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1.  Non-invasive detection of neurochemical changes prior to overt pathology in a mouse model of spinocerebellar ataxia type 1 
Journal of neurochemistry  2013;127(5):660-668.
Spinocerebellar ataxia type 1 (SCA1) is a hereditary, progressive and fatal movement disorder that primarily affects the cerebellum. Non-invasive imaging markers to detect early disease in SCA1 will facilitate testing and implementation of potential therapies. We have previously demonstrated the sensitivity of neurochemical levels measured by 1H magnetic resonance spectroscopy (MRS) to progressive neurodegeneration using a transgenic mouse model of SCA1. In order to investigate very early neurochemical changes related to neurodegeneration, here we utilized a knock-in mouse model, the Sca1154Q/2Q line, which displays milder cerebellar pathology than the transgenic model. We measured cerebellar neurochemical profiles of Sca1154Q/2Q mice and wild-type littermates using 9.4T MRS at ages 6, 12, 24, and 39 weeks and assessed the cerebellar pathology of a subset of the mice at each time point. The Sca1154Q/2Q mice displayed very mild cerebellar pathology even at 39 weeks, however, were distinguished from wild types by MRS starting at 6 weeks. Taurine and total choline levels were significantly lower at all ages and glutamine and total creatine levels were higher starting at 12 weeks in Sca1154Q/2Q mice than controls, demonstrating the sensitivity of neurochemical levels to neurodegeneration related changes in the absence of overt pathology.
PMCID: PMC4094372  PMID: 24032423
cerebellum; histology; magnetic resonance spectroscopy; mouse model; neurodegeneration; SCA1
2.  Neurochemical profile of patients with type 1 diabetes measured by 1H-MRS at 4 T 
The impact of type 1 diabetes mellitus (T1DM) on a comprehensive neurochemical profile of the human brain has not been reported yet. Our previous proton magnetic resonance spectroscopy (1H-MRS) studies on T1DM were focused exclusively on the assessment of brain glucose levels. In this study, we reexamined our previously acquired data to investigate concentration differences of a broad range of neurochemicals in T1DM subjects relative to nondiabetic controls. We selected MRS data from 13 subjects (4 F/9 M, age=41±11 years, body mass index=26±3 kg/m2) with well-controlled T1DM (disease duration=22±12 years, A1C=7.5%±2.0%) and 32 nondiabetic controls (14 F/18 M, age=36±10 years, body mass index=27±6 kg/m2) acquired during a hyperglycemic clamp (target [Glc]plasma=300±15 mg/dL). The 1H-MR spectra were collected from two 15.6-mL voxels localized in gray-matter-rich occipital lobe and in white-matter-rich parieto-occipital region using ultra-short echo-time STEAM at 4 T. LCModel analysis allowed reliable quantification of 17 brain metabolites. Lower levels of N-acetylaspartate (by 6%, P=0.007) and glutamate (by 6%, P=0.045) were observed in the gray matter of T1DM patients as compared with controls, which might indicate a partial neuronal loss or dysfunction as a consequence of long-term T1DM. No other differences in metabolites were observed between subjects with T1DM and controls.
PMCID: PMC3652707  PMID: 23403373
diabetes; glutamate; MR spectroscopy; neurochemistry; neurotransmitters
3.  Estimated plasma Stearoyl Co-A Desaturase-1 activity and risk of incident diabetes: the Atherosclerosis Risk in Communities (ARIC) study 
Evidence from pre-clinical studies suggests inhibition of Stearoyl Co-A Desaturase-1 (SCD-1) activity improves insulin sensitivity. Translation of these findings to humans remains less defined. The purpose of this research was to evaluate the association between different measures of SCD-1 activity and incident diabetes in a large, prospective human study.
In 2738 white participants (aged 45-64 yrs, 47% men) who were free of diabetes at baseline, SCD-1 activity was estimated at baseline by plasma fatty acid ratios in cholesterol esters (SCD16c=16:1n-7/16:0, SCD18c =18:1n-9/18:0) and in phospholipids (SCD16p=16:1n-7/16:0, SCD18p=18:1n-9/18:0). Incident diabetes was ascertained during 3 follow-up visits. Cox proportional hazards regression was used to determine the association between estimated SCD-1 activity and incident diabetes.
During follow-up (mean 8.0 ± SE 2.1 years), 207 (7.6%) participants developed diabetes. After adjusting for age and sex, higher SCD16c, higher SCD16p, and lower SCD18p were significantly associated with incident diabetes. After additional adjustment for education, parental history of diabetes, smoking, dietary intake (carbohydrate, fiber, saturated/monounsaturated/polyunsaturated fat), alcohol use, physical activity, body mass index (BMI), waist-hip ratio, blood pressure, and lipid composition – only SCD16c remained significantly associated with incident diabetes (Hazard Ratio=1.1 linearly across decreasing quintiles, 95% CI 1.01-1.30; p =0.03) which remained nominally associated after adjusting for insulin resistance (p=0.05).
