Prolonged clinical monitoring of cognitive performance and psychiatric symptoms among PACS

Prolonged clinical monitoring of cognitive performance and psychiatric symptoms among PACS | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Prolonged clinical monitoring of cognitive performance and psychiatric symptoms among PACS Del Duca Giulia, Camici Marta, Sperduti Isabella, Brita Anna Clelia, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6817736/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background To date, follow-up neurocognitive evaluations in individuals with Post-acute COVID-19 Syndrome (PACS) indicate that some level of impaired performance persists in at least one cognitive domain, typically affecting the same functions initially compromised. In the present study, we aim to enrich longitudinal evidence on cognitive dysfunction and psychiatric symptoms in an Italian sample with PACS. Material and method All patients performed a neurocognitive assessment (NCA) of 20 tests across 5 cognitive domains (memory, attention, language, executive functions, speed of psycho-motor processing) and neuropsychiatric symptoms questionnaires (anxiety, depression and sleep quality) to evaluate their possible influence on neurocognitive performance (NP) at three time points. Categorical variables were analyzed using Chi-Square or Fisher's exact tests, and quantitative variables were compared using the non-parametric Friedman test. Results Overall, 42 patients, 35.7% female, with a median age of 57 years (IQR 38–81) and 13 years of education (IQR 8–18) performed NCA. NP of six cognitive functions improved over time (verbal short-term learning, p = 0.032; short-term memory for visuo-spatial stimuli, p < 0.0001; working memory, p = 0.002; constructional praxis, p = 0.018; phonological verbal fluency, p = 0.05; speed of psychomotor processing, p = 0.002). Also sleep quality improved over time, p < 0.0001 (Table 2). Conclusion This study shows improvement over time in memory, executive functions and language during over the 18-month follow-up period in PACS. However, specific areas of neuropsychological performance may remain stable or decline during the follow-up period. post-COVID19 Long-COVID PACS cognitive outcomes neuropsychiatric symptoms longitudinal neuropsychological evaluation Figures Figure 1 Figure 2 Figure 3 Background After acute SARS-CoV-2 infection, the onset of a post-acute COVID-19 Syndrome condition (PACS), also known as long COVID, punctuated by a variety of persistent symptoms, including cognitive difficulties, fatigue, mood changes, and neurological manifestations, is often common and is a serious and growing problem in the primary health care setting [ 1 , 2 ]. Specifically, in hospitalized patients PACS-related cognitive disorders may occur during the initial subacute phase or within few days after hospital discharge, and can persist from 5–7 months up to a year, [ 3 , 4 , 5 ] potentially due to disruptions in the immune response [6,7,8,9]. The pathophysiological mechanisms underlying the onset or worsening of cognitive decline, or worsening of pre-existing cognitive disorders, in patients with COVID-19 are likely to be multifaceted and range from the detrimental effects of hypo-oxygenation of neural cells to the toxic effects of cytokines released in the context of widespread inflammation [10]. The cognitive functions most commonly impaired are executive functioning, attention, memory, and information processing speed [11]. To date, some studies have shown that at one-year follow-up, approximately 50% of patients with cognitive impairment continue to exhibit pathological performance in at least one cognitive domain, primarily in the same functions as at the initial assessment [12]. Although these cognitive changes may be reversible, overall cognitive function in individuals with mild post-COVID-19 shows improvement after 18 months of follow-up compared to those without prior infection, thought it remains below baseline levels [11]. Additionally, attention, verbal memory, and processing speed shows significant improvement after one year [13]. In particular, processing speed seems to be a reliable measure of subjective feelings of mental fatigue, as demonstrated recently in a study in which the variance of visual processing speed in a laboratory task was explained by a neurophysiological measure of central nervous arousal, pupillary agitation, and the level of subjective mental fatigue [14]. Furthermore, PACS and impaired cognitive functioning often impair quality of life [15] and, with it, work performance, potentially leading to work impairment, absenteeism, and even unemployment [16]. In the present study, we aim to enrich the longitudinal evidence on cognitive dysfunction and psychiatric symptoms by analyzing neuropsychological changes in an Italian sample with PACS, focusing on how cognitive and fatigue symptoms emerge and evolve over time. Methods Study design, setting and study population. The Neuro-COVID Study is an observational, longitudinal, retrospective, monocentric study, conducted at the post-COVID services of the National Institute for Infectious Diseases L. Spallanzani, in Rome, Italy. The study was approved by the Ethics Committee of INMI Lazzaro Spallanzani in accordance with Italian legislation for SARS-CoV-2 research (approval number 119/2020, dated 20/05/2020). We included patients with a documented history of SARS-CoV-2 infection and neurological symptoms, who underwent a neurocognitive assessment (NCA) conducted within 7 months following acute COVID-19, in patients with or without prior hospitalization. Participants were either referred by a clinician or self-referred to our Post-COVID-19 outpatient service for symptoms attributable to PACS, occurring at least four weeks after the acute SARS-CoV-2 infection, and who consented to participate in this observational neuropsychological screening program during the post-acute phase of COVID-19.This analysis pertains exclusively to the subset of patients who chose to participate in the NCA sub-study, with the aim of evaluating neurocognitive status during the post-acute phase of COVID-19, between September 2020 and January 2023 (Fig. 1 ). The study was conducted in accordance with the Declaration of Helsinki, and informed consent was obtained from all participants. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Study Procedures Neurocognitive assessment (NCA) NCA we conducted at approximally 3 months (t0; median number of weeks: 0 ± 8), 6 months (t1 median number of weeks: 6 ± 21) and 12 months (t2; median number of weeks: 12 ± 27) after the resolution of the acute infection. NCA was performed using a standardized battery of 20 tests across 5 cognitive domains (memory, attention, language, executive functions, speed of psycho-motor processing). The neurocognitive tests used were: Mini Mental State Examination (MMSE) [17] to assess global cognitive status, Rey Auditory Verbal Learning Test-Short Term (RAVLT-ST) to assess verbal short-term learning, Rey Auditory Verbal Learning Test-Delayed Recall (RAVLT-DR) and Rey Auditory Verbal Learning Test-Recognition (RAVLT-REC) [18] to assess verbal long-term memory and recognition of verbal stimuli in long-term memory; Digit Span Forward (DSF) and Backward (DSB) [19] to assess short-term and working memory capacity for verbal stimuli; Corsi Span Forward (CSF) and Backward (CSB) [19] to assess short-term and working memory capacity for visuo-spatial stimuli; Rey-Osterrieth Complex Figure- Copy (ROCF-C) [20] to assess constructional praxis; Rey-Osterrieth Complex Figure -Delayed Recall (ROCF-DR) [20] to assess long-term memory for visual-spatial stimuli; Trail Making Test A (TMTA) [21] and WAIS-R Digit Symbol (DS) [22] to assess speed of psycho-motor processing; Trail Making Test B (TMTB) [21] to assess shifting ability and Stroop Test Color-Word (ST) [23] to assess inhibition an automatic reply and mental flexibility; Multiple Features Target Cancellation (MFTC) [24] to assess attention and Phonological and Categorical Verbal Fluency (living and non-living, PVF and CVF) [25] to assess fluency and language programming. We use the Instrumental activities daily living scale (IADL) [26] to assess the degree of autonomy in instrumental activities of daily living. Epidemiological, demographic, and clinical data were collected and recorded anonymously. Raw neuropsychological test scores were adjusted for age, gender and education level. When available, these scores were converted into equivalent scores (ES) [27], which use an ordinal scale ranging from 0 to 4. ES = 0 Deficient comprising; ES = 1 Borderline performance; ES = 2–3 Middle-lower comprising performance; ES = 4 Middle-upper comprising performance. The ES allows for the comparison of a subject's position relative to normal subjects, net of the influence of variables related to gender, age and education. The presence of impairments was defined by scores below the normative reference value (< cutoff-ES = 0). Neuropsychiatric assessment The following questionnaires were administered to assess the presence of neuropsychiatric symptoms and their possible influence on neurocognitive performance: the Beck Anxiety Inventory (BAI) [29] which assess the cognitive and physiological symptoms of anxiety [range = 0–33 were classified as in: 0–9 = no symptoms, 10–19 = mild symptoms, 20–29 = moderate symptoms; 30–33 = severe symptoms scores (> 85%)]; the Beck Depression Inventory (BDI-II) [30], which assess cognitive, affective, and physiological symptoms of depression (Somatic-affective SA/ Cognitive C dimensions) [range = 0–33 were classified as in: 0–9 = no symptoms, 10–19 = mild symptoms, 20–29 = moderate symptoms; 30–33 = severe symptoms scores (> 85%)]; the Pittsburgh Sleep Quality Index (PSQI) [31] for sleep quality assessment (if score > 5 indicates the presence of poor sleep quality). Statistical