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.

The Role of Ascending Ventral-Tegmental Fibers for Recovery after Stroke.

OBJECTIVES: The integrity of cortical motor networks and their descending effector pathway (the corticospinal tract [CST]) is a major determinant motor recovery after stroke. However, this view neglects the importance of ascending tracts and their modulatory effects on cortical physiology. Here, we explore the role of such a tract that connects dopaminergic ventral tegmental midbrain nuclei to the motor cortex (the VTMC tract) for post-stroke recovery. METHODS: Lesion data and diffusivity parameters (fractional anisotropy) of the ipsi- and contralesional VTMC tract and CST were obtained from 133 patients (63.9 ± 13.4 years, 45 women) during the acute and chronic stage after the first ever ischemic stroke in the middle cerebral artery territory. Degeneration of VTMC tract and CST was quantified and related to clinical outcome parameters (National Institute of Health Stroke Scale with motor and cortical symptom subscores; modified Fugl-Meyer upper extremity score; modified Ranking Scale [mRS]). RESULTS: A significant post-stroke degeneration occurred in both tracts, but only VTMC degeneration was associated with lesion size. Using multiple regression models, we dissected the impact of particular tracts on recovery: Changes in VTMC tract integrity were stronger associated with independence in daily activities (mRS), upper limb motor impairment (modified Fugl-Meyer upper extremity score) and cortical symptoms (aphasia, neglect) captured by National Institute of Health Stroke Scale compared to CST. Changes in CST integrity merely were associated with the degree of hemiparesis (National Institute of Health Stroke Scale motor subscale). INTERPRETATION: Post-stroke outcome is influenced by ascending (VTMC) and descending (CST) fiber tracts. Favorable outcome regarding independence (modified Ranking Scale), upper limb motor function (modified Fugl-Meyer upper extremity score), and cortical symptoms (aphasia, neglect) was more strongly related to the ascending than descending tract. ANN NEUROL 2023;93:922-933.

High throughput spatial immune mapping reveals an innate immune scar in post-COVID-19 brains.

The underlying pathogenesis of neurological sequelae in post-COVID-19 patients remains unclear. Here, we used multidimensional spatial immune phenotyping and machine learning methods on brains from initial COVID-19 survivors to identify the biological correlate associated with previous SARS-CoV-2 challenge. Compared to healthy controls, individuals with post-COVID-19 revealed a high percentage of TMEM119+P2RY12+CD68+Iba1+HLA-DR+CD11c+SCAMP2+ microglia assembled in prototypical cellular nodules. In contrast to acute SARS-CoV-2 cases, the frequency of CD8+ parenchymal T cells was reduced, suggesting an immune shift toward innate immune activation that may contribute to neurological alterations in post-COVID-19 patients.

Cerebellar, Not Nigrostriatal Degeneration Impairs Dexterity in Multiple System Atrophy.

BACKGROUND: Multiple system atrophy (MSA) clinically manifests with either predominant nigrostriatal or cerebellopontine degeneration. This corresponds to two different phenotypes, one with predominant Parkinson's symptoms (MSA-P [multiple system atrophy-parkinsonian subtype]) and one with predominant cerebellar deficits (MSA-C [multiple system atrophy-cerebellar subtype]). Both nigrostriatal and cerebellar degeneration can lead to impaired dexterity, which is a frequent cause of disability in MSA. OBJECTIVE: The aim was to disentangle the contribution of nigrostriatal and cerebellar degeneration to impaired dexterity in both subtypes of MSA. METHODS: We thus investigated nigrostriatal and cerebellopontine integrity using diffusion microstructure imaging in 47 patients with MSA-P and 17 patients with MSA-C compared to 31 healthy controls (HC). Dexterity was assessed using the 9-Hole Peg Board (9HPB) performance. RESULTS: Nigrostriatal degeneration, represented by the loss of cells and neurites, leading to a larger free-fluid compartment, was present in MSA-P and MSA-C when compared to HCs. Whereas no intergroup differences were observed between the MSAs in the substantia nigra, MSA-P showed more pronounced putaminal degeneration than MSA-C. In contrast, a cerebellopontine axonal degeneration was observed in MSA-P and MSA-C, with stronger effects in MSA-C. Interestingly, the degeneration of cerebellopontine fibers is associated with impaired dexterity in both subtypes, whereas no association was observed with nigrostriatal degeneration. CONCLUSION: Cerebellar dysfunction contributes to impaired dexterity not only in MSA-C but also in MSA-P and may be a promising biomarker for disease staging. In contrast, no significant association was observed with nigrostriatal dysfunction. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dense dopaminergic innervation of the peri-infarct cortex despite dopaminergic cell loss after a pure motor-cortical stroke in rats.

