Reduced Cortical Thickness Correlates of Cognitive Dysfunction in Post-COVID-19 Condition: Insights from a Long-Term Follow-up

Abstract:

Background and purpose: There is a paucity of data on long-term neuroimaging findings from individuals who have developed the post-coronavirus 2019 (COVID-19) condition. Only 2 studies have investigated the correlations between cognitive assessment results and structural MR imaging in this population. This study aimed to elucidate the long-term cognitive outcomes of participants with the post-COVID-19 condition and to correlate these cognitive findings with structural MR imaging data in the post-COVID-19 condition.

Materials and methods: A cohort of 53 participants with the post-COVID-19 condition underwent 3T brain MR imaging with T1 and FLAIR sequences obtained a median of 1.8 years after Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection. A comprehensive neuropsychological battery was used to assess several cognitive domains in the same individuals. Correlations between cognitive domains and whole-brain voxel-based morphometry were performed. Different ROIs from FreeSurfer were used to perform the same correlations with other neuroimaging features.

Results: According to the Frascati criteria, more than one-half of the participants had deficits in the attentional (55%, n = 29) and executive (59%, n = 31) domains, while 40% (n = 21) had impairment in the memory domain. Only 1 participant (1.89%) showed problems in the visuospatial and visuoconstructive domains. We observed that reduced cortical thickness in the left parahippocampal region (t(48) = 2.28, P = .03) and the right caudal-middle-frontal region (t(48) = 2.20, P = .03) was positively correlated with the memory domain.

Conclusions: Our findings suggest that cognitive impairment in individuals with the post-COVID-19 condition is associated with long-term alterations in the structure of the brain. These macrostructural changes may provide insight into the nature of cognitive symptoms.

Source: Dacosta-Aguayo R, Puig J, Lamonja-Vicente N, Carmona-Cervelló M, Biaani León-Gómez B, Monté-Rubio G, López-Linfante VM, Zamora-Putin V, Montero-Alia P, Chacon C, Bielsa J, Moreno-Gabriel E, Garcia-Sierra R, Pachón A, Costa A, Mataró M, Prado JG, Martinez-Cáceres E, Mateu L, Massanella M, Violán C, Torán-Monserrat P; Aliança ProHEpiC-19 Cognitiu (The APC Collaborative Group). Reduced Cortical Thickness Correlates of Cognitive Dysfunction in Post-COVID-19 Condition: Insights from a Long-Term Follow-up. AJNR Am J Neuroradiol. 2024 Apr 4. doi: 10.3174/ajnr.A8167. Epub ahead of print. PMID: 38575319. https://pubmed.ncbi.nlm.nih.gov/38575319/

Machine learning algorithms for detection of visuomotor neural control differences in individuals with PASC and ME

Abstract:

The COVID-19 pandemic has affected millions worldwide, giving rise to long-term symptoms known as post-acute sequelae of SARS-CoV-2 (PASC) infection, colloquially referred to as long COVID. With an increasing number of people experiencing these symptoms, early intervention is crucial. In this study, we introduce a novel method to detect the likelihood of PASC or Myalgic Encephalomyelitis (ME) using a wearable four-channel headband that collects Electroencephalogram (EEG) data. The raw EEG signals are processed using Continuous Wavelet Transform (CWT) to form a spectrogram-like matrix, which serves as input for various machine learning and deep learning models. We employ models such as CONVLSTM (Convolutional Long Short-Term Memory), CNN-LSTM, and Bi-LSTM (Bidirectional Long short-term memory). Additionally, we test the dataset on traditional machine learning models for comparative analysis.

Our results show that the best-performing model, CNN-LSTM, achieved an accuracy of 83%. In addition to the original spectrogram data, we generated synthetic spectrograms using Wasserstein Generative Adversarial Networks (WGANs) to augment our dataset. These synthetic spectrograms contributed to the training phase, addressing challenges such as limited data volume and patient privacy. Impressively, the model trained on synthetic data achieved an average accuracy of 93%, significantly outperforming the original model.

