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1.  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.
doi:10.1007/s13365-014-0264-4
PMCID: PMC4305333  PMID: 24970235
HIV; Cognition; Risky Behavior; Neuropsychology; Executive Function
2.  Allodynia and Descending Pain Modulation in Migraine: A Resting State Functional Connectivity Analysis 
Pain medicine (Malden, Mass.)  2013;15(1):154-165.
Objective
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.
Design
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.
Results
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.
Conclusion
Atypical rs-fc of brainstem descending modulatory pain regions with other brainstem and higher-order pain modulating regions is associated with migraine-related allodynia.
doi:10.1111/pme.12267
PMCID: PMC4188437  PMID: 24165094
Migraine; Functional Connectivity; Functional Magnetic Resonance Imaging; Allodynia; Central Sensitization
3.  Functional Connectivity in Autosomal Dominant and Late-Onset Alzheimer Disease 
JAMA neurology  2014;71(9):1111-1122.
Importance
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.
Results
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.
doi:10.1001/jamaneurol.2014.1654
PMCID: PMC4240274  PMID: 25069482
Resting-state functional connectivity; autosomal dominant Alzheimer's disease; late-onset Alzheimer's disease; default mode network; apolipoprotein E (APOE)
4.  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
5.  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.
doi:10.1055/s-0034-1372346
PMCID: PMC4217280  PMID: 24715492
HIV; neuroimaging; magnetic resonance spectroscopy; volumetrics; diffusion tensor imaging; functional MRI
6.  HIV-Associated Neurocognitive Disorder (HAND) 
The Lancet infectious diseases  2013;13(11):976-986.
Summary
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.
doi:10.1016/S1473-3099(13)70269-X
PMCID: PMC4108270  PMID: 24156898
HAND; HAD; dementia; HIV; imaging; HIV therapy; biomarkers
7.  HIV Clades B and C are Associated With Reduced Brain Volumetrics 
Journal of neurovirology  2013;19(5):10.1007/s13365-013-0202-x.
Objective
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.
Design
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1007/s13365-013-0202-x
PMCID: PMC3845807  PMID: 24078556
HIV clade; brain volumetrics; magnetic resonance imaging; neuropsychological performance
8.  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.
doi:10.1007/s11481-014-9546-0
PMCID: PMC4157652  PMID: 24816714
HIV; CNS; Amyloid; cerebrospinal fluid (CSF); amyloid imaging; combination anti-retroviral therapy (cART); HIV associated neurocognitive disorders (HAND)
9.  Relationship Between Stroop Performance and Resting State Functional Connectivity in Cognitively Normal Older Adults 
Neuropsychology  2013;27(5):10.1037/a0033402.
Objective
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.
Methods
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.
Results
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.
Conclusions
A link exists between RSN composite scores and specific attentional performance measures. Both measures may be sensitive biomarkers for AD.
doi:10.1037/a0033402
PMCID: PMC3837537  PMID: 24040929
resting state functional connectivity; Stroop; Alzheimer’s disease
10.  Tumefactive demyelination in a patient with human immunodeficiency virus 
Journal of neurovirology  2013;19(3):265-269.
doi:10.1007/s13365-013-0165-y
PMCID: PMC3700605  PMID: 23645348
tumefaction; demyelination; HIV; viral inclusion; leukoencephalopathy
11.  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.
doi:10.1007/s11481-013-9505-1
PMCID: PMC4039628  PMID: 24114509
HIV; International HIV Dementia Scale (IHDS); HIV associated neurocognitive disorders (HAND)
12.  Cerebrospinal fluid amyloid β42, phosphorylated tau181, and resting state functional connectivity 
JAMA neurology  2013;70(10):1242-1248.
Importance
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).
Objective
To assess the relationship between default mode network (DMN) integrity and cerebrospinal fluid (CSF) biomarkers of AD pathology in cognitively normal older individuals
Design
Cross-sectional cohort study
Setting
Knight Alzheimer’s Disease Research Center at Washington University in St Louis, Missouri.
Participants
207 older adults with normal cognition (Clinical Dementia Rating of 0).
Main Outcome measures
rs-fcMRI measures of DMN integrity.
Results
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.