After ischemic stroke, the cortex directly adjacent to the ischemic core (i.e., the peri-infarct cortex, PIC) undergoes plastic changes that facilitate motor recovery. Dopaminergic signaling is thought to support this process. However, ischemic stroke also leads to the remote degeneration of dopaminergic midbrain neurons, possibly interfering with this beneficial effect. In this study, we assessed the reorganization of dopaminergic innervation of the PIC in a rat model of focal cortical stroke. Adult Sprague-Dawley rats either received a photothrombotic stroke (PTS) in the primary motor cortex (M1) or a sham operation. 30 days after PTS or sham procedure, the retrograde tracer Micro Ruby (MR) was injected into the PIC of stroke animals or into homotopic cortical areas of matched sham rats. Thus, dopaminergic midbrain neurons projecting into the PIC were identified based on MR signal and immunoreactivity against tyrosine hydroxylase (TH), a marker for dopaminergic neurons. The density of dopaminergic innervation within the PIC was assessed by quantification of dopaminergic boutons indicated by TH-immunoreactivity. Regarding postsynaptic processes, expression of dopamine receptors (D1- and D2) and a marker of the functional signal cascade (DARPP-32) were visualized histologically. Despite a 25% ipsilesional loss of dopaminergic midbrain neurons after PTS, the number and spatial distribution of dopaminergic neurons projecting to the PIC was not different compared to sham controls. Moreover, the density of dopaminergic innervation in the PIC was significantly higher than in homotopic cortical areas of the sham group. Within the PIC, D1-receptors were expressed in neurons, whereas D2-receptors were confined to astrocytes. The intensity of D1- and DARPP-32 expression appeared to be higher in the PIC compared to the contralesional homotopic cortex. Our data suggest a sprouting of dopaminergic fibers into the PIC and point to a role for dopaminergic signaling in reparative mechanisms post-stroke, potentially related to recovery.

Speaking in gestures: Left dorsal and ventral frontotemporal brain systems underlie communication in conducting.

Conducting constitutes a well-structured system of signs anticipating information concerning the rhythm and dynamic of a musical piece. Conductors communicate the musical tempo to the orchestra, unifying the individual instrumental voices to form an expressive musical Gestalt. In a functional magnetic resonance imaging (fMRI) experiment, 12 professional conductors and 16 instrumentalists conducted real-time novel pieces with diverse complexity in orchestration and rhythm. For control, participants either listened to the stimuli or performed beat patterns, setting the time of a metronome or complex rhythms played by a drum. Activation of the left superior temporal gyrus (STG), supplementary and premotor cortex and Broca's pars opercularis (F3op) was shared in both musician groups and separated conducting from the other conditions. Compared to instrumentalists, conductors activated Broca's pars triangularis (F3tri) and the STG, which differentiated conducting from time beating and reflected the increase in complexity during conducting. In comparison to conductors, instrumentalists activated F3op and F3tri when distinguishing complex rhythm processing from simple rhythm processing. Fibre selection from a normative human connectome database, constructed using a global tractography approach, showed that the F3op and STG are connected via the arcuate fasciculus, whereas the F3tri and STG are connected via the extreme capsule. Like language, the anatomical framework characterising conducting gestures is located in the left dorsal system centred on F3op. This system reflected the sensorimotor mapping for structuring gestures to musical tempo. The ventral system centred on F3Tri may reflect the art of conductors to set this musical tempo to the individual orchestra's voices in a global, holistic way.

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.

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.

Enhancing Post-Stroke Rehabilitation and Preventing Exo-Focal Dopaminergic Degeneration in Rats-A Role for Substance P.

