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Objective: Although the neurological and olfactory symptoms of coronavirus disease 2019 have been identified, the neurotropic properties of the causative virus, severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2), remain unknown. We sought to identify the susceptible cell types and potential routes of SARS-CoV-2 entry into the central nervous system, olfactory system, and respiratory system. Method(s): We collected single-cell RNA data from normal brain and nasal epithelium specimens, along with bronchial, tracheal, and lung specimens in public datasets. The susceptible cell types that express SARS-CoV-2 entry genes were identified using single-cell RNA sequencing and the expression of the key genes at protein levels was verified by immunohistochemistry. We compared the coexpression patterns of the entry receptor angiotensin-converting enzyme 2 (ACE2) and the spike protein priming enzyme transmembrane serine protease (TMPRSS)/cathepsin L among the specimens. Result(s): The SARS-CoV-2 entry receptor ACE2 and the spike protein priming enzyme TMPRSS/cathepsin L were coexpressed by pericytes in brain tissue;this coexpression was confirmed by immunohistochemistry. In the nasal epithelium, ciliated cells and sustentacular cells exhibited strong coexpression of ACE2 and TMPRSS. Neurons and glia in the brain and nasal epithelium did not exhibit coexpression of ACE2 and TMPRSS. However, coexpression was present in ciliated cells, vascular smooth muscle cells, and fibroblasts in tracheal tissue;ciliated cells and goblet cells in bronchial tissue;and alveolar epithelium type 1 cells, AT2 cells, and ciliated cells in lung tissue. Conclusion(s): Neurological symptoms in patients with coronavirus disease 2019 could be associated with SARS-CoV-2 invasion across the blood-brain barrier via pericytes. Additionally, SARS-CoV-2-induced olfactory disorders could be the result of localized cell damage in the nasal epithelium.Copyright © Wolters Kluwer Health, Inc. All rights reserved.
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Background: The continuous evolution of SARS-CoV-2 in the diverse immune landscape (natural, vaccine, hybrid) is giving rise to novel immune escape mutations. So far, the resulting new variants (BA.1, BA.2, BA.2.12.1) were observed to cause mild infections, however, BA.5 infections are associated with an increased risk of hospitalization.1 Therefore it is essential to investigate the pathogenesis of BA.5. Method(s): Here we compared the pathogenicity of Pre-Omicron (B.1.351) and Omicron (BA.1, BA.2.12.1, and BA.5) variants in wild-type C57BL/6J mice and K18-hACE2 mice. The virus replication kinetics was also studied in human Calu3, pulmonary alveolar type 2 (AT2) cells, and airway organoids (HAO). Cell-to-cell spread of virus was measured by syncytia formation assay and immunohistochemistry (IHC) of infected lungs. Result(s): In the results, infection in C57BL/6J mice showed severe weight loss ( >15%) for B.1.351 infected mice and moderate ( >5%) for BA.5 infected. C57BL/6J mice showed higher virus replication of B.1.351 followed by BA.5, BA.1, and BA.2.12.1. At the peak of virus replication (2 days) plaque-forming units from lung extract of BA.5 infected mice were two, and three logs higher compared to BA.1 and BA.2.12.1 respectively. BA.5 infection was lethal to 80% of infected K18-hACE2 mice, whereas the mice looked normal after infection with BA.1 and BA.2.12.1. BA.5 infected mice showed high virus replication in brain tissue. Surprisingly the syncytia formation assay and IHC for BA.5 was comparable to that of B.1.351, indicating the higher cell-to-cell spread of BA.5 and B.1.351 compared to BA.1 and BA.2.12.1, which is one of the measures of pathogenicity. Calu3 and HAO showed the same trend of virus replication as was observed in-vivo experiments however AT2 cells were found to be resistant to BA.5 replication. Conclusion(s): These results suggest that the BA.5 variant (lineage) of Omicron has the potential to regain the pathogenicity as it shows increased virulence compared to other Omicron sub-variants. Lethal infection of BA.5 in K18-hACE2 mice may be attributed to catastrophic encephalitis and increased cell-to-cell spread.
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The proceedings contain 23 papers. The topics discussed include: Mg and skeletal system: a link to osteoporosis and osteoarthritis;a putative impact of IL-6 on the expression of magnesiotropic genes through the activation of the JAK/STAT3 pathway;magnesium in pain therapy - historical notes and current aspects;Alzheimer's-associated variant rs708727 might be connected to dementia in Parkinson's disease;effect of magnesium citrate supplementation on the brain tissue of patients with Miyoshi dysferlinopathy measured by 31P magnetic resonance spectroscopy;clinical status of magnesium implants;Ionized magnesium: update 2022;magnesium in the treatment of selected types of muscular dystrophy;magnesium speciation analysis in blood serum;epigenetically-induced modulation of the HPA axis might improve resilience to chronic stress;magnesium status in patients with fibromyalgia syndrome;and post-covid-syndrome and transient microvascular pathology in pulse-wave-analysis - association with Mg/Ca ratio and magnesium therapy-options.
