Topic 01: Neurokognitive Erkrankungen, organische psychische Störungen, Demenz, F0
Methodological developments in neuroimaging and positive signals from disease modifying drugs have fueled a growing interest in impaired clearance of pathological proteins from the brain as a common pathogenic mechanism of neurodegenerative disorders, including Alzheimer’s disease (AD). Nowadays, minimally invasive and non-invasive neuroimaging approaches using magnetic resonance imaging (MRI) allow the study of this mechanism in vivo in patients with AD and other neurodegenerative disorders. They create novel opportunities to identify drug targets and monitor treatment effects. Alterations of brain clearance are closely linked with changes in sleep-wake cycle and excitability. As a complementary approach, recording of electroencephalographic (EEG) rhythms discloses the impact of AD and other neurodegenerative disorders on ascending activating and thalamocortical systems regulating sleep-wake cycle and vigilance, while non-invasive brain stimulation may modulate and restore those systems as a potential secondary preventive treatment.
The symposium will feature presenters from Italy, China, and Germany who will illustrate methods and findings on brain clearance in human studies and preclinical models of AD. Furthermore, they will report on new advanced EEG measures of sleep-wake cycle regulation in AD patients and the effect of non-invasive brain stimulation on cortical neural excitability, clearance and clinical performance in prodromal AD. The symposium will provide a new perspective on the exciting revelations of pathogenic mechanisms of neurodegenerative dementias and the combined use of innovative neuroimaging, EEG, and brain stimulation techniques with therapeutic implications in AD.
abgesagt: Abnormal resting state EEG and vigilance in neurodegenerative dementias
Findings of an Eurasian Consortium on cortical source activities and connectivity derived from resting state EEG in AD and related dementias
abgesagt: Measuring brain clearance in vivo – a new window into brain function
Brain clearance imaging revealed penetration of gadolinium-based contrast agents (GBCAs) into the anterior eye chamber (AC) in healthy humans. We investigated whether the degree of GBCA enhancement of the AC can predict histopathologic tumor features such as optic nerve (ON) infiltration in children suffering from retinoblastoma (RB).
Our local ethics committee approved this retrospective single-center study, which encompassed 539 orbital MRIs performed between 2010 and 2019. MRI was performed with an orbital coil and with the children in a state of general anesthesia.
Differences of signal intensity ratios of the AC to the lens (∆SIRs) were determined between native and GBCA-enhanced T1-weightings. Subsequently, ∆SIRs of RB eyes were compared to healthy eyes and correlated with histopathologic tumor features derived from enucleation such as infiltration of the ON, choroid, ciliary body, sclera and AC.
∆SIRs were significantly higher in RB eyes compared to healthy eyes (p < 0.001). ∆SIR of the RB eye was an independent, significant predictor for ON invasion in multivariate analysis with adjustment for tumor size (p < 0.05) and increased with infiltration level. ∆SIR was not predictive for any other assessed histopathologic tumor feature.
GBCA enhancement of the anterior eye chamber predicts optic nerve infiltration, which might be explained by disturbed retinal homeostasis with consecutive neovascularisation of the iris due to dysfunction of the orbital glymphatic system.
abgesagt: Sleep, excitability and glymphatic function in an animal model of Alzheimer’s disease
Accumulation of cerebral amyloid, one main pathological hallmark of Alzheimer’s disease (AD), results from dysbalanced amyloid-β (Aβ) production and clearance. Neuronal hyperexcitability, disruptions in circadian function and dysfunctional sleep are key pathogenic events downstream of amyloid pathology in AD. At the same time hyperexcitability and sleep disruption induce amyloid pathology at synaptic level, forming part of a vicious circle. More recently, disruption of brain clearance, especially of the glymphatic system, have been identified as contributors to AD pathogenesis.
Transgenic mouse models serve a better understanding of AD pathology and its consequences on neuronal function. A broadly used transgenic AD model are APPswe/PS1dE9 mice, which reproduce essential features of Aβ pathology like neuronal dysfunction as reflected in electrophysiological recordings of neuronal hyperexcitability. However, research on the influence of circadian function on brain clearance in this model is still scarce.
To characterize this influence in more detail, we performed histological analysis of the brain wide distribution of an intrahippocampal injected fluorescent dye. The dye was injected either at the end of the wake period (6am) or the end of the rest period (6pm) and analyzed at 1h or 3h post injection. With this experimental setup we were able to investigate clearance efficacy and its dependence on circadian rhythm in wildtype mice. In reminiscence of an already known dependency on circadian rhythm, we found improved clearance efficacy during the sleep phase. Furthermore, we were able to examine the influence of Aβ pathology on clearance efficacy in APPswe/PS1dE9 mice. Preliminary results obtained from these mice indicate a detrimental effect of Aβ pathology on brain clearance, shown by reduced dye dispersion compared to wildtype mice. Future experiments are required to confirm and extend these findings that are possibly relevant for translation to human studies.