Dopaminergic signaling is a prerequisite for motor learning. Delayed degeneration of dopaminergic neurons after stroke is linked to motor learning deficits impairing motor rehabilitation. This study investigates safety and efficacy of substance P (SP) treatment on post-stroke rehabilitation, as this neuropeptide combines neuroprotective and plasticity-promoting properties. Male Sprague Dawley rats received a photothrombotic stroke within the primary motor cortex (M1) after which a previously acquired skilled reaching task was rehabilitated. Rats were treated with intraperitoneal saline (control group, n = 7) or SP-injections (250 µg/kg) 30 min before (SP-pre; n = 7) or 16 h (SP-post; n = 6) after rehabilitation training. Dopaminergic neurodegeneration, microglial activation and substance P-immunoreactivity (IR) were analyzed immunohistochemically. Systemic SP significantly facilitated motor rehabilitation. This effect was more pronounced in SP-pre compared to SP-post animals. SP prevented dopaminergic cell loss after stroke, particularly in the SP-pre condition. Despite its proinflammatory propensity, SP administration did not increase stroke volumes, post-stroke deficits or activation of microglia in the midbrain. Finally, SP administration prevented ipsilesional hypertrophy of striatal SPergic innervation, particularly in the SP-post condition. Mechanistically, SP-pre likely involved plasticity-promoting effects in the early phase of rehabilitation, whereas preservation of dopaminergic signaling may have ameliorated rehabilitative success in both SP groups during later stages of training. Our results demonstrate the facilitating effect of SP treatment on motor rehabilitation after stroke, especially if administered prior to training. SP furthermore prevented delayed dopaminergic degeneration and preserved physiological endogenous SPergic innervation.

[Complaints and clinical findings six months after COVID-19: outpatient follow-up at the University Medical Center Freiburg]. / Persistierende Beschwerden 6 Monate nach COVID-19 ­ Erfahrungen aus der COVID-19-Nachsorgeambulanz des Universitätsklinikums Freiburg.

BACKGROUND: Increasing evidence suggests that some patients suffer from persistent symptoms for months after recovery from acute COVID-19. However, the clinical phenotype and its pathogenesis remain unclear. We here present data on complaints and results of a diagnostic workup of patients presenting to the post-COVID clinic at the University Medical Center Freiburg. METHODS: Retrospective data analysis of persistently symptomatic patients presenting to our clinic at least 6 months after onset of acute COVID-19. All patients were assessed by a doctor and routine laboratory analysis was carried out. Quality of life was assessed using SF-36 questionnaire. In case of specific persisting symptoms, further organ-specific diagnostic evaluation was performed, and patients were referred to respective departments/specialists. FINDINGS: 132 Patients (58 male, 74 female; mean age 53.8 years) presented to our clinic at least 6 months after COVID-19. 79 (60 %) had been treated as outpatients and 53 (40 %) as inpatients. Most common complaints were persistent fatigue (82 %) and dyspnea on exertion (61 %). Further common complaints were impairments of concentration (54 %), insomnia (43 %), and impairments of smell or taste (35 %). Quality of life was reduced in all sections of the SF-36 questionnaire, yielding a reduced working capacity. Significant pathological findings in laboratory, echocardiographic and radiological work-up were rare. Impairments in lung function tests were more common in previously hospitalized patients. CONCLUSION: Patients presenting 6 months after onset of acute COVID-19 suffer from a diverse spectrum of symptoms with impaired quality of life, also referred to as Long COVID or Post-Acute Sequelae of SARS-CoV-2 infection (PASC). Further research is needed to determine the frequency of these post-COVID syndromes and their pathogenesis, natural course and treatment options. Evaluation and management should be multi-disciplinary.

Approximation to pain-signaling network in humans by means of migraine.

Nociceptive signals are processed within a pain-related network of the brain. Migraine is a rather specific model to gain insight into this system. Brain networks may be described by white matter tracts interconnecting functionally defined gray matter regions. Here, we present an overview of the migraine-related pain network revealed by this strategy. Based on diffusion tensor imaging data from subjects in the Human Connectome Project (HCP) database, we used a global tractography approach to reconstruct white matter tracts connecting brain regions that are known to be involved in migraine-related pain signaling. This network includes an ascending nociceptive pathway, a descending modulatory pathway, a cortical processing system, and a connection between pain-processing and modulatory areas. The insular cortex emerged as the central interface of this network. Direct connections to visual and auditory cortical association fields suggest a potential neural basis of phono- or photophobia and aura phenomena. The intra-axonal volume (Vintra ) as a measure of fiber integrity based on diffusion microstructure was extracted using an innovative supervised machine learning approach in form of a Bayesian estimator. Self-reported pain levels of HCP subjects were positively correlated with tract integrity in subcortical tracts. No correlation with pain was found for the cortical processing systems.

