectivity within the DMN (p = 0.04) and SAL (p = 0.006) and with decreased magnitude of internetwork functional connectivity between DMN and SAL (p = 0.009) for both HIV+ and HIV− participants. No interaction was observed between HIV and aging.
HIV and aging may cause independent decreases in rs-fcMRI. HIV may lead to a baseline decrease in brain function similar to deterioration that occurs with aging.
PMCID: PMC3691785  PMID: 23446675
20.  Coupling of cerebral blood flow and oxygen metabolism is conserved for chromatic and luminance stimuli in human visual cortex 
NeuroImage  2012;68:221-228.
The ratio of the changes in cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) during brain activation is a critical determinant of the magnitude of the blood oxygenation level dependent (BOLD) response measured with functional magnetic resonance imaging (fMRI). Cytochrome oxidase (CO), a key component of oxidative metabolism in the mitochondria, is non-uniformly distributed in visual area V1 in distinct blob and interblob regions, suggesting significant spatial variation in the capacity for oxygen metabolism. The goal of this study was to test whether CBF/CMRO2 coupling differed when these subpopulations of neurons were preferentially stimulated, using chromatic and luminance stimuli to preferentially stimulate either the blob or interblob regions. A dual-echo spiral arterial spin labeling (ASL) technique was used to measure CBF and BOLD responses simultaneously in 7 healthy human subjects. When the stimulus contrast levels were adjusted to evoke similar CBF responses (mean 65.4%±19.0% and 64.6%±19.9%, respectively for chromatic and luminance contrast), the BOLD responses were remarkably similar (1.57%±0.39% and 1.59%±0.35%) for both types of stimuli. We conclude that CBF-CMRO2 coupling is conserved for the chromatic and luminance stimuli used, suggesting a consistent coupling for blob and inter-blob neuronal populations despite the difference in CO concentration.
PMCID: PMC3558279  PMID: 23238435
cerebral blood flow (CBF); cerebral metabolic rate of oxygen (CMRO2); blood oxygenation level dependent (BOLD); functional magnetic resonance imaging (fMRI); cytochrome-oxidase blobs
21.  HIV-Associated Neurocognitive Disorders and the Impact of Combination Antiretroviral Therapies 
HIV-associated neurocognitive disorders (HAND) are the most common preventable and treatable cause of dementia. While the incidence of the most severe form of HAND, HIV-associated dementia, has decreased since the introduction of combination antiretroviral therapy (cART), the prevalence of less severe forms of HAND has continued to rise. HAND leads to a subcortical dementia consisting of a triad of cognitive, behavior, and motor dysfunction. No single laboratory test can establish HAND, but ancillary studies including neuropsychological testing, neuroimaging studies, and cerebrospinal fluid (CSF) analysis are useful for supporting or refuting the diagnosis. More recent evidence has suggested that higher central nervous system–penetrating cART may lead to greater suppression of CSF HIV viral loads and improved cognition. Because viral control generally has been successful without eliminating cognitive dysfunction, further clinical studies that assess adjunctive neuroprotective drugs are likely to be required.
PMCID: PMC3932327  PMID: 18957181
22.  Impaired default network functional connectivity in autosomal dominant Alzheimer disease 
Neurology  2013;81(8):736-744.
To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network.
Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO).
We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p < 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p = 0.014) and right parietal cortex (p = 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO.
Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease.
PMCID: PMC3776464  PMID: 23884042
23.  Continued High Prevalence and Adverse Clinical Impact of Human Immunodeficiency Virus–Associated Sensory Neuropathy in the Era of Combination Antiretroviral Therapy 
Archives of neurology  2010;67(5):552-558.
To provide updated estimates of the prevalence and clinical impact of human immunodeficiency virus−associated sensory neuropathy (HIV-SN) and neuropathic pain due to HIV-SN in the combination antiretroviral therapy (CART) era.
Prospective, cross-sectional analysis. Clinical correlates for HIV-SN and neuropathic pain, including age, exposure to CART, CD4 levels, plasma viral load, hepatitis C virus infection, and alcohol use disorders, were evaluated in univariate and multivariate models.
Six US academic medical centers.
One thousand five hundred thirty-nine HIV-infected individuals enrolled in the CNS (Central Nervous System) HIV Anti-Retroviral Therapy Effects Research study.
Main Outcome Measures
The presence of HIV-SN, defined by 1 or more clinical signs (diminished vibration or sharp sensation in the legs and feet; reduced ankle reflexes) in a distal, symmetrical pattern. Neuropathic pain was defined as aching, stabbing, or burning in a similar distribution. The effect on quality of life was assessed with the Medical Outcomes Study HIV Health Survey.
