Ding Han’s research while affiliated with Capital Medical University and other places

Background Memory consolidation in sleep-dependent individuals involves the circuitry connections of cortex, thalamus and hippocampus, regulating via neural metabolites. However, the disruption of metabolic pattern in thalamus and hippocampus remains unclear. Objective We aim to explore the disruptive effects of insomnia on the metabolites during memory consolidation, particularly the underlying neurometabolic mechanisms in comorbidity of failed memory consolidation. Methods This study integrates clinical research with animal experiment. In clinical research, 49 participants were divided into four groups: healthy controls (HC, n = 11), insomnia with normal cognition (IS, n = 14), mild cognitive impairment without insomnia (MCI, n = 10), and insomnia with mild cognitive impairment (IS-MCI, n = 14). Magnetic resonance spectroscopy (MRS) was used to evaluate the neural γ-aminobutyric acid (GABA) and glutamate–glutamine (Glx) in bilateral thalamus. In experimental studies, the rat model of sleep deprivation combined with amyloid-β (Aβ) injection was established, after behavior testing, the levels of Glx, choline (Cho) and N-acetyl aspartate (NAA) in the bilateral hippocampus were evaluated with MRS. Results The patients in the IS-MCI group exhibited significantly lower GABA level than IS, MCI and HC groups. Results from rat studies showed that sleep deprivation exacerbated asymmetric alterations in Aβ-induced bilateral hippocampal metabolite abnormalities, which correlated with cognition. These neuro-metabolite disruption accompanied with synaptic loss and activation of astrocytes. Conclusions The lateralized decrease in GABA levels of thalamus and NAA, Cho, and Glx levels of hippocampus under conditions of sleep disturbance with cognitive decline may provide evidence for the neural metabolic mechanisms underlying the disruption of memory consolidation.

Sleep disturbance is a recognized risk factor for Alzheimer’s disease (AD), but the underlying micro-pathological evidence remains limited. To bridge this gap, we established an amyloid-β oligomers (AβO)-induced rat model of AD and subjected it to intermittent sleep deprivation (SD). Diffusion tensor imaging (DTI) and transmission electron microscopy were employed to assess white matter (WM) integrity and ultrastructural changes in myelin sheaths. Our findings demonstrated that SD exacerbated AβO-induced cognitive decline. Furthermore, we found SD aggravated AβO-induced asymmetrical impairments in WM, presenting with reductions in tract integrity observed in commissural fibers and association fasciculi, particularly the right anterior commissure, right corpus callosum, and left cingulum. Ultrastructural changes in myelin sheaths within the hippocampus and corpus callosum further confirmed a lateralized effect. Moreover, SD worsened AβO-induced lateralized disruption of the brain structural network, with impairments in critical nodes of the left hemisphere strongly correlated with cognitive dysfunction. This work represents the first identification of a lateralized impact of SD on the mesoscopic network and cognitive deficits in an AD rat model. These findings could deepen our understanding of the complex interplay between sleep disturbance and AD pathology, providing valuable insights into the early progression of the disease, as well as the development of neuroimaging biomarkers for screening early AD patients with self-reported sleep disturbances. Enhanced understanding of these mechanisms may pave the way for targeted interventions to alleviate cognitive decline and improve the quality of life for individuals at risk of or affected by AD. a AβO injection and sleep deprivation were conducted on adult rats. b Sleep deprivation and AβO-induced neurotoxicity aggravated cognitive disability with a synergistic effect. c Sleep deprivation and AβO-induced neurotoxicity reduced the integrity of specific association fasciculi and commissural fibers with ultrastructural demyelination. d On the basis of white matter integrity destruction, the structural connection was disrupted. The exacerbated topological properties with lateralized effects were correlated with cognitive decline.

For quite a long time, researches on Alzheimer's disease (AD) primarily focused on the cortex and hippocampus, while the cerebellum has been ignored because of its abnormalities considered to appear in the late stage of AD. In recent years, increasing evidence suggest that the cerebellar pathological changes possibly occur in the preclinical phase of AD, which is also associated with sleep disorder. Sleep disturbance is a high risk factor of AD. However, the changes and roles of cerebellum has rarely been reported under conditions of AD accompanied with sleep disorders. In this study, using an amyloid-β oligomers (AβO)-induced rat model of AD subjected to sleep deprivation, combining with a 7.0 T animals structural magnetic resonance imaging (MRI), we assessed structural changes of cerebellum in MRI. Our results showed that sleep deprivation combined with AβO led to an increased FA value in the anterior lobe of cerebellum, decreased ADC value in the cerebellar lobes and cerebellar nuclei, and increased cerebellum volume. Besides that, sleep deprivation exacerbated the damage of AβO to the cerebellar structural network. This study demonstrated that sleep deprivation could aggravate the damage to cerebellum induced by AβO. The present findings provide supporting evidence for the involvement of cerebellum in the early pathology of AD and sleep loss. Our data would contribute to advancing the understanding of the mysterious role of cerebellum in AD and sleep disorders, as well as would be helpful for developing non-invasive MRI biomarkers for screening early AD patients with self-reported sleep disturbances.