High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms.

BACKGROUND: COVID-19 intensive care patients can present with neurological syndromes, usually in the absence of SARS-CoV-2 in cerebrospinal fluid (CSF). The recent finding of some virus-neutralizing antibodies cross-reacting with brain tissue suggests the possible involvement of specific autoimmunity. DESIGN: Blood and CSF samples from eleven critically ill COVID-19 patients presenting with unexplained neurological symptoms including myoclonus, oculomotor disturbance, delirium, dystonia and epileptic seizures, were analyzed for anti-neuronal and anti-glial autoantibodies. RESULTS: Using cell-based assays and indirect immunofluorescence on unfixed murine brain sections, all patients showed anti-neuronal autoantibodies in serum or CSF. Antigens included intracellular and neuronal surface proteins, such as Yo or NMDA receptor, but also various specific undetermined epitopes, reminiscent of the brain tissue binding observed with certain human monoclonal SARS-CoV-2 antibodies. These included vessel endothelium, astrocytic proteins and neuropil of basal ganglia, hippocampus or olfactory bulb. CONCLUSION: The high frequency of autoantibodies targeting the brain in the absence of other explanations suggests a causal relationship to clinical symptoms, in particular to hyperexcitability (myoclonus, seizures). Several underlying autoantigens and their potential molecular mimicry with SARS-CoV-2 still await identification. However, autoantibodies may already now explain some aspects of multi-organ disease in COVID-19 and can guide immunotherapy in selected cases.

[Neuropsychiatric sequelae of the COVID-19 pandemic]. / Neuropsychiatrische Folgen der COVID-19-Pandemie.

The COVID-19 pandemic has a significant impact on mental health. On the one hand, fears about one's economic situation, own health and the health of others can lead to psychosocial consequences. On the other hand, social isolation through physical distancing can affect mental health. Finally, the infection itself can lead to psychiatric and neuropsychiatric symptoms as part of a systemic manifestation. In this paper, different mechanisms are presented, which can lead directly or indirectly to neuropsychological and psychopathological symptoms in the context of the COVID-19 pandemic.

Topography and collateralization of dopaminergic projections to primary motor cortex in rats.

Dopaminergic signaling within the primary motor cortex (M1) is necessary for successful motor skill learning. Dopaminergic neurons projecting to M1 are located in the ventral tegmental area (VTA, nucleus A10) of the midbrain. It is unknown which behavioral correlates are encoded by these neurons. The objective here is to investigate whether VTA-M1 fibers are collaterals of projections to prefrontal cortex (PFC) or nucleus accumbens (NAc) or if they form a distinct pathway. In rats, multiple-site retrograde fluorescent tracers were injected into M1, PFC and the core region of the NAc and VTA sections investigated for concomitant labeling of different tracers. Dopaminergic neurons projecting to M1, PFC and NAc were found in nucleus A10 and to a lesser degree in the medial nucleus A9. Neurons show high target specificity, minimal collateral branching to other than their target area and hardly cross the midline. Whereas PFC- and NAc-projecting neurons are indistinguishably intermingled within the ventral portion of dopaminergic nuclei in middle and caudal midbrain, M1-projecting neurons are only located within the dorsal part of the rostral midbrain. Within M1, the forelimb representation receives sevenfold more dopaminergic projections than the hindlimb representation. This strong rostro-caudal gradient as well as the topographical preference to dorsal structures suggest that projections to M1 emerged late in the development of the dopaminergic systems in and form a functionally distinct system.

Morpho-physiological criteria divide dentate gyrus interneurons into classes.

GABAergic inhibitory interneurons control fundamental aspects of neuronal network function. Their functional roles are assumed to be defined by the identity of their input synapses, the architecture of their dendritic tree, the passive and active membrane properties and finally the nature of their postsynaptic targets. Indeed, interneurons display a high degree of morphological and physiological heterogeneity. However, whether their morphological and physiological characteristics are correlated and whether interneuron diversity can be described by a continuum of GABAergic cell types or by distinct classes has remained unclear. Here we perform a detailed morphological and physiological characterization of GABAergic cells in the dentate gyrus, the input region of the hippocampus. To achieve an unbiased and efficient sampling and classification we used knock-in mice expressing the enhanced green fluorescent protein (eGFP) in glutamate decarboxylase 67 (GAD67)-positive neurons and performed cluster analysis. We identified five interneuron classes, each of them characterized by a distinct set of anatomical and physiological parameters. Cross-correlation analysis further revealed a direct relation between morphological and physiological properties indicating that dentate gyrus interneurons fall into functionally distinct classes which may differentially control neuronal network activity.

