Frontal Lobe White Matter Research Articles

Frontal lobe metabolic alterations in autism spectrum disorder: a 1H-magnetic resonance spectroscopy study.

PurposeRecently, neuroimaging studies were performed using 1H-magnetic resonance spectroscopy (1H-MRS), revealing a quantitative alteration of neurochemicals (such as neurotransmitters and metabolites) in several brain regions of patients with autism spectrum disorder (ASD). The involvement of the frontal lobe in the neurobiology of ASD has long been documented in the literature. Therefore, the aim of this study was to analyze the alterations of N-acetylaspartate/creatine (NAA/Cr) and choline/Cr (Cho/Cr) ratios in the frontal lobe subcortical white matter (WM) in ASD patients, in order to reveal any alteration of metabolites that might be the expression of specific clinical features of the disorder.Patients and methodsAn 1H-MRS study of the frontal lobe subcortical WM was performed in 75 children with ASD and in 50 age-matched controls to evaluate the functional activity of this brain region.ResultsNAA/Cr and Cho/Cr ratios were significantly altered in ASD, compared to control subjects. Moreover, in the ASD group, NAA/Cr was significantly lower in patients with a cognitive impairment.ConclusionResults from this study confirm the existence of brain metabolites’ alterations in frontal lobe WM in children with ASD, supporting the relevance of this brain region in the clinical expressions of this disorder, including its role in the cognitive impairment. Further 1H-MRS investigations will allow to comprehensively explain the relationship between metabolic alteration in a specific brain region and specific clinical features of ASD.

Effects of Uric Acid on the Alterations of White Matter Connectivity in Patients with Major Depression.

Objective Uric acid is a non-enzymatic antioxidant associated with depression. Despite its known protective role in other brain disorders, little is known about its influence on the structural characteristics of brains of patients with major depressive disorder (MDD). This study explored the association between uric acid and characteristics of white matter (WM) in patients with MDD. Methods A total of 32 patients with MDD and 23 healthy controls (HCs) were examined. All participants were scored based on the Beck Depression Inventory and Beck Anxiety Inventory at baseline. All patients were also rated with the Hamilton Depression Rating Scale. We collected blood samples from all participants immediately after their enrollment and before the initiation of antidepressants in case of patients. Tract-based spatial statistics were used for all imaging analyses. Results Lower fractional anisotropy (FA) and higher radial diffusivity (RD) values were found in the MDD group than in the HC group. Voxelwise correlation analysis revealed that the serum uric acid levels positively correlated with the FA and negatively with the RD in WM regions that previously showed significant group differences in the MDD group. The correlated areas were located in the left anterior corona radiata, left frontal lobe WM, and left anterior cingulate cortex WM. Conclusion The present study suggests a significant association between altered WM connectivity and serum uric acid levels in patients with MDD, possibly through demyelination.

Does bilingualism increase brain or cognitive reserve in patients with temporal lobe epilepsy?

Bilingual healthy adults have been shown to exhibit an advantage in executive functioning (EF) that is associated with microstructural changes in white matter (WM) networks. Patients with temporal lobe epilepsy (TLE) often show EF deficits that are associated with WM compromise. In this study, we investigate whether bilingualism can increase cognitive reserve and/or brain reserve in bilingual patients with TLE, mitigating EF impairment and WM compromise. Diffusion tensor imaging was obtained in 19 bilingual and 26 monolingual patients with TLE, 12 bilingual healthy controls (HC), and 21 monolingual HC. Fractional anisotropy (FA) and mean diffusivity (MD) were calculated for the uncinate fasciculus (Unc) and cingulum (Cing), superior frontostriatal tract (SFS), and inferior frontostriatal tract (IFS). Measures of EF included Trail Making Test-B (TMT-B) and Delis-Kaplan Executive Function System Color-Word Inhibition/Switching. Analyses of covariance were conducted to compare FA and MD of the Unc, Cing, SFS, and IFS and EF performance across groups. In bilingual patients, FA was lower in the ipsilateral Cing and Unc compared to all other groups. For both patient groups, MD of the ipsilateral Unc was higher relative to HC. Despite more pronounced reductions in WM integrity, bilingual patients performed similarly to monolingual TLE and both HC groups on EF measures. By contrast, monolingual patients performed worse than HC on TMT-B. In addition, differences in group means between bilingual and monolingual patients on TMT-B approached significance when controlling for the extent of WM damage (P = .071; d = 0.62), suggesting a tendency toward higher performance for bilingual patients. Despite poorer integrity of regional frontal lobe WM, bilingual patients performed similarly to monolingual patients and HC on EF measures. These findings align with studies suggesting that bilingualism may provide a protective factor for individuals with neurological disease, potentially through reorganization of EF networks that promote greater cognitive reserve.