analysis Data are summarized using basic descriptive statistics. The Chi Square test or Fisher exact test were used for categorical variables, when appropriate. In case of quantitative variables, the comparison between matched cognitive functions and psychiatric symptoms were evaluated with non-parametric Friedman test. Statistical significance was defined as p < 0.05. Statistical evaluation was performed by use of the SPSS 29.0 (SPSS Inc., Chicago, IL, USA) for Windows. Results Study population The analysis included 42 patients with a median age of 57 years (IQR 38–81), 35.7% were female, with a median of 13 years of education (range 8–18), 42.9% had hypertension, 73.8% complaints neuropsychological symptoms, 81% were previously hospitalized (PH), 66.7% received oxygen therapy and 16.7% with a previous pulmonary embolism. PH patients have taken therapies such as Tocilizumab/Sarilumab (7.1%), Remdesivir (47.6%), Hydroxychloroquine (21.4%), steroids (66.7%) and prophylaxis with low molecular weight heparin (LMWH, 66.7%), therapeutic alternatives mostly present in the first two pandemic waves, from which the study population is derived. General characteristics of study population are shown in Table 1 . Table 1 Baseline clinical characteristics for the study population Variables Sample N = 42 Age, median (IQR) 57 (38–81) Female 15 (35.7%) Education, median (IQR) 13 (8–18) Smoking 2 (4.8%) Comorbidities Previous acute myocardial infarction 2 (4.8%) Hypertension 18 (42.9%) Diabetes 5 (11.9%) Cardiac Disease 3 (7.1%) Neurological disease 2 (4.8%) Respiratory diseases 0 (0%) Cancer 0 (0%) Neuropsychological symptoms 31 (73.8%) Oxygen therapy 28 (66.7%) Pulmonary Embolism 7 (16.7%) Previous hospitalization (PH) 34 (81.0%) Anti-SARS-CoV-2 therapy Tocilizumab/sarilumab 3 (7.1%) Kaletra 4 (9.5%) Steroids 28 (66.7%) Remdesivir 20 (47.6%) Plasma 1 (2.4%) Hydroxychloroquine 9 (21.4%) LMWH 28 (66.7%) ACE_I 6 (14.3%) ARB 2 (4.8%) Statine 5 (11.9%) Neuropsychological performance trend analysis Our results indicate that neurocognitive performance across six assessed functions changed over time. Specifically: verbal short-term learning (RAVLT-ST) was impaired in 10 patients at t0, 5 patients at t1 and 4 patients at t2 (23.8% vs 11.9% vs 9.5%, p = 0.032); short-term memory for visuo-spatial stimuli (CSF) and working memory for visuo-spatial (CSB) were impaired in 13 and 14 pts at t0, 1 and 5 pts at t1, 0 and 3 pts at t2 (31% vs 2.4% vs 0, p = < 0.0001; 33.3% vs 11.9% vs 7.1%, p = 0.002, respectively). In addition, constructional praxis (ROCF-C) was impaired in 7 pts at t0, 3 pts at t1 and 1 pts at t2 (16.7% vs 7.1% vs 2.4%, p = 0.018). In phonological verbal fluency (PVF), the neurocognitive performance was impaired in 8 pts at t0, 6 pts at t1 and 4 pts at t2 (19% vs 14.3% vs 9.5%, p = 0.05) and speed of psychomotor processing (DS) was impaired in 17 pts at t0, 6 pts at t1 and 6 pts at t2 (40.5% vs 14.3% vs 14.3%, p = 0.002). Regarding neuropsychiatric symptoms, sleep quality was impaired in 13 pts at t0, 3 pts at t1 and 1 pts at t2 (31% vs 7.1% vs 2.4%, p = < 0.0001). Individual trends are reported in Table 2 . Table 2 Temporal changes in cognitive functions and neuropsychiatric symptoms (t0-t1-t2) T0 T1 T2 P value NCA normal impaired normal impaired normal impaired MMSE 42 (100%) 0 42 (100%) 0 42 (100%) 0 1 RAVLT-ST 32 (76.2%) 10 (23.8%) 37 (88.1%) 5 (11.9%) 38 (90.5%) 4 (9.5%) 0.032 RAVLT-RD 36 (85.7%) 6 (14.3%) 39 (92.9%) 3 (7.1%) 39 (92.9%) 3 (7.1%) 0.276 RAVLT-REC 30 (71.4%) 12 (28.6%) 31 (73.8%) 11 (26.2%) 34 (81%) 8 (19%) 0.486 ROCF-DR 27 (64.3%) 15 (35.7%) 31 (73.8%) 11 (26.2%) 32 (76.2%) 10 (23.8%) 0.148 DSF 39 (92.9%) 3 (7.1%) 37 (88.1%) 5 (11.9%) 35 (83.3%) 7 (16.7%) 0.223 DSB 38 (90.5%) 4 (9.5%) 36 (85.7%) 6 (14.3%) 40 (95.2%) 2 (4.8%) 0.264 CSF 29 (69%) 13 (31%) 41 (97.6%) 1 (2.4%) 42 (100%) 0 < 0.0001 CSB 28 (66.7%) 14 (33.3%) 37 (88.1%) 5 (11.9%) 39 (92.9%) 3 (7.1%) 0.002 ROCF-C 35 (83.3%) 7 (16.7%) 39 (92.9%) 3 (7.1%) 41 (97.6%) 1 (2.4%) 0.018 MFTC-ACC 30 (71.4%) 12 (28.6%) 36 (85.7%) 6 (14.3%) 36 (85.7%) 6 (14.3%) 0.105 MFTC-ERR 42 (100%) 0 42 (100%) 0 42 (100%) 0 1 MFTC-T 42 (100%) 0 42 (100%) 0 42 (100%) 0 1 PVF 34 (81%) 8 (19%) 36 (85.7%) 6 (14.3%) 38 (90.5%) 4 (9.5%) 0.05 CVF 26 (61.9%) 16 (38.1%) 32 (76.2%) 10 (23.8%) 30 (71.4%) 12 (28.6%) 0.116 ST-T 41 (97.6%) 1 (2.4%) 39 (92.9%) 3 (7.1%) 41 (97.6%) 1 (2.4%) 0.368 ST-ERR 40 (95.2%) 2 (4.8%) 42 (100%) 0 42 (100%) 0 0.135 TMTA 41 (97.6%) 1 (2.4%) 42 (100%) 0 42 (100%) 0 0.368 TMTB 42 (100%) 0 42 (100%) 0 42 (100%) 0 1 DS 25 (59.5%) 17 (40.5%) 36 (85.7%) 6 (14.3%) 36 (85.7%) 6 (14.3%) 0.002 BAI 27 (64.3%) 15 (35.7%) 28 (66.7%) 14 (33.3%) 30 (71.4%) 12 (28.6%) 0.705 BDI-II 22 (52.4%) 20 (47.6%) 26 (61.9%) 16 (38.1%) 25 (59.5%) 17 (40.5%) 0.395 BDI-II SA 24 (57.1%) 18 (42.9%) 29 (69%) 13 (31%) 29 (69%) 13 (31%) 0.249 BDI-II C 20 (47.6%) 22 (52.4%) 19 (45.2%) 23 (54.8%) 23 (54.8%) 19 (45.2%) 0.504 PSQI 29 (69%) 13 (31%) 39 (92.9%) 3 (7.1%) 41 (97.6%) 1 (2.4%) < 0.0001 Abbreviations: Mini Mentale State Examination (MMSE); Rey Auditory Verbal Learning Test-Short Term (RAVLT-ST); Rey Auditory Verbal Learning Test-Delayed Recall (RAVLT-RD); Rey Auditory Verbal Learning Test-Recognition (RAVLT-REC); Rey-Osterrieth Complex Figure- Delayed Recall (ROCF-DR); Digit Span Forward (DSF); Digit Span Backward (DSB); Corsi Span Forward (CSF); Corsi Span Backward (CSB); Rey-Osterrieth Complex Figure- Copy (ROCF-C); Multiple Features Target Cancellation-Accuracy (MFTC-ACC); Multiple Features Target Cancellation-Errors (MFTC-ERR); Multiple Features Target Cancellation-Time (MFTC-T); Phonological Verbal Fluency (PVF); Categorical Verbal Fluency (CVF); Stroop test Color Word- Time (ST-T); Stroop test Color Word- Errors (ST-ERR); Trial Making Test A (TMTA); Trial Making Test B (TMTB);Digit Symbol Test (DS); Beck Anxiety Inventory (BAI); Beck Depression Inventory (BDI-II); Beck Depression Inventory Somatic-Affective (BDI-II SA); Beck Depression Inventory Cognitive (BDI-II C); Pittsburgh Sleep Quality Index (PSQI). Improved, worsened and stable neurocognitive performance Neurocognitive performance was categorized as follow: “ stable performance ,” indicated consistent performance over time without fluctuations, “ improved performance ,” referred to initially pathological performance that later rose above the clinical cut-off, and “ worsened performance ” described, initially normal performance subsequently declined below the cut-off threshold. We observed improved performance in verbal episodic short-term learning (RAVLT-ST, 14.3%), visuo-spatial short-term memory (CSF, 2.4%), visuo-spatial working memory (CSB, 4.8%), constructional praxis (ROCF-C, 16.7%) and speed of psycho-motor processing (DS, 28.6%). Conversely, worsened performance , was observed in verbal episodic short-term learning (9.5%), visuo-spatial short-term memory (16.7%), visuo-spatial working memory (4.8%), in constructional praxis (0%) and in speed of psycho-motor processing (14.3%). All percentages are shown in Fig. 2 . Association between neurocognitive performance and neuropsychiatric symptoms At t0 we found significant associations between increased anxiety symptoms (BAI) and worse neurocognitive performance on verbal short-term memory (DSF; p = 0.040) and speed of psycho-motor processing (DS; p = 0.020) tests. In addition, increased disturbances in sleep quality (PSQI) were associated with worse neurocognitive performance in speed of psycho-motor processing (DS; p = 0.018). Conversely, increased depressive symptoms (BDI-II), somatic-affective manifestations (BDI-II SA) and cognitive depressive symptoms (BDI-II C) are found to be significantly associated with normal neurocognitive performance in visual-spatial short-term memory (CSF; p = 0.007, p = 0.021, p = 0.002, respectively) and visual-spatial working memory tests (CSB: p = 0.023, p = 0.057, p = 0.008, respectively). In t1, increased anxious symptoms (BAI) are significantly associated with worse verbal learning performance (RAVLT-ST; p = 0.035) and increased cognitive depressive symptoms (BDI-II C) are significantly associated with worse visual-spatial working memory performance (CSB; p = 0.053). Increased sleep quality disorders (PSQI) are significantly associated with worse verbal learning tests (RAVLT-ST; p = 0.033) and verbal long-term memory performance (RAVLT-DR; p = 0.010). Finally, in t2 increased depressive symptoms (BDI-II; p = 0.059) and somatic-affective manifestations (BDI-II SA; p = 0.025) are significantly associated with a worse verbal long-term memory performance (RAVLT-DR). Extensive data on associations are available in Supplementary material (Fig. 3 A, 3 B, 3 C). Discussion The present study investigated neurocognitive outcomes in patients with previous acute COVID-19, regardless of the presence of subjective cognitive complaints. This approach allowed for the detection of even subtle cognitive alterations, that might otherwise go unnoticed. Our findings indicate a global improvement in neuropsychological functioning overtime, particularly in verbal short-term learning, short-term memory for visuo-spatial stimuli, working memory for visuo-spatial, constructional praxis, phonological verbal fluency and speed of psychomotor processing. There results align with recent literature reporting gradual recovery of cognitive function following COVID-19[32,33,34,35]. In particular, it has been widely demonstrated that attentional-executive functions may continue to improve for up to one year after the acute illness. [ 5 ] It is possible that the observed improvement in general cognitive symptoms is partly attributable to SARS-CoV-2 vaccination, which was administered between the two follow-up assessments. Additionally, passage of time since the acute event contributed to the resolution of the systemic inflammatory state, further supporting cognitive recovery [36]. Despite the positive changes