Fatigue in Multiple Sclerosis: Assessing Pontine Involvement Using Proton MR Spectroscopic Imaging

Background/Objective

The underlying mechanism of fatigue in multiple sclerosis (MS) remains poorly understood. Our study investigates the involvement of the ascending reticular activating system (ARAS), originating in the pontine brainstem, in MS patients with symptoms of fatigue.

Methods

Female relapsing-remitting MS patients (n = 17) and controls (n = 15) underwent a magnetic resonance spectroscopic imaging protocol at 1.5T. Fatigue was assessed in every subject using the Fatigue Severity Scale (FSS). Using an FSS cut-off of 36, patients were categorized into a low (n = 9, 22 ± 10) or high (n = 10, 52 ± 6) fatigue group. The brain metabolites N-acetylaspartate (NAA) and total creatine (tCr) were measured from sixteen 5x5x10 mm³ spectroscopic imaging voxels in the rostral pons.

Results

MS patients with high fatigue had lower NAA/tCr concentration in the tegmental pons compared to control subjects. By using NAA and Cr values in the cerebellum for comparison, these NAA/tCr changes in the pons were driven by higher tCr concentration, and that these changes were focused in the WM regions.

Discussion/Conclusion

Since there were no changes in NAA concentration, the increase in tCr may be suggestive of gliosis, or an imbalanced equilibrium of the creatine and phosphocreatine ratio in the pons of relapsing-remitting MS patients with fatigue.     

Elevated pontine and putamenal GABA levels in mild-moderate Parkinson disease detected by 7 tesla proton MRS

Background

Parkinson disease (PD) is characterized by the degeneration of nigrostriatal dopaminergic neurons. However, postmortem evidence indicates that the pathology of lower brainstem regions, such as the pons and medulla, precedes nigral involvement. Consistently, pontomedullary damage was implicated by structural and PET imaging in early PD. Neurochemical correlates of this early pathological involvement in PD are unknown.

Methodology/Principal Finding

To map biochemical alterations in the brains of individuals with mild-moderate PD we quantified neurochemical profiles of the pons, putamen and substantia nigra by 7 tesla (T) proton magnetic resonance spectroscopy. Thirteen individuals with idiopathic PD (Hoehn & Yahr stage 2) and 12 age- and gender-matched healthy volunteers participated in the study. γ-Aminobutyric acid (GABA) concentrations in the pons and putamen were significantly higher in patients (N = 11, off medications) than controls (N = 11, p<0.001 for pons and p<0.05 for putamen). The GABA elevation was more pronounced in the pons (64%) than in the putamen (32%). No other neurochemical differences were observed between patients and controls.

Conclusion/Significance

The GABA elevation in the putamen is consistent with prior postmortem findings in patients with PD, as well as with in vivo observations in a rodent model of PD, while the GABA finding in the pons is novel. The more significant GABA elevation in the pons relative to the putamen is consistent with earlier pathological involvement of the lower brainstem. This study provides in vivo evidence for an alteration in the GABAergic tone in the lower brainstem and striatum in early-moderate PD, which may underlie disease pathogenesis and may provide a biomarker for disease staging.     

Neural Mechanisms Underlying Breathing Complexity

Breathing is maintained and controlled by a network of automatic neurons in the brainstem that generate respiratory rhythm and receive regulatory inputs. Breathing complexity therefore arises from respiratory central pattern generators modulated by peripheral and supra-spinal inputs. Very little is known on the brainstem neural substrates underlying breathing complexity in humans. We used both experimental and theoretical approaches to decipher these mechanisms in healthy humans and patients with chronic obstructive pulmonary disease (COPD). COPD is the most frequent chronic lung disease in the general population mainly due to tobacco smoke. In patients, airflow obstruction associated with hyperinflation and respiratory muscles weakness are key factors contributing to load-capacity imbalance and hence increased respiratory drive. Unexpectedly, we found that the patients breathed with a higher level of complexity during inspiration and expiration than controls. Using functional magnetic resonance imaging (fMRI), we scanned the brain of the participants to analyze the activity of two small regions involved in respiratory rhythmogenesis, the rostral ventro-lateral (VL) medulla (pre-Bötzinger complex) and the caudal VL pons (parafacial group). fMRI revealed in controls higher activity of the VL medulla suggesting active inspiration, while in patients higher activity of the VL pons suggesting active expiration. COPD patients reactivate the parafacial to sustain ventilation. These findings may be involved in the onset of respiratory failure when the neural network becomes overwhelmed by respiratory overload We show that central neural activity correlates with airflow complexity in healthy subjects and COPD patients, at rest and during inspiratory loading. We finally used a theoretical approach of respiratory rhythmogenesis that reproduces the kernel activity of neurons involved in the automatic breathing. The model reveals how a chaotic activity in neurons can contribute to chaos in airflow and reproduces key experimental fMRI findings.     