Clinical and imaging characteristics of subacute combined degeneration complicated with white matter lesions in the brain: a report of five cases

Purpose: To report five cases of subacute combined degeneration (SCD) with brain involvement and explore its clinical and imaging characteristics.Methods: A retrospective study was performed on the clinical data and brain MRI of five patients with subacute combined degeneration with brain involvement (out of 107 cases with SCD in total). White matter lesions (WML) assessment was performed qualitatively using Fazekas scale score.Results: The main symptoms in four patients were weakness in both lower extremities and unstable walking (limb weakness in three patients, dizziness in three patients, and blurred vision in one patient). One patient had memory loss and cognitive dysfunction. The MMSE scale indicated mild dementia in one patient. On head MRI (Magnetic Resonance Imaging), multifocal and symmetrical high signals of T2WI and FLAIR were observed in the frontal lobe and periventricular white matter in four patients, while another patient showed preferential atrophy in frontal regions. Fazekas scale scores ranged from 1–6.Conclusion: Adult subacute combined degeneration seldom involves the brain. Multifocal and symmetrical high signal white matter lesions can be found on FLAIR and T2WI, as well as frontal atrophy on head MRI.

Association of Cerebrospinal Fluid Biomarkers of Central Nervous System Injury With Neurocognitive and Brain Imaging Outcomes in Children Receiving Chemotherapy for Acute Lymphoblastic Leukemia

Little is known about treatment-related neurotoxic mechanisms in children with acute lymphoblastic leukemia (ALL) treated with chemotherapy only. To examine concentration of cerebrospinal fluid (CSF) biomarkers of brain injury at ALL diagnosis and during cancer therapy and to evaluate associations with long-term neurocognitive and neuroimaging outcomes and relevant genetic polymorphisms. This prospective cohort study included 235 patients with ALL who received a chemotherapy-only protocol. Patients provided CSF samples after diagnosis and throughout treatment. At 5 or more years after the diagnosis, 138 (69.7%) of 198 eligible survivors participated in long-term follow-up assessments. Children were treated from June 1, 2000, through October 31, 2010. Follow-up was completed on October 21, 2014, and data were analyzed from August 1, 2015, through September 30, 2016. Plasma concentration of high-dose intravenous methotrexate sodium and number of triple intrathecal chemotherapy injections. The CSF samples were assayed at 5 points from diagnosis to reinduction for biomarkers of myelin degradation (myelin basic protein [MBP]), neuronal damage (nerve growth factor [NGF] and total and phosphorylated tau protein), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuroinflammation (chitotriosidase). DNA was genotyped for polymorphisms in drug metabolism, oxidative stress, and neurodevelopment. Leukoencephalopathy was evaluated by brain imaging. At 5 or more years after the diagnosis, survivors completed neurocognitive testing and brain imaging of white matter integrity. Among the 235 patients with CSF samples (120 boys [51.1%] and 115 girls [48.9%]; mean [SD] age at diagnosis, 6.8 [4.7] years), MBP and GFAP levels were elevated at baseline and through consolidation. The number of intrathecal injections was positively correlated with NGF level increase at consolidation (r = 0.19; P = .005). Increases in GFAP (risk ratio [RR], 1.23; 95% CI, 1.09-1.40), MBP (RR, 1.06; 95% CI, 1.01-1.11), and total tau (RR, 1.76; 95% CI, 1.11-2.78) levels were associated with a higher risk for leukoencephalopathy and higher apparent diffusion coefficient in frontal lobe white matter 5 years after diagnosis (standardized estimate, 0.05; P < .001). Increase in total tau at consolidation was associated with worse attention (omissions z score estimate, -0.20; P = .04). Glial injury may be present at diagnosis of ALL. Neuronal injury was associated with intrathecal chemotherapy. The CSF biomarkers may be useful in identifying individuals at risk for worse neurologic outcomes, particularly those with genetic susceptibility to poor brain function.

