Increased [18F]Fluorodeoxyglucose Uptake in the Left Pallidum in Military Veterans with Blast-Related Mild Traumatic Brain Injury: Potential as an Imaging Biomarker and Mediation with Executive Dysfunction and Cognitive Impairment.

Blast-related mild traumatic brain injury (blast-mTBI) can result in a spectrum of persistent symptoms leading to substantial functional impairment and reduced quality of life. Clinical evaluation and discernment from other conditions common to military service can be challenging and subject to patient recall bias and the limitations of available assessment measures. The need for objective biomarkers to facilitate accurate diagnosis, not just for symptom management and rehabilitation but for prognostication and disability compensation purposes is clear. Toward this end, we compared regional brain [18F]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) intensity-scaled uptake measurements and motor, neuropsychological, and behavioral assessments in 79 combat Veterans with retrospectively recalled blast-mTBI with 41 control participants having no lifetime history of TBI. Using an agnostic and unbiased approach, we found significantly increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI versus control participants, p < 0.0001; q = 3.29 × 10-9 [Cohen's d, 1.38, 95% confidence interval (0.96, 1.79)]. The degree of left pallidum [18F]FDG-uptake correlated with the number of self-reported blast-mTBIs, r2 = 0.22; p < 0.0001. Greater [18F]FDG-uptake in the left pallidum provided excellent discrimination between Veterans with blast-mTBI and controls, with a receiver operator characteristic area under the curve of 0.859 (p < 0.0001) and likelihood ratio of 21.19 (threshold:SUVR ≥ 0.895). Deficits in executive function assessed using the Behavior Rating Inventory of Executive Function-Adult Global Executive Composite T-score were identified in Veterans with blast-mTBI compared with controls, p < 0.0001. Regression-based mediation analyses determined that in Veterans with blast-mTBI, increased [18F]FDG-uptake in the left pallidum-mediated executive function impairments, adjusted causal mediation estimate p = 0.021; total effect estimate, p = 0.039. Measures of working and prospective memory (Auditory Consonant Trigrams test and Memory for Intentions Test, respectively) were negatively correlated with left pallidum [18F]FDG-uptake, p < 0.0001, with mTBI as a covariate. Increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI compared with controls did not covary with dominant handedness or with motor activity assessed using the Unified Parkinson's Disease Rating Scale. Localized increased [18F]FDG-uptake in the left pallidum may reflect a compensatory response to functional deficits following blast-mTBI. Limited imaging resolution does not allow us to distinguish subregions of the pallidum; however, the significant correlation of our data with behavioral but not motor outcomes suggests involvement of the ventral pallidum, which is known to regulate motivation, behavior, and emotions through basal ganglia-thalamo-cortical circuits. Increased [18F]FDG-uptake in the left pallidum in blast-mTBI versus control participants was consistently identified using two different PET scanners, supporting the generalizability of this finding. Although confirmation of our results by single-subject-to-cohort analyses will be required before clinical deployment, this study provides proof of concept that [18F]FDG-PET bears promise as a readily available noninvasive biomarker for blast-mTBI. Further, our findings support a causative relationship between executive dysfunction and increased [18F]FDG-uptake in the left pallidum.

Reduced Glx and GABA Inductions in the Anterior Cingulate Cortex and Caudate Nucleus Are Related to Impaired Control of Attention in Attention-Deficit/Hyperactivity Disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that impairs the control of attention and behavioral inhibition in affected individuals. Recent genome-wide association findings have revealed an association between glutamate and GABA gene sets and ADHD symptoms. Consistently, people with ADHD show altered glutamate and GABA content in the brain circuitry that is important for attention control function. Yet, it remains unknown how glutamate and GABA content in the attention control circuitry change when people are controlling their attention, and whether these changes can predict impaired attention control in people with ADHD. To study these questions, we recruited 18 adults with ADHD (31-51 years) and 16 adults without ADHD (28-54 years). We studied glutamate + glutamine (Glx) and GABA content in the fronto-striatal circuitry while participants performed attention control tasks. We found that Glx and GABA concentrations at rest did not differ between participants with ADHD or without ADHD. However, while participants were performing the attention control tasks, participants with ADHD showed smaller Glx and GABA increases than participants without ADHD. Notably, smaller GABA increases in participants with ADHD significantly predicted their poor task performance. Together, these findings provide the first demonstration showing that attention control deficits in people with ADHD may be related to insufficient responses of the GABAergic system in the fronto-striatal circuitry.

