Ovaj projekt financiran je potporom Hrvatske zaklade za znanost pod brojem 2020-12-5588

Summary of the Project Proposal
Rationale:

SARS-CoV-2 invades the brain, and appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including primary respiratory and cardiovascular control centre in the medulla oblongata. Presumable transsynaptic transfer potentiated by vascular endothelial spread and by leukocyte migration across BBB and by systematic inflammation cause neuropsychiatric manifestations in 22.5% patients of all COVID-19 severities. Documented involvement of brain limbic structures important in decision making, memory, and emotional behaviour may be particularly detrimental on a longer-term. Olfactory dysfunction affects up to 87% patients, with no apparent association with otolaryngologic symptoms. Olfactory bulb abnormalities and neuroinvasion through bulbar tract is confirmed postmortem even in cases without downstream olfactory tract abnormalities. Transolfactory spread may represent a distinct pattern of invasion with more likely detrimental outcome to emotional, memory, decision making, and other higher cognitive processing, due to functional interconnectivity of olfactory nuclei and tuberculi with limbic system of frontal and temporal piriform cortices, amygdala, uncus, anterior parahippocampal gyrus, and of orbitofrontal areas. This type of spread would even potentiate known deterioration of cognitive, visceral, emotional, and homeostatic behaviours second to loss of olfactory cues for any cause. Documented post-acute COVID-19 pathologies inlcude micro/macro haemorrhages, ischaemic lesions, leukoencephalopathies, extrapyramidal manifestations, gait abnormalities, pain syndromes, memory impairments, anxiety, emotional and mood changes, and sleep disorders, while the entire pattern of disruptions may display broad resemblance to Braak staging, a concept used to describe progressive deterioration in Parkinson’s and Alzheimer’s diseases. Longitudinal follow-up studies are recognised as essential to determine the underlying neuro-pathobiological mechanism. Due to possible deteriorative potential of viral spread originating from bulbar tract, it is considered relevant to identify MR imaging biomarkers of olfactory bulb involvement, including signal and volume changes.

Research goals: We aim to prove CNS involvement in the spread of SARS-CoV-2 by displaying brain structural, functional, and neuropsychiatric and cognitive behavioural correlates of neuronal affection in vivo, and to map the interlink of their phenomenologies. We hypothesize that that synergy of approaches is a sensitive and specific method to detect and predict different trajectories in clinical presentation and outcomes. We also hypothesize that transneural spread with primary point of entry in olfactory tract leads to more severe brain invasion and with more severe neruopsychiatric and cognitive consequences, and assume females are more vulnerable to neurological and psychiatric residua of transbulbar invasion, due to increased bulbar tract cellularity. Identification of markers of brain invasion may result in increased treatment potential and in improved prevention strategies.

Methodology: Our research will include three study groups – two groups of COVID-19 patients that will differ on neurological/psychiatric sequelae and are stratified for presence of anosmia, and of third group that will consist of sex and age matched controls: 1. 40 COVID-19 patients who tested positive for SARS-CoV-2, exhibiting neuropsychiatric and/or cognitive residua – (1a) With anosmia; (1b) Without anosmia; 2. 40 COVID-19 patients who tested positive for SARS-CoV-2, not exhibiting neuropsychiatric and/or cognitive residua– (2a) With anosmia; (2b) Without anosmia, and 3. 30 Healthy controls who tested negative for SARS-CoV-2. We will recruit patients from: (A) Dubrava University Hospital, COVID-19 Treatment Centre; (B) University Hospital for Infectious Diseases; (C) Vrapče University Hospital and (4) primary health care. Over 200 patient-candidates are already pre-screened. Presence of CNS-related COVID-19 pathological substrate will be evaluated by magnetic resonance imaging protocols (MRI) at baseline and 1 year later (220 scans in total). Neuroimaging analyses will consist of T1 and T2, 3D magnetization prepared rapid gradient-echo imaging (3D MP-RAGE), functional MR imaging (fMRI), proton magnetic resonance spectroscopy (1H-MRS) and diffusion-tensor imaging (DTI). COVID-19-related symptoms and psychometric and neurological parameters will be tracked continuously by validated rating scales and by structured clinical interviews and will be supplemented by means of videoconference and mobile app platforms and other available laboratory and functional evaluations that will be integrated into final analysis.
Expected results: We expect to prove CNS involvement in SARS-CoV-2 by displaying differences in parameters of structure and/or function between COVID-19 patients, stratified by anosmia, and after adjustment for severity of disease and inflammation, in comparison with unaffected matched controls. We expect particularly to: (a) Identify major neurostructural, neurofunctional, cognitive and behavioural correlates of brain invasion in COVID-19; (b) to differentiate patterns of structure and function attributable of transolfactory neuroinvasion; (c) to recognise trajectories and correlates preceding the turning points in neuropsychiatric pathologies in post-acute COVID-19 course; (d) to map the interlink between impairments in brain structure and function with behavioural phenomenologies over the course of the disease; (e) to recognise major behavioural, structural and functional predictors, moderators, and mediators of treatment outcome; (f) to recognise therapies modulating course of illness and (g) to contribute to improvement of treatment potential by identifying early signs that precede preventable neurological and psychiatric conditions.

Overall impact: Acute phase is not the end of risk period for neuropsychiatric COVID-19 repercussions, and the relevance of project goes far beyond the current pandemic due to similar brain-related symptomatology across different human corona species.