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1.  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
2.  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)
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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)
16.  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
17.  Neuroimaging markers of Human Immunodeficiency Virus infection in South Africa 
Journal of neurovirology  2012;18(3):151-156.
Previous studies have reported cognitive deficits among HIV-positive individuals infected with clade C virus. However, no study has examined whether individuals predominately infected with clade C virus exhibit brain atrophy relative to healthy controls. This study examined volumetric differences between 28 HIV+ individuals and 23 HIV− controls from South Africa. Volumetric measures were obtained from six regions of interest--caudate, thalamus, corpus callosum, total cortex, total gray matter, and total white matter. HIV+ participants had significantly lower volumes in the total white matter (p<.01), thalamus (p<.01) and total gray matter (inclusive of cortical and subcortical regions, p<.01). The current study is the first to provide evidence of brain atrophy among HIV+ individuals in South Africa, where HIV Clade C predominates. Additional research that integrates neuroimaging, comprehensive neuropsychological testing, genetic variance in clade-specific proteins, and the impact of treatment with ARVs are necessary to understand the development of HIV-related neurocognitive disorders in South Africa.
doi:10.1007/s13365-012-0090-5
PMCID: PMC3715135  PMID: 22528474
18.  The More Things Change the More They Stay the Same: A Case Report of Neurology Residency Experiences 
Journal of Neurology  2011;259(7):1321-1325.
This study compared the neurology residency training experience for a single neurology resident at the University of Pennsylvania from the years 2002–2005. The prevalence of encounters seen during this residency was compared to the prevalence of neurological disorders typically observed by ambulatory neurologists in the United States (US). A total of 1,333 patients were evaluated during this residency. Ischemic stroke/ transient ischemic accident, epilepsy, metabolic encephalopathy, peripheral neuropathy, and multiple sclerosis were the most common neurological disorders observed. The four most common reasons for an outpatient visit to a neurologist (i.e. headache/migraine, epilepsy, cerebrovascular disease, and peripheral neuropathy) typically account for ~ 49–55% of all appointments, but only contributed to ~40% of patient encounters during this neurology residency. While these results reflect the encounters of a single neurology resident, both the total number and distribution of neurological diagnoses were similar to previous experiences over two decades ago at US academic medical centers despite significant changes in health care delivery and policy. This case report demonstrates that neurology residency programs continue to overemphasize acute management of inpatient neurological disorders compared to outpatient care of more prevalent neurological complaints. Additional measures could be instituted to ensure a broader range of experiences during residency (i.e. online resident log). These methods could allow residency coordinators to identify certain areas of deficiency in regards to exposure to patients for a resident and ensure greater competency during residency.
doi:10.1007/s00415-011-6347-8
PMCID: PMC3358425  PMID: 22186851
Education; Residency
19.  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.
Highlights
•We studied functional connectivity changes in patients with temporal lobe epilepsy.•Patients had decreased local and inter-hemispheric functional connectivity.•Patients had increased intra-hemispheric connectivity, ipsilateral to seizure focus.•Functional changes involved several neocortical sites, including the insula.•This pattern may have usefulness as a non-invasive method for presurgical planning.
doi:10.1016/j.nicl.2013.06.011
PMCID: PMC3777845  PMID: 24073391
Epilepsy; Temporal lobe; Hippocampus; Insula; fMRI; Functional connectivity
20.  Independent Effects of HIV, Aging, and HAART on Brain Volumetric Measures 
Background
Neurocognitive impairment remains prevalent in HIV infected (HIV+) individuals despite highly active anti-retroviral therapy (HAART). We assessed the impact of HIV, HAART, and aging using structural neuroimaging.
Methods
Seventy-eight participants (HIV− (n=26), HIV+ on stable HAART (HIV+/HAART+; n=26), HIV+ naive to HAART (HIV+/HAART−; n=26)) completed neuroimaging and neuropsychological testing. A subset of HIV+ subjects (n = 12) performed longitudinal assessments before and after initiating HAART. Neuropsychological tests evaluated memory, psychomotor speed, and executive function and a composite neuropsychological score was calculated based on normalized performances (NPZ-4). Volumetrics were evaluated for the amygdala, caudate, thalamus, hippocampus, putamen, corpus callosum, cerebral grey and white matter. A three-group one way analysis of variance assessed differences in neuroimaging and neuropsychological indices. Correlations were examined between NPZ-4 and volumetrics. Exploratory testing using a broken stick regression model evaluated self-reported duration of HIV infection on brain structure.
Results
HIV+ individuals had significant reductions in brain volumetrics within select subcortical regions (amygdala, caudate, and corpus callosum) compared to HIV− participants. However, HAART did not affect brain structure as regional volumes were similar for HIV+/HAART− and HIV+/HAART+. No association existed between NPZ-4 and volumetrics. HIV and aging were independently associated with volumetric reductions. Exploratory analyses suggest caudate atrophy due to HIV slowly occurs after self-reported seroconversion.