In a large community-based prospective cohort study, the estimate of SCD-1 activity by SCD16c had the strongest association with incident diabetes. Refinement of SCD-1 measurement and replication of its association with incident diabetes in an independent cohort is recommended.
PMCID: PMC3518662  PMID: 22819528
fatty acid ratio; Type 2 Diabetes; prospective study
4.  Influence of Foot Orientation on the Appearance and Quantification of 1H Magnetic Resonance Muscle Spectra Obtained from the Soleus and the Vastus Lateralis 
Muscle 1H magnetic resonance (MR) spectroscopy non-invasively measures intramyocellular lipid (IMCL) levels, which correlate with obesity, insulin resistance, and type 2 diabetes. The appearance of muscle MR spectra is influenced by bulk magnetic susceptibility and residual dipolar couplings which depend on the angle between the muscle fibers and the main magnetic field. This study used a 4 T magnet to examine the influence of foot orientation on the appearance and quantification of muscle MR spectra from the soleus and the vastus lateralis. For each individual, IMCL, EMCL and creatine concentrations were quantified in the soleus and the vastus lateralis during one session. Foot orientation was found to influence the appearance of muscle spectra from the soleus, but not from the vastus lateralis. It was concluded that quantifying IMCL by the standard LCModel using a water reference may be more appropriate than using a creatine reference in the presence of residual dipolar couplings.
PMCID: PMC3381854  PMID: 22298295
intramyocellular lipids; LCModel; creatine; carnosine
5.  Hypoglycemia-induced increases in thalamic cerebral blood flow are blunted in subjects with type 1 diabetes and hypoglycemia unawareness 
The thalamus has been found to be activated during the early phase of moderate hypoglycemia. Here, we tested the hypothesis that this region is less activated during hypoglycemia in subjects with type 1 diabetes (T1DM) and hypoglycemia unawareness relative to controls. Twelve controls (5 F/7 M, age 40±14 years, body mass index 24.2±2.7 kg/m2) and eleven patients (7 F/4 M, age 39±13 years, body mass index 26.5±4.4 kg/m2) with well-controlled T1DM (A1c 6.8±0.4%) underwent a two-step hyperinsulinemic (2.0 mU/kg per minute) clamp. Cerebral blood flow (CBF) weighted images were acquired using arterial spin labeling to monitor cerebral activation in the midbrain regions. Blood glucose was first held at 95 mg/dL and then allowed to decrease to 50 mg/dL. The CBF image acquisition during euglycemia and hypoglycemia began within a few minutes of when the target blood glucose values were reached. Hypoglycemia unaware T1DM subjects displayed blunting of the physiologic CBF increase that occurs in the thalamus of healthy individuals during the early phase of moderate hypoglycemia. A positive correlation was observed between thalamic response and epinephrine response to hypoglycemia, suggesting that this region may be involved in the coordination of the counter regulatory response to hypoglycemia.
PMCID: PMC3494000  PMID: 22892724
diabetes; glucose; hypoglycemia; imaging
6.  Prevalence and Factors Associated With Sleep Disturbances Among Early-Treated HIV-Infected Persons 
Persons infected with human immunodeficiency virus (HIV) have a high prevalence of insomnia (46%) and daytime drowsiness (30%). Factors associated with insomnia among patients with HIV infection include depression and increased waist size. Screening for sleep disturbances should be considered among HIV-infected persons.
Background. Sleep disturbances are reportedly common among persons infected with human immunodeficiency virus (HIV), but recent data, including comparisons with HIV-uninfected persons, are limited.
Methods. We performed a cross-sectional study among early-treated HIV-infected military beneficiaries (n = 193) to determine the prevalence and factors associated with insomnia (Pittsburgh Sleep Quality Index [PSQI]) and daytime sleepiness (Epworth Sleepiness Scale [ESS]). Data were compared with HIV-uninfected persons (n = 50) matched by age, sex, race or ethnicity, and military rank.
Results. Forty-six percent of HIV-infected persons had insomnia (PSQI >5), and 30% reported daytime drowsiness (ESS ≥10). The prevalence of insomnia and daytime sleepiness was not significantly higher compared with the HIV-uninfected group (38% [P = .30] and 20% [P = .18], respectively). In the multivariate model, factors associated with insomnia among HIV infected patients included depression (odds ratio [OR], 16.8; 95% confidence interval [CI], 2.0–142.1; P = .01), increased waist size (OR, 2.7; 95% CI, 1.4–5.1; P = .002), and fewer years of education (OR, 0.8; 95% CI, .7–.95; P = .006). Neurocognitive impairment (diagnosed in 19% of HIV-infected participants) was not associated with insomnia; however, HIV-infected persons with insomnia were 3.1-fold more likely to have a decline in activities of daily living than those without insomnia (23% vs 9%; P = .01). Only 18% of HIV-infected persons reported using a sleep medication at least weekly.