Diffusion Tensor Imaging Changes Do Not Affect Long-Term Neurodevelopment following Early Erythropoietin among Extremely Preterm Infants in the Preterm Erythropoietin Neuroprotection Trial.

We aimed to evaluate diffusion tensor imaging (DTI) in infants born extremely preterm, to determine the effect of erythropoietin (Epo) on DTI, and to correlate DTI with neurodevelopmental outcomes at 2 years of age for infants in the Preterm Erythropoietin Neuroprotection (PENUT) Trial. Infants who underwent MRI with DTI at 36 weeks postmenstrual age were included. Neurodevelopmental outcomes were evaluated by Bayley Scales of Infant and Toddler Development (BSID-III). Generalized linear models were used to assess the association between DTI parameters and treatment group, and then with neurodevelopmental outcomes. A total of 101 placebo- and 93 Epo-treated infants underwent MRI. DTI white matter mean diffusivity (MD) was lower in placebo- compared to Epo-treated infants in the cingulate and occipital regions, and occipital white matter fractional isotropy (FA) was lower in infants born at 24-25 weeks vs. 26-27 weeks. These values were not associated with lower BSID-III scores. Certain decreases in clustering coefficients tended to have lower BSID-III scores. Consistent with the PENUT Trial findings, there was no effect on long-term neurodevelopment in Epo-treated infants even in the presence of microstructural changes identified by DTI.

Paclitaxel Reduces Brain Injury from Repeated Head Trauma in Mice.

Repetitive mild traumatic brain injury (rmTBI) is known to disturb axonal integrity and may play an important role in the pathogenic cascades leading to neurodegeneration. One critical approach to reduce the future onset of neurodegeneration is to intervene in this process at an early stage following a brain injury. Previously we showed that direct application of the microtubule-stabilizing drug, paclitaxel, on the brain following controlled cortical impact improved motor function and reduced lesion size. Herein, we extended these findings to a model of mild brain injury induced by repeated closed-skull impacts. Paclitaxel was administered intranasally to circumvent its poor transport across the blood-brain barrier. Mice received five mild closed-skull impacts (one per day for five days). Intranasal paclitaxel was administered once only, immediately after the first impact. We found that paclitaxel prevented injury-induced deficits in a spatial memory task in a water tread maze. In vivo magnetic resonance imaging (MRI) and positron emission tomography with 18F-flurodeoxyglucose (FDG-PET) revealed that paclitaxel prevented structural injury and hypometabolism. On MRI, apparent, injury-induced microbleeds were observed in 100% of vehicle-treated rmTBI mice, but not in paclitaxel-treated subjects. FDG-PET revealed a 42% increase in whole brain glucose metabolism in paclitaxel-treated mice as compared to vehicle-treated rmTBI. Immunohistochemistry found reduced evidence of axonal injury and synaptic loss. Our results indicate that intranasal paclitaxel administration imparts neuroprotection against brain injury and cognitive impairment in mice. The results from this study support the idea that microtubule-stabilization strategies hold therapeutic promise in mitigating traumatic brain injury.

Behavioral and brain evidence for language by ear, mouth, eye, and hand and motor skills in literacy learning.

Two studies were conducted of students with and without persisting Specific Learning Disabilities (SLDs-WL) in Grades 4 to 9 (M = 11 years, 11 months) that supported the hypotheses that CELF 4 parent ratings for listening (language by ear), speaking (language by mouth), reading (language by eye), and writing (language by hand) were correlated with both (a) normed, standardized behavioral measures of listening, speaking, reading, and writing achievement (Study 1, 94 boys and 61 girls); and (b) fMRI connectivity or DTI white matter integrity involving brain regions for primary motor functions or motor planning and control, or motor timing in a subsample of right handers who did not wear metal (Study 2, 28 boys and 16 girls). Results of these assessment studies, which have implications for planning instruction for three SLDs-WL (dysgraphia, dyslexia, and oral and written language learning disability [OWL LD]), show that more than multisensory instruction is relevant. Language by ear, by mouth, by eye, and by hand, as well as motor planning, control, and output skills and motor timing should also be considered. Research is also reviewed that supports other processes beyond multisensory input alone that should also be considered for students with SLDs-WL.