The long-term effect of erythropoiesis stimulating agents given to preterm infants: a proton magnetic resonance spectroscopy study on neurometabolites in early childhood.

Erythropoiesis stimulating agents (ESAs) are neuroprotective in cell and animal models of preterm birth. Prematurity has been shown to alter neurometabolite levels in children in studies using proton magnetic resonance spectroscopy (1H-MRS). We hypothesized that ESA treatment in premature infants would tend to normalize neurometabolites by 4-6years of age. Children in a longitudinal study of neurodevelopment underwent MRI and 1H-MRS at approximately 4years and 6years of age. Prematurely born children (500-1,250g birth weight) received ESAs (erythropoietin or darbepoetin) or placebo during their neonatal hospitalization, and these groups were compared to healthy term controls. 1H-MRS spectra were obtained from the anterior cingulate (gray matter) and frontal lobe white matter, assessing combined N-acetylaspartate and N-acetylaspartylglutamate (tNAA), myo-inositol, choline compounds (Cho), combined creatine and phosphocreatine, and combined glutamate and glutamine. No significant (P≤0.5) group differences were observed for any metabolite level. Significant age-related increases in white-matter tNAA and Cho were observed, as well as a trend for increased gray-matter tNAA. Neither prematurity nor neonatal ESA treatment was associated with differences in brain metabolite levels in the children of this study at a significance level of 0.05. These findings suggest that earlier differences that might have existed had normalized by 4-6years of age or were too small to be statistically significant in the current sample.

Longitudinal structural and molecular neuroimaging in agrammatic primary progressive aphasia.

The agrammatic variant of primary progressive aphasia affects normal grammatical language production, often occurs with apraxia of speech, and is associated with left frontal abnormalities on cross-sectional neuroimaging studies. We aimed to perform a detailed assessment of longitudinal change on structural and molecular neuroimaging to provide a complete picture of neurodegeneration in these patients, and to determine how patterns of progression compare to patients with isolated apraxia of speech (primary progressive apraxia of speech). We assessed longitudinal structural MRI, diffusion tensor imaging and 18F-fluorodeoxyglucose PET in 11 agrammatic aphasia subjects, 20 primary progressive apraxia of speech subjects, and 62 age and gender-matched controls with two serial assessments. Rates of change in grey matter volume and hypometabolism, and white matter fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity were assessed at the voxel-level and for numerous regions of interest. The greatest rates of grey matter atrophy in agrammatic aphasia were observed in inferior, middle, and superior frontal gyri, premotor and motor cortices, as well as medial temporal lobe, insula, basal ganglia, and brainstem compared to controls. Longitudinal decline in metabolism was observed in the same regions, with additional findings in medial and lateral parietal lobe. Diffusion tensor imaging changes were prominent bilaterally in inferior and middle frontal white matter and superior longitudinal fasciculus, as well as right inferior fronto-occipital fasciculus, superior frontal and precentral white matter. More focal patterns of degeneration of motor and premotor cortex were observed in primary progressive apraxia of speech. Agrammatic aphasia showed greater rates of grey matter atrophy, decline in metabolism, and white matter degeneration compared to primary progressive apraxia of speech in the left frontal lobe, predominantly inferior and middle frontal grey and white matter. Correlations were also assessed between rates of change on neuroimaging and rates of clinical decline. Progression of aphasia correlated with rates of degeneration in frontal and temporal regions within the language network, while progression of parkinsonism and limb apraxia correlated with degeneration of motor cortex and brainstem. These findings demonstrate that disease progression in agrammatic aphasia is associated with widespread neurodegeneration throughout regions of the language network, as well as connecting white matter tracts, but also with progression to regions outside of the language network that are responsible for the development of motor symptoms. The fact that patterns of progression differed from primary progressive apraxia of speech supports the clinical distinction of these syndromes.

