Inflammation-Triggered Enlargement of Choroid Plexus in Subacute COVID-19 Patients with Neurological Symptoms.

OBJECTIVE: To investigate whether choroid plexus volumes in subacute coronavirus disease 2019 (COVID-19) patients with neurological symptoms could indicate inflammatory activation or barrier dysfunction and assess their association with clinical data. METHODS: Choroid plexus volumes were measured in 28 subacute COVID-19 patients via cerebral magnetic resonance imaging (MRI), compared with those in infection-triggered non-COVID-19 encephalopathy patients (n = 25), asymptomatic individuals after COVID-19 (n = 21), and healthy controls (n = 21). Associations with inflammatory serum markers (peak counts of leukocytes, C-reactive protein [CRP], interleukin 6), an MRI-based marker of barrier dysfunction (CSF volume fraction [V-CSF]), and clinical parameters like olfactory performance and cognitive scores (Montreal Cognitive Assessment) were investigated. RESULTS: COVID-19 patients showed significantly larger choroid plexus volumes than control groups (p < 0.001, η2 = 0.172). These volumes correlated significantly with peak leukocyte levels (p = 0.001, Pearson's r = 0.621) and V-CSF (p = 0.009, Spearman's rho = 0.534), but neither with CRP nor interleukin 6. No significant correlations were found with clinical parameters. INTERPRETATION: In patients with subacute COVID-19, choroid plexus volume is a marker of central nervous system inflammation and barrier dysfunction in the presence of neurologic symptoms. The absence of plexus enlargement in infection-triggered non-COVID-19 encephalopathy suggests a specific severe acute respiratory syndrome coronavirus 2 effect. This study also documents an increase in choroid plexus volume for the first time as a parainfectious event. ANN NEUROL 2024.

Widespread white matter oedema in subacute COVID-19 patients with neurological symptoms.

While neuropathological examinations in patients who died from COVID-19 revealed inflammatory changes in cerebral white matter, cerebral MRI frequently fails to detect abnormalities even in the presence of neurological symptoms. Application of multi-compartment diffusion microstructure imaging (DMI), that detects even small volume shifts between the compartments (intra-axonal, extra-axonal and free water/CSF) of a white matter model, is a promising approach to overcome this discrepancy. In this monocentric prospective study, a cohort of 20 COVID-19 inpatients (57.3 ± 17.1 years) with neurological symptoms (e.g. delirium, cranial nerve palsies) and cognitive impairments measured by the Montreal Cognitive Assessment (MoCA test; 22.4 ± 4.9; 70% below the cut-off value <26/30 points) underwent DMI in the subacute stage of the disease (29.3 ± 14.8 days after positive PCR). A comparison of whole-brain white matter DMI parameters with a matched healthy control group (n = 35) revealed a volume shift from the intra- and extra-axonal space into the free water fraction (V-CSF). This widespread COVID-related V-CSF increase affected the entire supratentorial white matter with maxima in frontal and parietal regions. Streamline-wise comparisons between COVID-19 patients and controls further revealed a network of most affected white matter fibres connecting widespread cortical regions in all cerebral lobes. The magnitude of these white matter changes (V-CSF) was associated with cognitive impairment measured by the MoCA test (r = -0.64, P = 0.006) but not with olfactory performance (r = 0.29, P = 0.12). Furthermore, a non-significant trend for an association between V-CSF and interleukin-6 emerged (r = 0.48, P = 0.068), a prominent marker of the COVID-19 related inflammatory response. In 14/20 patients who also received cerebral 18F-FDG PET, V-CSF increase was associated with the expression of the previously defined COVID-19-related metabolic spatial covariance pattern (r = 0.57; P = 0.039). In addition, the frontoparietal-dominant pattern of neocortical glucose hypometabolism matched well to the frontal and parietal focus of V-CSF increase. In summary, DMI in subacute COVID-19 patients revealed widespread volume shifts compatible with vasogenic oedema, affecting various supratentorial white matter tracts. These changes were associated with cognitive impairment and COVID-19 related changes in 18F-FDG PET imaging.

Neuropsychologic Profiles and Cerebral Glucose Metabolism in Neurocognitive Long COVID Syndrome.