Conclusions. HIV-infected persons have a high prevalence of insomnia, but among an early-treated cohort this rate was not significantly higher compared with HIV-uninfected persons. Factors associated with insomnia among HIV-infected patients include depression and increased waist size. Prompt diagnosis and treatment of sleep disturbances are advocated and may improve quality of life.
PMCID: PMC3334363  PMID: 22431801
7.  Brain glycogen content and metabolism in subjects with type 1 diabetes and hypoglycemia unawareness 
Supercompensated brain glycogen may contribute to the development of hypoglycemia unawareness in patients with type 1 diabetes by providing energy for the brain during periods of hypoglycemia. Our goal was to determine if brain glycogen content is elevated in patients with type 1 diabetes and hypoglycemia unawareness. We used in vivo 13C nuclear magnetic resonance spectroscopy in conjunction with [1-13C]glucose administration in five patients with type 1 diabetes and hypoglycemia unawareness and five age-, gender-, and body mass index-matched healthy volunteers to measure brain glycogen content and metabolism. Glucose and insulin were administered intravenously over ∼51 hours at a rate titrated to maintain a blood glucose concentration of 7 mmol/L. 13C-glycogen levels in the occipital lobe were measured at ∼5, 8, 13, 23, 32, 37, and 50 hours, during label wash-in and wash-out. Newly synthesized glycogen levels were higher in controls than in patients (P<0.0001) for matched average blood glucose and insulin levels, which may be due to higher brain glycogen content or faster turnover in controls. Metabolic modeling indicated lower brain glycogen content in patients than in controls (P=0.07), implying that glycogen supercompensation does not contribute to the development of hypoglycemia unawareness in humans with type 1 diabetes.
PMCID: PMC3272603  PMID: 21971353
13C nuclear magnetic resonance spectroscopy; glucose; glycogen; hypoglycemia unawareness
8.  Adaptive Control of the False Discovery Rate in Voxel-Based Morphometry 
Human brain mapping  2009;30(7):2304-2311.
Voxel-based morphometry (VBM) is widely used as a high-resolution approach to understanding the relationship between anatomical structures and variables of interest. Controlling for the false discovery rate (FDR) is an attractive choice for thresholding the resulting statistical maps and has been commonly used in fMRI studies. However, we caution against the use of nonadaptive FDR control procedures, such as the most commonly used Benjamini–Hochberg procedure (B-H), in VBM analyses. This is because, in VBM analyses, specific risk factors may be associated with volume change in a global, rather than local, manner, which means the proportion of truly associated voxels among all voxels is large. In such a case, the achieved FDR obtained by nonadaptive procedures can be substantially lower than the nominal, or controlled, level. Such conservatism deprives researchers of power for detecting true associations. In this article, we advocate for the use of adaptive FDR control in VBM-type analyses. Specifically, we examine two representative adaptive procedures: the two-stage step-up procedure by Benjamini, Krieger and Yekutieli ([2006]: Biometrika 93:491-507) and the procedure of Storey and Tibshirani ([2003]: Proc Natl Acad Sci USA 100:9440-9445). We demonstrate mathematically, with simulations, and with a data example that these procedures provide improved performance over the B-H procedure.
PMCID: PMC3530395  PMID: 19034901
voxel-based morphometry; false discovery rate; Benjamini and Hochberg procedure
Experimental neurology  2011;232(2):290-298.
Reliable and objective markers of neuronal function and pathology that can directly assess the effects of neuroprotective treatments in the brain are urgently needed for clinical trials in neurodegenerative diseases. Here we assessed the sensitivity of high field proton magnetic resonance spectroscopy (1H MRS) to monitor reversal of neurodegeneration by taking advantage of a well characterized conditional mouse model of spinocerebellar ataxia type 1 (SCA1), where the cerebellar pathology and ataxic phenotype are reversible by doxycycline administration. Transgene expression was suppressed by feeding the mice with chow that contains doxycycline from 6 – 12 weeks of age in an early stage group and from 12 – 24 weeks in a mid-stage group. Cerebellar neurochemical profiles of treated and untreated conditional mice were measured at 9.4 tesla (T) before and after treatment and compared to those of wild type (WT) controls, as well as to histology measures (molecular layer thickness in the primary fissure and a global pathological severity score). Concentrations of N-acetylaspartate (NAA) and myo-inositol in the treated mice trended towards normalization to WT levels in both the early and mid-stage groups. The NAA-to-myo-inositol ratio was significantly different between the treated vs. untreated SCA1 mice and demonstrated partial reversal to WT values both at early and mid-stage, consistent with the histological measures. Taurine and total creatine levels were completely normalized in early and mid-stage treatment groups, respectively. The MRS markers were a more sensitive measure of treatment response than the histological measures from the same volume-of-interest in the early stage group. NAA, myo-inositol and taurine levels were significantly correlated with the histology measures in data combined from all groups. These data demonstrate that MRS markers reliably detect rescue from neuronal pathology and imply that the neurochemical levels measured by MRS accurately reflect treatment efficacy. Therefore this study presents an important step in validating MRS biomarkers as potential surrogate markers to evaluate therapeutics in pre-clinical and clinical trials in SCA1.