Microstructural Changes across Different Clinical Milestones of Disease in Amyotrophic Lateral Sclerosis

Neurodegenerative process in amyotrophic lateral sclerosis (ALS) has been proven to involve several cortical and subcortical brain regions within and beyond motor areas. However, how ALS pathology spreads progressively during disease evolution is still unknown. In this cross-sectional study we investigated 54 ALS patients, divided into 3 subsets according to the clinical stage, and 18 age and sex-matched healthy controls, by using tract-based spatial statistics (TBSS) diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) analyses. We aimed to identify white (WM) and gray matter (GM) patterns of disease distinctive of each clinical stage, corresponding to specific clinical milestones. ALS cases in stage 2A (i.e., at diagnosis) were characterized by GM and WM impairment of left motor and premotor cortices and brainstem at ponto-mesenchephalic junction. ALS patients in clinical stage 2B (with impairment of two functional regions) exhibited decreased fractional anisotropy (FA) (p<0.001, uncorrected) and increased mean (MD) and radial diffusivity (RD) (p<0.001, uncorrected) in the left cerebellar hemisphere and brainstem precerebellar nuclei, as well as in motor areas, while GM atrophy (p<0.001, uncorrected) was detected only in the left inferior frontal gyrus and right cuneus. Finally, ALS patients in stage 3 (with impairment of three functional regions) exhibited decreased FA and increased MD and RD (p<0.05, corrected) within WM underneath bilateral pre and postcentral gyri, corpus callosum midbody, long associative tracts and midbrain, while no significant clusters of GM atrophy were observed. Our findings reinforce the hypothesis that the neurodegenerative process propagates along the axonal pathways and develops beyond motor areas from early stages, involving progressively several frontotemporal regions and their afferents and efferents, while the detection of GM atrophy in earlier stages and its disappearance in later stages may be the result of reactive gliosis.     

Frontal White Matter Alterations in Short-Term Medicated Panic Disorder Patients without Comorbid Conditions: A Diffusion Tensor Imaging Study

The frontal cortex might play an important role in the fear network, and white matter (WM) integrity could be related to the pathophysiology of panic disorder (PD). A few studies have investigated alterations of WM integrity in PD. The aim of this study was to determine frontal WM integrity differences between patients with PD without comorbid conditions and healthy control (HC) subjects by using diffusion tensor imaging. Thirty-six patients with PD who had used medication within 1 week and 27 age- and sex-matched HC subjects participated in this study. Structural brain magnetic resonance imaging was performed on all participants. Panic Disorder Severity Scale and Beck Anxiety Inventory (BAI) scores were assessed. Tract-based spatial statistics (TBSS) was used for image analysis. TBSS analysis showed decreased fractional anisotropy (FA) in frontal WM and WM around the frontal lobe, including the corpus callosum of both hemispheres, in patients with PD compared to HC subjects. Moreover, voxel-wise correlation analysis revealed that the BAI scores for patients with PD were positively correlated with their FA values for regions showing group differences in the FA of frontal WM of both hemispheres. Altered integrity in frontal WM of patients with PD without comorbid conditions might represent the structural pathophysiology in these patients, and these changes could be related to clinical symptoms of PD.     

