Anastasia Levina

Background/Objectives: Normal-appearing white (WM) and gray (GM) matter outside focal demyelinating lesions (WMH) has been found impaired in many diseases and normal aging. The present study aimed to compare global GM and WM alterations in patients with multiple sclerosis (MS), Parkinson’s disease, long COVID (LC) and normal aging. Methods: The study population comprised 196 participants including patients with MS (n = 42), PD (n = 16), LC (n = 75), and healthy volunteers (n = 63). All participants underwent MR scanning using the fast macromolecular fraction (MPF) mapping protocol and routine clinical sequences. MPF in global normal-appearing WM, GM, and mixed WM-GM was measured after exclusion of segmented focal lesions. To eliminate the influence of gender, age, and brain atrophy on the results, the corresponding covariates were included in the analysis. Results: Significant WMH volume increase and MPF decrease in global WM, WM-GM, and GM were found both in normal aging (75–85 years) and MS, PD, and LC patients (except for WM and WMH volume in LC patients). The greatest MPF decrease was observed in MS patients. The youngest (18–24 years) controls had a significant MPF decrease in global WM, WM-GM, and GM compared to middle-aged (35–44 years) participants. Among LC patients, the greatest global MPF reduction was found in patients with depression and insomnia as COVID-19 complications. In healthy controls, the peak age of myelination was estimated as 42.2 years for WM, 46.5 years for WM-GM, and 45.4 years for GM. Significant correlations were found between MPF and EDSS in MS patients (r = −0.71 in GM, r = −0.58 in WM-GM, r = −0.44 in WM) and stage of PD in PD patients (r = −0.58 in GM, r = −0.55 in WM-GM, r = −0.52 in WM). Conclusions: MPF mapping showed high sensitivity to age-related and disease-related differences in brain myelination, particularly in GM. Our results confirm the feasibility of using MPF mapping in large-scale clinical studies.

Insomnia and depression are severe sequelae of COVID-19 and often occur simultaneously. Our study examined associations of insomnia and/or depression with cognitive impairments, white matter changes, and serum biomarkers. In total, 76 long COVID patients and 22 healthy controls were examined using neuropsychiatric (ISI, HADS, and HDRS) and cognitive (MoCA, Stroop, WMT, and TMT) tests, with their blood biomarkers (anti-SARS-CoV-2, BDNF, anti-S100, anti-MBP, and anti-PLP) investigated, and underwent MRI using macromolecular proton fraction (MPF) mapping to quantify myelination. The Insomnia (n = 14), Depression (n = 12), InsDep (comorbid insomnia–depression, n = 13), and PostCovid (long COVID without depression and insomnia, n = 32) groups were identified based on psychiatric/neurological diagnoses and neuropsychiatric assessment. Cognitive performance was most affected in the Insomnia group in the MoCA and CW Stroop tests. The Depression group underperformed in the TMT and W Stroop task; the InsDep group underperformed in the WMT. The Insomnia group showed the greatest demyelination, affecting commissural (CC and tapetum), projection (CR, IC, CST, cerebral peduncles, CP, and ML), and some association pathways (SLF, SFOF), as well as most juxtacortical regions, the thalamus, and the midbrain; these changes correlated with insomnia severity. The Depression and InsDep groups showed smaller but significant overall demyelination correlated with depression severity. The Depression group exhibited the highest MPF decrease in the globus pallidus, putamen, and external capsule, while the InsDep group demonstrated the highest demyelination of the association pathways IFOF, UF, and cingulum. The anti-PLP levels were the highest in the Insomnia group and correlated with both the persistence of insomnia/depression symptoms and demyelination. Demyelination in long COVID is associated with high levels of myelin-specific autoantibodies, but symptoms of insomnia and/or depression are associated with demyelination of a different set of brain structures.

Normal-appearing white (WM) and grey (GM) matter outside focal demyelinating lesions (WMH) has been found impaired in many diseases and normal aging. The present study aimed to compare global GM and WM alterations in patients with multiple sclerosis (MS), Parkinson's disease, long COVID (LC) and normal aging. The study population comprised 196 participants including patients with MS (n=42), PD (n = 16), LC (n = 75), and age- and gender-matched controls selected from healthy volunteers (n = 63). All participants underwent MR scanning using the fast macromolecular fraction (MPF) mapping protocol and routine clinical sequences. MPF in global normal-appearing WM, GM, and mixed WM-GM was measured after exclusion of segmented focal lesions. Significant WMH volume increase and MPF decrease in global WM, WM-GM, and GM were found both in normal aging and MS, PD, and LC patients (except for WM in PD patients). The greatest MPF decrease was observed in MS patients. Both MS, PD, LC patients and the oldest (75-85 years) controls had significant demyelination in global GM. Among LC patients, the greatest global MPF reduction was found in patients with depression and insomnia as COVID-19 complications. In healthy controls, the peak age of myelination was estimated as 42.2 years for WM, 46.5 years for WM-GM, and 45.4 years for GM. MPF mapping showed high sensitivity to age-related and disease-related changes in brain myelination, particularly in GM. Our results confirm the feasibility of using MPF mapping in large-scale clinical studies.