PMCID: PMC3221464  PMID: 21963649
SCA1; mouse model; MRS; cerebellum; neurodegeneration
10.  Identification of an Abbreviated Test Battery for Detection of HIV-Associated Neurocognitive Impairment in an Early-Managed HIV-Infected Cohort 
PLoS ONE  2012;7(11):e47310.
HIV-associated neurocognitive disorders (HAND) remain prevalent despite improved antiretroviral treatment (ART), and it is essential to have a sensitive and specific HAND screening tool.
Participants were 200 HIV-infected US military beneficiaries, managed early in the course of HIV infection, had few comorbidities, and had open access to ART. Participants completed a comprehensive, seven-domain (16-test), neuropsychological battery (∼120 min); neurocognitive impairment (NCI) was determined using a standardized score derived from demographically adjusted T-scores (global deficit score ≥0.5). Restricting the estimated administration time of the screening battery to < = 20 minutes, we examined the sensitivity and specificity of detecting NCI for all possible combinations of 2-, 3-, and 4- tests from the comprehensive battery.
Participants were relatively healthy (median CD4 count: 546 cells/mm3) with 64% receiving ART. Prevalence of NCI was low (19%). The best 2-test screener included the Stroop Color Test and the Hopkins Verbal Learning Test-Revised (11 min; sensitivity = 73%; specificity = 83%); the best 3-test screener included the above measures plus the Paced Auditory Serial Addition Test (PASAT; 16 min; sensitivity = 86%; specificity = 75%). The addition of Action Fluency to the above three tests improved specificity (18 min; sensitivity = 86%; specificity = 87%).
Combinations of widely accepted neuropsychological tests with brief implementation time demonstrated good sensitivity and specificity compared to a time intensive neuropsychological test battery. Tests of verbal learning, attention/working memory, and processing speed are particularly useful in detecting NCI. Utilizing validated, easy to administer, traditional neuropsychological tests with established normative data may represent an excellent approach to screening for NCI in HIV.
PMCID: PMC3493574  PMID: 23144815
11.  Smoking and Incidence of Atrial Fibrillation: Results from the Atherosclerosis Risk in Communities (ARIC) Study 
Cigarette smoking increases the risk of coronary heart disease, but whether smoking increases atrial fibrillation (AF) is uncertain.
To determine the association of cigarette smoking with incident AF in a population-based cohort of blacks and whites.
We determined the risk of incident AF through December 2002 in relation to baseline (1987–1989) smoking status and cigarette-years of smoking in over 15,000 participants of the prospective Atherosclerosis Risk in Communities study.
Over a mean follow-up of 13.1 years, 876 incident AF events were identified. Compared to never smokers, the multivariable-adjusted hazard ratios (HR) for AF were 1.32 (95% CI, 1.10–1.57) in former smokers, 2.05 (95% CI, 1.71–2.47) in current smokers, and 1.58 (95% CI, 1.35–1.85) in ever smokers. In the highest tertile of accumulated smoking amount (>675 cigarette-years), the incidence of AF was 2.10-times greater (95% CI, 1.74–2.53) than those who never smoked. Associations were similar by gender, race, and type of event (AF and atrial flutter), and also when only AF events identified by study exam ECGs were included. Finally, individuals who quit smoking exhibited a trend indicating a slightly lower risk of developing AF (HR, 0.88; 95% CI, 0.65–1.17) compared to those who continued to smoke.
Smoking was associated with the incidence of AF, with more than a 2-fold increased risk of AF attributed to current smoking. In addition, a trend toward a lower incidence of AF appeared among smokers who quit compared to continued smokers.
PMCID: PMC3139831  PMID: 21419237
smoking; cigarette; arrhythmia; atrial fibrillation
12.  Clinical, demographic and laboratory parameters at HAART initiation associated with decreased post-HAART survival in a U.S. military prospective HIV cohort 
Although highly active antiretroviral therapy (HAART) has improved HIV survival, some patients receiving therapy are still dying. This analysis was conducted to identify factors associated with increased risk of post-HAART mortality.
We evaluated baseline (prior to HAART initiation) clinical, demographic and laboratory factors (including CD4+ count and HIV RNA level) for associations with subsequent mortality in 1,600 patients who began HAART in a prospective observational cohort of HIV-infected U.S. military personnel.