Imaging mass spectrometry of frontal white matter lipid changes in human alcoholics.

Chronic alcohol use disorders (AUD) are associated with white matter (WM) degeneration with altered myelin integrity. Matrix assisted laser desorption ionization-imaging mass spectrometry (MALDI-IMS) enables high throughput analysis of myelin lipid biochemical histopathology to help characterize disease mechanisms. This study utilized MALDI-IMS to investigatefrontal lobe WM myelin lipid abnormalities in AUD. Standardized cores of formalin-fixed WM from Brodmann Area 4 (BA4) and BA8/9 of 20 postmortem AUD and 19 control adult human brains were embedded in carboxymethyl-cellulose, cryo-sectioned (8μm), thaw-mounted onto indium tin oxide (ITO) -coated glass slides, and sublimed with 2,5-dihydroxybenzxoic acid (DHB) matrix. Lipids were imaged by MALDI-time of flight in the negative ionization mode. Data were visualized with FlexImaging software v4.0 and analyzed with ClinProTools v3.0. Principal component analysis (PCA) and data bar plots of MALDI-IMS data differentiated AUD from control WM. The dominant effect of AUD was to broadly reduce expression of sphingolipids (sulfatides and ceramides) and phospholipids. Data bar plots demonstrated overall similar responses to AUD in BA4 and BA8/9. However, differential regional effects of AUD on WM lipid profiles were manifested by non-overlapping expression or discordant responses to AUD for a subset of lipid ions. Human AUD is associated with substantial inhibition of frontal lobe WM lipid expression with regional variability in these effects. MALDI-IMS can be used to characterize the nature of AUD-associated lipid biochemical abnormalities for correlation with lifetime exposures and WM degeneration, altered gene expression, and responses to abstinence or treatment.

Biomarkers of brain injury and neurologic outcomes in children treated with chemotherapy for acute lymphoblastic leukemia (ALL).

10521 Background: Little is known about neurotoxic mechanisms associated with chemotherapy in children with ALL. Cerebrospinal fluid (CSF) biomarkers of brain injury may provide insight into this process. Methods: 235 patients (51% male; mean [SD] age diagnosed 6.8 [4.7] years) treated on a chemotherapy only protocol provided CSF samples following diagnosis and through consolidation. CSF was assayed for biomarkers of myelin degradation (myelin basic protein [MBP]), neuronal damage (nerve growth factor [NGF], total-Tau [T-Tau]) and astrogliosis (glial fibrillary acidic protein [GFAP]). Leukoencephalopathy was evaluated by brain MRI’s during therapy. At ≥5 years post-diagnosis, 138 (70%) of the 198 still eligible survivors (without relapse and unrelated neurologic injury) completed neurocognitive testing and brain diffusion tensor imaging of white matter integrity at age 13.6 [4.6] years. Log-binomial and general linear models were used to examine whether biomarker changes from baseline through consolidation were related to serum methotrexate exposure, acute leukoencephalopathy, and long-term brain outcomes. Results: NGF and T-Tau increased from baseline to consolidation ( P's &lt; 0.001), while MBP and GFAP were elevated at baseline and remained so through consolidation. The number of intrathecal injections (methotrexate, hydrocortisone, cytarabine) was positively correlated with NGF increase at consolidation ( P= 0.005). Increases in GFAP (RR 1.2; 95% CI [1.0 – 1.4]), MBP (RR 1.1 [1.0 – 1.1]) and T-Tau (RR 1.8 [1.1 – 2.8]) were related to higher risk for acute leukoencephalopathy, and higher diffusivity in frontal lobe white matter at ≥5 years post-diagnosis ( P’s &lt; 0.05). Increase in T-Tau at consolidation was associated with worse long-term sustained attention ( P= 0.03), and visual- ( P= 0.04) and visual-motor ( P= 0.02) processing speed. Conclusions: Glial injury, which is evident at diagnosis, may be related to leukemia and methotrexate exposure. Neuronal injury is associated with intrathecal chemotherapy and long-term neurocognitive and brain imaging outcomes. Monitoring CSF biomarkers may be useful in identifying individuals at risk for poor neurological outcomes.