Background: The fundamental question of normal brain myelination in human is still poorly understood. Methods: Age-dependent global, regional, and interhemispheric sex-related differences in brain myelination of 42 (19 men, 23 women) healthy adults (19–67 years) were explored using the MRI method of fast macromolecular fraction (MPF) mapping. Results: Higher brain myelination in males compared to females was found in global white matter (WM), most WM tracts, juxtacortical WM regions, and putamen. The largest differences between men and women, exceeding 4%, were observed bilaterally in the frontal juxtacortical WM; angular, inferior occipital, and cuneus WM; external capsule; and inferior and superior fronto-orbital fasciculi. The majority of hemispheric differences in MPF were common to men and women. Sex-specific interhemispheric differences were found in juxtacortical WM; men more often had left-sided asymmetry, while women had right-sided asymmetry. Most regions of deep gray matter (GM), juxtacortical WM, and WM tracts (except for projection pathways) showed a later peak age of myelination in women compared to men, with a difference of 3.5 years on average. Body mass index (BMI) was associated with higher MPF and later peak age of myelination independent of age and sex. Conclusions: MPF mapping showed high sensitivity to assess sex-related differences in normal brain myelination, providing the basis for using this method in clinics.

Background: Depression is one of the most severe sequelae of COVID-19, with major depressive disorder often characterized by disruption in white matter (WM) connectivity stemming from changes in brain myelination. This study aimed to quantitatively assess brain myelination in clinically diagnosed post-COVID depression (PCD) using the recently proposed MRI method, macromolecular proton fraction (MPF) mapping. Methods: The study involved 63 recovered COVID-19 patients (52 mild, 11 moderate, and 2 severe) at 13.5 ± 10.0 months post-recovery, with matched controls without prior COVID-19 history (n = 19). A post-COVID depression group (PCD, n = 25) was identified based on psychiatric diagnosis, while a comparison group (noPCD, n = 38) included participants with neurological COVID-19 complications, excluding clinical depression. Results: Fast MPF mapping revealed extensive demyelination in PCD patients, particularly in juxtacortical WM (predominantly occipital lobe and medial surface), WM tracts (inferior fronto-occipital fasciculus (IFOF), posterior thalamic radiation, external capsule, sagittal stratum, tapetum), and grey matter (GM) structures (hippocampus, putamen, globus pallidus, and amygdala). The noPCD group also displayed notable demyelination, but with less magnitude and propagation. Multiple regression analysis highlighted IFOF demyelination as the primary predictor of Hamilton scores, PCD presence, and severity. The number of post-COVID symptoms was a significant predictor of PCD presence, while the number of acute symptoms was a significant predictor of PCD severity. Conclusions: This study, for the first time, reveals extensive demyelination in numerous WM and GM structures in PCD, outlining IFOF demyelination as a key biomarker.

Background: Depression and cognitive impairment are recognized complications of COVID-19. This study aimed to assess cognitive performance in clinically diagnosed post-COVID depression (PCD, n = 25) patients using neuropsychological testing. Methods: The study involved 71 post-COVID patients with matched control groups: recovered COVID-19 individuals without complications (n = 18) and individuals without prior COVID-19 history (n = 19). A post-COVID depression group (PCD, n = 25) was identified based on psychiatric diagnosis, and a comparison group (noPCD, n = 46) included participants with neurological COVID-19 complications, excluding clinical depression. Results: The PCD patients showed gender-dependent significant cognitive impairment in the MoCA, Word Memory Test (WMT), Stroop task (SCWT), and Trail Making Test (TMT) compared to the controls and noPCD patients. Men with PCD showed worse performances on the SCWT, in MoCA attention score, and on the WMT (immediate and delayed word recall), while women with PCD showed a decline in MoCA total score, an increased processing time with less errors on the TMT, and worse immediate recall. No differences between groups in Sniffin’s stick test were found. Conclusions: COVID-related direct (post-COVID symptoms) and depression-mediated (depression itself, male sex, and severity of COVID-19) predictors of decline in memory and information processing speed were identified. Our findings may help to personalize the treatment of depression, taking a patient’s gender and severity of previous COVID-19 disease into account.

