CANTAB Research Grant assists research into structural and functional changes in memory-associated networks in patients expressing cognitive deficits after a COVID-19 infection

Let us know a little about yourself?

First of all, many thanks to Cambridge Cognition for selecting me as the winner of the 2021 CANTAB Research Grant. Receiving this grant has been a great honour to my colleagues and I. Just a few words to introduce myself: I have been working as a clinician scientist & medical resident in the clinic for Neurology at the University Hospital Schleswig-Holstein (UKSH, Kiel, Germany) since April 2019. My prior work was focused on hippocampal function in the disease state of a special lesion model (LGi1 associated limbic encephalitis) and involved diagnostic approaches such as neurocognitive assessments, sleep analyses, and cranial MRIs. Together with my colleagues Dr. Annika Hanert and Sarah Philippen, I am a member of a research group for dementia, memory disorders, and neuroplasticity, led by Prof. Thorsten Bartsch.

What inspired or motivated you to undertake this research project?

In our hospital´s memory clinic, a rapidly increasing number of people present themselves with cognitive symptoms that have occurred in the post-acute course of a COVID-19 infection. The reported symptoms range from disturbances in attention and concentration, to executive function and mnestic deficits, which tend to persist long after recovery from the initial COVID-19 infection and are particularly detrimental to their daily life (Zubair et al. 2020; Baker et al. 2021; Raman et al. 2021; Heneka et al. 2020; Serrano-Castro et al. 2020).

Since a thorough cognitive examination has not been performed it remains unclear to what extent these changes are associated with expressed cognitive concerns. A structured and thorough study of COVID associated cognitive sequela in the context of a longer follow-up examination has not been conducted so far. Relevant questions regarding the pathogenesis of subjective cognitive complaints could not be clarified in previous studies and remain open. Considering this, we wish to study post-COVID-19 patients using a multimodal comprehensive diagnostic approach.

What is your study design?

We plan the follow-up examination of a large cohort of > 100 patients (age between 18 and 75 years) at several time-points after a COVID-19 infection (positive PCR detection). These patients are part of a nationwide German COVID-19 study taking place at our site in Kiel, Germany. We are going to compare this cohort with a healthy post-COVID-19 control population with no complaints of cognitive decline. We will carry out a broad neuropsychological, clinical and neuroradiologic examination.

What methods do you plan to use, and why?

By means of using the CANTAB we would like to objectively quantify and characterise the deficits for this patient group and examine them translationally in connection with any structural changes in cognitive networks. We focus in our study on usage of the CANTAB test battery, since it is recognised as well-validated, established, and has been proven to be sensitive in the testing of patients with even mild cognitive deficits (Egerházi et al. 2007). In summary, CANTAB gives us the ideal diagnostic tool for our translational neurocognitive-neuroradiologic diagnostic approach.

Cognitive status will be assessed by means of the following tests:

• Spatial Working Memory (SWM) - Working memory and strategy
• Paired Associates Learning (PAL) - Visual episodic memory
• One Touch Stockings of Cambridge (OTS) - Planning and executive function
• Delayed Matching to Sample (DMS) - Attention and short term visual memory
• Rapid Visual Information Processing (RVP) - Sustained attention and processing speed

Our particular focus will be on hippocampal functions as the hippocampus represents a particularly vulnerable memory structure (Bartsch und Wulff 2015) which has been discussed to be vulnerable to COVID-19 associated damage in particular (Ritchie et al. 2020). Interestingly, studies with diffusion tensor imaging (DTI) revealed the first hints of a possible disruption of micro-structural and functional brain integrity in the recovery stages of COVID-19 (Lu et al. 2020).

Keeping the neurotropy of the virus in mind, it seems plausible that via the olfactory bulb, anatomical related structures such as the frontal lobe and the entorhinal cortex and the hippocampus become affected (Strauss et al. 2020). Thus, we will use cranial MRIs in these patients in a hypothesis-guided manner. We will investigate the question of inflammation and demyelination processes as well as volumetric changes and strategic lesions to further elucidate the sstructure-function relationship of cognitive networks.

In summary, we will explore alterations in the above-named cognitive networks neuropsychologically. We will do this not only in a follow-up manner but also translationally in conjunction with three tesla cranial MRI imaging. Through this multimodal approach, it is hoped our study will help to clarify the nature of cognitive decline in patients with COVID-19 and give way to potential therapeutic solutions.

References:

1. Baker, Hanan A.; Safavynia, Seyed A.; Evered, Lisbeth A. (2021): The 'third wave'. Impending cognitive and functional decline in COVID-19 survivors. In: British journal of anaesthesia 126 (1), S. 44–47. DOI: 10.1016/j.bja.2020.09.045.

2. Bartsch, T.; Wulff, P. (2015): The hippocampus in aging and disease. From plasticity to vulnerability. In: Neuroscience 309, S. 1–16. DOI: 10.1016/j.neuroscience.2015.07.084.

3. Egerházi, Anikó; Berecz, Roland; Bartók, Eniko; Degrell, István (2007): Automated Neuropsychological Test Battery (CANTAB) in mild cognitive impairment and in Alzheimer's disease. In: Progress in neuro-psychopharmacology & biological psychiatry 31 (3), S. 746–751. DOI: 10.1016/j.pnpbp.2007.01.011.

4. Heneka, Michael T.; Golenbock, Douglas; Latz, Eicke; Morgan, Dave; Brown, Robert (2020): Immediate and long-term consequences of COVID-19 infections for the development of neurological disease. In: Alzheimer's research & therapy 12 (1), S. 69. DOI: 10.1186/s13195-020-00640-3.

5. Lu, Yiping; Li, Xuanxuan; Geng, Daoying; Mei, Nan; Wu, Pu-Yeh; Huang, Chu-Chung et al. (2020): Cerebral Micro-Structural Changes in COVID-19 Patients – An MRI-based 3-month Follow-up Study. In: EClinicalMedicine 25. DOI: 10.1016/j.eclinm.2020.100484.

6. Raman, Betty; Cassar, Mark Philip; Tunnicliffe, Elizabeth M.; Filippini, Nicola; Griffanti, Ludovica; Alfaro-Almagro, Fidel et al. (2021): Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge. In: EClinicalMedicine 31, S. 100683. DOI: 10.1016/j.eclinm.2020.100683.

7. Ritchie, Karen; Chan, Dennis; Watermeyer, Tam (2020): The cognitive consequences of the COVID-19 epidemic. Collateral damage? In: Brain communications 2 (2), fcaa069. DOI: 10.1093/braincomms/fcaa069

8. Serrano-Castro, P. J.; Estivill-Torrús, G.; Cabezudo-García, P.; Reyes-Bueno, J. A.; Ciano Petersen, N.; Aguilar-Castillo, M. J. et al. (2020b): Influencia de la infección SARS-CoV-2 sobre enfermedades neurodegenerativas y neuropsiquiátricas. ¿una pandemia demorada? In: Neurologia (Barcelona, Spain) 35 (4), S. 245–251. DOI: 10.1016/j.nrl.2020.04.002.

9. Zubair, Adeel S.; McAlpine, Lindsay S.; Gardin, Tova; Farhadian, Shelli; Kuruvilla, Deena E.; Spudich, Serena (2020): Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019. A Review. In: JAMA neurology 77 (8), S. 1018–1027. DOI: 10.1001/jamaneurol.2020.2065.

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