Conclusions
Both Aβ and tau pathology affect DMN integrity prior to clinical onset of AD.
doi:10.1001/jamaneurol.2013.3253
PMCID: PMC3836828  PMID: 23959173
13.  Pathways to neurodegeneration 
Neurology  2013;80(13):1186-1193.
Objective:
Resting-state functional connectivity MRI (rs-fcMRI) may provide insight into the neurophysiology of HIV and aging.
Methods:
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.
Results:
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.
Conclusions:
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.
doi:10.1212/WNL.0b013e318288792b
PMCID: PMC3691785  PMID: 23446675
14.  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.
doi:10.1016/j.neuroimage.2012.11.050
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
15.  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
16.  Impaired default network functional connectivity in autosomal dominant Alzheimer disease 
Neurology  2013;81(8):736-744.
Objective:
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.
Methods:
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).
Results:
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.
Conclusion:
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.
doi:10.1212/WNL.0b013e3182a1aafe
PMCID: PMC3776464  PMID: 23884042
17.  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.
Objective
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.
Design
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.
Setting
Six US academic medical centers.
Patients
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.
Results
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.
Conclusions
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.
doi:10.1001/archneurol.2010.76
PMCID: PMC3924778  PMID: 20457954
18.  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.
doi:10.1007/s00415-012-6664-6
PMCID: PMC3651672  PMID: 22968768
Creutzfeldt-Jakob disease; diffusion magnetic resonance imaging; cerebrospinal fluid
19.  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.
doi:10.1007/s13365-012-0147-5
PMCID: PMC3655767  PMID: 23345074
HIV; Neurocognitive Disorder; MoCA; AD-8; Neuropsychological Testing; Cognition
20.  Luminance contrast of a visual stimulus modulates the BOLD response more than the cerebral blood flow response in the human brain 
NeuroImage  2012;64:104-111.
The blood oxygenation level dependent (BOLD) response measured with functional magnetic resonance imaging (fMRI) depends on the evoked changes in cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) in response to changes in neural activity. This response is strongly modulated by the CBF/CMRO2 coupling relationship with activation, defined as n, the ratio of the fractional changes. The reliability of the BOLD signal as a quantitative reflection of underlying physiological changes depends on the stability of n in response to different stimuli. The effect of visual stimulus contrast on this coupling ratio was tested in 9 healthy human subjects, measuring CBF and BOLD responses to a flickering checkerboard at four visual contrast levels. The theory of the BOLD effect makes a robust prediction—independent of details of the model—that if the CBF/CMRO2 coupling ratio n remains constant, then the response ratio between the lowest and highest contrast levels should be higher for the BOLD response than the CBF response because of the ceiling effect on the BOLD response. Instead, this response ratio was significantly lower for the BOLD response (BOLD response: 0.23 ± 0.13, mean ± SD; CBF response: 0.42 ± 0.18; p=0.0054). This data is consistent with a reduced dynamic range (strongest/weakest response ratio) of the CMRO2 response (~1.7-fold) compared to the CBF response (~2.4-fold) as luminance contrast increases, corresponding to an increase of n from 1.7 at the lowest contrast level to 2.3 at the highest contrast level. The implication of these results for fMRI studies is that the magnitude of the BOLD response does not accurately reflect the magnitude of underlying physiological processes.
doi:10.1016/j.neuroimage.2012.08.077
PMCID: PMC3545642  PMID: 22963855
visual contrast; functional magnetic resonance imaging (fMRI); cerebral blood flow (CBF); cerebral metabolic rate of oxygen consumption (CMRO2); blood oxygen level dependent (BOLD) effect; arterial spin labeling (ASL); visual cortex
21.  Impaired and Facilitated Functional Networks in Temporal Lobe Epilepsy 
NeuroImage : clinical  2013;2:862-872.
