Repetitive head impacts (RHI) and traumatic brain injuries are risk factors for the neurodegenerative diseases chronic traumatic encephalopathy (CTE) and amyotrophic lateral sclerosis (ALS). Although distinct, these diseases can share an overlapping pathology (e.g. TDP-43) and affect similar brain regions. However, the pathways involved and biomarkers for diagnosis are unknown. MicroRNAs (miRNAs) are altered in disease, are involved in gene regulation, and may be useful as stable biomarkers. Thus, we set out to determine associations between miRNA levels and disease state within the prefrontal cortex in a group of deceased participants with no pathology (controls), CTE, ALS, or comorbid CTE+ALS. Of the 47 miRNAs previously implicated in neurological disease, 27 were significantly different between pathology groups. Of these, seventeen (63%) were upregulated in both ALS and CTE and included miRNAs involved in inflammatory, apoptotic and cell growth/differentiation pathways. Nine miRNAs (33%) were specifically upregulated only in ALS as opposed to only one miRNA (4%) with CTE specific upregulation. Surprisingly, few miRNAs (14%) were significantly altered in comorbid CTE+ALS, which may reflect the milder disease present at death in participants with both conditions. Overall, we found patterns of miRNA expression that are common and unique to CTE and ALS and that suggest common pathways of pathogenesis.

BACKGROUND. Neuropathological processes affecting the left frontotemporal lobes and their connections with subcortical structures have been reported in individuals who sexually assault minors. However, these findings are not necessarily conclusive, and knowledge is limited as to how such factors influence the 'blocking' adult sexual relations, disinhibition, emotional congruence and sexual arousal to children; or indeed if functional disorders are more significant. METHOD. A combination of neuropsychological (LNNB Form II) and personality (MMPI-2) probes where used to ascertain the profiles of male subjects satisfying DSM-III criteria for paedophilia, and a comparison was made with male rapist and homicide offenders to identify a characteristic neuro-behavioural syndrome. All groups were matched for premorbid intelligence, drug/alcohol abuse, socio-economic status and incarceration period. Hypotheses of greater dysfunction localised to the lefthemisphere fronto-temporal lobe areas, and more disturbed personality and psychopathology in the paedophile offenders were tested. The Multiphasic Sex Inventory (MSI) was also used to confirm the diagnoses of the sexual offenders and to assess psychosexual functioning. RESULTS. The offender groups were undifferentiated in terms of frequency of overall neuropsychological dysfunction, yet 26.8 per cent had clinically significant cognitive impairment, and a further 23.2 per cent were diagnosed as 'Borderline.' However, pattern of expressive speech and writing deficits in the paedophile group's LNNB-11 profile was consistent with subclinical features of Transcortical Motor Aphasia-Type I syndrome (i.e. non-fluent verbal output - decreased spontaneity of expression and impoverished narrative speech, but with intact comprehension, repetition of spoken language; clumsily produced letters and hypereconomy of written content; and apathy). Damage to the left-hemisphere dorsolateral prefrontal cortex (DLPFC) is known to be associated with this type of aphasia, which in tum increases the probability of dysexecutive syndrome (i.e. limited planning and maintenance of goal-directed behaviour and behavioural flexibility). The impact of this syndrome was clearly reflected by socialdeficit type features found in the paedophile's MMPI-2 48' /84' profile which are consistent with a schizotypal personality disorder (i.e. apathy, social withdrawal, constricted affect, odd speech and behaviour). Additionally, psychosexual functioning, rationalisations and cognitive distortions relating to offence behaviours was found to be more deviant in paedophiles than rapists. CONCLUSION. From a developmental perspective, neuropathology of the circuits connecting the dorsolateral prefrontal cortex with sub-cortical areas, presenting as dysexecutive syndrome, may be significant in explaining the paedophile' s lack of adjustment to, indifference for, and alienation from the adult world; increasing the probability for emotional and sexual dependency on children. Several possibilities for future research are identified and practical uses for the findings of this study are presented.

Potential differences in developmental trajectory were investigated in autism at both the macro- and micro-scopic scale, using regional volumetric measurements from in-vivo scans and measurements of minicolumnar organisation of the cortex in post-mortem tissue. In addition, a study was carried out to investigate the sensitivity of measures of cortical diffusion to cortical architecture. Three key regions of interest were studied throughout this thesis, orbital frontal cortex (BA11), primary auditory cortex (BA41) and part of the inferior parietal lobe (BA40). Subjects with ASD showed increases in grey matter in left parietal cortex and decreases in left BA11 compared to controls. In addition, subjects with ASD showed increased grey matter volume with age in both BA41 and the inferior parietal lobe, whereas controls only showed a negative correlation between grey matter volume in BA41 and age. Wider minicolumns were found in ASD in all regions, suggesting pathology is not restricted to higher order association areas. Differences seemed more pronounced at younger ages suggesting an altered developmental trajectory in ASD. Such an increase in minicolumnar width arguably underlies the feature-based processing style seen in ASD. A pilot study using post-mortem DTI scans of MS brains revealed a relationship between measures of the directionality of diffusion and the width of axonal bundles in the cortex, an aspect of the minicolumnar arrangement. When extending this investigation to a set of ASD and control brains, evidence was found for different relationships between axon bundle width and measures of the directionality of diffusion in the cortex, suggesting that although differences in axon bundle width were not seen between groups, there may be differences in the composition of the axon bundles between ASD and control groups.