observed, a high percentage of cognitive performance remained stable over time. Additionally, a subset of individuals who initially showed normal performance (i.e. above clinical cut-offs) experienced a decline in subsequent assessments, withscores falling below the normative thresholds. This finding is consistent with previous studies reporting that a significant percentage of cognitive scores retain pathological features over time [5, 37]. These borderline or declining scores may sometimes reflect underlying psychoemotional distress or indicate persistent cognitive problems. Therefore, it is essential that such changes are not underestimated and are carefully monitored over the long term. Interestingly, the perception of sleep quality shows significant improvement over time. As is now well known, sleep disturbances represented one of the most prevalent and persistent neuropsychiatric symptoms in patients with PACS [38, 39]. For this reason, it is possible to assume that a better sleep quality has positively affected the neurocognitive performance [40]. This is consistent with our finding showing that during the first NCA, increased sleep quality disturbances are associated with worse performance in psycho-motor processing speed. During the second NCA, sleep disturbances were instead linked to poorer performance in verbal learning and verbal long-term memory. The association between cognitive and neuropsychiatric symptoms has been previously described, suggesting a strong interconnection. In particular, anxiety and depression have been found to be more prevalent among individuals with cognitive disorders [38, 41, 42, 43]. At the first NCA, increased anxiety symptoms are associated with worse performance in terms of verbal short-term memory, which remains stable even at the second NCA, and in terms of psycho-motor processing speed. The association between depressive symptoms and cognitive performance showed interesting fluctuations over time. At the first NCA, an increase in depressive symptoms (both somatic-affective manifestations and depressive cognitive symptomatology) was significantly associated with normal performance in visual-spatial short-term memory and visual-spatial working memory. However, by the second NCA, performance in these domains appeared impaired. Finally, at the third and final NCA, depressive symptoms were associated with worse performance in verbal long-term memory. These findings highlight the complex and evolving relationship between mood disturbances and cognitive function in the post-acute phase of COVID-19. The associations between neuropsychiatric and cognitive symptoms are in line with recent findings suggesting that alterations in cognitive functioning in COVID-19 patients cannot be fully understood without considering psychological aspects [44]. This relationship is in fact biunivocal and determined by complex relationships: at risk are not only memory, concentration and attention, but also language, constructive skills and executive functions. Given these findings, it may seem intuitive to assume that cognitive symptoms are a product of the manifestation of anxiety and depression. However, numerous theoretical models suggest that cognitive impairments may also play a causal or maintaining role in the persistence of anxiety-depressive symptoms. In this view, cognitive dysfunction not only coexists with but may actively contribute to and perpetuate the cycle of neuropsychiatric symptoms, reinforcing a vicious cycle between emotional and cognitive disturbances [45, 46]. These results should be interpreted in light of several limitations. First, the lack of NCA previous to COVID-19 acute infection, which could allow differences to be observed in both those with neurocognitive impairment and normal profiles. Second, the lack of a control group that was compatible in sociodemographic characteristics, age, and sex. Finally, a relatively small sample size, which could cause bias in statistical analyses. Participants who chose to return for follow-up NCA likely had a more pronounced perception of neurocognitive impairment, triggered by comparison with their own cognitive abilities before COVID-19 infection. This perception was therefore a strong motivation to monitor their cognitive profile, with the aim of achieving a better quality of life. The strengths of this study were the accurate and in-depth neurocognitive and neuropsychiatric assessment, carried out in the presence and not online. In addition, this study was able to longitudinally monitor participants to observe changes in neurocognitive and neuropsychiatric measures at three different times, for a combined total of 12 months of observation. Conclusions Our results provide an additional reinforcing element to the literature, confirming the improvement in cognitive performance as a consequence of PACS and that alteration in a smaller proportion of cognitive functions may instead persist over time. Such cognitive alterations are often accompanied by psychological distress. Anxiety and depression, in fact, often have an influence on cognitive performance and a negative impact on quality of life. More attention should be paid to borderline scores, ensuring neuropsychological monitoring. Given the prevalence of PACS, treatment strategies should take into account the persistent effects of COVID-19 on mood and cognition, and new treatment approaches should be developed, specifically targeting cognitive disorders. Declarations Contributors MC, AA and CP conceived and designed the study. MC, CP, GDD and ACB developed the study protocol; GDD, MM and ACB performed all the neurocognitive assessment (NCA) and are responsible for data curation; IS performed the data analysis. MC, IM and VM clinically evaluated patients and refer to NCA; GDD, ACB and MC wrote the first draft. AA supervised this work. All authors read and approved the final manuscript. Data Availability Declaration The datasets generated and/or analyzed during the current study are not publicly available due to patient privacy reasons, but are available from the corresponding author on reasonable request. Competing Interest declaration All the authors declare no competing interests. Acknowledgements The author gratefully acknowledges all the participants, the statistician and the clinical study assistants of the National Institute for Infectious Diseases, “Lazzaro Spallanzani” (Sperduti I., Brita A.C., Maresca M., Camici M., Pinnetti C., Mastrorosa I., Mazzotta V., Antinori A.). References NICE. COVID-19 rapid guideline: managing the long-term effects of COVID-19. November 11, 2021. Accessed April 30, 2021. https://www.nice.org.uk/guidance/ng188 Jaywant A, Gunning FM, Oberlin LE, et al. Cognitive Symptoms of Post–COVID-19 Condition and Daily Functioning. JAMA Netw Open. 2024;7(2):e2356098. doi:10.1001/jamanetworkopen.2023.56098 F. Alemanno, E. Houdayer, A. Parma, A. Spina, A. Del Forno, A. Scatolini, …, S. Iannaccone. COVID-19 cognitive deficits after respiratory assistance in the subacute phase: a COVID-rehabilitation unit experience. PLoS One, 16 (2) (2021)e0246590; V. Beaud, S. Crottaz-Herbette, V. Dunet, J. Vaucher, R. Bernard-Valnet, R. Du Pasquier, …, S. 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J Neurol 271, 46–58 (2024). https://doi.org/10.1007/s00415-023-12069-3 Mastrorosa I, Del Duca G, Pinnetti C, Lorenzini P, Vergori A, Brita AC, Camici M, Mazzotta V, Baldini F, Chinello P, Mencarini P, Giancola ML, Abdeddaim A, Girardi E, Vaia F, Antinori A. What is the impact of post-COVID-19 syndrome on health-related quality of life and associated factors: a cross-sectional analysis. Health Qual Life Outcomes. 2023 Mar 22;21(1):28. doi: 10.1186/s12955-023-02107-z. PMID: 36949439; PMCID: PMC10031164. Perlis RH, Lunz Trujillo K, Safarpour A, et al. Association of post-COVID-19 condition symptoms and employment status.  JAMA Netw Open . 2023;6(2):e2256152. doi:10.1001/jamanetworkopen.2022.56152 Measso G, et al. The Mini-Mental State Examination: normative study of an italian random sample. Developmental Neuropsycol 1993; 9:77-85. DOI: 10.1111/j.1468-1331.1996.tb00423.x Carlesimo GA, Caltagirone C, Gainotti G. The mental deterioration battery: normative data diagnostic reliability and qualitative analyses of cognitive impariment. The group for the standardization of the mental deterioration battery. Eur Neurol. 1996;36(6):378-84. DOI: 10.1159/000117297 Monaco M, et al. Forward and backward span for verbal and visuo-spatial data: standardization and normative data from an italian adult population. Neurol Sci. 212 Jun12. DOI: 10.1007/s10072-012-1130-x Caffarra P, et al. Rey-Osterrieth complex figure: normative values in an italian population sample. Neurol sci. 2002 Mar; 22(6):443-7. DOI: 10.1007/s100720200003 Giovagnoli AR, et al. Trail making test: normative values from 287 normal adult controls. Ital J Neurol Sci. 1996 Aug; 17(4):305. DOI: 10.1007/BF01997792 Orsini A, Laicardi C. WAIS-R. Contributo Alla Taratura Italiana. Firenze: Giunti O.S. Organizzazioni Speciali,1997. Caffarra P, et al. Una versione abbreviata del test di Stroop: dati normativi nella popolazione italiana. Rivista di neurologia 2002; 12: n4. Marra C, et al. The multiple features target cancellation (MFTC): an attenzional visual conjunction search test. Normative values for the italian population. Neurol Sci. 2012 Feb 19 DOI: 10.1007/s10072-012-0975-3 Marra C, Ferraccioli M, Gainotti G. Gender-related dissociations of categorical fluency in normal subjects and in subjects with Alzheimer’s disease. Neuropsychology. 2007 Mar; 21(2):207-11 DOI: 10.1037/0894-4105.21.2.207 Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist. 1969 Autumn;9(3):179-86. PMID: 5349366. E. Capitani, M. Laiacona, Composite neuropsychological batteries and demographic correction: standardization based on equivalent scores, with a review of published data, J. Clin. Exp. Neuropsychol. 