COGNITIVE IMPAIRMENTS AS A SYMPTOM OF POST-COVID SYNDROME AMONG THE BULGARIAN POPULATION IN THE CONTEXT OF A GLOBAL PANDEMIC: AN ONGOING STUDY

: Isolated in China at the end of 2019, the novel Corona virus - SARS-CoV 2 spread worldwide with remarkable speed, causing a state of global health emergency just a few months later. And yet as we passed the acute phase of the COVID 19 pandemics, healthcare workers face the challenge of its late consequences. Therefore, the World Health Organization defined a new condition - post-COVID syndrome (PCS, Post-acute COVID Syndrome or long-COVID). According to several studies, the incidence of PCS varies from 10% to 35% among non-hospitalized patients and up to 85% among hospitalized patients. Moreover, various study results show that the syndrome affects both patients with a symptomatic form of the infection and those with an asymptomatic course. The syndrome itself presents with a wide range of non-specific complaints, most frequent of which are fatigue, shortness of breath and impaired cognitive functions. The exact pathogenetic mechanisms, responsible for these prolonged neuropsychological manifestations of long COVID 19 are yet to be established but most authors assume that they are caused by chronic neuroinflammation. Purpose:

INTRODUCTION residual symptoms, with only a third of them having experienced a severe COVID-19 infection. According to the prospective follow-up study of Logue et al. (2021) 5 about 30% of those affected by COVID 19 reported residual symptoms such as fatigue, headache, impaired memory, difficult concentration, hypo/ anosmia and impaired taste, depression and anxiety. According to another study by Woo et al. (2020) 78% of those, who have recovered from a mild or moderately severe form of COVID 19, experience cognitive difficulties. In 2021 Graham et al. 7 conducted a prospective study among the first 100 patients of a Neuro-COVID clinic in the USA. They found that the most common symptoms, persisting for more than 6 weeks are: "brain fog" (81%), headache (68%), paresthesia (60%), impaired taste (59%), anosmia (55%) and muscle aches (55%). These results prove that medical professionals are already facing the challenges of this new postacute condition and its impact on everyday life and professional functioning.
Thus, the WHO defined a new condition -post acute COVID syndrome (PACS) or long-COVID. According to the official definition, PACS is a condition that occurs in people with laboratory-proven or probable COVID 19 infection and is established at least 3 months after the initial infection. The syndrome includes new or residual symptoms that persist for at least another 2 months ant cannot be explained by another diagnosis. The most frequent complaints are fatigue, shortness of breath and cognitive dysfunction, with yet no proven correlation between the severity of the initial infection and the likelihood of developing post-COVID syndrome. correlation between the severity of the initial infection and the likelihood of developing post-COVID syndrome.
The first studies, trying to determine the specifics of the cognitive impairments as a symptom of PACS, were conducted in some of the most affected countries. In 2021, in the USA, Frontera et al. (2021) 6 selected a group of 382 hospitalized SARS-CoV-2 positive patients, aged between 55 and 77 years. Some of them (196/382) had neurological symptoms during the acute phase of the disease, while others were treated at an intensive care unit. After discharge, patients were followed-up at the 6th month using the the Montreal Cognitive Assessment (MoCA) and Barthel Index (BI -to assess the ability to cope with daily activities). Of all examined, 50% showed cognitive impairments and MoCA results below 18 points, and 44% experienced difficulties in performing some daily tasks. Similar are the results obtained by Walle-Hansen et al. (2021.) 7 who also used the MoCA to assess the cognitive functions in a group of 106 patients. Six months after hospitalization, 43% of them showed impaired cognition. Lamontagne et al. (2021)8 conducted a study, including 50 healthy controls and 50 patients who had recovered from COVID 19 infection and had no previous evidence of neuropsychiatric complaints. The authors used a computer test to assess executive functions, orientation and active attention (ANT -Attention Network Test). The final analysis showed that cognitive impairments were most pronounced during the first 1 to 4 months after the acute infection, with executive functions and memory being predominantly affected, while orientation and active attention were relatively intact. These data correlate with the changes in brain glucose metabolism found by Blazhenets et al. (2021) 9. The authors followed-up a small cohort of 8 patients using 18F-FDG PET and neuropsychological assessment (MoCA) -once during the subacute phase and again approximately 6 months after the initial diagnosis. The results of the first 18F-FDG PET showed neocortical glucose hypometabolism, predominantly in the frontoparietal and, to a lesser extent, in the temporal regions. These results were corresponding to lower MoCA results. Re-examination in the chronic phase of COVID 19 revealed an improvement in cognitive function and MoCA scores, accompanied by a significant reduction in neocortical glucose hypometabolism, but without full recovery. One possible hypothesis is that this residual glucose hypometabolism is secondary to other pathohistological changes of the brain parenchyma.
There is still no consensus on the exact pathogenetic mechanisms by which the SARS-CoV-2 virus causes persistent symptoms. There are a few hypotheses, but most authors accept that SARS-CoV-2 may induce persistent inflammation in the body, which can possibly have a central role in the pathogenesis of PACS. Chronic inflammation is also associated with increased plasma levels of proinflammatory cytokines (IL-1, IL-6, IL-10, TNF-α). The latter disrupt the permeability of the blood-brain barrier, pass into the Central nervous system (CNS) and activate microglial cells. In general microglia have anti-inflammatory functions and promote recovery processes. However, their prolonged activation leads to alteration, abnormal proliferation and induction of pro-apoptotic processes, as well as in situ synthesis of inflammatory cytokines and factors, promoting neurodegeneration. This way the impaired permeability of the blood-brain barrier and the high levels of cytokines in the CNS and plasma, potentiate each other and thus support the process of neuroinflammation in the CNS. Prolonged microglial activation leads to subsequent disruption of neuroplasticity, synaptic function, and myelination. This chronic neuroinflammation is very similar to that in some other chronic diseases of CNS like Alzheimer's disease.  Sun et al. 2021-Hristova, M., & Massaldjieva, R. (2023. Cognitive impairments as a symptom of post-covid syndrome among the Bulgarian population in the context of a global pandemic: an ongoing study, MEDIS -Medical Science and Research, 2(2), 25-28. doi: 10.35120/medisij020225h UDK: 364.622:[616.98:578.834(497.2) 10, 11,12,13,14,15,16,17,18).