No description available.

名古屋大学博士学位論文 学位の種類 : 博士(医学)(論文) 学位授与年月日:平成5年4月6日 氏平伸子氏の博士論文として提出された

No description available.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that results in severe cognitive impairment and eventually is fatal. In addition to memory loss, AD patients also present with psychosis and emotional psychological symptoms. Neuropathologically, the disease is characterized by aggregation of amyloid-beta protein that accumulates into plaques and hyperphosporylation of tau protein which results in neurofibrillary tangles. Further, neuropathology in AD results in broad neuroinflammation. In recent years, there has been a research focus on novel treatments for AD because current medications have not been particularly effective and have significant side effects. In the current study, we analyzed whether PD340, a novel anti-inflammatory which inhibits the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα) would be effective to alleviate behavioral impairments in the 3xTg mouse model of AD. The 3xTg model is unique in comparison to previous rodent models of AD because it express three dementia-related transgenes and demonstrates a clear age-dependent onset of AD pathology. Mice were bred in our animal colony. Beginning at four months of age, a specialized diet was presented to the animals that contained 0, 3, 10, or 25 mg/kg of PD340. At approximately 6 months of age, which is before any neuropathology presents in this model, animals were behaviorally tested on three different tasks: The Barnes maze, which is a test of spatial memory; Prepulse inhibition (PPI), which is a measure of sensorimotor gating and is related to psychosis and cognition; and the elevated T-maze, which is a test of anxiety. Both males and females were tested. Results from Barnes maze testing revealed that females, but not males, administered 25 mg/kg of PD340 demonstrated a significant improvement in spatial bias towards the goal during acquisition. Regarding PPI, there were no sex differences, but groups receiving the 3 or 25 mg/kg dose of PD340 demonstrated significantly improved performance over animals administered the 0 mg/kg dose of PD340 dependent upon the auditory decibel level of the stimulus presented. On the elevated T-maze, there were no significant group differences, demonstrating anxiety is not present at 6 months of age in this model. Behavioral tests will also be performed at 12 and 15 months of age in these animals. However, at 6 months of age, it appears that PD340 is effective in alleviating behavioral deficits related to cognitive impairment in a mouse model of AD. Future work will analyze neuropathology in the hippocampus and prefrontal cortex, two brain areas that degenerate in AD and are important in cognitive function.

Based on evidence of abnormalities in axon thickness and neuronal disorganization, autism spectrum disorder (ASD) is commonly considered to be a condition resulting from neuronal dysfunction. Yet, recent findings suggest that non-neuronal cell types also contribute to ASD pathology. To investigate the role of glial cells in ASD, a combination of protein and gene expression analyses were used to determine levels of two glial markers, glial fibrillary acidic protein (GFAP) and myelin oligodendrocyte glycoprotein (MOG), in the postmortem brain tissue from control and ASD donors. Levels of GFAP immunoreactivity (ir) were significantly elevated (P = 0.008) in anterior cingulate cortex (Brodmann area 24; BA24) white matter of ASD donors compared to control donors. In contrast, GFAP-ir levels were similar in BA24 gray matter from ASD and control donors. MOG-ir was also similar in both BA24 white and gray matter from ASD and control donors. In anterior prefrontal cortex (BA10), there were no significant differences in GFAP-ir or MOG-ir in either white or gray matter comparing ASD to control donors. Levels of expression of the genes GFAP and MOG also showed no differences between control and ASD donors in BA24 and BA10 white and gray matter. Collectively, these data imply that ASD is associated with an activation of white matter astrocytes in the anterior cingulate cortex as a result of a yet undefined cellular insult. Research is needed to investigate the molecular pathways that underlie this astrocyte reaction and such research may yield important clues regarding the etiology of ASD.