Assessing bolus peak position in CT perfusion: High variance persisting despite age-dependency in a large cohort.

PURPOSE: CT perfusion (CTP) is a valuable tool in suspected acute ischemic stroke. A substantial variability of the delay between contrast injection and bolus arrival in the brain is conceivable. We investigated the distribution of the peak positions of the concentration time curves measured in an artery (arterial input function, AIF) and - in cases with ischemia - also measured in the penumbra. METHODS: We report on 2624 perfusion scans (52 % female, mean age 72.2 ± 14.4 years) with stroke present in 1636 cases. From the attenuation time curves of the AIF and the penumbra, we calculated the respective bolus peak positions and investigated the distribution of the peak positions. Further, we analyzed the bolus peak positions for associations with age. RESULTS: The bolus peaked significantly later in older patients, both in the AIF and in the penumbra (all p < 0.001). In the whole cohort, we found a significant association of age with the bolus peak position of the AIF (ρ = 0.334; p < 0.001). In patients with stroke, age was also associated to the peak position of the AIF (ρ = 0.305; p < 0.001), and the penumbra (ρ = 0.246, p < 0.001). However, a substantial range of peak positions of the AIF and penumbra was noted across all age ranges. CONCLUSIONS: This study revealed a strong age-dependency of the contrast bolus arrival in both healthy and ischemic tissue. This variability makes non-uniform sampling schemes, which have been suggested to reduce radiation dose, problematic, as they might not always optimally capture the bolus in all cases.

Complemental Value of Microstructural and Macrostructural MRI in the Discrimination of Neurodegenerative Parkinson Syndromes.

PURPOSE: Various MRI-based techniques were tested for the differentiation of neurodegenerative Parkinson syndromes (NPS); the value of these techniques in direct comparison and combination is uncertain. We thus compared the diagnostic performance of macrostructural, single compartmental, and multicompartmental MRI in the differentiation of NPS. METHODS: We retrospectively included patients with NPS, including 136 Parkinson's disease (PD), 41 multiple system atrophy (MSA) and 32 progressive supranuclear palsy (PSP) and 27 healthy controls (HC). Macrostructural tissue probability values (TPV) were obtained by CAT12. The microstructure was assessed using a mesoscopic approach by diffusion tensor imaging (DTI), neurite orientation dispersion and density imaging (NODDI), and diffusion microstructure imaging (DMI). After an atlas-based read-out, a linear support vector machine (SVM) was trained on a training set (n = 196) and validated in an independent test cohort (n = 40). The diagnostic performance of the SVM was compared for different inputs individually and in combination. RESULTS: Regarding the inputs separately, we observed the best diagnostic performance for DMI. Overall, the combination of DMI and TPV performed best and correctly classified 88% of the patients. The corresponding area under the receiver operating characteristic curve was 0.87 for HC, 0.97 for PD, 1.0 for MSA, and 0.99 for PSP. CONCLUSION: We were able to demonstrate that (1) MRI parameters that approximate the microstructure provided substantial added value over conventional macrostructural imaging, (2) multicompartmental biophysically motivated models performed better than the single compartmental DTI and (3) combining macrostructural and microstructural information classified NPS and HC with satisfactory performance, thus suggesting a complementary value of both approaches.

Cerebral microstructural alterations in Post-COVID-condition are related to cognitive impairment, olfactory dysfunction and fatigue.

After contracting COVID-19, a substantial number of individuals develop a Post-COVID-Condition, marked by neurologic symptoms such as cognitive deficits, olfactory dysfunction, and fatigue. Despite this, biomarkers and pathophysiological understandings of this condition remain limited. Employing magnetic resonance imaging, we conduct a comparative analysis of cerebral microstructure among patients with Post-COVID-Condition, healthy controls, and individuals that contracted COVID-19 without long-term symptoms. We reveal widespread alterations in cerebral microstructure, attributed to a shift in volume from neuronal compartments to free fluid, associated with the severity of the initial infection. Correlating these alterations with cognition, olfaction, and fatigue unveils distinct affected networks, which are in close anatomical-functional relationship with the respective symptoms.