How epilepsy affects brain functional networks remains poorly understood. Here we investigated resting state functional connectivity of the temporal region in temporal lobe epilepsy. Thirty-two patients with unilateral temporal lobe epilepsy underwent resting state blood-oxygenation level dependent functional magnetic resonance imaging. We defined regions of interest a priori focusing on structures involved, either structurally or metabolically, in temporal lobe epilepsy. These structures were identified in each patient based on their individual anatomy. Our principal findings are decreased local and inter-hemispheric functional connectivity and increased intra-hemispheric functional connectivity ipsilateral to the seizure focus compared to normal controls. Specifically, several regions in the affected temporal lobe showed increased functional coupling with the ipsilateral insula and immediately neighboring subcortical regions. Additionally there was significantly decreased functional connectivity between regions in the affected temporal lobe and their contralateral homologous counterparts. Intriguingly, decreased local and inter-hemispheric connectivity was not limited or even maximal for the hippocampus or medial temporal region, which is the typical seizure onset region. Rather it also involved several regions in temporal neo-cortex, while also retaining specificity, with neighboring regions such as the amygdala remaining unaffected. These findings support a view of temporal lobe epilepsy as a disease of a complex functional network, with alterations that extend well beyond the seizure onset area, and the specificity of the observed connectivity changes suggests the possibility of a functional imaging biomarker for temporal lobe epilepsy.
doi:10.1016/j.nicl.2013.06.011
PMCID: PMC3777845  PMID: 24073391
epilepsy; temporal lobe; hippocampus; insula; fMRI; functional connectivity
22.  Resting state functional connectivity of the striatum in Parkinson’s disease 
Brain  2012;135(12):3699-3711.
Classical accounts of the pathophysiology of Parkinson’s disease have emphasized degeneration of dopaminergic nigrostriatal neurons with consequent dysfunction of cortico–striatal–thalamic loops. In contrast, post-mortem studies indicate that pathological changes in Parkinson’s disease (Lewy neurites and Lewy bodies) first appear primarily in the lower brainstem with subsequent progression to more rostral parts of the neuraxis. The nigrostriatal and histological perspectives are not incompatible, but they do emphasize different anatomical structures. To address the question of which brain structures are functionally most affected by Parkinson’s disease, we performed a resting-state functional magnetic resonance imaging study focused on striatal functional connectivity. We contrasted 13 patients with advanced Parkinson’s disease versus 19 age-matched control subjects, using methodology incorporating scrupulous attention to minimizing the effects of head motion during scanning. The principal finding in the Parkinson’s disease group was markedly lower striatal correlations with thalamus, midbrain, pons and cerebellum. This result reinforces the importance of the brainstem in the pathophysiology of Parkinson’s disease. Focally altered functional connectivity also was observed in sensori-motor and visual areas of the cerebral cortex, as well the supramarginal gyrus. Striatal functional connectivity with the brainstem was graded (posterior putamen > anterior putamen > caudate), in both patients with Parkinson’s disease and control subjects, in a manner that corresponds to well-documented gradient of striatal dopaminergic function loss in Parkinson’s disease. We hypothesize that this gradient provides a clue to the pathogenesis of Parkinson’s disease.
doi:10.1093/brain/aws281
PMCID: PMC3525055  PMID: 23195207
Parkinson’s disease; functional MRI; striatum; brainstem; functional reorganization
23.  Alzheimer’s disease family history impacts resting state functional connectivity 
Annals of neurology  2012;72(4):571-577.
Objective
Offspring whose parents have Alzheimer’s disease (AD) are at increased risk for developing dementia. Patients with AD typically exhibit disruptions in the default mode network (DMN). The aim of this study was to investigate the effect of a family history of late-onset AD on DMN integrity in cognitively normal individuals. In particular, we determined whether a family history effect is detectable in apolipoprotein E (APOE) ε4 allele non-carriers.
Method
We studied a cohort of 348 cognitively normal participants with or without family history of late-onset AD. DMN integrity was assessed by resting state functional connectivity magnetic resonance imaging.
Results
A family history of late-onset AD was associated with reduced resting state functional connectivity between particular nodes of the DMN, namely the posterior cingulate and medial temporal cortex. The observed functional connectivity reduction was not attributable to medial temporal structural atrophy. Importantly, we detected a family history effect on DMN functional connectivity in APOE ε4 allele non-carriers.
Interpretation
Unknown genetic factors, embodied in a family history of late-onset AD, may affect DMN integrity prior to cognitive impairment.
doi:10.1002/ana.23643
PMCID: PMC3490438  PMID: 23109152
24.  The Effects of HIV and Combination Antiretroviral Therapy on White Matter Integrity 
AIDS (London, England)  2012;26(12):1501-1508.