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Background: Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. Method(s): We performed a broad translational investigation, employing brain imaging and cognitive tests in 81 living COVID-19 patients (mildly infected individuals) as well as flow cytometry, respirometry, microscopy, proteomics, and metabolomics in postmortem brain samples, and in preclinical in vitro and ex vivo models. Result(s): We observed orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms in living individuals. Postmortem brain tissue from 26 individuals who died of COVID-19 revealed histopathological signs of brain damage. Five individuals out of the 26 exhibited foci of SARS- CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a non-canonical mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that significantly reduces neuronal viability. Conclusion(s): Our data support the model in which COVID-19 alter cortical thickness, promoting psychiatric symptoms. In addition, SARS-CoV-2 is able to reach the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients. Funding Source: Sao Paulo Research Foundation (FAPESP) Keywords: COVID-19, Anxiety, Astrocytes, Multi-omics, Brain Magnetic Resonance Imaging (MRI)Copyright © 2023
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The proceedings contain 48 papers. The topics discussed include: mental and physical health in informal caregiving and associations with relationship quality between caregiver and care recipient - a pilot study;immune-mediated early endocrine response during tumorigenesis;characterization of circulating dendritic cells in major depressive disorder;immune age correlates with cardiorespiratory fitness, but not with general intelligence;investigation of the relationship between immune age and vaccination against SARS-CoV-2;the steroid hormone dehydroepiandrosterone (DHEA) counteracts the consequences of psychological trauma on immunocellular ageing and mitochondrial bioenergetics;prediction of antibody levels after COVD-19 vaccination: evidence for immune interoception;and temporal dynamics of cytokine changes in blood, cerebrospinal fluid and brain tissue of endotoxemic rats.
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Case Report: Initial History/Presentation: A term vaccinated 7-month-old male with a history of eczema presents with two hours of right-sided hemiplegia and hemidystonia. Parents deny loss of consciousness, altered mental status, or facial symptoms. He has no known history of recent or remote head trauma. Patient may have had COVID two months prior when he had upper respiratory symptoms, with his mother testing COVID+ at that time. Of note, he received a Moderna COVID vaccination one day prior to onset of symptoms. Physical Exam: Pertinent exam findings include CN II-XII intact, right-sided upper and lower extremity strength 3/5, sensation intact, and truncal ataxia while seated. Physical exam is otherwise unremarkable. Diagnostic Evaluation: Initial lab work revealed leukocytosis (20.9), but otherwise a reassuring CMP, triglycerides, HDL, and LDL. PTT was elevated, but normal on recheck. Protein C antigen and activity were low, but deemed non-concerning by hematology. All other hypercoagulable labs were normal. On imaging, CT Brain showed linear calcifications in bilateral basal ganglia suggestive of mineralizing angiopathy. HisCTA head/neckwas negative.MRI Brain revealed an acute infarct of the body/tail of the left caudate nucleus, posterior limb of internal capsule, and posterior putamen. Clinical Course/Follow-up: Our patient was started on Aspirin 4 mg/kg daily. Throughout the course of his 3-day inpatient stay, he had mild improvement of right-sided strength and function, and continued improvement upon follow-up with his pediatrician. Given the short interval between receiving his COVID vaccination and onset of symptoms, his case was reported to the Vaccine Adverse Event Reporting System. Conclusion(s): From a radiological perspective, mineralizing angiopathy is an uncommon but familiar finding seen in up to 5% of all neonatal head ultrasounds and increasing to nearly 20% in preterm infants. It is most commonly associated with infection, hypoxia, and chromosomal abnormalities but is usually of minimal clinical significance. However, there are numerous reports of basal ganglia and thalamic strokes following minor head trauma in children with mineralizing angiopathy. For radiologists, this association is important to recognize and relay to the primary team so targeted history and MRI, if indicated, may be obtained to expedite definitive diagnosis and initiation of treatment to preserve precious brain tissue. Without a history of head trauma, in this case, stroke provocation is unclear, and other infectious or inflammatory disorders could appear similarly if they induced vasospasm or blood pressure lability. A short-interval timeframe between COVID vaccine administration and symptom onset is likely incidental, but research to exclude or illicit any link may be of benefit. Findings of mineralizing angiopathy on CT in the appropriate clinical setting should prompt further evaluation with emergent MRI to determine the presence of basal ganglia or thalamic stroke. Copyright © 2023 Southern Society for Clinical Investigation.