These results demonstrate the feasibility and effectiveness of our proposed method in detecting the effects of PASC and ME, paving the way for early identification and management of the condition. The proposed approach holds significant potential for various practical applications, particularly in the clinical domain. It can be utilized for evaluating the current condition of individuals with PASC or ME, and monitoring the recovery process of those with PASC, or the efficacy of any interventions in the PASC and ME populations. By implementing this technique, healthcare professionals can facilitate more effective management of chronic PASC or ME effects, ensuring timely intervention and improving the quality of life for those experiencing these conditions.

Source: Harit Ahuja, Smriti Badhwar, Heather Edgell, Lauren E. Sergio, Marin Litoiu. Machine learning algorithms for detection of visuomotor neural control differences in individuals with PASC and ME. Front. Hum. Neurosci. Sec. Brain-Computer Interfaces, Volume 18 – 2024 | doi: 10.3389/fnhum.2024.1359162 https://www.frontiersin.org/articles/10.3389/fnhum.2024.1359162/full (Full text)

Pituitary–Adrenal Axis and Peripheral Immune Cell Profile in Long COVID

Abstract:

In Long COVID, dysfunction in the pituitary–adrenal axis and alterations in immune cells and inflammatory status are warned against. We performed a prospective study in a cohort of 42 patients who suffered COVID-19 at least 6 months before attending the Long COVID unit at Althaia Hospital.
Based on Post-COVID Functional Status, 29 patients were diagnosed with Long COVID, while 13 were deemed as recovered. The hormones of the pituitary–adrenal axis, adrenocorticotropin stimulation test, and immune cell profiles and inflammatory markers were examined. Patients with Long COVID had significantly lower EuroQol and higher mMRC scores compared to the recovered individuals. Their symptoms included fatigue, myalgia, arthralgia, persistent coughing, a persistent sore throat, dyspnoea, a lack of concentration, and anxiety.
We observed the physiological levels of cortisol and adrenocorticotropin in individuals with or without Long COVID. The results of the adrenocorticotropin stimulation test were similar between both groups. The absolute number of neutrophils was lower in the Long COVID patients compared to recovered individuals (p < 0.05). The total count of B lymphocytes remained consistent, but Long COVID patients had a higher percentage of mature B cells compared to recovered participants (p < 0.05) and exhibited a higher percentage of circulating resident memory CD8+ T cells (p < 0.05) and Treg-expressing exonucleases (p < 0.05).
Our findings did not identify adrenal dysfunction related to Long COVID, nor an association between adrenal function and clinical symptoms. The data indicated a dysregulation in certain immune cells, pointing to immune activation. No overt hyperinflammation was observed in the Long COVID group.
Source: Alijotas-Reig J, Anunciacion-Llunell A, Esteve-Valverde E, Morales-Pérez S, Rivero-Santana S, Trapé J, González-García L, Ruiz D, Marques-Soares J, Miro-Mur F. Pituitary–Adrenal Axis and Peripheral Immune Cell Profile in Long COVID. Biomedicines. 2024; 12(3):581. https://doi.org/10.3390/biomedicines12030581 https://www.mdpi.com/2227-9059/12/3/581 (Full text)

The Effect of Sex on the Risk of Long-COVID and Cardiovascular Complications in Healthy Patients without Comorbidities: Data from a Polish Long-COVID Cardiovascular (PoLoCOV-CVD) Study

Abstract:

Background: The prevalence of long-COVID (LC) presents a significant challenge to healthcare systems globally. There are still some discrepancies on the role of sex as an independent risk factor of LC complications. Thus, we aimed to determine the differences in clinical and cardiovascular complications between males and females without comorbidities after COVID-19.
Methods: Clinical data on the course of the disease with the accompanying symptoms and post-COVID-19 symptoms were compiled from both male and female subjects with a minimum 12-week interval after COVID-19 recovery. Next, the patients were followed for 12 months. ECG, echocardiography, 24 h ECG monitoring, 24 h ambulatory blood pressure monitoring (ABPM), and selected biochemical tests were performed. LC was diagnosed based on the World Health Organization (WHO) definition. To reduce the impact of confounders, i.e., body mass index (BMI) and age, on the results of the study, the nearest neighbour (NN) propensity score matching (PSM) method with a 1:1 ratio was used.
Results: The results were obtained following the removal of cases with comorbidities from the database consisting of 1237 males and 2192 females, and PSM of the new database included 886 cases (443 males and 443 females). At both the 3-month and 1-year post-recovery marks, females consistently reported a higher frequency of LC symptoms compared to males (p < 0.001 for both comparisons). Moreover, after 1 year of follow-up, females exhibited a higher prevalence of LC compared to males, with rates of 14% versus 8.3%, respectively (p = 0.013).
The symptoms that significantly differed between females and males in the 12-month follow-up were hair loss (5.4 vs. 0.7%, p < 0.001), memory and concentration disturbances (8.4 vs. 4.3%, p = 0.013), and headaches (4.3 vs. 1.4%, p = 0.008). Females presented lower mean arterial pressure (MAP) [89 (83–95) mmHg versus (vs.) 94 (89–100); p < 0.001] and lower pulse pressure (PP) [46 (42–52) mmHg vs. 51 (48–57); p < 0.001] in 24 h ABPM and more elevated heart rates (HRs) in 24 h ECG monitoring as well as arrhythmia (p < 0.001 and p = 0.018, respectively). Males had a higher occurrence of ECG abnormalities such as QRS >= 120 ms, ST-T changes, T inversion, arrhythmia, and QRS fragmentation (27.3% vs. 19.2%; p = 0.004). No significant differences were observed between males and females concerning physical activity levels, stress, fatigue, alcohol consumption, and smoking habits.
Conclusions: One year post-COVID-19 recovery, regardless of age and BMI, healthy females more often suffered from LC symptoms than males. They had lower MAP and PP in 24 h ABPM, more often had higher HRs and arrhythmia in 24 h ECG monitoring, and fewer ECG abnormalities than males.
Source: Bielecka-Dabrowa A, Sakowicz A, Gryglewska-Wawrzak K, Kapusta J, Banach M, Jankowski P, Chudzik M. The Effect of Sex on the Risk of Long-COVID and Cardiovascular Complications in Healthy Patients without Comorbidities: Data from a Polish Long-COVID Cardiovascular (PoLoCOV-CVD) Study. Journal of Clinical Medicine. 2024; 13(6):1559. https://doi.org/10.3390/jcm13061559 https://www.mdpi.com/2077-0383/13/6/1559 (Full text)

Brain temperature and free water increases after mild COVID-19 infection

Abstract:

The pathophysiology underlying the post-acute sequelae of COVID-19 remains understudied and poorly understood, particularly in healthy adults with a history of mild infection. Chronic neuroinflammation may underlie these enduring symptoms, but studying neuroinflammatory phenomena in vivo is challenging, especially without a comparable pre-COVID-19 dataset.

In this study, we present a unique dataset of 10 otherwise healthy individuals scanned before and after experiencing mild COVID-19. Two emerging MR-based methods were used to map pre- to post-COVID-19 brain temperature and free water changes. Post-COVID-19 brain temperature and free water increases, which are indirect biomarkers of neuroinflammation, were found in structures functionally associated with olfactory, cognitive, and memory processing.

The largest pre- to post-COVID brain temperature increase was observed in the left olfactory tubercle (p = 0.007, 95% CI [0.48, 3.01]), with a mean increase of 1.75 °C. Notably, the olfactory tubercle is also the region of the primary olfactory cortex where participants with chronic olfactory dysfunction showed the most pronounced increases as compared to those without lingering olfactory dysfunction (adjusted pFDR = 0.0189, 95% CI [1.42, 5.27]). These preliminary insights suggest a potential link between neuroinflammation and chronic cognitive and olfactory dysfunction following mild COVID-19, although further investigations are needed to improve our understanding of what underlies these phenomena.

Source: Sharma AA, Nenert R, Goodman AM, Szaflarski JP. Brain temperature and free water increases after mild COVID-19 infection. Sci Rep. 2024 Mar 28;14(1):7450. doi: 10.1038/s41598-024-57561-6. PMID: 38548815; PMCID: PMC10978935. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10978935/ (Full text)

Use of testosterone replacement therapy to treat long-COVID-related hypogonadism

Abstract:

Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can impair pituitary-gonadal axis and a higher prevalence of hypogonadism in post-coronavirus disease 2019 (COVID-19) patients compared with the general population has been highlighted. Here we report the first case of a patient affected with a long-COVID syndrome leading to hypogonadism and treated with testosterone replacement therapy (TRT) and its effects on clinical and quality of life (QoL) outcomes.