HIV preferentially affects white matter (WM) in the brain. While combination antiretroviral therapy (cART) reduces HIV viral load within the brain, continued inflammation can persist. Diffusion tensor imaging (DTI) provides a non-invasive method to assess WM structural integrity in the cART era. We examined the impact of HIV and cART on WM integrity within the corpus callosum (CC) and centrum semiovale (CSO) using DTI. Neuropsychological testing and DTI scans were acquired for a cross-sectional cohort consisting of 63 individuals that were divided into one of three groups: 21 HIV-uninfected (HIV-) controls, 21 HIV-infected (HIV+) subjects naïve to cART (HIV+/cART-), and 21 HIV+ subjects receiving stable cART (HIV+/cART+). DTI measures (fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD)) were obtained for the genu, splenium, and body of the CC as well as the CSO. A subset of the HIV+/cART- individuals (n=10) were also longitudinally assessed immediately before and approximately 6 months after receiving stable therapy. Differences among the cross-sectional groups were assessed using an ANOVA while paired t-tests evaluated longitudinal changes. The HIV+/cART- participants had significantly lower MD, AD, and RD for each CC region and the CSO compared to HIV- controls and HIV+/cART+ individuals. Observed decreases in DTI parameters could reflect the presence of inflammatory cells or cytotoxic edema in the WM of HIV+/cART- subjects. No significant difference existed between HIV- controls and HIV+/cART+ subjects. In some HIV+ subjects, initiation of cART led to significant increases in MD, RD, and AD but not FA in the CC and CSO regions. Observed changes in DTI parameters in the WM after initiating cART could reflect reduced neuro-inflammation. Future DTI studies may be useful in evaluating the efficacy of cART regimens with higher brain penetration.
doi:10.1097/QAD.0b013e3283550bec
PMCID: PMC3752399  PMID: 22546990
HIV; Diffusion Tensor Imaging (DTI); Combination Antiretroviral Therapy (cART); Corpus Callosum (CC); Centrum Semiovale (CSO)
25.  Hypertriglyceridemia in combination antiretroviral-treated HIV-positive individuals: potential impact on HIV sensory polyneuropathy 
AIDS (London, England)  2011;25(2):F1-F6.
Objective
In HIV populations that are aging due to improved longevity with combination antiretroviral therapy (CART), both hypertriglyceridemia (hTRG) and sensory neuropathy have become increasingly common. Sensory neuropathy is associated with substantial long-term disability and frequently requires management with analgesics. Elevated serum triglycerides (TRGs) are associated with an increased risk for sensory neuropathy in diabetes mellitus. However, the contribution of hTRG to sensory neuropathy in HIV has not been carefully evaluated.
Design
Prospective, comparative, single-center, cross-sectional cohort study.
Methods
Clinical correlates of sensory neuropathy were assessed in HIV-positive and HIV-negative participants. HIV-sensory neuropathy was defined as one or more clinical signs of reduced distal sensation or ankle reflexes; symptoms were distal leg and foot pain, parasthesias or numbness. TRG levels were assessed along with concomitant metabolic and other risk factors including glucose, lipids, age, height, current and nadir CD4, and past or current use of protease inhibitors, dideoxynucleoside antiretrovirals (d-drugs), and statins in univariable and multivariable logistic regression.
Results
Of 436 HIV patients (median age 52 years; 75% on CART), 27% had sensory neuropathy; 48% were symptomatic. TRG levels were significantly higher in HIV-positive than HIV-negative individuals (mean ± SD, 245 ± 242 versus 160 ± 97 mg/dl; P < 0.001). Among HIV-positive patients, those with TRG levels in the highest tertile (≥ 244 mg/dl) were more likely to have sensory neuropathy than those in the lowest tertile (reference, ≤ 142 mg/dl) after adjusting for concurrent predictors (adjusted odds ratio 2.7, 95% confidence interval 1.4–5.5).
Conclusions
Elevated triglyceride levels increased the risk for HIV-sensory neuropathy in HIV-positive individuals independently of other known risk factors.
doi:10.1097/QAD.0b013e328341dd68
PMCID: PMC3729045  PMID: 21150557
antiretroviral; HIV; sensory neuropathy; triglyceride

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