Cumulative mortality was 5%, 10% and 18% at 4, 8 and 12 years post-HAART. Mortality was highest (6.23 deaths/100 person-years [PY]) in those with ≤ 50 CD4+ cells/mm3 before HAART initiation, and became progressively lower as CD4+ counts increased (0.70/100 PY with ≥ 500 CD4+ cells/mm3). In multivariate analysis, factors significantly (p < 0.05) associated with post-HAART mortality included: increasing age among those ≥ 40 years (Hazard ratio [HR] = 1.32 per 5 year increase), clinical AIDS events before HAART (HR = 1.93), ≤ 50 CD4+ cells/mm3 (vs. CD4+ ≥ 500, HR = 2.97), greater HIV RNA level (HR = 1.36 per one log10 increase), hepatitis C antibody or chronic hepatitis B (HR = 1.96), and HIV diagnosis before 1996 (HR = 2.44). Baseline CD4+ = 51-200 cells (HR = 1.74, p = 0.06), and hemoglobin < 12 gm/dL for women or < 13.5 for men (HR = 1.36, p = 0.07) were borderline significant.
Although treatment has improved HIV survival, defining those at greatest risk for death after HAART initiation, including demographic, clinical and laboratory correlates of poorer prognoses, can help identify a subset of patients for whom more intensive monitoring, counseling, and care interventions may improve clinical outcomes and post-HAART survival.
PMCID: PMC3320559  PMID: 22339893
Highly active antiretroviral therapy; mortality; CD4+ lymphocyte count
13.  Immunogenicity of a Monovalent 2009 Influenza A (H1N1) Vaccine in an Immunocompromised Population: A Prospective Study Comparing HIV-Infected Adults with HIV-Uninfected Adults 
Background. Limited data exist on the immunogenicity of the 2009 influenza A (H1N1) vaccine among immunocompromised persons, including those with human immunodeficiency virus (HIV) infection.
Methods. We compared the immunogenicity and tolerability of a single dose of the monovalent 2009 influenza A (H1N1) vaccine (strain A/California/7/2009H1N1) between HIV-infected and HIV-uninfected adults 18–50 years of age. The primary end point was an antibody titer of ≥1:40 at day 28 after vaccination in those with a prevaccination level of ≤1:10, as measured by hemagglutination-inhibition assay. Geometric mean titers, influenza-like illnesses, and tolerability were also evaluated.
Results. One hundred thirty-one participants were evaluated (65 HIV-infected and 66 HIV-uninfected patients), with a median age of 35 years (interquartile range, 27–42 years). HIV-infected persons had a median CD4 cell count of 581 cells/mm3 (interquartile range, 476–814 cells/mm3) , and 82% were receiving antiretroviral medications. At baseline, 35 patients (27%) had antibody titers of >1:10. HIV-infected patients (29 [56%] of 52), compared with HIV-uninfected persons (35 [80%] of 44), were significantly less likely to develop an antibody response (odds ratio, .20; P = .003). Changes in the median geometric mean titer from baseline to day 28 were also significantly lower in HIV-infected patients than in HIV-uninfected persons (75 vs 153; P = .001). Five influenza-like illnesses occurred (2 cases in HIV-infected persons), but none was attributable to the 2009 influenza H1N1 virus. The vaccine was well tolerated in both groups.
Conclusions. Despite high CD4 cell counts and receipt of antiretroviral medications, HIV-infected adults generated significantly poorer antibody responses, compared with HIV-uninfected persons. Future studies evaluating a 2-dose series or more-immunogenic influenza A (H1N1) vaccines among HIV-infected adults are needed ( NCT00996970).
PMCID: PMC3060889  PMID: 21148532
14.  Impulsive Behavior and Associated Clinical Variables in Parkinson's Disease 
Psychosomatics  2011;52(1):41-47.
Parkinson's disease (PD) is a degenerative brain disorder accompanied by the loss of dopaminergic neurons and the presence of motor and non-motor symptoms. We performed a cross-sectional, questionnaire-based analysis of impulsive behavior in our PD clinic population to assess prevalence and associated characteristics. We found a higher prevalence of impulsive behavior (29.7%) than previously reported, and found multiple, concurrent impulsive behaviors in 26% of subjects reporting impulsive behavior. Our findings contribute to the growing awareness of impulsive behavior in PD, and support the need for longitudinal studies to assess changes in impulsive behaviors in Parkinson's patients.
