Background: Children with chromosome 22q11.2 deletion syndrome (22q11.2DS) exhibit nonverbal learning disability that may manifest in part because of working memory (WM) deficits. 22q11.2DS is a complex developmental disorder with serious physical, learning, cognitive, and psychiatric symptoms including a risk of developing schizophrenia 30 times that of the general population. WM impairment likely contributes to and exacerbates learning difficulties, school problems, existing neuropsychological disorders such as attention deficit hyperactivity disorder (ADHD); and a poor WM may be a biological risk marker for future mental illness. WM impairment is established in this population, but less is known about its neurological origins. Frontoparietal cortical development and function are key to WM processing. In the neurotypical developing brain, studies indicate activation associated with WM shifts from parietal to frontal regions with age. However, in children with 22q11.2DS, activation is restricted to the frontal cortex, and volumes are reduced in parietal regions where abnormal tractography abides. The overarching aim of this study was to determine the neural origins of WM impairment in people with 22q11.2DS. Methods: We measured WM in children and adolescents with (n = 29) and without (n = 27) 22q11.2DS using the WISC-IV and a computer-based spatial working memory task (SWMT) task. Participants’ brains were scanned using high-resolution magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Focusing on brain morphometry and structural connectivity within frontoparietal networks, we investigated neural underpinnings of WM processing in 22 children with 22q11.2DS and 19 typically developing (TD) controls ages 7 to 16 (M = 12.13 ± 2.41). A connectome mapping network involved in WM processing was constructed by superimposing cortical segmentations on white-matter tractography. Results: Children with 22q11.2DS had impaired working memory performance. Individuals’ performance on our SWMT moderated the association between diagnosis and gray and white matter macro and microstructure. Children with 22q11.2DS with better working memory had larger lateral orbitofrontal volumes, greater axial diffusivity in the left superior frontal to superior parietal tract, and smaller volume in the right superior frontal to lateral orbitofrontal tract. Poorer performance in children with 22q11.2DS was associated with smaller right superior parietal and superior frontal cortical volumes. Conclusions: Children with 22q11.2DS performed worse on measures of working memory. Their performance was related to regional cortical volume differences and white matter microstructure abnormalities in the frontal and parietal lobes. These are brain regions consistently implicated in WM processing.

Magister Pharmaceuticae - MPharm / Neurodegenerative disorders (NDs) are a range of chronic brain disorders that includes amongst others motor function loss. Parkinson’s disease (PD) is one of the common NDs that has an insidious onset and diagnosed when dopaminergic neurons in the substantia nigra are already lost. The loss creates a deficiency of the dopamine (neurotransmitter) thereby causing neurochemical imbalance resulting in the signs and symptoms of PD. NDs overlap at multiple levels so some of the symptoms overlap as well. NDs currently have no cure yet and current drug therapies only improve the quality of life of the patients by targeting the symptoms mainly. Treatment of PD currently involves different classes of drugs and depending on the stages of the disease, some drugs can be only used as an adjunct therapy. Anti-oxidants and monoamine oxidase inhibitors (MAO-I) are part of the treatment options.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19004号 / 工博第4046号 / 新制||工||1623(附属図書館) / 31955 / 京都大学大学院工学研究科分子工学専攻 / (主査)教授 白川 昌宏, 教授 渡辺 宏, 教授 跡見 晴幸 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

Yes / ... Sustaining a sport-related concussion (SRC) has been associated with negative consequences to emotion and cognition in recent years,4,5 and head impacts are no different.1 Moreover, there is a consistent link reported with neurodegenerative diseases such as motor-neuron disease, Parkinson’s disease, and dementia. Although this is well-known within the scientific community, and becoming so in the general population, we still place children at risk. Promoting attitude change toward SRC and head impacts in sport is difficult enough with adults as many are accustomed to the way their contact sports are played and spectated. However, a redeeming feature for many researchers is that the evidence is there, and the rhetoric is being discussed in the mainstream media across the world.

TAR DNA Binding Protein-43 (TDP-43) proteinopathy is a disease pathology that underlies a broad field of neurodegenerative disorders. Most prominently, TDP-43 aggregates are the hallmark of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). The implication of TDP-43 in ALS, in particular, has helped initiate a cascade of research to determine the properties of the previously obscure protein. From these studies, it is now known that TDP-43 is a DNA and RNA binding protein, important for the splicing and regulation of many transcripts. In the disease state, TDP-43 is modified in a way that fuels its accumulation into cytoplasmic aggregates called inclusions. This paper will delineate the current understanding of the mechanisms behind TDP-43 proteinopathy and the resultant clinical conditions. The body of evidence firmly supports a clinical spectrum of TDP-43 proteinopathy that ranges between pure motor neuron disease (MND) and pure frontotemporal dementia (FTD). It also appears that the root cause of neurodegeneration in these disorders comes about through a combination of a gain of toxic function and a loss of normal TDP-43. Continued research into the molecular processes leading to the capitulation of TDP-43 holds great promise for the development of new drug targets to help treat the spectrum of TDP-43 proteinopathy.

Riboflavin transport is mediated, in part, by riboflavin transporter proteins 2 and 3, encoded by SLC52A2 and SLC52A3, respectively. Biallelic mutations in SLC52A2 and SLC52A3 impair riboflavin transporter protein function and riboflavin transport, causing disruptions to mitochondrial metabolism which result in sensory and motor neurodegeneration and give rise to riboflavin transporter deficiency (RTD) in humans. RTD is a rare neurodegenerative disease characterised by respiratory compromise, muscle and limb weakness, and vision and hearing impairments. RTD patients are treated with high-dose riboflavin supplementation which is effective in over 70% of cases but can be ineffective due to rapid excretion of riboflavin when its plasma concentration exceeds 0.5 μM. To address the need for alternative or supplemental RTD treatment, this study generated morpholino-mediated knockdown and CRISPR/Cas9 models of RTD in zebrafish. An RTD-like phenotype is observed in these RTD models including hearing loss, decreased motor axon length, and impaired locomotor activity. The slc52a3 morphant phenotype was found to be specific via coinjection of slc52a3 morpholino/human SLC52A3 mRNA, which achieved effective rescue of the morphant phenotype, as well as slc52a3 morpholino/p53 morpholino coinjection, which maintains the slc52a3 morphant phenotype. In line with clinical findings, riboflavin supplementation resulted in some improvement of the morphant phenotype. Probenecid was selected as a candidate drug due to its inhibitory effect on OAT-3, which mediates riboflavin excretion. However, supplementing riboflavin treatment with probenecid provided no additional benefit to the slc52a3 knockdown model. Further development of CRISPR/Cas9-knockout lines of slc52a2 and slc52a3, as well continued therapeutic screening of riboflavin and probenecid and consideration of alternative therapeutics will provide more opportunities to uncover novel therapeutic strategies to improve RTD treatment.

No description available.

No description available.

No description available.

No description available.