Some new angles on the magic angle: what MSK radiologists know and don't know about this phenomenon.

PURPOSE: Magic angle effects (MAE) are well-recognized in musculoskeletal (MSK) MRI. With short TE acquisitions, the signal intensity of tendons, ligaments, and menisci depend on their orientation relative to the main magnetic field (B0). An interactive resident physics teaching module simulating MR imaging of a tendon forced us to identify and correct several misconceptions we had about MAE. We suspected these misconceptions were shared by other MSK radiologists. MATERIALS AND METHODS: We surveyed members of the Society of Academic Bone Radiologists (SABR) regarding which pulse sequences, acquisition parameters, tissues and angles relative to B0 were most likely to produce MAE. RESULTS: Survey respondents knew that MAE strongly depend on TE and commonly appear on T1W, FSE and PD sequences, but were less aware that MAE may also appear on T2W, STIR and DWI sequences. They knew of MAE effects in tendons, ligaments and cartilage, but were less aware of those in entheses, peripheral nerves and intervertebral discs. Respondents underestimated the wide angular range (full-width at half-maximum ≈ 40∘) over which significant MAE can be seen with short TE. CONCLUSIONS: Collagen-containing tissues with parallel molecular alignment exhibit increased signal intensity when oriented at 55∘ relative to B0. Experienced MSK radiologists were found to underestimate the combinations of image parameters, pulse sequences, tissues and collagen orientations in which significant MAE may be seen. Our survey results highlight the need for ongoing MR physics education for practicing radiologists.

Brain's functional network clustering coefficient changes in response to instruction (RTI) in students with and without reading disabilities: Multi-leveled reading brain's RTI.

In students in grades 4 to 9 (22 males, 20 females), two reading disability groups-dyslexia (n = 20) or oral and written language learning disability (OWL LD) (n = 6)-were compared to each other and two kinds of control groups-typical readers (n = 6) or dysgraphia (n = 10) on word reading/spelling skills and fMRI imaging before and after completing 18 computerized reading lessons. Mixed ANOVAs showed significant time effects on repeated measures within participants and between groups effects on three behavioral markers of reading disabilities-word reading/spelling: All groups improved on the three behavioral measures, but those without disabilities remained higher than those with reading disabilities. On fMRI reading tasks, analyzed for graph theory derived clustering coefficients within a neural network involved in cognitive control functions, on a word level task the time × group interaction was significant in right medial cingulate; on a syntax level task the time × group interaction was significant in left superior frontal and left inferior frontal gyri; and on a multi-sentence text level task the time × group interaction was significant in right middle frontal gyrus. Three white matter-gray matter correlations became significant only after reading instruction: axial diffusivity in left superior frontal region with right inferior frontal gyrus during word reading judgments; mean diffusivity in left superior corona radiata with left middle frontal gyrus during sentence reading judgments; and mean diffusivity in left anterior corona radiata with right middle frontal gyrus during multi-sentence reading judgments. Significance of results for behavioral and brain response to reading instruction (RTI) is discussed.

Right Forceps Minor and Anterior Thalamic Radiation Predict Executive Function Skills in Young Bilingual Adults.