PMCID: PMC3073776  PMID: 21300194
impulsive behavior; impulsivity; Parkinson's disease; prevalence
15.  Impact of Weight on Immune Cell Counts among HIV-Infected Persons▿ 
Prior studies have shown that weight may impact immune cell counts. However, few data exist about the relationship of weight and immune cell counts among HIV-infected patients. We examined documented HIV seroconverters (mean window, 15.7 months) in a prospective U.S. Military HIV Natural History Study (1 January 1986 to 20 January 2010). We estimated the association of the time-updated body mass index (BMI) category with changes in immune cell counts from HIV diagnosis across time (mean follow-up of 5.1 years) using multiply adjusted longitudinal linear mixed-effects models. Of 1,097 HIV seroconverters, 448 (41%) were overweight and 93 (8%) were obese at HIV diagnosis. Immune cell counts at HIV diagnosis did not significantly differ by BMI category. In the longitudinal models for those diagnosed before the advent of the highly active antiretroviral therapy (HAART) era, mean postdiagnosis decreases in the white cell count, total lymphocyte count, CD4 count, CD4 percentage, and CD4/CD8 ratio were less as the BMI category increased (all with P values of <0.05). Among HIV seroconverters diagnosed in the HAART era, obese compared to normal-weight patients had significantly smaller increases in CD4 counts, CD4 percentages, and the CD4/CD8 ratio (all with P values of <0.05). Similar findings were also noted among underweight versus normal-weight patients. In conclusion, although BMI was not associated with immune cell levels at the time of HIV diagnosis, weight appears to affect immune cells counts over the course of infection. In the HAART era, being either underweight or obese was associated with smaller increases in several important immune cell levels, including the CD4/CD8 ratio.
PMCID: PMC3122603  PMID: 21525303
16.  1H MR Spectroscopy in Friedreich's Ataxia and Ataxia with Oculomotor Apraxia Type 2 
Brain research  2010;1358:200-210.
Background and aim
Friedreich's ataxia (FRDA) and ataxia with oculomotor apraxia type 2 (AOA2) are the two most frequent forms of autosomal recessive cerebellar ataxias. However, brain metabolism in these disorders is poorly characterized and biomarkers of the disease progression are lacking. We aimed at assessing the neurochemical profile of the pons, the cerebellar hemisphere and the vermis in patients with FRDA and AOA2 to identify potential biomarkers of these diseases.
Short-echo, single voxel proton (1H) magnetic resonance spectroscopy data were acquired from 8 volunteers with FRDA, 9 volunteers with AOA2, and 38 control volunteers at 4T. Disease severity was assessed by the Friedreich's Ataxia Rating Scale (FARS).
Neuronal loss/dysfunction was indicated in the cerebellar vermis and hemispheres in both diseases by lower total N-acetylaspartate levels than controls. The putative gliosis marker myo-inositol was higher than controls in the vermis and pons in AOA2 and in the vermis in FRDA. Total creatine, another potential gliosis marker, was higher in the cerebellar hemispheres in FRDA relative to controls. Higher glutamine in FRDA and lower glutamate in AOA2 than controls were observed in the vermis, indicating different mechanisms possibly leading to altered glutamatergic neurotransmission. In AOA2, total N-acetylaspartate levels in the cerebellum strongly correlated with the FARS score (p < 0.01).
Distinct neurochemical patterns were observed in the two patient populations, warranting further studies with larger patient populations to determine if the alterations in metabolite levels observed here may be utilized to monitor disease progression and treatment.
PMCID: PMC2949538  PMID: 20713024
MRS; Friedreich's; AOA2; ataxia; brain; metabolites
17.  Are HIV-Positive Persons Progressing Faster After Diagnosis Over the Epidemic? 
PMCID: PMC2901894  PMID: 20611033
HIV; epidemiology; progression; CD4 counts
Robust biomarkers of neurodegeneration are critical for testing of neuroprotective therapies. The clinical applicability of such biomarkers requires sufficient sensitivity to detect disease in individuals. Here we tested the sensitivity of high field (4 tesla) proton magnetic resonance spectroscopy (1H MRS) to neurochemical alterations in the cerebellum and brainstem in spinocerebellar ataxia type 1 (SCA1). We measured neurochemical profiles that consisted of 10–15 metabolite concentrations in the vermis, cerebellar hemispheres and pons of patients with SCA1 (N=9) and healthy controls (N=15). Total NAA (N-acetylaspartate + N-acetylaspartylglutamate, tNAA) and glutamate were lower and glutamine, myo-inositol and total creatine (creatine + phosphocreatine, tCr) were higher in patients relative to controls, consistent with neuronal dysfunction/loss, gliotic activity and alterations in glutamate-glutamine cycling and energy metabolism. Changes in tNAA, tCr, myo-inositol and glutamate levels were discernible in individual spectra and the tNAA/myo-inositol ratio in the cerebellar hemipheres and pons differentiated the patients from controls with 100% specificity and sensitivity. In addition, tNAA, myo-inositol and glutamate levels in the cerebellar hemispheres and the tNAA and myo-inositol levels in the pons correlated with ataxia scores (Scale for the Assessment and Rating of Ataxia, SARA). Two other biomarkers measured in the cerebrospinal fluid (CSF) of a subset of the volunteers (F2-isoprostanes as a marker of oxidative stress and glial fibrillary acidic protein (GFAP) as a marker of gliosis) were not different between patients and controls. These data demonstrate that 1H MRS biomarkers can be utilized to non-invasively assess neuronal and glial status in individual ataxia patients.