Polymorphism of INS VNTR is associated with glutamic acid decarboxylase antibodies and postprandial C-peptide in patients with onset of diabetes after 35 years of age

Variability in the number of tandem repeats of the insulin gene (INS VNTR) is probably involved in the genetic regulation of insulin secretion. The aim of this study was to investigate the association of INS VNTR polymorphism with the presence of glutamic acid decarboxylase antibodies (GADA) and C-peptide levels in patients with the onset of diabetes after 35 years of age. We investigated 117 patients, median of age 63 (range 40-83) years, median of diabetes duration 8 (range 1-30) years; 31 GADA-positive and 86 GADA-negative subjects. INS VNTR polymorphism was typed indirectly using - 23HphI (T/A) polymorphism, which is in complete linkage disequilibrium with INS VNTR. The I/I, I/III and III/III genotypes were found in 22 (71 %), 8 (26 %), 1 (3 %) GADA-positive individuals and in 39 (45 %), 35 (41 %), 12 (14 %) GADA-negative individuals, respectively. The Class I allele and the genotype I/I were significantly associated with the presence of GADA (OR=2.72, CI 95 %=1.29-5.73 and OR=2.95, CI 95 %=1.22-7.13). The presence of Class III allele was significantly associated with a higher level of postprandial C-peptide in GADA-positive subjects, even when regarding the duration of diabetes. Our results of INS VNTR polymorphism in patients with the onset of diabetes after 35 years of age confirm the association of Class I INS VNTR with autoimmune diabetes and the protective effect of Class III INS VNTR on the insulin secretion in GADA-positive subjects.     

Assessing corpus callosum changes in Alzheimer's disease: comparison between tract-based spatial statistics and atlas-based tractography

Tractography based on Diffusion Tensor Imaging (DTI) represents a valuable tool for investigating brain white matter (WM) microstructure, allowing the computation of damage-related diffusion parameters such as Fractional Anisotropy (FA) in specific WM tracts. This technique appears relevant in the study of pathologies in which brain disconnection plays a major role, such as, for instance, Alzheimer's Disease (AD). Previous DTI studies have reported inconsistent results in defining WM abnormalities in AD and in its prodromal stage (i.e., amnestic Mild Cognitive Impairment; aMCI), especially when investigating the corpus callosum (CC). A reason for these inconsistencies is the use of different processing techniques, which may strongly influence the results. The aim of the current study was to compare a novel atlas-based tractography approach, that sub-divides the CC in eight portions, with Tract-Based Spatial Statistics (TBSS) when used to detect specific patterns of CC FA in AD at different clinical stages. FA data were obtained from 76 subjects (37 with mild AD, 19 with aMCI and 20 elderly healthy controls, HC) and analyzed using both methods. Consistent results were obtained for the two methods, concerning the comparisons AD vs. HC (significantly reduced FA in the whole CC of AD patients) and AD vs. aMCI (significantly reduced FA in the frontal portions of the CC in AD patients), thus identifying a relative preservation of the frontal CC regions in aMCI patients compared to AD. Conversely, the atlas-based method but not the TBSS showed the ability to detect a selective FA change in the CC parietal, left temporal and occipital regions of aMCI patients compared to HC. This finding indicates that an analysis including a higher number of voxels (with no restriction to tract skeletons) may detect characteristic pattern of FA in the CC of patients with preclinical AD, when brain atrophy is still modest.     

The Importance of Group-Wise Registration in Tract Based Spatial Statistics Study of Neurodegeneration: A Simulation Study in Alzheimer's Disease

Tract-based spatial statistics (TBSS) is a popular method for the analysis of diffusion tensor imaging data. TBSS focuses on differences in white matter voxels with high fractional anisotropy (FA), representing the major fibre tracts, through registering all subjects to a common reference and the creation of a FA skeleton. This work considers the effect of choice of reference in the TBSS pipeline, which can be a standard template, an individual subject from the study, a study-specific template or a group-wise average. While TBSS attempts to overcome registration error by searching the neighbourhood perpendicular to the FA skeleton for the voxel with maximum FA, this projection step may not compensate for large registration errors that might occur in the presence of pathology such as atrophy in neurodegenerative diseases. This makes registration performance and choice of reference an important issue. Substantial work in the field of computational anatomy has shown the use of group-wise averages to reduce biases while avoiding the arbitrary selection of a single individual. Here, we demonstrate the impact of the choice of reference on: (a) specificity (b) sensitivity in a simulation study and (c) a real-world comparison of Alzheimer''s disease patients to controls. In (a) and (b), simulated deformations and decreases in FA were applied to control subjects to simulate changes of shape and WM integrity similar to what would be seen in AD patients, in order to provide a “ground truth” for evaluating the various methods of TBSS reference. Using a group-wise average atlas as the reference outperformed other references in the TBSS pipeline in all evaluations.     