Author response: Cognitive reserve in frontotemporal degeneration: Neuroanatomic and neuropsychological evidence.

Letter fluency is a verbally mediated measure of executive control and we agree that it is a complex task. In our study, we demonstrated in patients with frontotemporal degeneration (FTD) that higher cognitive reserve (CR) and higher frontal gray matter density are selectively associated with superior performance on letter fluency and not on the Boston Naming Test.1 Prior work demonstrated that inferior frontal gyrus and frontal lobe white matter support letter fluency task performance.2,3 Our observations converge with these prior demonstrations.

Advanced MRI techniques: biomarkers in neuropsychiatric lupus.

Objectives The objective of this study was to determine whether advanced MRI could provide biomarkers for diagnosis and prognosis in neuropsychiatric systemic lupus erythematosus (NPSLE). Methods Our prospective study included 28 systemic lupus erythematosus (SLE) patients with primary central NPSLE, 22 patients without NPSLE and 20 healthy controls. We used visual scales to evaluate atrophy and white matter hyperintensities, voxel-based morphometry and Freesurfer to measure brain volume, plus diffusion-tensor imaging (DTI) to assess white matter (WM) and gray matter (GM) damage. We compared the groups and correlated MRI abnormalities with clinical data. Results NPSLE patients had less GM and WM than controls ( p = 0.042) in the fronto-temporal regions and corpus callosum. They also had increased diffusivities in the temporal lobe WM ( p < 0.010) and reduced fractional anisotropy in the right frontal lobe WM ( p = 0.018). High clinical scores, longstanding disease, and low serum C3 were associated with atrophy, lower fractional anisotropy and higher diffusivity in the fronto-temporal lobes. Antimalarial treatment correlated negatively with atrophy in the frontal cortex and thalamus; it was also associated with lower diffusivity in the fronto-temporal WM clusters. Conclusions Atrophy and microstructural damage in fronto-temporal WM and GM in NPSLE correlate with severity, activity and the time from disease onset. Antimalarial treatment seems to give some brain-protective effects.

White matter correlates of psychosis-linked traits support continuity between personality and psychopathology.

The link between diagnoses of psychotic disorders and attenuated white matter connectivity is well established, but little is known about the degree to which similar white matter differences predict traits linked to psychosis-proneness in the general population. Moreover, intelligence is too rarely considered as a covariate in neural endophenotype studies, despite its known protective role against psychopathology in general and its associations with broad aspects of neural structure and function. To determine whether psychosis-linked personality traits are linearly associated with white matter microstructure, we examined white matter correlates of Psychoticism, Absorption, and Openness to Experience in a large community sample, covarying for sex, age, and IQ. Findings support our hypothesis that the white matter correlates of the shared variance of these traits overlap substantially with the frontal lobe white matter connectivity patterns characteristic of psychotic spectrum disorders. These findings provide biological support for the notion that liability to psychosis is distributed throughout the population, is evident in brain structure, and manifests as normal personality variation at subclinical levels. (PsycINFO Database Record

Brain metabolite alterations in infants born preterm with intrauterine growth restriction: association with structural changes and neurodevelopmental outcome