Age-related myelination decrease is considered one of the likely mechanisms of cognitive decline. The present preliminary study is based on the longitudinal assessment of global and regional myelination of the normal adult human brain using fast macromolecular fraction (MPF) mapping. Additional markers were age-related changes in white matter (WM) hyperintensities on FLAIR-MRI and the levels of anti-myelin autoantibodies in serum. Eleven healthy subjects (33–60 years in the first study) were scanned twice, seven years apart. An age-related decrease in MPF was found in global WM, grey matter (GM), and mixed WM–GM, as well as in 48 out of 82 examined WM and GM regions. The greatest decrease in MPF was observed for the frontal WM (2–5%), genu of the corpus callosum (CC) (4.0%), and caudate nucleus (5.9%). The age-related decrease in MPF significantly correlated with an increase in the level of antibodies against myelin basic protein (MBP) in serum (r = 0.69 and r = 0.63 for global WM and mixed WM–GM, correspondingly). The volume of FLAIR hyperintensities increased with age but did not correlate with MPF changes and the levels of anti-myelin antibodies. MPF mapping showed high sensitivity to age-related changes in brain myelination, providing the feasibility of this method in clinics.

Depression and cognitive impairment are recognized complications of COVID-19. This study aimed to assess cognitive performance in clinically diagnosed post-COVID depression (PCD) patients using neuropsychological testing. The study involved 71 post-COVID patients, with matched control groups: recovered COVID-19 individuals without complications (n=18) and individuals without prior COVID-19 history (n=19). A post-COVID depression group (PCD, n=25) was identified based on psychiatric diagnosis, a comparison group (noPCD, n=46) included participants with neurological COVID-19 complications, excluding clinical depression. The PCD patients showed significantly less scores in the MoCA test, decreased immediate memory recall in the Word Memory Test, decreased processing speed and higher accuracy in the Trail Making Test, and near to significant worse executive control and processing speed in the Stroop task compared to controls and the noPCD patients. The number of post-COVID symptoms negatively correlated with immediate word memory recall and processing speed among all post-COVID patients. In PCD patients, negative correlations between number of post-COVID symptoms and delayed recall, between time after recovery and immediate recall, and positive correlation between the number of acute symptoms and processing speed in the incongruent condition of the Stroop task were found. No differences between groups in Sniffin’s stick olfactory test was found. Overall, our study revealed cognitive impairment in PCD patients similar to those in major depressive disorder.

Depression is one of the most severe sequelae of COVID-19, with major depressive disorder often characterized by disruption in white matter (WM) connectivity , stemming from changes in brain myelination. This study aimed to quantitatively assess brain myelination in clinically diagnosed post-COVID depression using recently proposed MRI method, macromolecular proton fraction (MPF) mapping. The study involved 63 recovered COVID-19 patients (52 mild, 11 moderate, 2 severe) at 13.5±10.0 months post-recovery, with matched controls without prior COVID-19 history (n=19). A post-COVID depression group (PCD, n=25) was identified based on psychiatric diagnosis, while a comparison group (noPCD, n=38) included participants with neurological COVID-19 complications, excluding clinical depression. Fast MPF mapping revealed extensive demyelination in PCD patients, particularly in juxtacortical WM (predominantly occipital lobe and medial surface), WM tracts (inferior fronto-occipital fasciculus (IFOF), posterior thalamic radiation, external capsule, sagittal stratum, tapetum), and grey matter (GM) structures (hippocampus, putamen, globus pallidus, and amygdala). The noPCD group also displayed notable demyelination but with less magnitude and propagation. Multiple regression analysis highlighted IFOF demyelination as the primary predictor of PCD presence and severity according to Hamilton scores. The number of post-COVID symptoms was a significant predictor of PCD presence while the number acute of symptoms was a significant predictor of PCD severity. This study, for the first time, reveals extensive demyelination in numerous WM and GM structures in PCD, outlining IFOF demyelination as a key biomarker.

Age-related myelination decrease is considered one of the likely mechanisms of cognitive decline. The present study is based on the longitudinal assessment of global and regional myelination of the normal adult human brain using the fast macromolecular fraction (MPF) mapping. Additional markers were age-related changes in white matter (WM) hyperintensities on FLAIR-MRI and the levels of anti-myelin autoantibodies in serum. Eleven healthy subjects (33–60 years in the first study) were scanned twice, 7 years apart. An age-related decrease in MPF was found in global WM, GM, and mixed WM-GM, as well as in 48 out of 82 examined WM and GM regions. The greatest decrease in MPF was observed for the frontal WM (2-5%), genu of the corpus callosum (CC) (4.0%) and caudate nucleus (5.9%). The age-related decrease in MPF significantly correlated with an increase in the level of antibodies against myelin basic protein (MBP) in serum (r = 0.69 and r = 0.63 for global WM and mixed WM-GM, correspondingly). The volume of FLAIR hyperintensities increased with age but did not correlate with MPF changes and the levels of anti-myelin antibodies. MPF mapping showed high sensitivity to age-related changes in brain myelination, providing the feasibility of this method in clinics.