Chronic adiponectin deficiency leads to Alzheimer’s disease-like cognitive impairments and pathologies through AMPK inactivation and cerebral insulin resistance in aged mice

BACKGROUND: Insulin resistance is the major pathogenesis underlying type 2 diabetes mellitus (T2DM) and these patients have doubled risk of Alzheimer's disease (AD). Increasing evidence suggests that insulin resistance plays an important role in AD pathogenesis, possibly due to abnormal GSK3β activation, causing intra- and extracellular amyloid-beta (Aβ) accumulation. Adiponectin (APN) is an adipokine with insulin-sensitizing and anti-inflammatory effects. Reduced circulatory APN level is associated with insulin resistance and T2DM. The role of APN in AD has not been elucidated. In this study, we aim to examine if adiponectin deficiency would lead to cerebral insulin resistance, cognitive decline and Alzheimer's-like pathology in mice. METHODS: To study the role of adiponectin in cognitive functions, we employed adiponectin-knockout (APN-KO) mice and demonstrated chronic APN deficiency in their CNS. Behavioral tests were performed to study the cognitions of male APN-KO mice. Brains and tissue lysates were collected to study the pathophysiological and molecular changes in the brain of APN-KO mice. SH-SY5Y neuroblastoma cell line was used to study the molecular mechanism upon APN and insulin treatment. RESULTS: Aged APN-deficient mice displayed spatial memory and learning impairments, fear-conditioned memory deficit as well as anxiety. These mice also developed AD pathologies including increased cerebral Aβ42 level, Aβ deposition, hyperphosphorylated Tau proteins, microgliosis and astrogliosis with increased cerebral IL-1β and TNFα levels that associated with increased neuronal apoptosis and reduced synaptic proteins levels, suggesting APN deficiency may lead to neuronal and synaptic loss in the brain. AD pathologies-associated APN-KO mice displayed attenuated AMPK phosphorylation and impaired insulin signaling including decreased Akt induction and increased GSK3β activation in the hippocampus and frontal cortex. Aged APN-KO mice developed hippocampal insulin resistance with reduced pAkt induction upon intracerebral insulin injection. Consistently, APN treatment in SH-SY5Y cells with insulin resistance and overexpressing Aβ induce higher pAkt levels through AdipoR1 upon insulin treatment whereas the induction was blocked by compound C, indicating APN can enhance neuronal insulin sensitivity through AMPK activation. CONCLUSION: Our results indicated that chronic APN deficiency inactivated AMPK causing insulin desensitization and elicited AD-like pathogenesis in aged mice which also developed significant cognitive impairments and psychiatric symptoms.published_or_final_versio

Development of the infant foot as a load bearing structure : study protocol for a longitudinal evaluation (the Small Steps study)

Background An improved understanding of the structural and functional development of the paediatric foot is fundamental to a strong theoretical framework for health professionals and scientists. An infant’s transition from sitting, through crawling and cruising, to walking is when the structures and function of the foot must adapt to bearing load. The adaptation of skin and other hard and soft tissue, and foot and gait biomechanics, during this time is poorly understood. This is because data characterising the foot tissue and loading pre-walking onset does not exist. Of the existing kinematic and plantar pressure data, few studies have collected data which reflects the real-life activities of infants with modern equipment. Methods This is a longitudinal study and part of the Great Foundations Initiative, a collaborative project between the University of Brighton and the University of Salford, which is seeking to improve foot health in children. Two cohorts of 50 infants will be recruited at the two sites (University of Brighton, Eastbourne, UK and University of Salford, Salford, UK). Infants will be recruited when they first reach for their feet and attend four laboratory visits at milestones related to foot loading, with experienced independent walking being the final milestone. Data collection will include tissue characteristics (skin thickness, texture, elasticity, pH and tendon thickness and cross-sectional area), plantar pressures and kinematics captured during real world locomotion tasks. Discussion This study will provide a database characterising the development of the infant foot as it becomes a weight bearing structure. The data will allow effective comparison and quantification of changes in structure and function due to maturation and loading by measuring pre and post established walking. Additional variables which impact on the development of the foot (gender, ethnicity and body weight) will also be factored into our analysis. This will help us to advance understanding of the determinants of foot development in early childhood

Effect of EMG-biofeedback robotic-assisted body weight supported treadmill training on walking ability and cardiopulmonary function on people with subacute spinal cord injuries - a randomized controlled trial

201909 bcrcVersion of RecordPublishe

Brain involvement in neuromyelitis optica spectrum disorders

Background: Neuromyelitis optica spectrum disorders (NMOSDs) are severe inflammatory demyelinating disorders of the central nervous system. Brain involvement is increasingly recognized. Objective: To study brain involvement in NMOSDs among Hong Kong Chinese patients. Design: Retrospective study of patients with NMOSDs. Setting: Tertiary medical center in Hong Kong. Patients: Thirty-four Hong Kong Chinese patients with NMOSDs of 2 years or longer were recruited. Interventions: Brain and spinal cord magnetic resonance imaging was performed duringNMOSDattacks and was repeated yearly for the first 3 years. Main Outcome Measures: We evaluated clinical features of NMOSDs associated with brain involvement and brain lesions on magnetic resonance imaging. Results: Among 34 patients with NMOSDs of 2 years or longer, 20 (59%) had brain involvement. The mean age at onset among these 20 patients was 45.6 years (age range, 19-67 years); 18 were women. Eleven patients (32% of all the patients with NMOSDs) had clinical manifestation of brain involvement, 19 patients (56%) had brain abnormalities on magnetic resonance imaging consistent with inflammatory demyelination, and 2 patients (6%) fulfilled criteria for multiple sclerosis. Clinical manifestation of brain involvement included the following: trigeminal neuralgia; vomiting, vertigo, ataxia, dysphagia, and tetraparesis from lesions around the third and fourth ventricles and aqueduct; homonymous hemianopia, aphasia, hemiparesis, and cognitive impairment from extensive hemispheric white matter lesions; and ataxia, diplopia, hiccups, facial sensory loss, internuclear ophthalmoplegia, hemisensory loss, and hemiparesis from other lesions in the midbrain, pons, cerebellar peduncles, and medulla. Eight patients (24%) developed brainstem encephalitis clinically, and brainstem encephalitis was the initial clinical manifestation in 6 patients (18%). Brain abnormalities on magnetic resonance imaging were detected in brainstem in 15 patients (44%), hemispheric periventricular white matter in 7 patients (21%), deep white matter in 7 patients (21%), corpus callosum in 4 patients (12%), subcortical white matter in 3 patients (9%), thalamus in 2 patients (6%), hypothalamus in 1 patient (3%), basal ganglia in 1 patient (3%), internal capsule in 1 patient (3%), periaqueductal gray matter in 1 patient (3%), and around the third and fourth ventricles in 1 patient (3%); large confluent lesions were detected in 2 patients (6%). Conclusion: Brain involvement manifesting clinically as brainstem encephalitis is common among Hong Kong Chinese patients with NMOSDs. ©2011 American Medical Association. All rights reserved.link_to_subscribed_fulltex