On the problem of cooperation of the reactions of hands: III. Cooperation of hand reactions to auditory and visual stimuli in patients with focal lesions of the brainstem and diencephalon

The response time (simple mental reaction time) cooperation was estimated in 53 patients with focal lesions of the brainstem and diencephalon (thalamus). The cooperation between the left-and right-hand simple mental reactions to auditory and visual stimuli presented after a warning stimulus was analyzed to determine the morphological structures responsible for the cooperation of responses. The cooperation of the simple mental reaction remained normal in some of the subjects and was disturbed in others. In the latter case, the correlation coefficient between the left-and right-hand simple mental reactions to an auditory or visual stimulus or both stimuli simultaneously was changed. The disturbances were detected in patients with lesions of the tectum at the boundary between the medulla and the pons and in those with affected lateral regions of the thalamus.     

Cerebellum abnormalities in idiopathic generalized epilepsy with generalized tonic-clonic seizures revealed by diffusion tensor imaging

Although there is increasing evidence suggesting that there may be subtle abnormalities in idiopathic generalized epilepsy (IGE) patients using modern neuroimaging techniques, most of these previous studies focused on the brain grey matter, leaving the underlying white matter abnormalities in IGE largely unknown, which baffles the treatment as well as the understanding of IGE. In this work, we adopted multiple methods from different levels based on diffusion tensor imaging (DTI) to analyze the white matter abnormalities in 14 young male IGE patients with generalized tonic-clonic seizures (GTCS) only, comparing with 29 age-matched male healthy controls. First, we performed a voxel-based analysis (VBA) of the fractional anisotropy (FA) images derived from DTI. Second, we used a tract-based spatial statistics (TBSS) method to explore the alterations within the white matter skeleton of the patients. Third, we adopted region-of-interest (ROI) analyses based on the findings of VBA and TBSS to further confirm abnormal brain regions in the patients. At last, considering the convergent evidences we found by VBA, TBSS and ROI analyses, a subsequent probabilistic fiber tractography study was performed to investigate the abnormal white matter connectivity in the patients. Significantly decreased FA values were consistently observed in the cerebellum of patients, providing fresh evidence and new clues for the important role of cerebellum in IGE with GTCS.     

Multimodal Brain Connectivity Analysis in Unmedicated Late-Life Depression

Late-life depression (LLD) is a common disorder associated with emotional distress, cognitive impairment and somatic complains. Structural abnormalities have been suggested as one of the main neurobiological correlates in LLD. However the relationship between these structural abnormalities and altered functional brain networks in LLD remains poorly understood. 15 healthy elderly comparison subjects from the community and 10 unmedicated and symptomatic subjects with geriatric depression were selected for this study. For each subject, 87 regions of interest (ROI) were generated from whole brain anatomical parcellation of resting state fMRI data. Whole-brain ROI-wise correlations were calculated and compared between groups. Group differences were assessed using an analysis of covariance after controlling for age, sex and education with multiple comparison correction using the false discovery rate. Structural connectivity was assessed by tract-based spatial statistics (TBSS). LLD subjects had significantly decreased connectivity between the right accumbens area (rA) and the right medial orbitofrontal cortex (rmOFC) as well as between the right rostral anterior cingulate cortex (rrACC) and bilateral superior frontal gyrus (bsSFG). Altered connectivity of rrACC with the bsSFG was significantly correlated with depression severity in depressed subjects. TBSS analysis showed a 20% reduction in fractional anisotropy (FA) in the right Forceps Minor (rFM) in depressed subjects. rFM FA values were positively correlated with rA-rmOFC and rrACC-bsFG functional connectivity values in our total study sample. Coordinated structural and functional impairment in circuits involved in emotion regulation and reward pathways play an important role in the pathophysiology of LLD.     

Fully Automated Segmentation of the Pons and Midbrain Using Human T1 MR Brain Images

Purpose

This paper describes a novel method to automatically segment the human brainstem into midbrain and pons, called LABS: Landmark-based Automated Brainstem Segmentation. LABS processes high-resolution structural magnetic resonance images (MRIs) according to a revised landmark-based approach integrated with a thresholding method, without manual interaction.

Methods

This method was first tested on morphological T1-weighted MRIs of 30 healthy subjects. Its reliability was further confirmed by including neurological patients (with Alzheimer''s Disease) from the ADNI repository, in whom the presence of volumetric loss within the brainstem had been previously described. Segmentation accuracies were evaluated against expert-drawn manual delineation. To evaluate the quality of LABS segmentation we used volumetric, spatial overlap and distance-based metrics.

