bioRxiv Science⌕ Search

Biology subjects

Yakushev, I.

Publications and source records attributed to Yakushev, I..

3 recordsLinked to original sources
bioRxiv2023

Increasing hub disruption parallels dementia severity in autosomal dominant Alzheimer disease

Hub regions in the brain, recognized for their roles in ensuring efficient information transfer, are vulnerable to pathological alterations in neurodegenerative conditions, including Alzheimer Disease (AD). Given their essential role in neural communication, disruptions to these hubs have profound implications for overall brain network integrity and functionality. Hub disruption, or targeted impairment of functional connectivity at the hubs, is recognized in AD patients. Computational models paired with evidence from animal experiments hint at a mechanistic explanation, suggesting that these hubs may be preferentially targeted in neurodegeneration, due to their high neuronal activity levels--a phenomenon termed "activity-dependent degeneration". Yet, two critical issues were unresolved. First, past research hasnt definitively shown whether hub regions face a higher likelihood of impairment (targeted attack) compared to other regions or if impairment likelihood is uniformly distributed (random attack). Second, human studies offering support for activity-dependent explanations remain scarce. We applied a refined hub disruption index to determine the presence of targeted attacks in AD. Furthermore, we explored potential evidence for activity-dependent degeneration by evaluating if hub vulnerability is better explained by global connectivity or connectivity variations across functional systems, as well as comparing its timing relative to amyloid beta deposition in the brain. Our unique cohort of participants with autosomal dominant Alzheimer Disease (ADAD) allowed us to probe into the preclinical stages of AD to determine the hub disruption timeline in relation to expected symptom emergence. Our findings reveal a hub disruption pattern in ADAD aligned with targeted attacks, detectable even in pre-clinical stages. Notably, the disruptions severity amplified alongside symptomatic progression. Moreover, since excessive local neuronal activity has been shown to increase amyloid deposition and high connectivity regions show high level of neuronal activity, our observation that hub disruption was primarily tied to regional differences in global connectivity and sequentially followed changes observed in A{beta} PET cortical markers is consistent with the activity-dependent degeneration model. Intriguingly, these disruptions were discernible 8 years before the expected age of symptom onset. Taken together, our findings not only align with the targeted attack on hubs model but also suggest that activity-dependent degeneration might be the cause of hub vulnerability. This deepened understanding could be instrumental in refining diagnostic techniques and developing targeted therapeutic strategies for AD in the future.

neuroscience↗
bioRxiv2023

Multimodally trackable and clinically translatable platform for modelling human demyelinating brain diseases by temporally dispersed chemically induced lesions in thepig brain

BackgroundDespite advances in therapy, inflammatory demyelinating diseases of the central nervous system, such as multiple sclerosis, remain important causes of morbidity among young adults. Translation of remyelinating paradigms from current murine models is encumbered by the small size and low white matter content of the brains, limiting the spatial resolution of diagnostic imaging. Large animal models might be more suited for this purpose but pose significant technological, ethical and logistical challenges. MethodWe induced reversible and targeted cerebral demyelinating lesions by controlled injection of lysophosphatidylcholine in the minipig brain. One strength of the approach is the serial induction, allowing parallel imaging of successive stages of de-/remyelination. FindingsWe demonstrate controlled, clinically unapparent, reversible and multimodally trackable brain white matter demyelination in a large animal model. Lesions were amenable to follow-up using the same clinical imaging modalities (3T magnetic resonance imaging, 11C-PIB positron emission tomography) and standard histopathology protocols as for human diagnostics, as well as electron microscopy to compare against biopsy data from two patients with cerebral demyelination. InterpretationBy employing human diagnostic tools and validating the model against data from related human diseases, our platform overcomes one important translational barrier of current animal brain demyelination models while having the potential for developing diagnostic procedures and imaging biomarkers. Remyelination and axon preservation dynamics diverge from classical rodent models. FundingThis work was supported by the DFG under Germanys Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198) and TRR 274/1 2020, 408885537 (projects B03 and Z01). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSInflammatory demyelinating diseases of the central nervous system (CNS), targeting primarily the white matter (WM) of the brain and spinal cord, such as multiple sclerosis (MS), still represent some of the most important non-traumatic causes of disability in young adults. Current animal models based on murine species, for example, experimental autoimmune encephalomyelitis, have been demonstrated to reliably depict pathophysiological facets of human disease. However, they are nevertheless encumbered by the low WM content and the small size of murine brains, which still pose a translational barrier to diagnostic imaging tools used in a clinical context in human patients. Minipigs are increasingly being used to model human neurological diseases, as yet primarily in the context of neurodegenerative disorders. Added value of this studyHere, we establish a platform for Minipig Stereotactic White-matter Injection using Navigation by Electromagnetism (MiniSWINE) and validate such a tool in a clinical multimodal imaging and microscopy setting against biopsy and imaging data from human demyelinating disorders across different disease stages, as well as against existing and potentially emerging human diagnostic imaging. Moreover, in order to overcome the neuroanatomical challenges of stereotactic injection in the pig brain, we designed a new electromagnetic-guided tracking system whose key advantage is the direct measurement of the injection cannula tip position in situ. Another strength of our study lies in its setup, characterized by the serial induction of successive stages of de- and remyelination, allowing for multimodal assessment via imaging and histopathology or electron microscopy of multiple stages in parallel. The remyelination dynamics inferred in this context diverge from the classical rodent studies, by exhibiting incomplete remyelination at the subacute stage, persistent astroglial and microglial activation as well as a minor degree of secondary axonal degeneration. Thus, they more closely resemble human inflammatory demyelinating brain plaques. Implications of all the available evidenceWe believe that MiniSWINE links evidence from well-established demyelination-induction methods from rodent models of CNS demyelinating disorders, as well as from human imaging and biopsy data, while at the same time providing a novel platform for the potential development of diagnostic procedures, discovery of imaging biomarkers and testing of remyelinating agents in diseases such as MS. Thus, it can have particular relevance to human health in the context of future translational animal model-based research in inflammatory demyelinating disorders of the CNS. Additionally, our electromagnetic-guided injection technique may enhance stereotactic substance delivery in human neurosurgery.

neuroscience↗
bioRxiv2023

An energy costly architecture of neuromodulators for human brain evolution and cognition

Humans spend more energy on the brain than any other species. However, the high energy demand cannot be fully explained by brain size scaling alone. We hypothesized that energy-demanding signaling strategies may have contributed to human cognitive development. We measured the energy distribution along signaling pathways using multimodal brain imaging and found that evolutionarily novel connections have up to 67% higher energetic costs of signaling than sensory-motor pathways. Additionally, histology, transcriptomic data, and molecular imaging independently reveal an upregulation of signaling at G-protein coupled receptors in energy-demanding regions. We found that neuromodulators are predominantly involved in complex cognition such as reading or memory processing. Our study suggests that the upregulation of neuromodulator activity, alongside increased brain size, is a crucial aspect of human brain evolution.

neuroscience↗