PMCID: PMC2916651  PMID: 20310029
SCA1; MRS; ataxia; cerebellum; neurochemical profile
19.  Obesity among HIV-Infected Persons: Impact of Weight on CD4 Cell Count 
AIDS (London, England)  2010;24(7):1069-1072.
To assess the effect of obesity on CD4 counts, we estimated the association of time-updated BMI categories with CD4 changes among 1,001 documented HIV seroconverters. During the pre-HAART era, a higher BMI was associated with less reduction in CD4 counts over time. However during the HAART era, obese versus normal weight patients had smaller increases in CD4 counts (+69 v. +116 cells, p=0.01). Lower CD4 counts may now be another adverse consequence of obesity.
PMCID: PMC2878190  PMID: 20216300
HIV; immunology; obesity; CD4 counts; antiretroviral therapy
20.  Long-term CD4+ lymphocyte response following HAART initiation in a U.S. Military prospective cohort 
Among HIV-infected persons initiating highly active antiretroviral therapy (HAART), early CD4+ lymphocyte count increases are well described. However, whether CD4+ levels continue to increase or plateau after 4-6 years is controversial.
To address this question and identify other determinants of CD4+ response, we analyzed data for 1,846 persons from a prospective HIV military cohort study who initiated HAART, who had post-HAART CD4+ measurements, and for whom HIV seroconversion (SC) date was estimated.
CD4+ count at HAART initiation was ≤ 200 cells/mm3 for 23%, 201-349 for 31%, 350-499 for 27%, and ≥500 for 19%. The first 6 months post-HAART, the greatest CD4+ increases (93-151 cells) occurred, with lesser increases (22-36 cells/year) through the first four years. Although CD4+ changes for the entire cohort were relatively flat thereafter, HIV viral load (VL) suppressors showed continued increases of 12-16 cells/year. In multivariate analysis adjusting for baseline CD4+ and post-HAART time interval, CD4+ responses were poorer in those with: longer time from HIV SC to HAART start, lower pre-HAART CD4+ nadir, higher pre-HAART VL, and clinical AIDS before HAART (P < 0.05).
Small but positive long-term increases in CD4+ count in virally suppressed patients were observed. CD4+ response to HAART is influenced by multiple factors including duration of preceding HIV infection, and optimized if treatment is started with virally suppressive therapy as early as possible.
PMCID: PMC3037838  PMID: 21244701
21.  In Vitro Activity of the Aminoglycoside Antibiotic Arbekacin against Acinetobacter baumannii-calcoaceticus Isolated from War-Wounded Patients at Walter Reed Army Medical Center▿  
We determined the in vitro MIC of arbekacin against 200 Acinetobacter isolates recovered from wounded soldiers. The median MIC was 2 μg/ml (range, 0.5 to >64 μg/ml). A total of 97.5% of the isolates had arbekacin MICs of <8 μg/ml and 86.5% had MICs of ≤4 μg/ml. There was no association between the arbekacin MIC and susceptibility to 16 other antibiotics or the specimen source (P = 0.7239). Synergy testing suggested an enhanced effect of arbekacin-carbapenem combinations.
PMCID: PMC2897312  PMID: 20404121
Recent studies with a conditional mouse model of spinocerebellar ataxia type 1 (SCA1) suggest that neuronal dysfunction is reversible and neurodegeneration preventable with early interventions. Success of such interventions will depend on early detection of neuronal and glial abnormalities prior to cell loss and availability of objective methods to monitor progressive neurodegeneration. Cerebellar concentrations of N-acetylaspartate (NAA), myo-inositol and glutamate as measured by magnetic resonance spectroscopy (MRS) correlate with ataxia scores of patients with SCA1, indicating their potential as reliable biomarkers of neurodegeneration. Here we investigated if neurochemical levels are altered by early, pre-symptomatic disease and if they gauge disease progression in a mouse model of SCA1. Cerebellar neurochemical profiles of transgenic mice that overexpress the mutant human ataxin-1 (the SCA1[82Q] line) were measured longitudinally up to 1 year by MRS at 9.4 tesla and compared to those of transgenic mice that overexpress the normal human ataxin-1 (the SCA1[30Q] line) and wild-type controls. Multiple neurochemicals distinguished the SCA1[82Q] mice from controls with no overlap at all ages. Six neurochemicals were significantly different in SCA1[82Q] mice at 6 weeks, prior to major pathological and neurological changes. Alterations in NAA, myo-inositol and glutamate progressively worsened and were significantly correlated (p < 0.0001) with disease progression as assessed by histology (molecular layer thickness and an overall severity score). Therefore, the neurochemicals that correlate with clinical status in patients reflected progressive pathology in the mouse model. These data demonstrate that pre-symptomatic and progressive neurodegeneration in SCA1 can be non-invasively monitored using MRS.