Results

The comparison between the quantitative measurements provided by LABS against manual segmentations revealed excellent results in healthy controls when considering either the midbrain (DICE measures higher that 0.9; Volume ratio around 1 and Hausdorff distance around 3) or the pons (DICE measures around 0.93; Volume ratio ranging 1.024–1.05 and Hausdorff distance around 2). Similar performances were detected for AD patients considering segmentation of the pons (DICE measures higher that 0.93; Volume ratio ranging from 0.97–0.98 and Hausdorff distance ranging 1.07–1.33), while LABS performed lower for the midbrain (DICE measures ranging 0.86–0.88; Volume ratio around 0.95 and Hausdorff distance ranging 1.71–2.15).

Conclusions

Our study represents the first attempt to validate a new fully automated method for in vivo segmentation of two anatomically complex brainstem subregions. We retain that our method might represent a useful tool for future applications in clinical practice.     

Brainstem areas involved in the aspiration reflex: c-Fos study in anesthetized cats

Expression of the immediate-early gene c-fos, a marker of neuronal activation was employed in adult anesthetized non-decerebrate cats, in order to localize the brainstem neuronal populations functionally related to sniff-like (gasp-like) aspiration reflex (AR). Tissues were immunoprocessed using an antibody raised against amino acids of Fos and the avidin-biotin peroxidase complex method. The level of Fos-like immunoreactivity (FLI) was identified and counted in particular brainstem sections under light microscopy using PC software evaluations in control, unstimulated cats and in cats where the AR was elicited by repeated mechanical stimulation of the nasopharyngeal region. Fourteen brainstem regions with FLI labeling, including thirty-seven nuclei were compared for the number of labeled cells. Compared to the control, a significantly enhanced FLI was determined bilaterally in animals with the AR, at various medullary levels. The areas included the nuclei of the solitary tract (especially the dorsal, interstitial and ventrolateral subnuclei), the ventromedial part of the parvocellular tegmental field (FTL -- lateral nuclei of reticular formation), the lateral reticular nucleus, the ambigual and para-ambigual regions, and the retrofacial nucleus. FLI was also observed in the gigantocellular tegmental field (FTG -- medial nuclei of reticular formation), the spinal trigeminal nucleus, in the medullar raphe nuclei (ncl. raphealis magnus and parvus), and in the medial and lateral vestibular nuclei. Within the pons, a significant FLI was observed bilaterally in the parabrachial nucleus (especially in its lateral subnucleus), the Kolliker-Fuse nucleus, the nucleus coeruleus, within the medial region of brachium conjunctivum, in the ventrolateral part of the pontine FTG and the FTL. Within the mesencephalon a significantly enhanced FLI was found at the central tegmental field (area ventralis tegmenti Tsai), bilaterally. Positive FLI found in columns extending from the caudal medulla oblongata, through the pons up to the mid-mesencephalon suggests that the aspiration reflex is thus co-ordinated by a long loop of medullary-pontine-mesencephalic control circuit rather than by a unique "center".     

The Microstructural Status of the Corpus Callosum Is Associated with the Degree of Motor Function and Neurological Deficit in Stroke Patients

Human neuroimaging studies and animal models have suggested that white matter damage from ischemic stroke leads to the functional and structural reorganization of perilesional and remote brain regions. However, the quantitative relationship between the transcallosal tract integrity and clinical motor performance score after stroke remains unexplored. The current study employed a tract-based spatial statistics (TBSS) analysis on diffusion tensor imaging (DTI) to investigate the relationship between white matter diffusivity changes and the clinical scores in stroke patients. Probabilistic fiber tracking was also used to identify structural connectivity patterns in the patients. Thirteen ischemic stroke patients and fifteen healthy control subjects participated in this study. TBSS analyses showed that the corpus callosum (CC) and bilateral corticospinal tracts (CST) in the stroke patients exhibited significantly decreased fractional anisotropy and increased axial and radial diffusivity compared with those of the controls. Correlation analyses revealed that the motor and neurological deficit scores in the stroke patients were associated with the value of diffusivity indices in the CC. Compared with the healthy control group, probabilistic fiber tracking analyses revealed that significant changes in the inter-hemispheric fiber connections between the left and right motor cortex in the stroke patients were primarily located in the genu and body of the CC, left anterior thalamic radiation and inferior fronto-occipital fasciculus, bilateral CST, anterior/superior corona radiate, cingulum and superior longitudinal fasciculus, strongly suggesting that ischemic induces inter-hemispheric network disturbances and disrupts the white matter fibers connecting motor regions. In conclusion, the results of the present study show that DTI-derived measures in the CC can be used to predict the severity of motor skill and neurological deficit in stroke patients. Changes in structural connectivity pattern tracking between the left and right motor areas, particularly in the body of the CC, might reflect functional reorganization and behavioral deficit.     