MATERIALS AND METHODS
The aim of our study is to determine the most common cognitive impairments among the Bulgarian population, thus providing information about their characteristics and incidence. For this purpose, we selected a group of 75 patients (to date) 75 patients, all of which have recovered from COVID 19 infection at least 3 months prior to testing. All participants are between 20 and 60 years old and have no medical history of previous neurological or/and psychiatric disease, cancer or substance abuse. Patients who were reinfected with SARS-CoV 2 between the initial testing ant the follow-up were excluded. All participants signed a consent form.
In order to assess cognitive functions, we used a computer test -the Cogstate Brief Battery, which provides a measure of four core cognitive domains: processing speed, attention, visual learning and working memory. All tests are conducted under the supervision of a member of the research team. The test was performed on a laptop. This CogState battery (CAB) included several subtests: • Continuous Paired Associate Learning (CPAL -"In what locations do these pictures belong?")measures delayed visual memory through paired associate learning. Administration time for healthy participants is 7 minutes.
• Groton Maze learning test (GML) -to asses executive function. Administration time for healthy participants is 7 minutes.
• One-card learning (OCL -" Have you seen this card before?") and One-back memory (ONB -"Is the previous card the same?") -measures working memory. Administration time for healthy participants is respectively 6 and 4 minutes.
• Identification test ("Is the card red?") -to assess attention. Administration time for healthy participants is 4 minutes.
All participants will perform the same test on a follow-up meeting 6 months after the first testing.

RESULTS
Since our study is still ongoing, we intend to include at least 25 more patients before the final analysis. To date however we do notice slight deficits in the tests, assessing executive functions, speed of visual processing and working memories. Most of the participants who are confident at the beginning show unsatisfiable speed in performing the subtests and a noticeable number of mistakes. These deficits are more pronounced in patients with a more recent COVID 19 infection, despite the lack of subjective complaints in many cases.

DISCUSSION
Most of the studies, evaluating cognitive functions as a symptom of long COVID, are being conducted in the countries, affected most by the pandemic (China, Great Britain, USA, Italy). Although there are still many uanswered questions, the studies to date provide useful information about the specifics of the observed cognitive impairments, revealing a predominant involvement of executive functions and memory. The published results prove that the subjective complaints of "brain fog" and impaired concentration are associated with objective findings, giving invaluable guidance to clinicians to look for specific deviations in cognitive functions when examining recovering patients. Regarding pathogenesis, the role of neuroinflammation and glucose hypometabolism is emphasized, which expands potential possibilities for prevention and treatment.

CONCLUSION
The results of these studies give us a clearer clinical and diagnostic picture of a new syndrome, allowing the scientific and medical community to apply a more targeted approach in dealing with this new challenge. This data is useful especially for small countries, where a timely screening for cognitive disorders at the beginning of the chronic, or even in the subacute phase of the infection, would allow early