19 (6) (1997) 795–809. E. Capitani, M. Laiacona, Outer and inner tolerance limits: their usefulness for the construction of norms and the standardization of neuropsychological tests, Clin. Neuropsychol. 31 (6–7) (2017) 1219–1230 Beck, A. T., & Steer, R. A. Manual for the Beck anxiety inventory. San Antonio, TX: Psychological Corporation 1990. Beck A., Steer R., & Brown G. Beck Depression Inventory. 2nd edition. San Antonio, Tex, USA: The Psychological Corporation 1996. Curcio G, Tempesta D, Scarlata S, et al. Validity of the Italian version of the Pittsburgh Sleep Quality Index (PSQI). Neurol Sci. 2013;34(4):511-51 DOI: 10.1007/s10072-012-1085-y Almeria M, Cejudo JC, Deus J, Krupinski J. Long Neurocognitive and Neuropsychiatric Sequelae in Participants with Post-COVID-19 Infection: A Longitudinal Study. Neurol Int. 2024 Aug 16;16(4):853-868. doi: 10.3390/neurolint16040064. PMID: 39195566; PMCID: PMC11357167. S.J. Ferrando, R. Dornbush, S. Lynch, et al.Neuropsychological, medical, and psychiatric findings after recovery from acute COVID-19: a cross-sectional study J Acad Consult Liaison Psychiatry, 63 (2022), pp. 474-484 D. Prabhakaran, G.S. Day, B. Munipalli, et al. Neurophenotypes of covid-19: risk factors and recovery outcomes Brain Behav Immun Health, 30 (2023), Article 100648 R. Ferrucci, M. Dini, C. Rosci, et al. One-year cognitive follow-up of Covid-19 hospitalized patients Eur J Neurol, 29 (2022), pp. 2006 Camici M, Del Duca G, Brita AC, Antinori A. Connecting dots of long COVID-19 pathogenesis: a vagus nerve- hypothalamic-pituitary- adrenal-mitochondrial axis dysfunction. Front Cell Infect Microbiol. 2024 Dec 13;14:1501949. doi: 10.3389/fcimb.2024.1501949. PMID: 39735263; PMCID: PMC11671747. M. Taquet, R. Sillett, L. Zhu, et al. Neurological and psychiatric risk trajectories after SARS-COV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients Lancet Psychiatry, 9 (2022), pp. 815-827 Vergori A, Del Duca G, Borrelli P, Brita AC, Pinnetti C, Mastrorosa I, Camici M, Mondi A, Mazzotta V, Chinello P, Mencarini P, Giancola ML, Abdeddaim A, Girardi E, Antinori A. Cognitive outcomes and psychological symptoms in an Italian cohort with post-acute COVID-19 condition (PACC). Heliyon. 2024 Oct 16;10(20):e39431. doi: 10.1016/j.heliyon.2024.e39431. PMID: 39469684; PMCID: PMC11513557. Pilotto A, Cristillo V, Cotti Piccinelli S, Zoppi N, Bonzi G, Sattin D, Schiavolin S, Raggi A, Canale A, Gipponi S, Libri I, Frigerio M, Bezzi M, Leonardi M, Padovani A. Long-term neurological manifestations of COVID-19: prevalence and predictive factors. Neurol Sci. 2021 Dec;42(12):4903-4907. doi: 10.1007/s10072-021-05586-4. Epub 2021 Sep 15. PMID: 34523082; PMCID: PMC8439956. Almeria M., Cejudo J.C., Sotoca J., Deus J., Krupinski J. Cognitive profile following COVID-19 infection: Clinical predictors leading to neuropsychological impairment. Brain Behav. Immun. Health. 2020;9:100163. doi: 10.1016/j.bbih.2020.100163. Hampshire A., Azor A., Atchison C., Trender W., Hellyer P.J., Giunchiglia V., Husain M., Cooke G.S., Cooper E., Lound A., Donnelly C.A., Chadeau-Hyam M., Ward H., Elliott P. Cognition and memory after covid-19 in a large community sample. N. Engl. J. Med. 2024 Feb 29;390(9):806–818. doi: 10.1056/NEJMoa2311330. PMID: 38416429; PMCID: PMC7615803. Jaywant A., Vanderlind W.M., Alexopoulos G.S., et al. Frequency and profile of objective cognitive deficits in hospitalized patients recovering from COVID-19. Neuropsychopharmacol. 2021;46:2235–2240. doi: 10.1038/s41386-021-00978-8. Gebhard C.E., Sütsch C., Bengs S., Deforth M., Buehler K.P., Hamouda N., et al. Sex- and gender-specific risk factors of post-COVID-19 syndrome: a population-based cohort study in Switzerland. medRxiv. 2021;06.30 Poletti S., Palladini M., Mazza M.G., De Lorenzo R., Furlan R., Ciceri F.…Benedetti F. Long-term consequences of COVID-19 on cognitive functioning up to 6 months after discharge: role of depression and impact on quality of life. Eur. Arch. Psychiatry Clin. Neurosci. 2022;272(5):773–782. doi: 10.1007/s00406-021-01346-9. Kassem AM, Ganguli M, Yaffe K, et al. Anxiety symptoms and risk of dementia and mild cognitive impairment in the oldest old women. Aging Ment Health 2017:1-9. Wetherell JL, Petkus AJ, White KS, et al. Antidepressant medication augmented with cognitive-behavioral theray for generalized anxiety disorder in older adults. Am J Psychiatry 2013;170:782-9 Additional Declarations No competing interests reported. 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chart\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6817736/v1/3e45713f403bd37c0c45b5d1.jpg"},{"id":90793998,"identity":"4e1ddeaf-f59d-4814-ab2a-6ec1c94e8d8d","added_by":"auto","created_at":"2025-09-08 08:40:50","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":167794,"visible":true,"origin":"","legend":"\u003cp\u003eTemporal changes percentages in memory (RAVLT-ST, CSF, CSB), constructional praxis (ROCF-C) and speed of psycho-motor processing performance (DS)\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6817736/v1/d0f39e9aa22fe71cd3e77119.jpg"},{"id":90793999,"identity":"2a248b53-cec4-4db4-bc93-dfc85a180f21","added_by":"auto","created_at":"2025-09-08 08:40:50","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":82569,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e Longitudinal association between neurocognitive performance [short-term memory for verbal stimuli (Digit Span Forward), speed of psycho-motor processing (DS), short-term memory for visuo-spatial stimuli (CSF) and working memory for visuo-spatial stimuli (CSB)] and neuropsychiatric symptoms [anxiety (BAI) and depression (BDI-II)] at t0.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB\u003c/strong\u003e Longitudinal association between neurocognitive performance [short-term memory for visuo-spatial stimuli (CSF) and working memory for visuo-spatial stimuli (CSB), speed of psychomotor processing (DS)] and neuropsychiatric symptoms [depression – cognitive dimension (BDI-II C), sleep quality (PSQI)] at t0.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC\u003c/strong\u003e Longitudinal association between neurocognitive performance [episodic verbal short-term memory (RAVLT-ST) and recognition of verbal stimuli in long-term memory (RAVLT-RD), working memory for visuo-spatial stimuli (CSB)] and neuropsychiatric symptoms [anxiety (BAI), depression – cognitive dimension (BDI-II C), sleep quality (PSQI)] at t1.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6817736/v1/82c51154ebfed6aced4a5c56.png"},{"id":101615840,"identity":"6c53ab4b-5fdb-4d27-b366-d523f407e19b","added_by":"auto","created_at":"2026-02-01 21:54:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1603059,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6817736/v1/604b02f8-fe39-4944-b482-e62a84584e63.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Prolonged clinical monitoring of cognitive performance and psychiatric symptoms among PACS","fulltext":[{"header":"Background","content":"\u003cp\u003eAfter acute SARS-CoV-2 infection, the onset of a post-acute COVID-19 Syndrome condition (PACS), also known as long COVID, punctuated by a variety of persistent symptoms, including cognitive difficulties, fatigue, mood changes, and neurological manifestations, is often common and is a serious and growing problem in the primary health care setting [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSpecifically, in hospitalized patients PACS-related cognitive disorders may occur during the initial subacute phase or within few days after hospital discharge, and can persist from 5\u0026ndash;7 months up to a year, [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] potentially due to disruptions in the immune response [6,7,8,9].\u003c/p\u003e\u003cp\u003eThe pathophysiological mechanisms underlying the onset or worsening of cognitive decline, or worsening of pre-existing cognitive disorders, in patients with COVID-19 are likely to be multifaceted and range from the detrimental effects of hypo-oxygenation of neural cells to the toxic effects of cytokines released in the context of widespread inflammation [10].\u003c/p\u003e\u003cp\u003eThe cognitive functions most commonly impaired are executive functioning, attention, memory, and information processing speed [11]. To date, some studies have shown that at one-year follow-up, approximately 50% of patients with cognitive impairment continue to exhibit pathological performance in at least one cognitive domain, primarily in the same functions as at the initial assessment [12]. Although these cognitive changes may be reversible, overall cognitive function in individuals with mild post-COVID-19 shows improvement after 18 months of follow-up compared to those without prior infection, thought it remains below baseline levels [11]. Additionally, attention, verbal memory, and processing speed shows significant improvement after one year [13].\u003c/p\u003e\u003cp\u003eIn particular, processing speed seems to be a reliable measure of subjective feelings of mental fatigue, as demonstrated recently in a study in which the variance of visual processing speed in a laboratory task was explained by a neurophysiological measure of central nervous arousal, pupillary agitation, and the level of subjective mental fatigue [14].\u003c/p\u003e\u003cp\u003eFurthermore, PACS and impaired cognitive functioning often impair quality of life [15] and, with it, work performance, potentially leading to work impairment, absenteeism, and even unemployment [16].\u003c/p\u003e\u003cp\u003eIn the present study, we aim to enrich the longitudinal evidence on cognitive dysfunction and psychiatric symptoms by analyzing neuropsychological changes in an Italian sample with PACS, focusing on how cognitive and fatigue symptoms emerge and evolve over time.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eStudy design, setting and study population.