During the coronavirus disease 2019 (COVID-19) pandemic, Long COVID syndrome, which impairs patients through cognitive deficits, fatigue, and exhaustion, has become increasingly relevant. Its underlying pathophysiology, however, is unknown. In this study, we assessed cognitive profiles and regional cerebral glucose metabolism as a biomarker of neuronal function in outpatients with long-term neurocognitive symptoms after COVID-19. Methods: Outpatients seeking neurologic counseling with neurocognitive symptoms persisting for more than 3 mo after polymerase chain reaction (PCR)-confirmed COVID-19 were included prospectively between June 16, 2020, and January 29, 2021. Patients (n = 31; age, 53.6 ± 2.0 y) in the long-term phase after COVID-19 (202 ± 58 d after positive PCR) were assessed with a neuropsychologic test battery. Cerebral 18F-FDG PET imaging was performed in 14 of 31 patients. Results: Patients self-reported impaired attention, memory, and multitasking abilities (31/31), word-finding difficulties (27/31), and fatigue (24/31). Twelve of 31 patients could not return to the previous level of independence/employment. For all cognitive domains, average group results of the neuropsychologic test battery showed no impairment, but deficits (z score < -1.5) were present on a single-patient level mainly in the domain of visual memory (in 7/31; other domains ≤ 2/31). Mean Montreal Cognitive Assessment performance (27/30 points) was above the cutoff value for detection of cognitive impairment (<26 points), although 9 of 31 patients performed slightly below this level (23-25 points). In the subgroup of patients who underwent 18F-FDG PET, we found no significant changes of regional cerebral glucose metabolism. Conclusion: Long COVID patients self-report uniform symptoms hampering their ability to work in a relevant fraction. However, cognitive testing showed minor impairments only on a single-patient level approximately 6 mo after the infection, whereas functional imaging revealed no distinct pathologic changes. This clearly deviates from previous findings in subacute COVID-19 patients, suggesting that underlying neuronal causes are different and possibly related to the high prevalence of fatigue.

Slow but Evident Recovery from Neocortical Dysfunction and Cognitive Impairment in a Series of Chronic COVID-19 Patients.

Cognitive impairment is a frequent complaint in coronavirus disease 2019 (COVID-19) and can be related to cortical hypometabolism on 18F-FDG PET at the subacute stage. However, it is unclear if these changes are reversible. Methods: We prospectively assessed the Montreal Cognitive Assessment scores and 18F-FDG PET scans of 8 COVID-19 patients at the subacute stage (once no longer infectious) and the chronic stage (˜6 mo after symptom onset). The expression of the previously established COVID-19-related covariance pattern was analyzed at both stages to examine the time course of post-COVID-19 cognitive impairment. For further validation, we also conducted a conventional group analysis. Results: Follow-up 18F-FDG PET revealed that there was a significant reduction in the initial frontoparietal and, to a lesser extent, temporal hypometabolism and that this reduction was accompanied by a significant improvement in cognition. The expression of the previously established COVID-19-related pattern was significantly lower at follow-up and correlated inversely with Montreal Cognitive Assessment performance. However, both 18F-FDG PET and cognitive assessment suggest a residual impairment. Conclusion: Although a significant recovery of regional neuronal function and cognition can be clearly stated, residuals are still measurable in some patients 6 mo after manifestation of COVID-19. Given the current pandemic situation and tremendous uncertainty concerning the long-term effects of COVID-19, the present study provides novel insights of the highest medical and socioeconomic relevance.

Cognitive impairment and altered cerebral glucose metabolism in the subacute stage of COVID-19.