Intrauterine growth restriction and premature birth represent 2 independent problems that may occur simultaneously and contribute to impaired neurodevelopment. The objective of the study was to assess changes in the frontal lobe metabolic profiles of 1 year old intrauterine growth restriction infants born prematurely and adequate-for-gestational-age controls, both premature and term adequate for gestational age and their association with brain structural and biophysical parameters and neurodevelopmental outcome at 2 years. A total of 26 prematurely born intrauterine growth restriction infants (birthweight <10th centile for gestational age), 22 prematurely born but adequate for gestational age controls, and 26 term adequate-for-gestational-age infants underwent brain magnetic resonance imaging and magnetic resonance spectroscopy at 1 year of age during natural sleep, on a 3 Tesla scanner. All brain T1-weighted and diffusion-weighted images were acquired along with short echo time single-voxel proton spectra from the frontal lobe. Magnetic resonance imaging/magnetic resonance spectroscopy data were processed to derive structural, biophysical, and metabolic information, respectively. Neurodevelopment was evaluated at 2 years of age using the Bayley Scales 3rd edition, assessing cognitive, language, motor, socioemotional, and adaptive behavior. Prematurely born intrauterine growth restriction infants had slightly smaller brain volumes and increased frontal lobe white matter mean diffusivity compared with both prematurely born but adequate for gestational age and term adequate for gestational age controls. Frontal lobe N-acetylaspartate levels were significantly lower in prematurely born intrauterine growth restriction than in prematurely born but adequate for gestational age infants but increased in prematurely born but adequate for gestational age compared with term adequate-for-gestational-age infants. The prematurely born intrauterine growth restriction group also showed slightly lower choline compounds, borderline decrements of estimated glutathione levels, and increased myoinositol to choline ratios, compared with prematurely born but adequate for gestational age controls. These specific metabolite changes were locally correlated to lower gray matter content and increased mean diffusivity and reduced white matter fraction and fractional anisotropy. Prematurely born intrauterine growth restriction infants also showed a tendency for poorer neurodevelopmental outcome at 2 years, associated with lower levels of frontal lobe N-acetylaspartate at 1year within the preterm subset. Preterm intrauterine growth restriction infants showed altered brain metabolite profiles during a critical stage of brainmaturation, which correlate with brain structural and biophysical parameters and neurodevelopmental outcome. Our results suggest alteredneurodevelopmental trajectories in preterm intrauterine growth restriction and adequate-for-gestational-age infants, compared with termadequate-for-gestational-age infants, which require further characterization.

Progressive Focal Gray Matter Volume Loss in a Former High School Football Player: A Possible Magnetic Resonance Imaging Volumetric Signature for Chronic Traumatic Encephalopathy

Here a case is presented of a 51-year-old former high school football player with multiple concussions, including one episode with loss of consciousness. The patient experienced 6 years of cognitive and mood decline, and his wife corroborated increasing memory loss, attentional difficulties, and depressed mood without suicidal ideation. He had been unable to maintain full-time employment because of progressive decline. Based on his presentation, he had been previously diagnosed with attention deficit hyperactivity disorder and bipolar disorder, type II. Neuropsychological tests indicated domain-specific cognitive impairment, and longitudinal volumetric magnetic resonance imaging (MRI) of the brain showed progressive brainstem, diencephalic, and frontal lobe atrophy. This regional volume loss correlated with the increased signal seen on tau and amyloid imaging (FDDNP-PET scan) of a separate case of suspected chronic traumatic encephalopathy (CTE). Visual assessment of the MRI also showed evidence of old petechial hemorrhages in the frontal and temporal-parietal lobe white matter. This case raises the possibility of distinct quantitative and visual brain MRI findings in suspected CTE.

Dietary Nitrate and the Epidemiology of Cardiovascular Disease: Report From a National Heart, Lung, and Blood Institute Workshop.

In view of continuing unanswered questions regarding the geographical and demographic distribution of cardiovascular disease, and recent discoveries about the effects of dietary nitrate on cardiovascular physiology, the National Heart, Lung, and Blood Institute (NHLBI) convened a workshop to