Conclusions
HIV associated volumetric reductions within the amygdala, caudate, and corpus callosum occurs despite HAART. A gradual decline in caudate volume occurs after self-reported seroconversion. HIV and aging independently increase brain vulnerability. Additional longitudinal structural MRI studies, especially within older HIV+ participants, are required.
doi:10.1097/QAI.0b013e318249db17
PMCID: PMC3302928  PMID: 22269799
HIV; HAART; aging; brain volume
21.  Comparison of Regional Cerebral Blood Flow Responses to Hypoglycemia Using Pulsed Arterial Spin Labeling and Positron Emission Tomography 
PLoS ONE  2013;8(3):e60085.
Different brain regions sense and modulate the counterregulatory responses that can occur in response to declining plasma glucose levels. The aim of this study was to determine if changes in regional cerebral blood flow (rCBF) during hypoglycemia relative to euglycemia are similar for two imaging modalities–pulsed arterial spin labeling magnetic resonance imaging (PASL-MRI) and positron emission tomography (PET). Nine healthy non-diabetic participants underwent a hyperinsulinemic euglycemic (92±3 mg/dL) – hypoglycemic (53±1 mg/dL) clamp. Counterregulatory hormone levels were collected at each of these glycemic levels and rCBF measurements within the previously described network of hypoglycemia-responsive regions (thalamus, medial prefrontal cortex and globus pallidum) were obtained using PASL-MRI and [15O] water PET. In response to hypoglycemia, rCBF was significantly increased in the thalamus, medial prefrontal cortex, and globus pallidum compared to euglycemia for both PASL-MRI and PET methodologies. Both imaging techniques found similar increases in rCBF in the thalamus, medial prefrontal cortex, and globus pallidum in response to hypoglycemia. These brain regions may be involved in the physiologic and symptom responses to hypoglycemia. Compared to PET, PASL-MRI may provide a less invasive, less expensive method for assessing changes in rCBF during hypoglycemia without radiation exposure.
doi:10.1371/journal.pone.0060085
PMCID: PMC3610825  PMID: 23555895
22.  HIV Associated Neurocognitive Disorder (HAND) is Not Associated with Increased Fibrillar Amyloid Deposits Using 11C-PiB in Middle-Aged HIV+ Participants 
Archives of neurology  2012;69(1):72-77.
Objectives
Diagnostic challenges exist for differentiating HIV associated neurocognitive disorders (HAND) from symptomatic Alzheimer’s disease (AD) in HIV+ participants. Both disorders have cerebral amyloid containing plaques associated with abnormalities in amyloid beta protein 1–42 (Aβ42) metabolism. We evaluated if the amyloid-binding agent 11C-Pittsburgh compound B (11C-PiB) could discriminate AD from HAND in middle-aged HIV+ participants.
Design
11C-PiB scanning, clinical assessment, and cerebrospinal fluid (CSF) analysis were performed. χ2 and t-tests assessed differences in clinical and demographic variables between HIV+ participants and community-living individuals followed by Alzheimer Disease Research Center (ADRC). An analysis of variance (ANOVA) assessed for regional differences in Aβ42 using 11C-PiB.
Setting
ADRC and HIV clinic
Participants
16 HIV+ participants (11 cognitively normal, 5 with HAND) and 19 ADRC participants (8 cognitively normal, 11 with symptomatic AD).
Main Outcome Measure(s)
Mean and regional 11C-PiB binding potentials
Results
Symptomatic AD were older (p < 0.001), had lower CSF Aβ42 (p < 0.001), and had higher CSF tau levels (p < 0.001) than other groups. Regardless of degree of impairment, HIV+ participants did not have increased 11C-PiB. Mean and regional binding potentials were elevated for symptomatic AD participants (p <0.0001).
Conclusions
Middle-aged HIV+ participants, even with HAND, do not exhibit increased 11C-PiB while symptomatic AD individuals have increased fibrillar Aβ42 deposition in cortical and subcortical regions. Observed dissimilarities between HAND and AD may reflect differences in Aβ42 metabolism. 11C-PiB may provide a diagnostic biomarker for distinguishing symptomatic AD from HAND in middle-aged HIV+ participants. Future cross sectional and longitudinal studies are required to assess utility of 11C-PiB in older HAND individuals.
