COVID-19 Neuroimaging Update: Pathophysiology, Acute Findings, and Post-Acute Developments.

COVID-19 has prominent effects on the nervous system with important manifestations on neuroimaging. In this review, we discuss the neuroimaging appearance of acute COVID-19 that became evident during the early stages of the pandemic. We highlight the underlying pathophysiology mediating nervous system effects and neuroimaging appearances including systemic inflammatory response such as cytokine storm, coagulopathy, and para/post-infections immune mediated phenomena. We also discuss the nervous system manifestations of COVID-19 and the role of imaging as the pandemic has evolved over time, including related to the development of vaccines and the emergence of post-acute sequalae such as long COVID.

Cerebrospinal Fluid in Posterior Reversible Encephalopathy Syndrome: Implications of Elevated Protein and Pleocytosis.

BACKGROUND AND PURPOSE: Patients with posterior reversible encephalopathy syndrome (PRES) sometimes undergo analysis of cerebrospinal fluid (CSF) to exclude alternative diagnoses. This study's objectives were to describe the CSF characteristics in patients with PRES and to identify clinical and radiologic findings associated with distinct CSF abnormalities. METHODS: We identified a retrospective cohort of patients with PRES. We compared clinical and radiographic characteristics of those who did versus did not undergo lumbar puncture, described the observed range of CSF findings, and analyzed clinical and radiographic features associated with specific CSF abnormalities. RESULTS: A total of 188 patients were included. Patients with (n = 77) and without (n = 111) CSF analysis had similar clinical and radiographic characteristics. Cerebrospinal fluid protein was elevated in 46 (60%) of 77, with median CSF protein 53 mg/dL (upper limit of normal 45 mg/dL). Protein elevation was significantly associated with radiographic severity (P = .0058) but not with seizure, time from symptom onset, radiographic evidence of diffusion restriction, or contrast enhancement. Five (7%) patients had elevated CSF white blood cells, all of whom had infarction and/or hemorrhage on neuroimaging, and 4 of whom had eclampsia. CONCLUSION: The CSF of most patients with PRES shows a mild protein elevation commensurate with radiographic severity. Cerebrospinal fluid pleocytosis may mark a distinct subtype of PRES with predisposition toward infarction and/or hemorrhage. These findings help clinicians interpret CSF findings in these patients and generate new hypotheses about the pathophysiology of this syndrome.

White matter microstructural abnormalities in blast-exposed combat veterans: accounting for potential pre-injury factors using consanguineous controls.

PURPOSE: Assess the prevalence of white matter microstructural changes in combat veterans, within the context of a highly matched control group comprising unexposed close relatives. METHODS: This prospective study had institutional review board approval, included written informed consent, and is HIPAA-compliant. Diffusion tensor imaging was analyzed in 16 male blast-exposed combat veterans of Operation Iraqi Freedom/Operation Enduring Freedom (mean age 31.0 years) and 18 unexposed males (mean age 30.4 years) chosen on the basis of a consanguineous relationship to a member of the subject group. Whole-brain voxel-based comparison of fractional anisotropy (FA) was performed using both group and individual analyses. Areas where effects on FA were detected were subsequently characterized by extracting radial diffusivity (RD), axial diffusivity (AD), and mean diffusivity (MD) from the regions of abnormal FA. RESULTS: Controls did not differ from veterans on any background demographic factor. In voxel-based group comparison, we identify high fractional anisotropy (FA) in veterans compared to controls (p < 0.01). Within individual veterans, we find multiple areas of both abnormally high and low FA (p < 0.01) in a heterogeneous distribution, consistent with multifocal traumatic axonal injury. In individualized analyses, low FA areas demonstrate high radial diffusivity, whereas high FA areas demonstrate low RD in both group and individual analyses. CONCLUSIONS: Combat-related blast exposure is associated with microstructural white matter abnormalities, and the nature of the control group decreases the likelihood that the findings reflect underlying background differences. Abnormalities are heterogeneously distributed across patients, consistent with TAI, and include areas of low and high FA.