LIPOPOLYSACCHARIDE AND E. COLI PROTEINS AND DNA IN ALZHEIMER’S DISEASE BRAINS COMPARED TO CONTROLS

Amyloid plaques in Alzheimer's disease (AD) are believed to be derived in part from clevage products of amyloid precursor protein (APP). However, Gram-negative Escherichia coli (E. coli) bacteria and other microorganisms can form extracellular amyloid. Moreover, administration of Gram-negative bacterial derived Lipopolysaccharide (LPS) followed by ischemia and hypoxia produce plaque-like aggregates of myelin and amyloid ß in adult rat brains. These findings led us to examine human brain for LPS and E. coli proteins and DNA. Brain samples from superior temporal gyrus gray matter and frontal lobe white matter were studied from AD patients (n=24) and age-matched controls (n=18). LPS and E. coli proteins including K99 pili protein were evaluated by Western blots and immunocytochemistry. DNA from human brains was assessed for E. coli DNA. LPS and E. coli K99 were detected immunocytochemically in brain parenchyma and vessels in all AD and control brains. K99 levels by Western blots were greater in AD compared to control brains (p < 0.01) and K99 was localized to neurons in AD but not control brains. LPS co-localized with Aß1-40/42 in amyloid plaques and with Aß1-40/42 around vessels in AD brains. E. coli DNA or the E. coli K99 pili protein were detected in 9/10 control and 13/13 AD brains. LPS and E. coli bacterial proteins and DNA are found in control and AD brains. LPS co-localization with Aß1-40/42 in amyloid plaques and around vessels in AD brain suggest that LPS and/or other bacterial components could play a role in AD pathogenesis.

Cigarette Smoke-Induced Alterations in Frontal White Matter Lipid Profiles Demonstrated by MALDI-Imaging Mass Spectrometry: Relevance to Alzheimer's Disease.

Meta-analysis has shown that smokers have significantly increased risks for Alzheimer's disease (AD), and neuroimaging studies showed that smoking alters white matter (WM) structural integrity. Herein, we characterize the effects of cigarette smoke (CS) exposures and withdrawal on WM myelin lipid composition using matrix assisted laser desorption and ionization-imaging mass spectrometry (MALDI-IMS). Young adult male A/J mice were exposed to air (8 weeks; A8), CS (4 or 8 weeks; CS4, CS8), or CS8 followed by 2 weeks recovery (CS8 + R). Frontal lobe WM was examined for indices of lipid and protein oxidation and lipid profile alterations by MALDI-IMS. Lipid ions were identified by MS/MS with the LIPID MAPS prediction tools database. Inter-group comparisons were made using principal component analysis and R-generated heatmap. CS increased lipid and protein adducts such that higher levels were present in CS8 compared with CS4 samples. CS8 + R reversed CS8 effects and normalized the levels of oxidative stress. MALDI-IMS demonstrated striking CS-associated alterations in WM lipid profiles characterized by either reductions or increases in phospholipids (phosphatidylinositol, phosphatidylserine, phosphatidylcholine, or phosphatidylethanolamine) and sphingolipids (sulfatides), and partial reversal of CS's inhibitory effects with recovery. The heatmap hierarchical dendrogram and PCA distinguished CS exposure, duration, and withdrawal effects on WM lipid profiles. CS-mediated WM degeneration is associated with lipid peroxidation, protein oxidative injury, and alterations in myelin lipid composition, including shifts in phospholipids and sphingolipids needed for membrane integrity, plasticity, and intracellular signaling. Future goals are to delineate WM abnormalities in AD using MALDI-IMS, and couple the findings with MRI-mass spectroscopy to improve in vivo diagnostics and early detection of brain biochemical responses to treatment.

Comparison of Diffusion Tensor Imaging and Magnetic Resonance Perfusion Imaging in Differentiating Recurrent Brain Neoplasm From Radiation Necrosis