doi:10.1001/archneurol.2011.761
PMCID: PMC3536500  PMID: 22232345
HIV; Pittsburgh compound B (PIB); amyloid; HIV associated neurocognitive disorders; Alzheimer’s disease
23.  Loss of Intra- and Inter-Network Resting State Functional Connections with Alzheimer’s Disease Progression 
Alzheimer’s disease (AD) is the most common cause of dementia. Much is known concerning AD pathophysiology but our understanding of the disease at the systems level remains incomplete. Previous AD research has used resting state functional connectivity magnetic resonance imaging (rs-fcMRI) to assess the integrity of functional networks within the brain. Most studies have focused on the default-mode network (DMN), a primary locus of AD pathology. However, other brain regions are inevitably affected with disease progression. We studied rs-fcMRI in five functionally defined brain networks within a large cohort of human participants of either gender (n=510) that ranged in AD severity from unaffected (clinical dementia rating, CDR 0) to very mild (CDR 0.5) to mild AD (CDR 1). We observed loss of correlations within not only the DMN but other networks at CDR 0.5. Within the salience network (SAL), increases were seen between CDR 0 and CDR 0.5. However, at CDR 1, all networks, including SAL, exhibited reduced correlations. Specific networks were preferentially affected at certain CDR stages. In addition, cross-network relations were consistently lost with increasing AD severity. Our results demonstrate that AD is associated with widespread loss of both intra- and inter-network correlations. These results provide insight into AD pathophysiology and reinforce an integrative view of the brain’s functional organization.
doi:10.1523/JNEUROSCI.5698-11.2012
PMCID: PMC3458508  PMID: 22745490
Alzheimer’s disease; fMRI; resting state functional connectivity; BOLD; default mode network; salience network
24.  HIV and Chronic Methamphetamine Dependence Affect Cerebral Blood Flow 
Human immunodeficiency virus (HIV) and methamphetamine (METH) dependence are independently associated with neuronal dysfunction. The coupling between cerebral blood flow (CBF) and neuronal activity is the basis of many task-based functional neuroimaging techniques. We examined the interaction between HIV infection and a previous history of METH dependence on CBF within the lenticular nuclei (LN). Twenty-four HIV−/METH−, eight HIV−/METH+, 24 HIV+/METH−, and 15 HIV+/METH+ participants performed a finger tapping paradigm. A multiple regression analysis of covariance assessed associations and two-way interactions between CBF and HIV serostatus and/or previous history of METH dependence. HIV+ individuals had a trend towards a lower baseline CBF (−10%, p=0.07) and greater CBF changes for the functional task (+32%, p=0.01) than HIV− subjects. Individuals with a previous history of METH dependence had a lower baseline CBF (–16%, p= 0.007) and greater CBF changes for a functional task (+33%, p=0.02). However, no interaction existed between HIV serostatus and previous history of METH dependence for either baseline CBF (p=0.53) or CBF changes for a functional task (p=0.10). In addition, CBF and volume in the LN were not correlated. A possible additive relationship could exist between HIV infection and a history of METH dependence on CBF with a previous history of METH dependence having a larger contribution. Abnormalities in CBF could serve as a surrogate measure for assessing the chronic effects of HIV and previous METH dependence on brain function.
doi:10.1007/s11481-011-9270-y
PMCID: PMC3251315  PMID: 21431471
Human immunodeficiency virus; Methamphetamine; Cerebral blood flow; Lenticular nuclei; Highly active antiretroviral therapy
25.  Rituximab-Associated Progressive Multifocal Leukoencephalopathy in Rheumatoid Arthritis 
Archives of neurology  2011;68(9):1156-1164.
Objective
To describe the development of progressive multifocal leukoencephalopathy (PML) in patients with rheumatoid arthritis (RA) treated with rituximab.
Design
Case study.
Setting
Clinical care for patients with rheumatologic diseases. Most were referred to academic centers for care after diagnosis (Washington University, St Louis, Missouri; Karolinska Insitute, Stockholm, Sweden; and Royal Melbourne Hospital, Melbourne, Australia) while one was cared for in a neurology practice in Dallas, Texas, with consultation by an academic neurovirologist from the University of Colorado in Denver.
Patients
Four patients developing PML in the setting of rituximab therapy for RA.
Intervention
Rituximab therapy.
Main Outcome Measures
Clinical and pathological observations.
Results
Four patients from an estimated population of 129 000 exposed to rituximab therapy for RA are reported in whom PML developed after administration of this drug. All were women older than 50 years, commonly with Sjögren syndrome and a history of treatment for joint disease ranging from 3 to 14 years. One case had no prior biologic and minimal immunosuppressive therapy. Progressive multifocal leukoencephalopathy presented as a progressive neurological disorder, with diagnosis confirmed by detection of JC virus DNA in the cerebrospinal fluid or brain biopsy specimen. Two patients died in less than 1 year from PML diagnosis, while 2 remain alive after treatment withdrawal. Magnetic resonance scans and tissue evaluation confirmed the frequent development of inflammatory PML during the course of the disease.
Conclusion
These cases suggest an increased risk, about 1 case per 25 000 individuals, of PML in patients with RA being treated with rituximab. Inflammatory PML may occur in this setting even while CD20 counts remain low.
doi:10.1001/archneurol.2011.103
PMCID: PMC3428054  PMID: 21555606

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