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COVID-19 disease is caused by Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2). In most of the cases the patients present with typical symptoms of fever, cough, dyspnea, sore throat etc. The involvement of central nervous system by SARS-CoV-2 resulting in encephalopathy, encephalitis and neuropsychiatric symptoms such as anxiety, depression, panic attack and post traumatic symptoms have been described in the literature. But the clinical presentation of Psychosis as a neuropsychiatric manifestation in COVID-19 patients has been described in very few literatures. Our aim of the study was to find out the incidence of Psychosis in COVID-19 patients and its association with elevated levels of inflammatory markers such as IL-6, CRP etc, and with that of elevated coagulation parameter such as D-dimer values. Severity of Pneumonia (by HRCT thorax), neuropsychiatric presentation of Psychosis and the various interventions received by the COVID-19 patients with Psychosis were also studied. Out of 2752 COVID-19 cases new onset COVID Psychosis was seen only in 36 cases with an incidence of 1.308%. Out of these, 30 cases were aged > 60 years (83.3%) with male predominance (n=25)(69.44%) Psychotic manifestations such as delusion, hallucinations and mania were seen in 34 (94%), 32(88.8%) and 28 (77.7%) cases respectively. Copyright © 2022, Research Journal of Pharmaceutical, Biological and Chemical Sciences. All Rights Reserved.
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Methods: Here, we sought to investigate the effects of TLR7 pathway activation on mouse behaviour 24 hours post-activation. Female CD1 mice received an intraperitoneal injection of the synthetic TLR7 agonist, R848, or an equivalent volume of saline and were subjected to the Open Field and Forced Swim Test 24 hours later (n=10/group). Brain and liver tissues were then collected for downstream gene expression analysis. Result(s): Independent T-tests confirmed that systemic R848 challenge induced a strong peripheral and central inflammatory response, as indicated by a 250-fold increase in hepatic SAA-2 mRNA expression (p<0.0001) and a 75-fold increase in CXCL10 mRNA expression in the prefrontal cortex (p<0.01), relative to controls. These changes in inflammatory markers were accompanied by evidence of sickness behaviour - in particular, a decrease in exploratory rearing (p<0.01). Conclusion(s): This demonstrates that R848 can be used to create a model reflective of viral-like illness and provides a useful tool for investigating the behavioural effects of TLR7-mediated inflammation. To further these results, we aim to explore the metabolic consequences of LPS and R848 challenge and relate these to inflammatory and behavioural changes. This will accompany our data on the metabolic signatures of SARS-CoV-2-infected cells and animals, and of long-COVID patients. Copyright © 2022
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Introduction: The effect of COVID-19 on brain pathology in multiple sclerosis patients is currently unknown. Objective(s):To describe changes in brain lesion activity as well as brain and spinal cord volumes following COVID-19. Method(s): We included 181 MS patients (McDonald 2017 criteria) with available MRI scans (N=650) before (#scans>=2) and after (>=1) COVID-19. All patients were clinically stable (no relapsing activity or disability progression), did not received highdose steroids, and did not change treatment status. All patients were scanned on a single 3T scanner (MAGNETOM Skyra, Siemens Healthcare, Erlangen, Germany). Brain MRI activity was assessed manually by neuroradiologist using automatic subtraction. Global and regional brain volumes were evaluated using the MorphoBox prototype software, and the mean upper cervical cord area (MUCCA) was assessed using ScanView software. Linear mixed models (with random intercept for patient) adjusted for sex age, disease duration, Expanded Disability Status Scale (EDSS), treatment status at infection, severity of COVID-19, and use of anti-covid treatment were used to analyze the difference in MRI measures before and after COVID-19. Result(s): The sample consisted of 75.7% of women, the mean duration of the age was 45.5 years, the mean disease was 15.1 years, and median EDSS was 2.0 (range 0-6.5). A total of 7.2% patients had not immunomodulatory treatment, 39.8% were on platform, 37.0% were on oral, and 16.0% were on high-efficiency monoclonal antibody immunomodulatory therapy. Together, 3.3% of the patients were asymptomatic, 82.3% had a mild infection, 14.4% had suspected or confirmed pneumonia. Patients with a higher age had a greater enlargement of the total ventricle volume (interaction age vs. COVID-19: b=0.0029;p=0.0027), right and left lateral ventricles (b=0.0012-0.0013;p=0.0069-0.0015), third ventricle (b=0.0002;p=0.027) and a greater reduction of mesencephalon volume (b=-0.0004;p=0.013) following the infection. In eleven patients on anti-CD20 treatment we found reduction of normalized white matter (b=-0.58;p=0.044) and hippocampal white matter volume (b=-1.73;p=0.0063). The brain lesion activity (occurrence of new and enlarging T2 lesions) was not influenced by the infection. Conclusion(s): Older MS patients had greater enlargement of brain ventricles after COVID-19. We did not find clear changes in lesion activity or brain tissue volumes following the infection.