To compare differences in diffusion tensor imaging (DTI) and dynamic susceptibility-weighted contrast-enhanced (DSC) magnetic resonance (MR) perfusion imaging characteristics of recurrent neoplasm and radiation necrosis in patients with brain tumors previously treated with radiotherapy with or without surgery and chemotherapy. Patients with a history of brain neoplasm previously treated with radiotherapy with or without chemotherapy and surgery who developed a new enhancing lesion on posttreatment surveillance MRI were enrolled. DSC perfusion MRI and DTI were performed. Region of interest cursors were manually drawn in the contrast-enhancing lesions, in the perilesional white matter edema, and in the contralateral normal-appearing frontal lobe white matter. DTI and DSC perfusion MR indices were compared in recurrent tumor versus radiation necrosis. Twenty-two patients with 24 lesions were included. Sixteen (67%) lesions were placed into the recurrent neoplasm group and eight (33%) lesions were placed into the radiation necrosis group using biopsy results as the gold standard in all but three patients. Mean apparent diffusion coefficient values, mean parallel eigenvalues, and mean perpendicular eigenvalues in the contrast-enhancing lesion were significantly lower, and relative cerebral blood volume was significantly higher for the recurrent neoplasm group compared to the radiation necrosis group (P < 0.01, P = 0.03, P < 0.01, and P < 0.01, respectively). The combined assessment of DTI and DSC MR perfusion properties of new contrast-enhancing lesions is helpful in distinguishing recurrent neoplasm from radiation necrosis in patients with a history of brain neoplasm previously treated with radiotherapy with or without surgery and chemotherapy.

NeuN+ neuronal nuclei in non-human primate prefrontal cortex and subcortical white matter after clozapine exposure

Increased neuronal densities in subcortical white matter have been reported for some cases with schizophrenia. The underlying cellular and molecular mechanisms remain unresolved.We exposed 26 young adult macaque monkeys for 6months to either clozapine, haloperidol or placebo and measured by structural MRI frontal gray and white matter volumes before and after treatment, followed by observer-independent, flow-cytometry-based quantification of neuronal and non-neuronal nuclei and molecular fingerprinting of cell-type specific transcripts.After clozapine exposure, the proportion of nuclei expressing the neuronal marker NeuN increased by approximately 50% in subcortical white matter, in conjunction with a more subtle and non-significant increase in overlying gray matter. Numbers and proportions of nuclei expressing the oligodendrocyte lineage marker, OLIG2, and cell-type specific RNA expression patterns, were maintained after antipsychotic drug exposure. Frontal lobe gray and white matter volumes remained indistinguishable between antipsychotic-drug-exposed and control groups.Chronic clozapine exposure increases the proportion of NeuN+ nuclei in frontal subcortical white matter, without alterations in frontal lobe volumes or cell type-specific gene expression. Further exploration of neurochemical plasticity in non-human primate brain exposed to antipsychotic drugs is warranted.

A study of diffusion tensor imaging in Duchenne muscular dystrophy

Objective To observe the white matter and gray matter impairment of Duchenne muscular dstrophy (DMD) patients with diffusion tensor imaging (DTI). Methods Forteen male patients with DMD (6-11 years old) and 10 age-matched healthy boys participated into this study. All patients' diagnosis was based on typical signs and symptoms, serum creatine kinase (CK), electromyography, multiplex ligation-dependent probe amplification (MLPA) for DMD gene test and muscle biopsy results. All participants were scanned by DTI. The fractional anisotropy (FA) values of regions of interest (ROIs), including bilateral parietal lobe white matter, bilateral frontal lobe white matter, genu of corpus callosum, splenium of corpus callosum, bilateral caput nuclei caudati, bilateral anterior cingulate gyrus, bilateral cingulate gyrus, bilateral posterior cingulate gyrus, bilateral lenticular nucleus, bilateral anterior limb of internal capsule, bilateral posterior limb of internal capsule, bilateral thalamus, bilateral occipital lobe whitematter, bilateral temporal lobe white matter, bilateral hippocampus, bilateral superior cerebellar peduncle and bilateral middle cerebellar peduncle, were measured. The data was analyzed and compared between control group and DMD group. Results Compared with control group, the FA value of splenium of corpuscallosum in DMD group was significantly reduced (t = -2.187, P = 0.045). No significant difference was found in FA values of other ROIs between 2 groups (P > 0.05, for all). Conclusions It is found in China for the first time that DMD patients had microstructural changes in splenium of corpus callosum. However, the correlation between this change and cognitive changes of DMD patients remains to be further studied. DOI: 10.3969/j.issn.1672-6731.2015.05.006