\u003c/span\u003e\u003c/p\u003e\u003cp\u003eThe Neuro-COVID Study is an observational, longitudinal, retrospective, monocentric study, conducted at the post-COVID services of the National Institute for Infectious Diseases L. Spallanzani, in Rome, Italy. The study was approved by the Ethics Committee of INMI Lazzaro Spallanzani in accordance with Italian legislation for SARS-CoV-2 research (approval number 119/2020, dated 20/05/2020).\u003c/p\u003e\u003cp\u003eWe included patients with a documented history of SARS-CoV-2 infection and neurological symptoms, who underwent a neurocognitive assessment (NCA) conducted within 7 months following acute COVID-19, in patients with or without prior hospitalization. Participants were either referred by a clinician or self-referred to our Post-COVID-19 outpatient service for symptoms attributable to PACS, occurring at least four weeks after the acute SARS-CoV-2 infection, and who consented to participate in this observational neuropsychological screening program during the post-acute phase of COVID-19.This analysis pertains exclusively to the subset of patients who chose to participate in the NCA sub-study, with the aim of evaluating neurocognitive status during the post-acute phase of COVID-19, between September 2020 and January 2023 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e The study was conducted in accordance with the Declaration of Helsinki, and informed consent was obtained from all participants. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy Procedures\u003c/h2\u003e\u003cdiv id=\"Sec4\" class=\"Section3\"\u003e\u003ch2\u003eNeurocognitive assessment (NCA)\u003c/h2\u003e\u003cp\u003eNCA we conducted at approximally 3 months (t0; median number of weeks: 0\u0026thinsp;\u0026plusmn;\u0026thinsp;8), 6 months (t1 median number of weeks: 6\u0026thinsp;\u0026plusmn;\u0026thinsp;21) and 12 months (t2; median number of weeks: 12\u0026thinsp;\u0026plusmn;\u0026thinsp;27) after the resolution of the acute infection. NCA was performed using a standardized battery of 20 tests across 5 cognitive domains (memory, attention, language, executive functions, speed of psycho-motor processing). The neurocognitive tests used were: Mini Mental State Examination (MMSE) [17] to assess global cognitive status, Rey Auditory Verbal Learning Test-Short Term (RAVLT-ST) to assess verbal short-term learning, Rey Auditory Verbal Learning Test-Delayed Recall (RAVLT-DR) and Rey Auditory Verbal Learning Test-Recognition (RAVLT-REC) [18] to assess verbal long-term memory and recognition of verbal stimuli in long-term memory; Digit Span Forward (DSF) and Backward (DSB) [19] to assess short-term and working memory capacity for verbal stimuli; Corsi Span Forward (CSF) and Backward (CSB) [19] to assess short-term and working memory capacity for visuo-spatial stimuli; Rey-Osterrieth Complex Figure- Copy (ROCF-C) [20] to assess constructional praxis; Rey-Osterrieth Complex Figure -Delayed Recall (ROCF-DR) [20] to assess long-term memory for visual-spatial stimuli; Trail Making Test A (TMTA) [21] and WAIS-R Digit Symbol (DS) [22] to assess speed of psycho-motor processing; Trail Making Test B (TMTB) [21] to assess shifting ability and Stroop Test Color-Word (ST) [23] to assess inhibition an automatic reply and mental flexibility; Multiple Features Target Cancellation (MFTC) [24] to assess attention and Phonological and Categorical Verbal Fluency (living and non-living, PVF and CVF) [25] to assess fluency and language programming. We use the Instrumental activities daily living scale (IADL) [26] to assess the degree of autonomy in instrumental activities of daily living.\u003c/p\u003e\u003cp\u003eEpidemiological, demographic, and clinical data were collected and recorded anonymously. Raw neuropsychological test scores were adjusted for age, gender and education level. When available, these scores were converted into equivalent scores (ES) [27], which use an ordinal scale ranging from 0 to 4. ES\u0026thinsp;=\u0026thinsp;0 Deficient comprising; ES\u0026thinsp;=\u0026thinsp;1 Borderline performance; ES\u0026thinsp;=\u0026thinsp;2\u0026ndash;3 Middle-lower comprising performance; ES\u0026thinsp;=\u0026thinsp;4 Middle-upper comprising performance. The ES allows for the comparison of a subject's position relative to normal subjects, net of the influence of variables related to gender, age and education. The presence of impairments was defined by scores below the normative reference value (\u0026lt;\u0026thinsp;cutoff-ES\u0026thinsp;=\u0026thinsp;0).\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\n\u003ch3\u003eNeuropsychiatric assessment\u003c/h3\u003e\n\u003cp\u003eThe following questionnaires were administered to assess the presence of neuropsychiatric symptoms and their possible influence on neurocognitive performance: the Beck Anxiety Inventory (BAI) [29] which assess the cognitive and physiological symptoms of anxiety [range\u0026thinsp;=\u0026thinsp;0\u0026ndash;33 were classified as in: 0\u0026ndash;9\u0026thinsp;=\u0026thinsp;no symptoms, 10\u0026ndash;19\u0026thinsp;=\u0026thinsp;mild symptoms, 20\u0026ndash;29\u0026thinsp;=\u0026thinsp;moderate symptoms; 30\u0026ndash;33\u0026thinsp;=\u0026thinsp;severe symptoms scores (\u0026gt;\u0026thinsp;85%)]; the Beck Depression Inventory (BDI-II) [30], which assess cognitive, affective, and physiological symptoms of depression (Somatic-affective SA/ Cognitive C dimensions) [range\u0026thinsp;=\u0026thinsp;0\u0026ndash;33 were classified as in: 0\u0026ndash;9\u0026thinsp;=\u0026thinsp;no symptoms, 10\u0026ndash;19\u0026thinsp;=\u0026thinsp;mild symptoms, 20\u0026ndash;29\u0026thinsp;=\u0026thinsp;moderate symptoms; 30\u0026ndash;33\u0026thinsp;=\u0026thinsp;severe symptoms scores (\u0026gt;\u0026thinsp;85%)]; the Pittsburgh Sleep Quality Index (PSQI) [31] for sleep quality assessment (if score\u0026thinsp;\u0026gt;\u0026thinsp;5 indicates the presence of poor sleep quality).\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eData are summarized using basic descriptive statistics. The Chi Square test or Fisher exact test were used for categorical variables, when appropriate. In case of quantitative variables, the comparison between matched cognitive functions and psychiatric symptoms were evaluated with non-parametric Friedman test. Statistical significance was defined as p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Statistical evaluation was performed by use of the SPSS 29.0 (SPSS Inc., Chicago, IL, USA) for Windows.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStudy population\u003c/h2\u003e\u003cp\u003eThe analysis included 42 patients with a median age of 57 years (IQR 38\u0026ndash;81), 35.7% were female, with a median of 13 years of education (range 8\u0026ndash;18), 42.9% had hypertension, 73.8% complaints neuropsychological symptoms, 81% were previously hospitalized (PH), 66.7% received oxygen therapy and 16.7% with a previous pulmonary embolism.\u003c/p\u003e\u003cp\u003ePH patients have taken therapies such as Tocilizumab/Sarilumab (7.1%), Remdesivir (47.6%), Hydroxychloroquine (21.4%), steroids (66.7%) and prophylaxis with low molecular weight heparin (LMWH, 66.7%), therapeutic alternatives mostly present in the first two pandemic waves, from which the study population is derived. General characteristics of study population are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline clinical characteristics for the study population\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSample\u003c/p\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;42\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge, median (IQR)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e57 (38\u0026ndash;81)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFemale\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15 (35.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eEducation, median (IQR)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 (8\u0026ndash;18)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSmoking\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (4.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eComorbidities\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePrevious acute myocardial infarction\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (4.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHypertension\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18 (42.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDiabetes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (11.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCardiac Disease\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (7.1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNeurological disease\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (4.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRespiratory diseases\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCancer\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNeuropsychological symptoms\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e31 (73.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOxygen therapy\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28 (66.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePulmonary Embolism\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (16.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePrevious hospitalization (PH)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34 (81.0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAnti-SARS-CoV-2 therapy\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTocilizumab/sarilumab\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (7.1%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eKaletra\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (9.5%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSteroids\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28 (66.