We encountered a 62-year-old man who had been diagnosed with hypogonadotropic hypogonadism about 2 months after recovery from COVID-19 underwent a complete physical examination, general and hormonal blood tests, and self-reported questionnaires administration before and after starting TRT. Following the TRT, both serum testosterone level and hypogonadism-related symptoms were improved, but poor effects occurred on general and neuropsychiatric symptoms and QoL.

Therefore, hypogonadism does not appear to be the cause of neurocognitive symptoms, but rather a part of the long-COVID syndrome; as a consequence, starting TRT can improve the hypogonadism-related symptoms without clear benefits on general clinical condition and QoL, which are probably related to the long-COVID itself. Longer follow-up might clarify whether post-COVID hypogonadism is a transient condition that can revert as the patient recovers from long-COVID syndrome.

Learning points: Hypogonadism is more prevalent in post-COVID-19 patients compared with the general population. In these patients, hypogonadism may be part of long-COVID syndrome, and it is still unclear whether it is a transient condition or a permanent impairment of gonadal function. Testosterone replacement therapy has positive effects on hypogonadism-related clinic without clear benefits on general symptomatology and quality of life, which are more likely related to the long-COVID itself.

Source: Amodeo A, Persani L, Bonomi M, Cangiano B. Use of testosterone replacement therapy to treat long-COVID-related hypogonadism. Endocrinol Diabetes Metab Case Rep. 2024 Mar 22;2024(1):23-0097. doi: 10.1530/EDM-23-0097. PMID: 38520748; PMCID: PMC10959025. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10959025/ (Full text)

Attenuating Post-exertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long-COVID: Is Blood Lactate Monitoring the Answer?

Highlights:

  • Lactate monitoring has the potential to extend beyond applied sports settings and could be used to monitor the physiologic and pathophysiological responses to external and internal stimuli in chronic disease areas such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Post-Covid syndrome or Long Covid.
  • It is applicable due to the recurrent, episodic and often disabling post-exertional symptom exacerbation (PESE) otherwise referred to as post-exertional malaise (PEM) which is a characteristic symptom of ME/CFS and Long Covid that can last for days and/or weeks.
  • Lactate monitoring presents an opportunity to support those living with ME/CFS and Long COVID, by allowing patients and practitioners to determine the intensity and anaerobic contribution to everyday tasks which could aid the development of pacing strategies that prevent PEM/PESE.

Source: Faghy PMA, Ashton DRE, McNeils MR, Arena R, Duncan DR. Attenuating Post-exertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long-COVID: Is Blood Lactate Monitoring the Answer? Curr Probl Cardiol. 2024 Mar 30:102554. doi: 10.1016/j.cpcardiol.2024.102554. Epub ahead of print. PMID: 38561114. https://www.sciencedirect.com/science/article/abs/pii/S0146280624001932

Blood Markers Show Neural Consequences of LongCOVID-19

Abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists throughout the world with over 65 million registered cases of survivors with post-COVID-19 sequelae, also known as LongCOVID-19 (LongC). LongC survivors exhibit various symptoms that span multiple organ systems, including the nervous system.
To search for neurological markers of LongC, we investigated the soluble biomolecules present in the plasma and the proteins associated with plasma neuronal-enriched extracellular vesicles (nEVs) in 33 LongC patients with neurological impairment (nLongC), 12 COVID-19 survivors without any LongC symptoms (Cov), and 28 pre-COVID-19 healthy controls (HC). COVID-19 positive participants were infected between 2020 and 2022, not hospitalized, and were vaccinated or unvaccinated before infection.
IL-1β was significantly increased in both nLongC and Cov and IL-8 was elevated in only nLongC. Both brain-derived neurotrophic factor and cortisol were significantly elevated in nLongC and Cov compared to HC. nEVs from people with nLongC had significantly elevated protein markers of neuronal dysfunction, including amyloid beta 42, pTau181 and TDP-43.
This study shows chronic peripheral inflammation with increased stress after COVID-19 infection. Additionally, differentially expressed nEV neurodegenerative proteins were identified in people recovering from COVID-19 regardless of persistent symptoms.
Source: Tang N, Kido T, Shi J, McCafferty E, Ford JM, Dal Bon K, Pulliam L. Blood Markers Show Neural Consequences of LongCOVID-19. Cells. 2024; 13(6):478. https://doi.org/10.3390/cells13060478 https://www.mdpi.com/2073-4409/13/6/478 (Full text)