Executive function (EF) skills enhance learning across domains, and are particularly linked to the acquisition of a second language. Previous studies have shown that bilingual individuals show enhanced EF skills in cognitive tasks where they attended a targeted dimension of a stimulus while inhibiting other competing cues. Brain imaging revealed that bilingual young adults' performances in the Stroop color-naming task were related to the volume of anterior cingulate cortex (ACC) and inferior frontal lobe. Subjects who had greater white-matter in the frontal cortex showed enhanced performances in the same task, suggesting that brain fiber pathways connecting ACC to the frontal region may be related to the Stroop color-naming task. No studies to date have examined the tissue properties of brain fiber pathways connecting these brain regions and their association with subjects' EF performances. Importantly, there are no data establishing whether bilingual subjects exhibit different reaction times when words are presented in their first versus second language. To study these questions, we used behavioral and unbiased whole-brain analyses, recruiting 21 Chinese students. Using the Stroop color-naming task, we measured subjects' reaction times (RTs) in which color names were displayed using fonts that matched the named color (congruent task) or mismatched the color (incongruent task). Students performed the task twice, first in English, the subjects' second language, then in Chinese, the subjects' primary language. Results from whole-brain analysis showed that students' RTs in both the English and Chinese tasks were significantly correlated with the mode of anisotropy (MO) in a brain cluster containing the forceps minor and anterior thalamic radiation in the right hemisphere. We also found that fractional anisotropy (FA) significantly predicted students' RTs, with higher FA predicting shorter RT. Taken together, our findings demonstrate that right forceps minor and anterior thalamic radiation predict EF skills, suggesting that this brain feature may be important for young bilingual adults using their first and second languages to direct their attention when conflicting cues are present.

Brain and Behavioral Assessment of Executive Functions for Self-Regulating Levels of Language in Reading Brain.

This brief research report examines brain-behavioral relationships specific to levels of language in the complex reading brain. The first specific aim was to examine prior findings for significant fMRI connectivity from four seeds (left precuneus, left occipital temporal, left supramarginal, left inferior frontal) for each of four levels of language-subword, word (word-specific spelling or affixed words), syntax (with and without homonym foils or affix foils), and multi-sentence text to identify significant fMRI connectivity (a) unique to the lower level of language when compared to the immediately higher adjacent level of language across subword-word, word-syntax, and syntax-text comparisons; and (b) involving a brain region associated with executive functions. The second specific aim was to correlate the magnitude of that connectivity with standard scores on tests of Focused Attention (D-K EFS Color Word Form Inhibition) and Switching Attention (Wolf & Denckla Rapid Automatic Switching). Seven correlations were significant. Focused Attention was significantly correlated with the word level (word-specific spellings of real words) fMRI task in left cingulum from left inferior frontal seed. Switching Attention was significantly correlated with the (a) subword level (grapheme-phoneme correspondence) fMRI task in left and right Cerebellum V from left supramarginal seed; (b) the word level (word-specific spelling) fMRI task in right Cerebellum V from left precuneus seed; (c) the syntax level (with and without homonym foils) fMRI task in right Cerebellum V from left precuneus seed and from left supramarginal seed; and (d) syntax level (with and without affix foils) fMRI task in right Cerebellum V from left precuneus seed. Results are discussed in reference to neuropsychological assessment of supervisory attention (focused and switching) for specific levels of language related to reading acquisition in students with and without language-related specific learning disabilities and self-regulation of the complex reading brain.

The Neurobiological Mechanism of Chemical Aversion (Emetic) Therapy for Alcohol Use Disorder: An fMRI Study.

A recent NIH epidemiology study found the lifetime prevalence of alcohol use disorder in the United States to be 29%. Alcohol drinking behavior is strongly "learned" via pleasure center activation/reinforcement. Alcohol craving is a powerful desire to drink alcoholic beverages. Craving was added as one of the defining criteria for alcohol use disorder in DSM5, and craving reduction is becoming an increasingly important treatment goal. In the current study, patients with alcohol use disorder received 10 days of inpatient multi-modal treatments at Schick Shadel Hospital (SSH) of Seattle. The treatments included five chemical aversion conditioning sessions that associated alcohol cues (and alcohol) with nausea and emesis. All patients met DSM4 criteria for alcohol use disorder, were heavy drinkers, and reported craving alcohol pre-treatment. Craving reduction was one of the primary treatment goals. This is the first fMRI study to measure the effects of chemical aversion therapy on alcohol craving-related brain activity. Patients were recruited as subjects for the University of Washington (UW) brain scan study following SSH admission but before treatment onset. Prior to treatment, patients reported craving/desire for alcohol. After treatment (after four SSH chemical aversion treatments, again after five SSH chemical treatments, 30 and 90-days post-discharge), these same patients reported avoidance/aversion to alcohol. Most of the participants (69%) reported being still sober 12 months post-treatment. Consistent with a craving reduction mechanism of how chemical aversion therapy facilitates sobriety, results of the UW fMRI brain scans showed significant pre- to post-treatment reductions in craving-related brain activity in the occipital cortex. Additional fMRI brain scan studies are needed to further explore the neurobiological mechanism of chemical aversion therapy treatment for alcohol use disorder, and other substance use disorders for which chemical aversion therapy is used (e.g., opioid dependence and cocaine dependence). Substance use disorders are estimated to affect well over one billion people worldwide.