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRemdesivir\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20 (47.6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePlasma\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (2.4%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHydroxychloroquine\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9 (21.4%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLMWH\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28 (66.7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eACE_I\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (14.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eARB\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (4.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eStatine\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (11.9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eNeuropsychological performance trend analysis\u003c/h3\u003e\n\u003cp\u003eOur results indicate that neurocognitive performance across six assessed functions changed over time.\u003c/p\u003e\u003cp\u003eSpecifically: verbal short-term learning (RAVLT-ST) was impaired in 10 patients at t0, 5 patients at t1 and 4 patients at t2 (23.8% vs 11.9% vs 9.5%, p\u0026thinsp;=\u0026thinsp;0.032); short-term memory for visuo-spatial stimuli (CSF) and working memory for visuo-spatial (CSB) were impaired in 13 and 14 pts at t0, 1 and 5 pts at t1, 0 and 3 pts at t2 (31% vs 2.4% vs 0, p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; 33.3% vs 11.9% vs 7.1%, p\u0026thinsp;=\u0026thinsp;0.002, respectively).\u003c/p\u003e\u003cp\u003eIn addition, constructional praxis (ROCF-C) was impaired in 7 pts at t0, 3 pts at t1 and 1 pts at t2 (16.7% vs 7.1% vs 2.4%, p\u0026thinsp;=\u0026thinsp;0.018). In phonological verbal fluency (PVF), the neurocognitive performance was impaired in 8 pts at t0, 6 pts at t1 and 4 pts at t2 (19% vs 14.3% vs 9.5%, p\u0026thinsp;=\u0026thinsp;0.05) and speed of psychomotor processing (DS) was impaired in 17 pts at t0, 6 pts at t1 and 6 pts at t2 (40.5% vs 14.3% vs 14.3%, p\u0026thinsp;=\u0026thinsp;0.002).\u003c/p\u003e\u003cp\u003eRegarding neuropsychiatric symptoms, sleep quality was impaired in 13 pts at t0, 3 pts at t1 and 1 pts at t2 (31% vs 7.1% vs 2.4%, p\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Individual trends are reported in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eTemporal changes in cognitive functions and neuropsychiatric symptoms (t0-t1-t2)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eT0\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eT1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003eT2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNCA\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003enormal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eimpaired\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003enormal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eimpaired\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003enormal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eimpaired\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMMSE\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e42 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e42 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e42 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRAVLT-ST\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e32 (76.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (23.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e37 (88.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5 (11.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e38 (90.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e4 (9.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e0.032\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRAVLT-RD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e36 (85.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 (14.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e39 (92.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (7.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e39 (92.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e3 (7.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.276\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRAVLT-REC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30 (71.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 (28.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e31 (73.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e11 (26.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e34 (81%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e8 (19%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.486\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eROCF-DR\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27 (64.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 (35.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e31 (73.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e11 (26.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e32 (76.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e10 (23.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.148\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDSF\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e39 (92.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (7.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e37 (88.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5 (11.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e35 (83.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e7 (16.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.223\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDSB\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38 (90.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (9.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e36 (85.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6 (14.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e40 (95.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2 (4.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.264\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCSF\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e29 (69%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (31%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e41 (97.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (2.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e42 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCSB\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28 (66.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14 (33.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e37 (88.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5 (11.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e39 (92.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e3 (7.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eROCF-C\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e35 (83.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (16.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e39 (92.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (7.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e41 (97.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1 (2.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e0.018\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMFTC-ACC\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30 (71.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 (28.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e36 (85.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6 (14.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36 (85.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e6 (14.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.105\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMFTC-ERR\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e42 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e42 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e42 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMFTC-T\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e42 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e42 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e42 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePVF\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34 (81%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (19%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e36 (85.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6 (14.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e38 (90.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e4 (9.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e0.05\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCVF\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26 (61.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16 (38.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e32 (76.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10 (23.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e30 (71.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e12 (28.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.116\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eST-T\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e41 (97.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (2.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e39 (92.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (7.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e41 (97.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1 (2.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.368\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eST-ERR\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e40 (95.