Explosions cause the majority of injuries in the current conflicts, accounting for 79% of combat related injuries (Ramasamy et al. 2008). Blast overpressure from explosions can cause barotrauma to the lungs and the brain. Blast-induced mild traumatic brain injury has been labeled the "signature wound" of current military conflicts in Iraq and Afghanistan (Snell and Halter 2010). In addition to elevated number of blast-induced traumatic brain injuries due to increased military conflicts overseas and the usage of improvised explosive devices, the incidence of blast-induced polytrauma has risen due to the prevalence of terrorist events around the world (Arnold et al. 2004, Rodoplu et al. 2004). Blast-induced polytrauma is a major concern as lung injury can cause immediate mortality and brain injury causes long-lasting neurocognitive impairment. There is a critical lack of understanding the pathology of blast-induced polytrauma since the needs are multifaceted and therefore few options for treatment. Thus, the research presented in this dissertation required the development of a military-relevant blast polytrauma model to examine injury pathology and subsequently study the effects of hemostatic nanoparticle therapy after blast-induced polytrauma. The pre-clinical model was characterized and static overpressure thresholds were determined for lethality risk. It was confirmed to have many of the classic hallmarks of primary blast lung injury (PBLI), as well as blast-induced neurotrauma (BINT) (Clemedson 1950). Global hemorrhaging was found in the lungs and well as reduced oxygen saturation. Markers of astrogliosis and blood-brain barrier disruption were examined in the amygdala after blast. The novel nanoparticle configuration (hemostatic dexamethasone-loaded nanoparticles (hDNP) functionalized with a peptide that binds with activated platelets) was investigated and hypothesized to increase survival, reduce cellular injury and reduce anxiety-like disorders after blast polytrauma. After investigating hDNP, it was found that the hDNP treatment benefited survival percentage after injury as well as reduced percent hemorrhage in the lungs and improved physiology. Elevated anxiety parameters found in the controls were lower as compared to the hDNP group. Glial fibrillary acidic protein (GFAP) and cleaved caspase-3 were significantly elevated in the controls compared to the hDNP group in the amygdala. SMI-71 was also significantly elevated with the hDNP and hemostatic nanoparticle (hNP) treatments, similar to sham. In addition to the nanoparticles offering immediate life-saving qualities, administration of hemostatic nanoparticles improved amygdala pathology attributed to secondary mechanisms of blast injury, including blood-brain barrier disruption. This model of polytrauma can serve as a foundation for detailed pathological studies as well as testing therapeutics for injury modalities. References (Abstract) Arnold, J. L., P. Halpern, M. C. Tsai and H. Smithline (2004). "Mass casualty terrorist bombings: a comparison of outcomes by bombing type." Ann Emerg Med 43(2): 263-273. Clemedson, C. J., Granstom, S.A. (1950). "Studies on the genesis of "rib markings" in lung blast injury." Acta Physiol Scand. 21: 131-144. Ramasamy, A., S. E. Harrisson, J. C. Clasper and M. P. Stewart (2008). "Injuries from roadside improvised explosive devices." J Trauma 65(4): 910-914. Rodoplu, U., Arnold, J. L., Tokyay, R., Ersoy, G., Cetiner, S., Yucel, T. (2004) "Mass-casualty terrorist bombings in Istanbul, Turkey, November 2003: reports of the events and the prehospital emergency response." Prehosp Disaster Med 19(2):133-145. Snell, F. I. and M. J. Halter (2010). "A signature wound of war: mild traumatic brain injury." J Psychosoc Nurs Ment Health Serv 48(2): 22-28. / Ph. D.

Sleep and circadian rhythm disturbance has been widely observed in neurological disorders although the mechanistic basis for this association remains unknown. In order to understand this association further, a combination of rest/activity and molecular profiling was carried out on mouse models of Parkinson’s Disease (PD), Lysosomal Storage Disorders (LSDs) and schizophrenia. Data from rest/activity behavioural screening of new BAC (Bacterial Artificial Chromosome) transgenic PD models displayed scotophase hyperactivity and decreased fragmentation patterns. Interestingly, rest/activity profiles of LSD models displayed possible core clock defects under constant conditions (Hexb^-/-) and potential re-entrainment deficits following a 6hr phase advance (Npc1^-/-). Together these data suggest new associations between disruptions in rest/activity cycles and neurodegeneration. The blind-drunk (Bdr) mutant is a mouse model of synaptosomal-associated protein (Snap)-25 exocytotic disruption that displays schizophrenic endophenotypes and phase advanced rest/activity cycles. Despite identification of phase advanced expression of signalling neuropeptides (e.g. arginine vasopressin) in the Bdr suprachiasmatic nucleus (SCN), the underlying mechanisms regulating circadian disruption in this model remain elusive; therefore, label-free shotgun proteomics was carried out over 24 hours to elucidate potential post-transcriptional pathways. A number of novel circadian patterns of protein expression were identified including myristoylated alanine-rich C-kinase substrate (MARCKS) which exhibited a robust phase advanced expression profile. This study has identified novel SCN post-transcriptional mechanisms that may link schizoaffective disorder biomarkers to dysfunctional rest/activity cycles.