Changes in DTI Diffusivity and fMRI Connectivity Cluster Coefficients for Students with and without Specific Learning Disabilities In Written Language: Brain's Response to Writing Instruction.

Before and after computerized writing instruction, participants completed assessment with normed measures and DTI and fMRI connectivity scanning. Evidence-based differential diagnosis was used at time 1 to assign them to diagnostic groups: typical oral and written language (n=6), dysgraphia (impaired handwriting, n=10), dyslexia (impaired word spelling and reading, n=20), and OWL LD (impaired syntax construction, n=6). The instruction was aimed at subword letter writing, word spelling, and syntax composing. With p <.001 to control for multiple comparisons, the following significant findings were observed in academic achievement, DTI (radial diffusivity RD, axial diffusivity AD, and mean diffusivity MD), and graph cluster coefficients for fMRI connectivity. A time effect (pre-post intervention increase) in handwriting and oral construction of sentence syntax was significant; but diagnostic group effects were significant for dictated spelling and creation of word-specific spellings, with the dyslexia and OWL LD groups scoring lower than the typical control or dysgraphia groups. For RD a time effect occurred in anterior corona radiata and superior frontal. For AD a time effect occurred in superior corona radiata, superior frontal region, middle frontal gyrus, and superior longitudinal fasciculus. For MD a time effect occurred in the same regions as AD and also anterior coronal radiata. A diagnostic group effect occurred for graph cluster coefficients in fMRI connectivity while writing the next letter in alphabet from memory; but the diagnostic group × time interaction was not significant. The only significant time × treatment interaction occurred in right inferior frontal gyrus associated with orthographic coding. Compared to time 1, cluster coefficients increased at time 2 in all groups except in the dysgraphia group in which they decreased. Implications of results are discussed for response to instruction (RTI) versus evidence-based differential diagnosis for identifying students with SLDs in writing which may be best understood at both the behavioral and brain levels of analysis.

Self-government of complex reading and writing brains informed by cingulo-opercular network for adaptive control and working memory components for language learning.

To understand mental self-government of the developing reading and writing brain, correlations of clustering coefficients on fMRI reading or writing tasks with BASC 2 Adaptivity ratings (time 1 only) or working memory components (time 1 before and time 2 after instruction previously shown to improve achievement and change magnitude of fMRI connectivity) were investigated in 39 students in grades 4 to 9 who varied along a continuum of reading and writing skills. A Philips 3T scanner measured connectivity during six leveled fMRI reading tasks (subword-letters and sounds, word-word-specific spellings or affixed words, syntax comprehension-with and without homonym foils or with and without affix foils, and text comprehension) and three fMRI writing tasks-writing next letter in alphabet, adding missing letter in word spelling, and planning for composing. The Brain Connectivity Toolbox generated clustering coefficients based on the cingulo-opercular (CO) network; after controlling for multiple comparisons and movement, significant fMRI connectivity clustering coefficients for CO were identified in 8 brain regions bilaterally (cingulate gyrus, superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus, superior temporal gyrus, insula, cingulum-cingulate gyrus, and cingulum-hippocampus). BASC2 Parent Ratings for Adaptivity were correlated with CO clustering coefficients on three reading tasks (letter-sound, word affix judgments and sentence comprehension) and one writing task (writing next letter in alphabet). Before instruction, each behavioral working memory measure (phonology, orthography, morphology, and syntax coding, phonological and orthographic loops for integrating internal language and output codes, and supervisory focused and switching attention) correlated significantly with at least one CO clustering coefficient. After instruction, the patterning of correlations changed with new correlations emerging. Results show that the reading and writing brain's mental government, supported by both CO Adaptive Control and multiple working memory components, had changed in response to instruction during middle childhood/early adolescence.