During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, neurological symptoms increasingly moved into the focus of interest. In this prospective cohort study, we assessed neurological and cognitive symptoms in hospitalized coronavirus disease-19 (COVID-19) patients and aimed to determine their neuronal correlates. Patients with reverse transcription-PCR-confirmed COVID-19 infection who required inpatient treatment primarily because of non-neurological complications were screened between 20 April 2020 and 12 May 2020. Patients (age > 18 years) were included in our cohort when presenting with at least one new neurological symptom (defined as impaired gustation and/or olfaction, performance < 26 points on a Montreal Cognitive Assessment and/or pathological findings on clinical neurological examination). Patients with ≥2 new symptoms were eligible for further diagnostics using comprehensive neuropsychological tests, cerebral MRI and 18fluorodeoxyglucose (FDG) PET as soon as infectivity was no longer present. Exclusion criteria were: premorbid diagnosis of cognitive impairment, neurodegenerative diseases or intensive care unit treatment. Of 41 COVID-19 inpatients screened, 29 patients (65.2 ± 14.4 years; 38% female) in the subacute stage of disease were included in the register. Most frequently, gustation and olfaction were disturbed in 29/29 and 25/29 patients, respectively. Montreal Cognitive Assessment performance was impaired in 18/26 patients (mean score 21.8/30) with emphasis on frontoparietal cognitive functions. This was confirmed by detailed neuropsychological testing in 15 patients. 18FDG PET revealed pathological results in 10/15 patients with predominant frontoparietal hypometabolism. This pattern was confirmed by comparison with a control sample using voxel-wise principal components analysis, which showed a high correlation (R2 = 0.62) with the Montreal Cognitive Assessment performance. Post-mortem examination of one patient revealed white matter microglia activation but no signs of neuroinflammation. Neocortical dysfunction accompanied by cognitive decline was detected in a relevant fraction of patients with subacute COVID-19 initially requiring inpatient treatment. This is of major rehabilitative and socioeconomic relevance.

Carbon Monoxide Exerts Functional Neuroprotection After Cardiac Arrest Using Extracorporeal Resuscitation in Pigs.

OBJECTIVES: Neurologic damage following cardiac arrest remains a major burden for modern resuscitation medicine. Cardiopulmonary resuscitation with extracorporeal circulatory support holds the potential to reduce morbidity and mortality. Furthermore, the endogenous gasotransmitter carbon monoxide attracts attention in reducing cerebral injury. We hypothesize that extracorporeal resuscitation with additional carbon monoxide application reduces neurologic damage. DESIGN: Randomized, controlled animal study. SETTING: University research laboratory. SUBJECTS: Landrace-hybrid pigs. INTERVENTIONS: In a porcine model, carbon monoxide was added using a novel extracorporeal releasing system after resuscitation from cardiac arrest. MEASUREMENTS AND MAIN RESULTS: As markers of cerebral function, neuromonitoring modalities (somatosensory-evoked potentials, cerebral oximetry, and transcranial Doppler ultrasound) were used. Histopathologic damage and molecular markers (caspase-3 activity and heme oxygenase-1 expression) were analyzed. Cerebral oximetry showed fast rise in regional oxygen saturation after carbon monoxide treatment at 0.5 hours compared with extracorporeal resuscitation alone (regional cerebral oxygen saturation, 73% ± 3% vs 52% ± 8%; p < 0.05). Median nerve somatosensory-evoked potentials showed improved activity upon carbon monoxide treatment, whereas post-cardiac arrest cerebral perfusion differences were diminished. Histopathologic damage scores were reduced compared with customary resuscitation strategies (hippocampus: sham, 0.4 ± 0.2; cardiopulmonary resuscitation, 1.7 ± 0.4; extracorporeal cardiopulmonary resuscitation, 2.3 ± 0.2; extracorporeal cardiopulmonary resuscitation with carbon monoxide application [CO-E-CPR], 0.9 ± 0.3; p < 0.05). Furthermore, ionized calcium-binding adaptor molecule 1 staining revealed reduced damage patterns upon carbon monoxide treatment. Caspase-3 activity (cardiopulmonary resuscitation, 426 ± 169 pg/mL; extracorporeal cardiopulmonary resuscitation, 240 ± 61 pg/mL; CO-E-CPR, 89 ± 26 pg/mL; p < 0.05) and heme oxygenase-1 (sham, 1 ± 0.1; cardiopulmonary resuscitation, 2.5 ± 0.4; extracorporeal cardiopulmonary resuscitation, 2.4 ± 0.2; CO-E-CPR, 1.4 ± 0.2; p < 0.05) expression were reduced after carbon monoxide exposure. CONCLUSIONS: Carbon monoxide application during extracorporeal resuscitation reduces injury patterns in neuromonitoring and decreases histopathologic cerebral damage by reducing apoptosis. This may lay the basis for further clinical translation of this highly salutary substance.