Longitudinal in vivo MRI in a Huntington’s disease mouse model: global atrophy in the absence of white matter microstructural damage

Huntington’s disease (HD) is a genetically-determined neurodegenerative disease. Characterising neuropathology in mouse models of HD is commonly restricted to cross-sectional ex vivo analyses, beset by tissue fixation issues. In vivo longitudinal magnetic resonance imaging (MRI) allows for disease progression to be probed non-invasively. In the HdhQ150 mouse model of HD, in vivo MRI was employed at two time points, before and after the onset of motor signs, to assess brain macrostructure and white matter microstructure. Ex vivo MRI, immunohistochemistry, transmission electron microscopy and behavioural testing were also conducted. Global brain atrophy was found in HdhQ150 mice at both time points, with no neuropathological progression across time and an elective sparing of the cerebellum. In contrast, no white matter abnormalities were detected from the MRI images or electron microscopy images alike. The relationship between motor function and MR-based structural measurements was different for the HdhQ150 and wild-type mice, although there was no relationship between motor deficits and histopathology. Widespread neuropathology prior to symptom onset is consistent with patient studies, whereas the absence of white matter abnormalities conflicts with patient data. The myriad reasons for this inconsistency require further attention to improve the translatability from mouse models of disease

Long-term outcome in relationship to neonatal transfusion volume in extremely premature infants: a comparative cohort study

<p>Abstract</p> <p>Background</p> <p>In premature born infants red blood cell (RBC) transfusions have been associated with both beneficial and detrimental sequels. Upon RBC transfusion, improvement in cerebral blood flow and oxygenation have been observed, while a more liberal transfusion policy may be associated with a better developmental outcome. The effect of the transfusion volume on long-term outcome is not known.</p> <p>Methods</p> <p>Observational follow-up study of a cohort of extremely premature born infants, treated in 2 neonatal intensive care units using a different transfusion volume (15 ml/kg in Unit A and 20 ml/kg in Unit B). The primary outcome was a composite of post discharge mortality, neuromotor developmental delay, blindness or deafness, evaluated at a mean corrected age (CA) of 24 months related to the transfusion volume/kg bodyweight administered during the postnatal hospital stay.</p> <p>Results</p> <p>Despite the difference in transfusion volume in clinically comparable groups of infants, they received a similar number of transfusions (5.5 ± 3.2 versus 5.5 ± 2.3 respectively in Unit A and B). The total transfused volume in unit A was 79 ± 47 ml/kg and 108 ± 47 ml/kg in unit B (p = 0.02). Total transfused RBC volume per kg bodyweight was not an independent predictor of the composite outcome (p = 0.96, OR 1.0 (CI 0.9-1.1).</p> <p>Conclusion</p> <p>There was no relationship between the composite outcome at 24 months CA and transfusion volume received during the post natal hospital stay. As there was no clinical advantage of the higher transfusion volume, a more restrictive volume will reduce total transfusion volume and donor exposure. Future research on the optimal transfusion volume per event to extreme preterm infants should include larger, prospective studies with a longer follow-up period through to childhood or even adolescence.</p

Cortico-cerebellar functional connectivity and sequencing of movements in schizophrenia

<p>Abstract</p> <p>Background</p> <p>Abnormal execution of several movements in a sequence is a frequent finding in schizophrenia. Successful performance of such motor acts requires correct integration of cortico-subcortical processes, particularly those related to cerebellar functions. Abnormal connectivity between cortical and cerebellar regions with resulting cognitive dysmetria has been proposed as the core dysfunction behind many signs and symptoms of schizophrenia. The aim of the present study was to assess if these proposed abnormalities in connectivity are a unifying feature of schizophrenia, or, rather, reflect a specific symptom domain of a heterogeneous disease. We predicted that abnormal functional connectivity between the motor cortex and cerebellum would be linked with abnormal performance of movement sequencing.</p> <p>Methods</p> <p>We examined 24 schizophrenia patients (SCH) and 24 age-, sex-, and handedness-matched healthy controls (HC) using fMRI during a modified finger-tapping task. The ability to perform movement sequencing was tested using the Neurological Evaluation Scale (NES). The subjects were categorized into two groups, with (SQ+) and without (SQ-) movement sequencing abnormalities, according to the NES-SQ score. The effects of diagnosis and movement sequencing abnormalities on the functional connectivity parameters between the motor cortex and cerebellum (MC-CRBL) and the supplementary motor cortex and cerebellum (SMA-CRBL) activated during the motor task were analyzed.</p> <p>Results</p> <p>We found no effect of diagnosis on the functional connectivity measures. There was, however, a significant effect on the SQ group: SQ + patients showed a lower level of MC-CRBL connectivity than SQ- patients and healthy controls. Moreover, the level of MC-CRBL and SMA-CRBL negatively correlated with the magnitude of NES-SQ abnormalities, but with no other NES domain.</p> <p>Conclusions</p> <p>Abnormal cortico-cerebellar functional connectivity during the execution of a motor task is linked with movement sequencing abnormalities in schizophrenia, but not with the diagnosis of schizophrenia per se. It seems that specific patterns of inter-regional connectivity are linked with corresponding signs and symptoms of clinically heterogeneous conditions such as schizophrenia.</p

High-Content Chemical and RNAi Screens for Suppressors of Neurotoxicity in a Huntington's Disease Model