Brain white matter structure and COMT gene are linked to second-language learning in adults.

Adult human brains retain the capacity to undergo tissue reorganization during second-language learning. Brain-imaging studies show a relationship between neuroanatomical properties and learning for adults exposed to a second language. However, the role of genetic factors in this relationship has not been investigated. The goal of the current study was twofold: (i) to characterize the relationship between brain white matter fiber-tract properties and second-language immersion using diffusion tensor imaging, and (ii) to determine whether polymorphisms in the catechol-O-methyltransferase (COMT) gene affect the relationship. We recruited incoming Chinese students enrolled in the University of Washington and scanned their brains one time. We measured the diffusion properties of the white matter fiber tracts and correlated them with the number of days each student had been in the immersion program at the time of the brain scan. We found that higher numbers of days in the English immersion program correlated with higher fractional anisotropy and lower radial diffusivity in the right superior longitudinal fasciculus. We show that fractional anisotropy declined once the subjects finished the immersion program. The relationship between brain white matter fiber-tract properties and immersion varied in subjects with different COMT genotypes. Subjects with the Methionine (Met)/Valine (Val) and Val/Val genotypes showed higher fractional anisotropy and lower radial diffusivity during immersion, which reversed immediately after immersion ended, whereas those with the Met/Met genotype did not show these relationships. Statistical modeling revealed that subjects' grades in the language immersion program were best predicted by fractional anisotropy and COMT genotype.

Repetitive blast exposure in mice and combat veterans causes persistent cerebellar dysfunction.

Blast exposure can cause mild traumatic brain injury (TBI) in mice and other mammals. However, there are important gaps in our understanding of the neuropathology underlying repetitive blast exposure in animal models compared to the neuroimaging abnormalities observed in blast-exposed veterans. Moreover, how an increase in the number of blast exposures affects neuroimaging endpoints in blast-exposed humans is not well understood. We asked whether there is a dose-response relationship between the number of blast-related mild TBIs and uptake of (18)F-fluorodeoxyglucose (FDG), a commonly used indicator of neuronal activity, in the brains of blast-exposed veterans with mild TBI. We found that the number of blast exposures correlated with FDG uptake in the cerebellum of veterans. In mice, blast exposure produced microlesions in the blood-brain barrier (BBB) predominantly in the ventral cerebellum. Purkinje cells associated with these BBB microlesions displayed plasma membrane disruptions and aberrant expression of phosphorylated tau protein. Purkinje cell loss was most pronounced in the ventral cerebellar lobules, suggesting that early-stage breakdown of BBB integrity may be an important factor driving long-term brain changes. Blast exposure caused reactive gliosis in mouse cerebellum, particularly in the deep cerebellar nuclei. Diffusion tensor imaging tractography of the cerebellum of blast-exposed veterans revealed that mean diffusivity correlated negatively with the number of blast-related mild TBIs. Together, these results argue that the cerebellum is vulnerable to repetitive mild TBI in both mice and humans.

Neuroanatomy of Handwriting and Related Reading and Writing Skills in Adults and Children with and without Learning Disabilities: French-American Connections.

In this article, we present recent neuroimaging studies performed to identify the neural network involved in handwriting. These studies, carried out in adults and in children, suggest that the mastery of handwriting is based on the involvement of a network of brain structures whose involvement and inter-connection are specific to writing alphabet characters. This network is built upon the joint learning of writing and reading and depends on the level of expertise of the writer. In addition, a part of this graphomotor network is also brought into play during the identification letters during visual reading. These skills are also the basis for the development of more complex language activities involving orthographic knowledge and composition of texts. The studies presented cover two perspectives: that of neuroscience and that of cognitive psychology, as both are necessary to understand a complex process of writing and both depend on natural interactions and the influence of educational exposure.