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Background: The main trigger for Parkinson's disease is a mutated version of a protein called alpha-synuclein.This protein accumulates in dopamine-producing neurons. COVID-19 can increase the risk of Parkinson's and other neurological diseases. Methods:This review study was conducted by the library method. Results: The results showed that the virus can cause neuroinflammation, which, as a predisposing event, predisposes the brain to overreaction to subsequent neurological events. This secondary neurological event can be anything from another viral infection to poisoning and even aging. A secondary neurological event triggers an abnormal brain response that leads to nerve degeneration and eventually Parkinson's disease. The results show that the SARS-CoV-2 virus as a neurotropic virus can enter brain tissue. Conclusion: Therefore, the virus certainly has the potential to act as a predisposing event in increasing the risk of Parkinson's disease.
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Background: Matrix therapy is a newly coined name emphasizing the importance of the extracellular matrix in regenerative medicine. Heparan sulfates (HS) are key elements of the extracellular matrix (ECM) scaffold which store and protect most growth factors/ cytokines controlling the cell migration and differentiation required for healing processes. We have engineered biodegradable nanopolymers (alpha 1-6 polyglucose carboxymethyl sulfate) mimicking (RGTA) to replace destroyed HS in the damaged ECM scaffolding and to protect cytokines produced by healthy neighboring cells, thereby restoring the ECM microenvironment and tissue homeostasis and, if needed, provide a homing niche for cell therapy. This matrix therapy approach has considerably improved the quality of healing in various animal tissue injury models including skin, cornea, digestive mucosa, muscle lung and brain tissues showing tissue protection with reduction or absence of fibrosis resulting in a regeneration process. Due to the ubiquity of HS, numerous clinical developments have been identified and over 200 000 patients have been treated in the last 10 years for skin and corneal wounds with dedicated products based on this technology. Material(s) and Method(s): RGTA OTR4120 and 4132 have been designed to optimize binding and protection of several chemokines and growth factors, are produced in GMP facilities and fulfill all preclinical requirements for quality, safety and pharmacological data for human clinical trials. Result(s): In this short presentation we shall describe some preclinical data supporting brain ischemia protection, lung fibrosis and skin scar reduction, as well as clinical data on going trials aiming at reducing stroke sequala (safety phase 1/2*), pilot study on 13 patients with Covid (showing safety and efficacy on reduction of fibrosis, time to recovery from dyspnoea and fatigue* *). Skin scar reduction studies and submitted RCT proposal. Conclusion(s): Matrix therapy using the RGTA strategy has taken time before optimizing molecules and dosages but is now mature for a wide variety of developments and treatments. In all the cases safety was assessed and efficacy needed to be supported by RCT which are now in progress.
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Background: Several lines of evidence suggest that neurological symptoms in patients suffering from Coronavirus disease 2019 (COVID-19) occur partially due to damage to small vessels in the brain. However, the potential mechanisms underlying this pathology are unclear. Aim: Here, we describe a novel pathway by which SARSCoV- 2 affects the brain vasculature and thereby potentially induces neurocognitive impairment in patients. Method: We examined brain tissue of deceased COVID- 19 patients and different animal models of this disease for microvascular pathology. Using several techniques like mass spectrometry, high resolution microscopy, transgenic animals, and AAV-mediated gene transfer, we investigated the effect of the SARS-CoV-2 main protease (Mpro) on brain endothelial cells. Results/Conclusions: In brains of SARS-CoV-2-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected, and that Mpro cleaves NEMO, the essential modulator of nuclear factor-jB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of RIPK3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. These data suggest a novel mechanism by which SARS-CoV-2 affects the brain vasculature and a potential therapeutic option to interfere with the neurological consequences of COVID-19.