PMCID: PMC2846771  PMID: 20220018
SCA1; mouse model; MRS; cerebellum; ataxia; neurodegeneration
23.  Human Brain Glycogen Metabolism During and After Hypoglycemia 
Diabetes  2009;58(9):1978-1985.
We tested the hypotheses that human brain glycogen is mobilized during hypoglycemia and its content increases above normal levels (“supercompensates”) after hypoglycemia.
We utilized in vivo 13C nuclear magnetic resonance spectroscopy in conjunction with intravenous infusions of [13C]glucose in healthy volunteers to measure brain glycogen metabolism during and after euglycemic and hypoglycemic clamps.
After an overnight intravenous infusion of 99% enriched [1-13C]glucose to prelabel glycogen, the rate of label wash-out from [1-13C]glycogen was higher (0.12 ± 0.05 vs. 0.03 ± 0.06 μmol · g−1 · h−1, means ± SD, P < 0.02, n = 5) during a 2-h hyperinsulinemic-hypoglycemic clamp (glucose concentration 57.2 ± 9.7 mg/dl) than during a hyperinsulinemic-euglycemic clamp (95.3 ± 3.3 mg/dl), indicating mobilization of glucose units from glycogen during moderate hypoglycemia. Five additional healthy volunteers received intravenous 25–50% enriched [1-13C]glucose over 22–54 h after undergoing hyperinsulinemic-euglycemic (glucose concentration 92.4 ± 2.3 mg/dl) and hyperinsulinemic-hypoglycemic (52.9 ± 4.8 mg/dl) clamps separated by at least 1 month. Levels of newly synthesized glycogen measured from 4 to 80 h were higher after hypoglycemia than after euglycemia (P ≤ 0.01 for each subject), indicating increased brain glycogen synthesis after moderate hypoglycemia.
These data indicate that brain glycogen supports energy metabolism when glucose supply from the blood is inadequate and that its levels rebound to levels higher than normal after a single episode of moderate hypoglycemia in humans.
PMCID: PMC2731528  PMID: 19502412
24.  The Effects of Resident and Nursing Home Characteristics on Activities of Daily Living 
Existing studies on the relationships between impairments and activities of daily living (ADLs) in nursing home residents have serious limitations. This study examines the relationships among admission impairments, including pain, depression, incontinence, balance, and falls, and follow-up ADLs, as well as the effect of the nursing home on follow-up ADLs of extended-stay nursing home residents.
This longitudinal cohort study consisted of 4,942 extended-stay residents who were admitted into 377 Minnesota nursing homes during 2004. General linear mixed models were used for all analyses, with 14 resident-level and 8 facility-level control variables.
Incontinence and balance function at admission were significantly associated with increases in ADL dependence at follow-up. Individual nursing homes had independent effects on all three ADL models. Similar findings were found after facility-level control variables were added.
Incontinence predicts subsequent ADL functional levels. The relationship between balance dysfunction and subsequent ADL dependence could be causal. Future studies of the causal relationships between impairments and ADL should examine the effectiveness of impairment interventions on ADL as well as these relationships in different subgroups of nursing home residents.
PMCID: PMC2657168  PMID: 19201787
Nursing homes; Activities of daily living; Impairments; Incontinence; Falls
25.  Neurochemical changes in the rat prefrontal cortex following acute phencyclidine treatment: an in vivo localized 1H MRS study† 
NMR in biomedicine  2009;22(7):737-744.
Acute phencyclidine (PCP) administration mimics some aspects of schizophrenia in rats, such as behavioral alterations, increased dopaminergic activity and prefrontal cortex dysfunction. In this study, we used single-voxel 1H-MRS to investigate neurochemical changes in rat prefrontal cortex in vivo before and after an acute injection of PCP. A short-echo time sequence (STEAM) was used to acquire spectra in a 32-μL voxel positioned in the prefrontal cortex area of 12 rats anesthetized with isoflurane. Data were acquired for 30 min before and for 140 min after a bolus of PCP (10 mg/kg, n=6) or saline (n=6). Metabolites were quantified with the LCModel. Time courses for 14 metabolites were obtained with a temporal resolution of 10 min. The glutamine/glutamate ratio was significantly increased after PCP injection (p < 0.0001, pre- vs. post-injection), while the total concentration of these two metabolites remained constant. Glucose was transiently increased (±70%) while lactate decreased after the injection (both p < 0.0001). Lactate, but not glucose and glutamine, returned to baseline levels after 140 min. These results show that an acute injection of PCP leads to changes in glutamate and glutamine concentrations, similar to what has been observed in schizophrenic patients, and after ketamine administration in humans. MRS studies of this pharmacological rat model may be useful for assessing the effects of potential anti-psychotic drugs in vivo.
PMCID: PMC2732191  PMID: 19338025
PCP; prefrontal cortex; glutamine; glutamate; 1H MRS

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