Posterior Cingulate Lactate as a Metabolic Biomarker in Amnestic Mild Cognitive Impairment.

Mitochondrial dysfunction represents a central factor within the pathogenesis of the Alzheimer's disease (AD) spectrum. We hypothesized that in vivo measurements of lactate (lac), a by-product of glycolysis, would correlate with functional impairment and measures of brain health in a cohort of 15 amnestic mild cognitive impairment (aMCI) individuals. Lac was quantified from the precuneus/posterior cingulate (PPC) using 2-dimensional J-resolved magnetic resonance spectroscopy (MRS). Additionally, standard behavioral and imaging markers of aMCI disease progression were acquired. PPC lac was negatively correlated with performance on the Wechsler logical memory tests and on the minimental state examination even after accounting for gray matter, cerebral spinal fluid volume, and age. No such relationships were observed between lac and performance on nonmemory tests. Significant negative relationships were also noted between PPC lac and hippocampal volume and PPC functional connectivity. Together, these results reveal that aMCI individuals with a greater disease progression have increased concentrations of PPC lac. Because lac is upregulated as a compensatory response to mitochondrial impairment, we propose that J-resolved MRS of lac is a noninvasive, surrogate biomarker of impaired metabolic function and would provide a useful means of tracking mitochondrial function during therapeutic trials targeting brain metabolism.

Paclitaxel improves outcome from traumatic brain injury.

Pharmacologic interventions for traumatic brain injury (TBI) hold promise to improve outcome. The purpose of this study was to determine if the microtubule stabilizing therapeutic paclitaxel used for more than 20 years in chemotherapy would improve outcome after TBI. We assessed neurological outcome in mice that received direct application of paclitaxel to brain injury from controlled cortical impact (CCI). Magnetic resonance imaging was used to assess injury-related morphological changes. Catwalk Gait analysis showed significant improvement in the paclitaxel group on a variety of parameters compared to the saline group. MRI analysis revealed that paclitaxel treatment resulted in significantly reduced edema volume at site-of-injury (11.92 ± 3.0 and 8.86 ± 2.2mm(3) for saline vs. paclitaxel respectively, as determined by T2-weighted analysis; p ≤ 0.05), and significantly increased myelin tissue preservation (9.45 ± 0.4 vs. 8.95 ± 0.3, p ≤ 0.05). Our findings indicate that paclitaxel treatment resulted in improvement of neurological outcome and MR imaging biomarkers of injury. These results could have a significant impact on therapeutic developments to treat traumatic brain injury.

Effects of dietary fat and saturated fat content on liver fat and markers of oxidative stress in overweight/obese men and women under weight-stable conditions.

Dietary fat and oxidative stress are hypothesized to contribute to non-alcoholic fatty liver disease and progression to steatohepatitis. To determine the effects of dietary fat content on hepatic triglyceride, body fat distribution and markers of inflammation and oxidative stress, overweight/obese subjects with normal glucose tolerance consumed a control diet (CONT: 35% fat/12% saturated fat/47% carbohydrate) for ten days, followed by four weeks on a low fat (LFD (n = 10): 20% fat/8% saturated fat/62% carbohydrate) or high fat diet (HFD (n = 10): 55% fat/25% saturated fat/27% carbohydrate). Hepatic triglyceride content was quantified by MRS and abdominal fat distribution by MRI. Fasting biomarkers of inflammation (plasma hsCRP, IL-6, IL-12, TNFα, IFN-γ) and oxidative stress (urinary F2-α isoprostanes) were measured. Body weight remained stable. Compared to the CONT, hepatic triglyceride decreased on the LFD (mean (95% CI): change -2.13% (-3.74%, -0.52%)), but did not change on the HFD and there was no significant difference between the LFD and HFD. Intra-abdominal fat did not change significantly on either diet, but subcutaneous abdominal fat increased on the HFD. There were no significant changes in fasting metabolic markers, inflammatory markers and urinary F2-α isoprostanes. We conclude that in otherwise healthy overweight/obese adults under weight-neutral conditions, a diet low in fat and saturated fat has modest effects to decrease liver fat and may be beneficial. On the other hand, a diet very high in fat and saturated fat had no effect on hepatic triglyceride or markers of metabolism, inflammation and oxidative stress.