Trans-synaptic EphB2-ephrin-B3 interaction regulates excitatory synapse density by inhibition of postsynaptic MAPK signaling.

Nervous system function requires tight control over the number of synapses individual neurons receive, but the underlying cellular and molecular mechanisms that regulate synapse number remain obscure. Here we present evidence that a trans-synaptic interaction between EphB2 in the presynaptic compartment and ephrin-B3 in the postsynaptic compartment regulates synapse density and the formation of dendritic spines. Observations in cultured cortical neurons demonstrate that synapse density scales with ephrin-B3 expression level and is controlled by ephrin-B3-dependent competitive cell-cell interactions. RNA interference and biochemical experiments support the model that ephrin-B3 regulates synapse density by directly binding to Erk1/2 to inhibit postsynaptic Ras/mitogen-activated protein kinase signaling. Together these findings define a mechanism that contributes to synapse maturation and controls the number of excitatory synaptic inputs received by individual neurons.

Ephrin-B1 and ephrin-B2 mediate EphB-dependent presynaptic development via syntenin-1.

The development of central nervous system synapses requires precise coordination between presynaptic and postsynaptic components. The EphB family controls postsynaptic development by interacting with glutamate receptors and regulating dendritic filopodia motility, but how EphBs induce the formation of presynaptic specializations is less well understood. Here, we show that knockdown of presynaptic ephrin-B1, ephrin-B2, or syntenin-1, but not ephrin-B3, prevents EphB-dependent presynaptic development. Ephrin-B1, ephrin-B2, and syntenin-1 are clustered together with presynaptic markers, suggesting that these molecules function jointly in presynaptic development. Knockdown of ephrin-B1 or ephrin-B2 reduces the number of synaptic specializations and the colocalization of syntenin-1 with synaptic markers. Simultaneous knockdown of ephrin-B1 and ephrin-B2 suggests that they function independently in the formation of synaptic contacts, but act together to recruit syntenin-1 to presynaptic terminals. Taken together, these results demonstrate that ephrin-B1 and ephrin-B2 function with EphB to mediate presynaptic development via syntenin-1.

Cell adhesion molecules: signalling functions at the synapse.

Many cell adhesion molecules are localized at synaptic sites in neuronal axons and dendrites. These molecules bridge pre- and postsynaptic specializations but do far more than simply provide a mechanical link between cells. In this review, we will discuss the roles these proteins have during development and at mature synapses. Synaptic adhesion proteins participate in the formation, maturation, function and plasticity of synaptic connections. Together with conventional synaptic transmission mechanisms, these molecules are an important element in the trans-cellular communication mediated by synapses.

Intracellular and trans-synaptic regulation of glutamatergic synaptogenesis by EphB receptors.

The majority of mature excitatory synapses in the CNS are found on dendritic spines and contain AMPA- and NMDA-type glutamate receptors apposed to presynaptic specializations. EphB receptor tyrosine kinase signaling has been implicated in both NMDA-type glutamate receptor clustering and dendritic spine formation, but it remains unclear whether EphB plays a broader role in presynaptic and postsynaptic development. Here, we find that EphB2 is involved in organizing excitatory synapses through the independent activities of particular EphB2 protein domains. We demonstrate that EphB2 controls AMPA-type glutamate receptor localization through PDZ (postsynaptic density-95/Discs large/zona occludens-1) binding domain interactions and triggers presynaptic differentiation via its ephrin binding domain. Knockdown of EphB2 in dissociated neurons results in decreased functional synaptic inputs, spines, and presynaptic specializations. Mice lacking EphB1-EphB3 have reduced numbers of synapses, and defects are rescued with postnatal reexpression of EphB2 in single neurons in brain slice. These results demonstrate that EphB2 acts to control the organization of specific classes of mature glutamatergic synapses.