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (4.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e42 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e42 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.135\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTMTA\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e41 (97.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (2.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e42 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e42 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.368\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTMTB\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e42 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e42 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e42 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDS\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 (59.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17 (40.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e36 (85.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6 (14.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36 (85.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e6 (14.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBAI\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27 (64.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 (35.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e28 (66.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e14 (33.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e30 (71.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e12 (28.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.705\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBDI-II\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22 (52.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20 (47.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e26 (61.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e16 (38.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e25 (59.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e17 (40.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.395\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBDI-II SA\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24 (57.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18 (42.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e29 (69%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e13 (31%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e29 (69%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e13 (31%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.249\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBDI-II C\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20 (47.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22 (52.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e19 (45.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e23 (54.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e23 (54.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e19 (45.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.504\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePSQI\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e29 (69%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (31%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e39 (92.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (7.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e41 (97.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1 (2.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.0001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAbbreviations: Mini Mentale State Examination (MMSE); Rey Auditory Verbal Learning Test-Short Term (RAVLT-ST); Rey Auditory Verbal Learning Test-Delayed Recall (RAVLT-RD); Rey Auditory Verbal Learning Test-Recognition (RAVLT-REC); Rey-Osterrieth Complex Figure- Delayed Recall (ROCF-DR); Digit Span Forward (DSF); Digit Span Backward (DSB); Corsi Span Forward (CSF); Corsi Span Backward (CSB); Rey-Osterrieth Complex Figure- Copy (ROCF-C); Multiple Features Target Cancellation-Accuracy (MFTC-ACC); Multiple Features Target Cancellation-Errors (MFTC-ERR); Multiple Features Target Cancellation-Time (MFTC-T); Phonological Verbal Fluency (PVF); Categorical Verbal Fluency (CVF); Stroop test Color Word- Time (ST-T); Stroop test Color Word- Errors (ST-ERR); Trial Making Test A (TMTA); Trial Making Test B (TMTB);Digit Symbol Test (DS); Beck Anxiety Inventory (BAI); Beck Depression Inventory (BDI-II); Beck Depression Inventory Somatic-Affective (BDI-II SA); Beck Depression Inventory Cognitive (BDI-II C); Pittsburgh Sleep Quality Index (PSQI).\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eImproved, worsened\u003c/span\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eand\u003c/span\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003estable\u003c/span\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eneurocognitive performance\u003c/span\u003e\u003c/p\u003e\u003cp\u003eNeurocognitive performance was categorized as follow: \u0026ldquo;\u003cem\u003estable performance\u003c/em\u003e,\u0026rdquo; indicated consistent performance over time without fluctuations, \u0026ldquo;\u003cem\u003eimproved performance\u003c/em\u003e,\u0026rdquo; referred to initially pathological performance that later rose above the clinical cut-off, and \u0026ldquo;\u003cem\u003eworsened performance\u003c/em\u003e\u0026rdquo; described, initially normal performance subsequently declined below the cut-off threshold.\u003c/p\u003e\u003cp\u003eWe observed \u003cem\u003eimproved performance\u003c/em\u003e in verbal episodic short-term learning (RAVLT-ST, 14.3%), visuo-spatial short-term memory (CSF, 2.4%), visuo-spatial working memory (CSB, 4.8%), constructional praxis (ROCF-C, 16.7%) and speed of psycho-motor processing (DS, 28.6%).\u003c/p\u003e\u003cp\u003eConversely, \u003cem\u003eworsened performance\u003c/em\u003e, was observed in verbal episodic short-term learning (9.5%), visuo-spatial short-term memory (16.7%), visuo-spatial working memory (4.8%), in constructional praxis (0%) and in speed of psycho-motor processing (14.3%). All percentages are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eAssociation between neurocognitive performance and neuropsychiatric symptoms\u003c/h3\u003e\n\u003cp\u003eAt t0 we found significant associations between increased anxiety symptoms (BAI) and worse neurocognitive performance on verbal short-term memory (DSF; p\u0026thinsp;=\u0026thinsp;0.040) and speed of psycho-motor processing (DS; p\u0026thinsp;=\u0026thinsp;0.020) tests. In addition, increased disturbances in sleep quality (PSQI) were associated with worse neurocognitive performance in speed of psycho-motor processing (DS; p\u0026thinsp;=\u0026thinsp;0.018). Conversely, increased depressive symptoms (BDI-II), somatic-affective manifestations (BDI-II SA) and cognitive depressive symptoms (BDI-II C) are found to be significantly associated with normal neurocognitive performance in visual-spatial short-term memory (CSF; p\u0026thinsp;=\u0026thinsp;0.007, p\u0026thinsp;=\u0026thinsp;0.021, p\u0026thinsp;=\u0026thinsp;0.002, respectively) and visual-spatial working memory tests (CSB: p\u0026thinsp;=\u0026thinsp;0.023, p\u0026thinsp;=\u0026thinsp;0.057, p\u0026thinsp;=\u0026thinsp;0.008, respectively).\u003c/p\u003e\u003cp\u003eIn t1, increased anxious symptoms (BAI) are significantly associated with worse verbal learning performance (RAVLT-ST; p\u0026thinsp;=\u0026thinsp;0.035) and increased cognitive depressive symptoms (BDI-II C) are significantly associated with worse visual-spatial working memory performance (CSB; p\u0026thinsp;=\u0026thinsp;0.053). Increased sleep quality disorders (PSQI) are significantly associated with worse verbal learning tests (RAVLT-ST; p\u0026thinsp;=\u0026thinsp;0.033) and verbal long-term memory performance (RAVLT-DR; p\u0026thinsp;=\u0026thinsp;0.010).\u003c/p\u003e\u003cp\u003eFinally, in t2 increased depressive symptoms (BDI-II; p\u0026thinsp;=\u0026thinsp;0.059) and somatic-affective manifestations (BDI-II SA; p\u0026thinsp;=\u0026thinsp;0.025) are significantly associated with a worse verbal long-term memory performance (RAVLT-DR). Extensive data on associations are available in Supplementary material (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e3\u003c/span\u003eA, \u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e3\u003c/span\u003eB,\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e3\u003c/span\u003eC).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study investigated neurocognitive outcomes in patients with previous acute COVID-19, regardless of the presence of subjective cognitive complaints. This approach allowed for the detection of even subtle cognitive alterations, that might otherwise go unnoticed.\u003c/p\u003e\u003cp\u003eOur findings indicate a global improvement in neuropsychological functioning overtime, particularly in verbal short-term learning, short-term memory for visuo-spatial stimuli, working memory for visuo-spatial, constructional praxis, phonological verbal fluency and speed of psychomotor processing. There results align with recent literature reporting gradual recovery of cognitive function following COVID-19[32,33,34,35]. In particular, it has been widely demonstrated that attentional-executive functions may continue to improve for up to one year after the acute illness. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eIt is possible that the observed improvement in general cognitive symptoms is partly attributable to SARS-CoV-2 vaccination, which was administered between the two follow-up assessments. Additionally, passage of time since the acute event contributed to the resolution of the systemic inflammatory state, further supporting cognitive recovery [36]. Despite the positive changes observed, a high percentage of cognitive performance remained stable over time. Additionally, a subset of individuals who initially showed normal performance (i.e. above clinical cut-offs) experienced a decline in subsequent assessments, withscores falling below the normative thresholds. This finding is consistent with previous studies reporting that a significant percentage of cognitive scores retain pathological features over time [5, 37]. These borderline or declining scores may sometimes reflect underlying psychoemotional distress or indicate persistent cognitive problems. Therefore, it is essential that such changes are not underestimated and are carefully monitored over the long term.\u003c/p\u003e\u003cp\u003eInterestingly, the perception of sleep quality shows significant improvement over time. As is now well known, sleep disturbances represented one of the most prevalent and persistent neuropsychiatric symptoms in patients with PACS [38, 39]. For this reason, it is possible to assume that a better sleep quality has positively affected the neurocognitive performance [40].\u003c/p\u003e\u003cp\u003eThis is consistent with our finding showing that during the first NCA, increased sleep quality disturbances are associated with worse performance in psycho-motor processing speed. During the second NCA, sleep disturbances were instead linked to poorer performance in verbal learning and verbal long-term memory. The association between cognitive and neuropsychiatric symptoms has been previously described, suggesting a strong interconnection. In particular, anxiety and depression have been found to be more prevalent among individuals with cognitive disorders [38, 41, 42, 43]. At the first NCA, increased anxiety symptoms are associated with worse performance in terms of verbal short-term memory, which remains stable even at the second NCA, and in terms of psycho-motor processing speed.\u003c/p\u003e\u003cp\u003eThe association between depressive symptoms and cognitive performance showed interesting fluctuations over time. At the first NCA, an increase in depressive symptoms (both somatic-affective manifestations and depressive cognitive symptomatology) was significantly associated with normal performance in visual-spatial short-term memory and visual-spatial working memory. However, by the second NCA, performance in these domains appeared impaired. Finally, at the third and final NCA, depressive symptoms were associated with worse performance in verbal long-term memory. These findings highlight the complex and evolving relationship between mood disturbances and cognitive function in the post-acute phase of COVID-19.\u003c/p\u003e\u003cp\u003eThe associations between neuropsychiatric and cognitive symptoms are in line with recent findings suggesting that alterations in cognitive functioning in COVID-19 patients cannot be fully understood without considering psychological aspects [44]. This relationship is in fact biunivocal and determined by complex relationships: at risk are not only memory, concentration and attention, but also language, constructive skills and executive functions. Given these findings, it may seem intuitive to assume that cognitive symptoms are a product of the manifestation of anxiety and depression. However, numerous theoretical models suggest that cognitive impairments may also play a causal or maintaining role in the persistence of anxiety-depressive symptoms. In this view, cognitive dysfunction not only coexists with but may actively contribute to and perpetuate the cycle of neuropsychiatric symptoms, reinforcing a vicious cycle between emotional and cognitive disturbances [45, 46]. These results should be interpreted in light of several limitations. First, the lack of NCA previous to COVID-19 acute infection, which could allow differences to be observed in both those with neurocognitive impairment and normal profiles. Second, the lack of a control group that was compatible in sociodemographic characteristics, age, and sex. Finally, a relatively small sample size, which could cause bias in statistical analyses. Participants who chose to return for follow-up NCA likely had a more pronounced perception of neurocognitive impairment, triggered by comparison with their own cognitive abilities before COVID-19 infection. This perception was therefore a strong motivation to monitor their cognitive profile, with the aim of achieving a better quality of life.\u003c/p\u003e\u003cp\u003eThe strengths of this study were the accurate and in-depth neurocognitive and neuropsychiatric assessment, carried out in the presence and not online. In addition, this study was able to longitudinally monitor participants to observe changes in neurocognitive and neuropsychiatric measures at three different times, for a combined total of 12 months of observation.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur results provide an additional reinforcing element to the literature, confirming the improvement in cognitive performance as a consequence of PACS and that alteration in a smaller proportion of cognitive functions may instead persist over time. Such cognitive alterations are often accompanied by psychological distress. Anxiety and depression, in fact, often have an influence on cognitive performance and a negative impact on quality of life. More attention should be paid to borderline scores, ensuring neuropsychological monitoring. Given the prevalence of PACS, treatment strategies should take into account the persistent effects of COVID-19 on mood and cognition, and new treatment approaches should be developed, specifically targeting cognitive disorders.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eContributors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMC, AA and CP conceived and designed the study. MC, CP, GDD and ACB developed the study protocol; GDD, MM and ACB performed all the neurocognitive assessment (NCA) and are responsible for data curation; IS performed the data analysis. MC, IM and VM clinically evaluated patients and refer to NCA; GDD, ACB and MC wrote the first draft. AA supervised this work. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to patient privacy reasons, but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interest declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author gratefully acknowledges all the participants, the statistician and the clinical study assistants of the National Institute for Infectious Diseases, “Lazzaro Spallanzani” (Sperduti I., Brita A.C., Maresca M., Camici M., Pinnetti C., Mastrorosa I., Mazzotta V., Antinori A.).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eNICE. 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Antidepressant medication augmented with cognitive-behavioral theray for generalized anxiety disorder in older adults. Am J Psychiatry 2013;170:782-9\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"post-COVID19, Long-COVID, PACS, cognitive outcomes, neuropsychiatric symptoms, longitudinal neuropsychological evaluation","lastPublishedDoi":"10.21203/rs.3.rs-6817736/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6817736/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eTo date, follow-up neurocognitive evaluations in individuals with Post-acute COVID-19 Syndrome (PACS) indicate that some level of impaired performance persists in at least one cognitive domain, typically affecting the same functions initially compromised. In the present study, we aim to enrich longitudinal evidence on cognitive dysfunction and psychiatric symptoms in an Italian sample with PACS.\u003c/p\u003e\u003ch2\u003eMaterial and method\u003c/h2\u003e\u003cp\u003eAll patients performed a neurocognitive assessment (NCA) of 20 tests across 5 cognitive domains (memory, attention, language, executive functions, speed of psycho-motor processing) and neuropsychiatric symptoms questionnaires (anxiety, depression and sleep quality) to evaluate their possible influence on neurocognitive performance (NP) at three time points. Categorical variables were analyzed using Chi-Square or Fisher's exact tests, and quantitative variables were compared using the non-parametric Friedman test.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eOverall, 42 patients, 35.7% female, with a median age of 57 years (IQR 38\u0026ndash;81) and 13 years of education (IQR 8\u0026ndash;18) performed NCA. NP of six cognitive functions improved over time (verbal short-term learning, p\u0026thinsp;=\u0026thinsp;0.032; short-term memory for visuo-spatial stimuli, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; working memory, p\u0026thinsp;=\u0026thinsp;0.002; constructional praxis, p\u0026thinsp;=\u0026thinsp;0.018; phonological verbal fluency, p\u0026thinsp;=\u0026thinsp;0.05; speed of psychomotor processing, p\u0026thinsp;=\u0026thinsp;0.002). Also sleep quality improved over time, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 (Table\u0026nbsp;2).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis study shows improvement over time in memory, executive functions and language during over the 18-month follow-up period in PACS. However, specific areas of neuropsychological performance may remain stable or decline during the follow-up period.\u003c/p\u003e","manuscriptTitle":"Prolonged clinical monitoring of cognitive performance and psychiatric symptoms among PACS","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-08 08:40:45","doi":"10.21203/rs.3.rs-6817736/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"28313ba3-1798-40b1-a524-2c51741bb63a","owner":[],"postedDate":"September 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-01T21:53:57+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-08 08:40:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6817736","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6817736","identity":"rs-6817736","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}