We found HIV-SN in 881 participants. Of these, 38.0% reported neuropathic pain. Neuropathic pain was significantly associated with disability in daily activities, unemployment, and reduced quality of life. Risk factors for HIV-SN after adjustment were advancing age (odds ratio, 2.1 [95%confidence interval, 1.8–2.5] per 10 years), lower CD4 nadir (1.2 [1.1–1.2] per 100-cell decrease), current CART use (1.6 [1.3–2.8]), and past “D-drug” use (specific dideoxynucleoside analogue antiretrovirals) (2.0 [1.3–2.6]). Risk factors for neuropathic pain were past D-drug use and higher CD4 nadir.
Neuropathic pain and HIV-SN remain prevalent, causing substantial disability and reduced quality of life even with successful CART. The clinical correlates of HIV-SN have changed with the evolution of treatment. These findings argue for redoubled efforts to determine HIV-SN pathogenesis and the development of symptomatic and neuroregenerative therapies.
PMCID: PMC3924778  PMID: 20457954
24.  Role of Magnetic Resonance Imaging, Cerebrospinal Fluid, and Electroencephalogram in Diagnosis of Sporadic Creutzfeldt-Jakob Disease 
Journal of neurology  2012;260(2):498-506.
Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive dementia (RPD) that can be difficult to identify ante-mortem, with definitive diagnosis requiring tissue confirmation. We describe the clinical, magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and electroencephalogram (EEG) measures of a small cohort of 30 patients evaluated for RPD. Clinical and diagnostic measures were cross-sectionally obtained from 17 sCJD patients (15 definite, 2 probable), 13 non-prion rapidly progressive dementia patients (npRPD), and 18 unimpaired controls. In a subset of patients (9 sCJD and 9 npRPD) diffusion tensor imaging (DTI) measures [fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD)] were also obtained for the caudate, corpus callosum, posterior limb of the internal capsule, pulvinar, precuneus, and frontal lobe. Differences among groups were assessed by an analysis of variance. Compared to npRPD individuals, sCJD patients had cerebellar dysfunction, significantly higher CSF tau, “positive” CSF 14-3-3, and hyperintensities on diffusion weighted imaging (DWI) that met previously established imaging criteria for sCJD. EEG changes were similar for the two groups. In addition, sCJD patients had significant decreases in DTI measures (MD, AD, RD but not FA) within the caudate and pulvinar compared to either npRPD patients or unimpaired controls. Our results confirm that CSF abnormalities and MRI (especially DWI) can assist in distinguishing sCJD patients from npRPD patients. Future longitudinal studies using multiple measures (including CSF and MRI) are needed for evaluating pathological changes seen in sCJD patients.
PMCID: PMC3651672  PMID: 22968768
Creutzfeldt-Jakob disease; diffusion magnetic resonance imaging; cerebrospinal fluid
25.  The Alzheimer Disease-8 and Montreal Cognitive Assessment as Screening Tools for Neurocognitive Impairment in HIV-Infected Persons 
Journal of neurovirology  2013;19(1):109-116.
The diagnosis of HIV-associated neurocognitive impairment is time-intensive and often omitted in busy outpatient settings. Brief screening tools are needed. The Montreal Cognitive Assessment (MoCA) and the Alzheimer’s disease (AD)-8 have been used in neurodegenerative disorders. We evaluated the sensitivity and specificity of these brief screening tools in HIV-infected persons. The AD-8, MoCA, and formal neuropsychological testing were administered to 200 HIV-infected patients followed at a single institution. Normalized scores on formal neuropsychological testing were used to define neurocognitive impairment. The sensitivity and specificity of the MoCA and AD-8 were assessed to diagnose impairment. Neurocognitive impairment was highly prevalent in this cohort: 127 persons (64%) were diagnosed with neurocognitive impairment based on formal testing. Using the AD-8 and MoCA, 113 (57%) and 101 (51%) persons were identified with neurocognitive impairment, respectively. The sensitivity and specificity of MoCA were 63% and 71%, respectively. The sensitivity and specificity of AD-8 were 61% and 51%, respectively. Our findings highlight that brief screening tools correlate with formal neuropsychological testing. However, the sensitivities of these screening tools are lower than desired. Nevertheless, given their ease in administration, these tools could assist as a first line for identifying individuals who may subsequently require formal neuropsychological testing.
PMCID: PMC3655767  PMID: 23345074
HIV; Neurocognitive Disorder; MoCA; AD-8; Neuropsychological Testing; Cognition

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