Afferent projections from the brainstem to the area hypothalamica dorsalis: a horseradish peroxidase study in the cat

Experiments using the retrograde transport of horseradish peroxidase were performed in order to identify the cells of origin the ascending projections from different brainstem regions to the area hypothalamica dorsalis (aHd) in the cat. The afferent inputs to this area originate mainly from the midbrain and medulla oblongata regions. The main afferent source of the area hypothalamica dorsalis arises from the substantia grisea centralis, where a large number of labeled cells were observed bilaterally, although more abundant on the ipsilateral side. Substantial afferents reach the aHd from the nuclei vestibularis medialis and inferior and the formatio reticularis mesencephali. A modest number of peroxidase-labeled neurons were observed in the nuclei ruber, interpeduncularis, substantia nigra, reticularis gigantocellularis, vestibularis lateralis, cuneatus and gracilis. From the pons, the nucleus raphe magnus sends a weak projection to the aHd. These anatomical data suggest that such area could be involved in visceral, sexual, nociceptive somatosensorial, sleep-waking and motor mechanisms.     

Nephrotic syndrome unfavorable course correlates with downregulation of podocyte vascular endothelial growth factor receptor (VEGFR)-2

Idiopathic nephrotic syndrome (INS) in children is most commonly caused by primary glomerulopathies. Morphological lesions observed in INS might be secondary to inflammatory factors of mainly extra-renal origin. The vascular endothelial growth factor (VEGF) family is regarded as playing a crucial role in this pathomechanism. The aim of the present work was to analyze the possible relation between VEGF-C and VEGF receptor (VEGFR)-2 expressions at electron microscopy level in different INS cases. The study group comprised 18 children with minimal change disease (MCD), 30 patients diagnosed with diffuse mesangial proliferation (DMP) and 11 subjects with focal segmental glomerulosclerosis (FSGS). An indirect immunohistochemical assay employing monoclonal anti-VEGF-C and anti-VEGFR-2 antibodies was applied in the study. The immunohistochemical expression of VEGF-C within podocyte cytoplasm was significantly increased in DMP subjects who were resistant to steroids and in all FSGS patients compared to MCD children and controls (p 〈 0.05). VEGF-C over-expression in these cases was followed by downregulation of VEGFR-2. Nephrotic syndrome progression correlates with the downregulation of podocyte VEGFR-2. For this reason, decreased VEGFR-2 expression in the podocyte processes of children with idiopathic nephrotic syndrome might be regarded as a potent factor of unfavorable prognosis.     

Antioxidant responses to chronic hypoxia in the rat cerebellum and pons

Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (CIH) and sleep fragmentation and deprivation. Exposure to CIH results in oxidative stress in the cortex, hippocampus and basal forebrain of rats and mice. We show that sustained and intermittent hypoxia induces antioxidant responses, an indicator of oxidative stress, in the rat cerebellum and pons. Increased glutathione reductase (GR) activity and thiobarbituric acid reactive substance (TBARS) levels were observed in the pons and cerebellum of rats exposed to CIH or chronic sustained hypoxia (CSH) compared with room air (RA) controls. Exposure to CIH or CSH increased GR activity in the pons, while exposure to CSH increased the level of TBARS in the cerebellum. The level of TBARS was increased to a greater extent after exposure to CSH than to CIH in the cerebellum and pons. Increased superoxide dismutase activity (SOD) and decreased total glutathione (GSHt) levels were observed after exposure to CIH compared with CSH only in the pons. We have previously shown that prolonged sleep deprivation decreased SOD activity in the rat hippocampus and brainstem, without affecting the cerebellum, cortex or hypothalamus. We therefore conclude that sleep deprivation and hypoxia differentially affect antioxidant responses in different brain regions.     

Beta-endorphin and neurotensin in brainstem and cerebrospinal fluid in the sudden infant death syndrome.