Transcranial Doppler-based assessment of cerebral autoregulation in critically ill children during diabetic ketoacidosis treatment.

OBJECTIVES: Impaired cerebral autoregulation may be associated with poor outcome in diabetic ketoacidosis. We examined change in cerebral autoregulation during diabetic ketoacidosis treatment. DESIGN: Prospective observational cohort study. SETTING: Tertiary care children's hospital. PATIENTS/SUBJECTS: Children admitted to the ICU with diabetic ketoacidosis (venous pH < 7.3, glucose > 300 mg/dL, HCO3 < 15 mEq/L, and ketonuria) constituted cases, and children with type I diabetes without diabetic ketoacidosis constituted controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between 2005 and 2009, 32 cases and 50 controls were enrolled. Transcranial Doppler ultrasonography was used to measure middle cerebral artery flow velocities, and cerebral autoregulation testing was achieved via tilt-table testing. Cases underwent two and controls underwent one cerebral autoregulation test. Cerebral autoregulation was quantified by the autoregulatory index (autoregulatory index < 0.4 = impaired and autoregulatory index 0.4-1.0 = intact autoregulation). The first autoregulation test was obtained early (time 1, 12-24 hr; median [interquartile range], 8 hr [5-18 hr]) during diabetic ketoacidosis treatment, and a second autoregulation test was obtained during recovery (time 2, 36-72 hr; median [ interquartile range], 46 hr [40-59 hr]) from time 0 (defined as time of insulin start). Cases had lower autoregulatory index at time 1 than time 2 (p < 0.001) as well lower autoregulatory index than control subjects (p < 0.001). Cerebral autoregulation was impaired in 40% (n = 13) of cases at time 1 and in 6% (n = 2) of cases at time 2. Five cases (17%) showed persistent impairment of cerebral autoregulation between times 1 and 2 of treatment. All control subjects had intact cerebral autoregulation. CONCLUSIONS: Impaired cerebral autoregulation was common early during diabetic ketoacidosis treatment. Although the majority improved during diabetic ketoacidosis treatment, 17% of subjects had impairment between 36 and 72 hours after start of insulin therapy. The observed impaired cerebral autoregulation appears specific to the diabetic ketoacidosis process in patients with type I diabetes.

Activity of P-Glycoprotein, a ß-Amyloid Transporter at the Blood-Brain Barrier, Is Compromised in Patients with Mild Alzheimer Disease.

UNLABELLED: Studies in animals and postmortem human brain tissue support a role for P-glycoprotein in clearance of cerebral ß-amyloid across the blood-brain barrier (BBB). We tested the hypothesis that BBB P-glycoprotein activity is diminished in Alzheimer disease (AD) by accounting for an AD-related reduction in regional cerebral blood flow (rCBF). METHODS: We compared P-glycoprotein activity in mild-AD patients (n = 9) and cognitively normal, age-matched controls (n = 9) using PET with a labeled P-glycoprotein substrate, (11)C-verapamil, and (15)O-water to measure rCBF. BBB P-glycoprotein activity was expressed as the (11)C-verapamil radioactivity extraction ratio ((11)C-verapamil brain distributional clearance, K1/rCBF). RESULTS: Compared with controls, BBB P-glycoprotein activity was significantly lower in the parietotemporal, frontal, and posterior cingulate cortices and hippocampus of mild AD subjects. CONCLUSION: BBB P-glycoprotein activity in brain regions affected by AD is reduced and is independent of rCBF. This study improves on prior work by eliminating the confounding effect that reduced rCBF has on assessment of BBB P-glycoprotein activity and suggests that impaired P-glycoprotein activity may contribute to cerebral ß-amyloid accumulation in AD. P-glycoprotein induction or activation to increase cerebral ß-amyloid clearance could constitute a novel preventive or therapeutic strategy for AD.