To identify Huntington's Disease therapeutics, we conducted high-content small molecule and RNAi suppressor screens using a Drosophila primary neural culture Huntingtin model. Drosophila primary neurons offer a sensitive readout for neurotoxicty, as their neurites develop dysmorphic features in the presence of mutant polyglutamine-expanded Huntingtin compared to nonpathogenic Huntingtin. By tracking the subcellular distribution of mRFP-tagged pathogenic Huntingtin and assaying neurite branch morphology via live-imaging, we identified suppressors that could reduce Huntingtin aggregation and/or prevent the formation of dystrophic neurites. The custom algorithms we used to quantify neurite morphologies in complex cultures provide a useful tool for future high-content screening approaches focused on neurodegenerative disease models. Compounds previously found to be effective aggregation inhibitors in mammalian systems were also effective in Drosophila primary cultures, suggesting translational capacity between these models. However, we did not observe a direct correlation between the ability of a compound or gene knockdown to suppress aggregate formation and its ability to rescue dysmorphic neurites. Only a subset of aggregation inhibitors could revert dysmorphic cellular profiles. We identified lkb1, an upstream kinase in the mTOR/Insulin pathway, and four novel drugs, Camptothecin, OH-Camptothecin, 18β-Glycyrrhetinic acid, and Carbenoxolone, that were strong suppressors of mutant Huntingtin-induced neurotoxicity. Huntingtin neurotoxicity suppressors identified through our screen also restored viability in an in vivo Drosophila Huntington's Disease model, making them attractive candidates for further therapeutic evaluation.National Institutes of Health (U.S.) (grant R01 EB007042)National Institutes of Health (U.S.

Morphological correlates to cognitive dysfunction in schizophrenia as studied with Bayesian regression

BACKGROUND: Relationships between cognitive deficits and brain morphological changes observed in schizophrenia are alternately explained by less gray matter in the brain cerebral cortex, by alterations in neural circuitry involving the basal ganglia, and by alteration in cerebellar structures and related neural circuitry. This work explored a model encompassing all of these possibilities to identify the strongest morphological relationships to cognitive skill in schizophrenia. METHODS: Seventy-one patients with schizophrenia and sixty-five healthy control subjects were characterized by neuropsychological tests covering six functional domains. Measures of sixteen brain morphological structures were taken using semi-automatic and fully manual tracing of MRI images, with the full set of measures completed on thirty of the patients and twenty controls. Group differences were calculated. A Bayesian decision-theoretic method identified those morphological features, which best explained neuropsychological test scores in the context of a multivariate response linear model with interactions. RESULTS: Patients performed significantly worse on all neuropsychological tests except some regarding executive function. The most prominent morphological observations were enlarged ventricles, reduced posterior superior vermis gray matter volumes, and increased putamen gray matter volumes in the patients. The Bayesian method associated putamen volumes with verbal learning, vigilance, and (to a lesser extent) executive function, while caudate volumes were associated with working memory. Vermis regions were associated with vigilance, executive function, and, less strongly, visuo-motor speed. Ventricular volume was strongly associated with visuo-motor speed, vocabulary, and executive function. Those neuropsychological tests, which were strongly associated to ventricular volume, showed only weak association to diagnosis, possibly because ventricular volume was regarded a proxy for diagnosis. Diagnosis was strongly associated with the other neuropsychological tests, implying that the morphological associations for these tasks reflected morphological effects and not merely group volumetric differences. Interaction effects were rarely associated, indicating that volumetric relationships to neuropsychological performance were similar for both patients and controls. CONCLUSION: The association of subcortical and cerebellar structures to verbal learning, vigilance, and working memory supports the importance of neural connectivity to these functions. The finding that a morphological indicator of diagnosis (ventricular volume) provided more explanatory power than diagnosis itself for visuo-motor speed, vocabulary, and executive function suggests that volumetric abnormalities in the disease are more important for cognition than non-morphological features

Prenatal Immune Challenge Is an Environmental Risk Factor for Brain and Behavior Change Relevant to Schizophrenia: Evidence from MRI in a Mouse Model

Objectives: Maternal infection during pregnancy increases risk of severe neuropsychiatric disorders, including schizophrenia and autism, in the offspring. The most consistent brain structural abnormality in patients with schizophrenia is enlarged lateral ventricles. However, it is unknown whether the aetiology of ventriculomegaly in schizophrenia involves prenatal infectious processes. The present experiments tested the hypothesis that there is a causal relationship between prenatal immune challenge and emergence of ventricular abnormalities relevant to schizophrenia in adulthood. Method: We used an established mouse model of maternal immune activation (MIA) by the viral mimic Polyl:C administered in early (day 9) or late (day 17) gestation. Automated voxel-based morphometry mapped cerebrospinal fluid across the whole brain of adult offspring and the results were validated by manual region-of-interest tracing of the lateral ventricles. Parallel behavioral testing determined the existence of schizophrenia-related sensorimotor gating abnormalities. Results: Polyl:C-induced immune activation, in early but not late gestation, caused marked enlargement of lateral ventricles in adulthood, without affecting total white and grey matter volumes. This early exposure disrupted sensorimotor gating, in the form of prepulse inhibition. Identical immune challenge in late gestation resulted in significant expansion of 4th ventricle volume but did not disrupt sensorimotor gating. Conclusions: Our results provide the first experimental evidence that prenatal immune activation is an environmental risk factor for adult ventricular enlargement relevant to schizophrenia. The data indicate immune-associated environmental insults targeting early foetal development may have more extensive neurodevelopmental impact than identical insults in late prenatal life. © 2009 Li et al.published_or_final_versio