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Objective: To describe the clinicopathological correlations of 141 confirmed postmortem cases of coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome-coronavirus -2 (SARS-CoV-2). Background: Analysis of 50 cases of COVID-19 with available neuropathology revealed three CNS findings. First, hypoxia-ischemia does not account for all relevant neuropathological features. Second, elevated levels of circulating cytokines suggest activation of post-infectious immunity indicative of a cytokine storm, with increased hypercoagulability leading to a risk for thrombotic and hemorrhagic parenchymal tissue infarction. Third, a minority of cases have acute demyelinating encephalomyelitis-(ADEM) like features or indolent brainstem encephalitis. Such cases may present with early altered sensorium and brainstem signs. Fourth, SARS-CoV-2 staining could not be confirmed due to paucity of available tissue specimens. Design/Methods: Ninety-four additional cases with available postmortem CNS neuropathology showed four additional findings. Results: First, positive SARS-CoV-2 genome by PCR testing is present in brain tissues especially in olfactory bulb neurons and glial cells lending support to a route of entry into the CNS and the importance of early anosmia. Second, SARS-CoV-2-positive neurons appear to be TUNEL positive and caspase-positive, displaying reversible pT231 Tau localization in some cell soma that may be highly neurotoxic and a driver of tauopathy. Third, expression of ACE2 in oligodendrocytes is associated with viral entry, while TMPRSS2 and TMPRSS4 staining is implicated in pruning of viral-decorating spikes. Fourth, meningeal and interstitial brainstem inflammation by cytotoxic T-cells coincides with the localization of SARS-CoV-2 viral proteins in cranial nerves and interstitial areas of lower brainstem encephalitis. The detection of brain microglial activation and sparse perivascular and leptomeningeal T-cell infiltrates correlates with critical illness encephalopathy. Conclusions: Genetic diversity, recombination, and viral mutation carries the foreseeable risk of continued fatality due to the direct and indirect effects of SARS-CoV-2 that include inflammatory vasculopathy, encephalitis, silent infarctions, and critical illness encephalopathy.
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Novel coronavirus causes the outbreak of COVID-19. There is still no verified treatment regimen against this novel virus;however, different drugs and compounds have been tested against it. Ample proposals have led to a good understanding of pathogenesis and drug efficacy against the novel virus disease. Excess systemic inflammation, which is described as cytokine storm, in the severe cases of COVID-19 can pass through the blood-brain barrier, enter the brain tissue, and activate the microglial cells and oligodenritcytes. Activation of the microglia cells and oligodenritcytes can increase generation of reactive oxygen species in the brain. Excess generation of reactive oxygen species can in turn increase neuro-inflammation in some cases of patients with COVID-19. Treatment of COVID-19 is far from clear. Today, some antiviral drugs such as remdisivir, favipiravir, ribavirin, kaletra, and arbidol are being tested against the disease. Besides these drugs, corticosteroids, anti-malaria drugs (such as chloroquine family), anticoagulants (such as heparin or enoxaparin) are repurposed. In this paper, first we explained the pathogenesis of COVID-19 particles, particularly in the brain. Second, we reviewed recent treatment options up to now, including interferon therapy, convalescent plasma exchange, plasmapheresis, immunoglobin therapy, and use of specified monoclonal anti-bodies in COVID-19 patients.
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Introduction: Progressive multifocal leukoencephalopathy (PML) is a demyelinating brain disease caused by reactivation of JC virus in immunocompromised patients. PML typically manifests with subacute neurologic deficits including altered mental status, motor deficits, limb ataxia, gait ataxia, and visual symptoms. We report an atypical presentation of PML in a lung transplant recipient (LTR). Case Report: A 71-year-old LTR received rituximab induction followed by a combination of mycophenolate mofetil, tacrolimus, and prednisone. He had a single episode of minimal acute cellular rejection early after LT, but never required significantly augmented immunosuppression. Notably, he had mild leukopenia throughout his post-LT course (WBC count 3-4 thousand/µL), and he had no response to 4 doses of the Pfizer SARS-CoV-2 vaccine, suggesting advanced immunosuppression. At 14 months after LT, the patient reported progressive anomia and aphasia, but no other neurologic deficits. MRI showed an abnormal increased T2/FLAIR signal in the left posterior parieto-occipital subcortical white matter, involving subcortical U fibers, characteristic of PML (Figure A, C). Serum JC virus PCR showed low-level viremia, but CSF from 2 lumbar punctures was PCR negative. Thus, he was diagnosed with possible PML, and immunosuppression was narrowed to a combination of tacrolimus (goal trough 4-6) and prednisone, 5 mg daily. Despite reduced immunosuppression, a repeat MRI 2 months after the initial diagnosis showed worsening PML (Figure B, D) and his symptoms progressed to severe anomia, aphasia, and cortical blindness, but still no motor deficits. PML is a rare, albeit well described, complication of LT, but presentation with only anomia and aphasia is unusual. Without CSF viral isolation, a definitive diagnosis requires brain tissue;however, MRI changes involving subcortical U fibers in the parieto-occipital area are highly characteristic. Early recognition allows for expeditious management.