Longitudinal Cytokine and Multi-Modal Health Data of an Extremely Severe ME/CFS Patient with HSD Reveals Insights into Immunopathology, and Disease Severity

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) presents significant challenges in patient care due to its intricate multisystem nature, comorbidities, and global prevalence. To address these complexities, we employed a comprehensive approach, integrating longitudinal cytokine profiling with extensive clinical, health, textual, pharmaceutical, and nutraceutical data, and performed personalized analyses using AI.

Focusing on an exceptionally severe ME/CFS patient with hypermobility spectrum disorder (HSD) and marginal symptom improvements, our study highlights the dynamic nature of symptoms, severity, triggers, and modifying factors. As part of this study, we introduced an updated platform and two applications, ME-CFSTrackerApp, and LexiTime, facilitating real-time symptom tracking and enhancing physician-patient communication.

Our longitudinal cytokine profiling underscores the significance of Th2-type cytokines and synergistic activities between mast cells and eosinophils, leading to skewing of Th1 toward Th2 immune responses in ME/CFS pathogenesis, especially in cognitive impairment and sensorial intolerance. This suggests a potentially shared underlying mechanism with major comorbidities.

Additionally, our data reveal potential roles of BCL6 and TP53 pathways in ME/CFS etiology and emphasize the importance of investigating low-dose drugs with partial agonist activity in ME/CFS treatment. Our analyses underscore the patient-centered care approach for better healthcare management.

Source: Fereshteh Jahanbani1, Justin C. Sing, Rajan D. Maynard, Shaghayegh Jahanbani, Janet Dafoe, Whitney Dafoe, Nathan Jones, Kelvin J. Wallace, Azuravesta Rastan, Hannes Rost, Holden Maecker, Michael P. Snyder, Ronald W. Davis. Longitudinal Cytokine and Multi-Modal Health Data of an Extremely Severe ME/CFS Patient with HSD Reveals Insights into Immunopathology, and Disease Severity. Front. Immunol. Sec. Autoimmune and Autoinflammatory Disorders: Autoinflammatory Disorders. Volume 15 – 2024 | doi: 10.3389/fimmu.2024.1369295 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1369295/abstract

The gastrointestinal microbiota in the development of ME/CFS: a critical view and potential perspectives

Abstract:

Like other infections, a SARS-CoV-2 infection can also trigger Post-Acute Infection Syndromes (PAIS), which often progress into myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS, characterized by post-exercise malaise (PEM), is a severe multisystemic disease for which specific diagnostic markers or therapeutic concepts have not been established.

Despite numerous indications of post-infectious neurological, immunological, endocrinal, and metabolic deviations, the exact causes and pathophysiology remain unclear. To date, there is a paucity of data, that changes in the composition and function of the gastrointestinal microbiota have emerged as a potential influencing variable associated with immunological and inflammatory pathways, shifts in ME/CFS. It is postulated that this dysbiosis may lead to intestinal barrier dysfunction, translocation of microbial components with increased oxidative stress, and the development or progression of ME/CFS.

In this review, we detailed discuss the findings regarding alterations in the gastrointestinal microbiota and its microbial mediators in ME/CFS. When viewed critically, there is currently no evidence indicating causality between changes in the microbiota and the development of ME/CFS. Most studies describe associations within poorly defined patient populations, often combining various clinical presentations, such as irritable bowel syndrome and fatigue associated with ME/CFS.

Nevertheless, drawing on analogies with other gastrointestinal diseases, there is potential to develop strategies aimed at modulating the gut microbiota and/or its metabolites as potential treatments for ME/CFS and other PAIS. These strategies should be further investigated in clinical trials.

Source: Andreas Stallmach, Stefanie Quickert, Christian Puta, Philipp A. Reuken. The gastrointestinal microbiota in the development of ME/CFS: a critical view and potential perspectives. Front. Immunol., 27 March 2024, Sec. Microbial Immunology, Volume 15 – 2024. https://doi.org/10.3389/fimmu.2024.1352744 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1352744/full (Full text)