Beta-endorphin (BE) and neurotensin (NT) are two neuropeptides which induce apneas. In infants who died of Sudden Infant Death Syndrome (SIDS) we measured, in brainstem and CSF, BE and NT by IRMA and RIA respectively. BE and NT levels are compared to same aged infant and adult controls. CSF BE level was significantly higher in SIDS than in the two control groups (86 +/- 14 vs 33 +/- 13 and 16 +/- 5 pmol/l). In 6 SIDS victims NT and BE were assayed in 5 brainstem sections, each of them divided in median, intermediate and lateral parts. We found high levels of BE in every fragment (3-11 pmol/mg protein) while NT elevated values were restricted to the mesencephalic regions (1.4-12 pmol/mg), the medial pons (6 pmol/mg) and the intermediate parts of the medulla (including the olive: 1.3-1.6 pmol/mg). These results support the hypothesis that NT and/or BE could induce or participate to the fetal issue of SIDS.     

Extramotor Damage Is Associated with Cognition in Primary Lateral Sclerosis Patients

Objectives

This is a cross-sectional study aimed at investigating cognitive performances in patients with primary lateral sclerosis (PLS) and using diffusion tensor (DT) magnetic resonance imaging (MRI) to determine the topographical distribution of microstructural white matter (WM) damage in patients with or without cognitive deficits.

Methods

DT MRI scans were obtained from 21 PLS patients and 35 age- and sex-matched healthy controls. All PLS patients underwent a comprehensive neuropsychological battery. Tract-based-spatial-statistics (TBSS) was used to perform a whole-brain voxel-wise analysis of fractional anisotropy (FA), axial, radial (radD) and mean diffusivity (MD).

Results

Ten PLS patients had abnormal scores in at least one neuropsychological test (PLS with cognitive deficits, PLS-cd). Compared with healthy controls and cognitively unimpaired PLS patients (PLS-cu), PLS-cd cases showed decreased FA and increased MD and radD in the corticospinal tract (CST), corpus callosum, brainstem, anterior limb of internal capsule, superior and inferior longitudinal fasciculi, fornix, thalamic radiations, and parietal lobes, bilaterally. Compared with healthy controls, PLS-cd patients showed further decreased FA and increased radD in the cerebellar WM, bilaterally. Compared with controls, PLS-cu patients showed decreased FA in the mid-body of corpus callosum. In PLS, executive and language test scores correlated with WM damage.

Conclusions

This is the first study evaluating the relationship between cognitive performance and WM tract damage in PLS patients. PLS can be associated with a multi-domain cognitive impairment. WM damage to interhemispheric, limbic and major associative WM tracts seem to be the structural correlate of cognitive abnormalities in these patients.     

Assessment of Type 1 Diabetes Risk Conferred by HLA-DRB1, INS-VNTR and PTPN22 Genes Using the Bayesian Network Approach

Background

Determining genetic risk is a fundamental prerequisite for the implementation of primary prevention trials for type 1 diabetes (T1D). The aim of this study was to assess the risk conferred by HLA-DRB1, INS-VNTR and PTPN22 single genes on the onset of T1D and the joint risk conferred by all these three susceptibility loci using the Bayesian Network (BN) approach in both population-based case-control and family clustering data sets.

Methodology/Principal Findings

A case-control French cohort, consisting of 868 T1D patients and 73 French control subjects, a French family data set consisting of 1694 T1D patients and 2340 controls were analysed. We studied both samples separately applying the BN probabilistic approach, that is a graphical model that encodes probabilistic relationships among variables of interest. As expected HLA-DRB1 is the most relevant susceptibility gene. We proved that INS and PTPN22 genes marginally influence T1D risk in all risk HLA-DRB1 genotype categories. The absolute risk conferred by carrying simultaneously high, moderate or low risk HLA-DRB1 genotypes together with at risk INS and PTPN22 genotypes, was 11.5%, 1.7% and 0.1% in the case-control sample and 19.8%, 6.6% and 2.2% in the family cohort, respectively.

Conclusions/Significance

This work represents, to the best of our knowledge, the first study based on both case-control and family data sets, showing the joint effect of HLA, INS and PTPN22 in a T1D Caucasian population with a wide range of age at T1D onset, adding new insights to previous findings regarding data sets consisting of patients and controls <15 years at onset.