Christian Cordano | UCSF - Academia.edu (original) (raw)

Papers by Christian Cordano

Neurology - Neuroimmunology Neuroinflammation

Background and ObjectivesWith the increasing use of visually evoked potentials (VEPs) as quantita... more Background and ObjectivesWith the increasing use of visually evoked potentials (VEPs) as quantitative outcome parameters for myelin in clinical trials, an in-depth understanding of longitudinal VEP latency changes and their prognostic potential for subsequent neuronal loss will be required. In this longitudinal multicenter study, we evaluated the association and prognostic potential of VEP latency for retinal neurodegeneration, measured by optical coherence tomography (OCT), in relapsing-remitting MS (RRMS).MethodsWe included 293 eyes of 147 patients with RRMS (age [years, median ± SD] 36 ± 10, male sex 35%, F/U [years, median {IQR} 2.1 {1.5–3.9}]): 41 eyes had a history of optic neuritis (ON) ≥6 months before baseline (CHRONIC-ON), and 252 eyes had no history of ON (CHRONIC-NON). P100 latency (VEP), macular combined ganglion cell and inner plexiform layer volume (GCIPL), and peripapillary retinal nerve fiber layer thickness (pRNFL) (OCT) were quantified.ResultsP100 latency change o...

Journal of Clinical Investigation

Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS. Increasin... more Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward-rectifying) and oligodendroglial Kir4.1 (inward-rectifying) potassium channels have important roles in regulating neuronal excitability at and around the nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE), with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs, and rescued neuronal pathology in oligodendrocyte-Kir4.1-deficient (OL-Kir4.1-deficient) mice. In summary, our findings indicate that neuron-OL compensatory interactions promoted resilience through Kv7 and Kir4.1 channels and identify pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination.

In recent years, the ability of conventional magnetic resonance imaging (MRI) to monitor high eff... more In recent years, the ability of conventional magnetic resonance imaging (MRI) to monitor high efficacy therapies and predict long-term disability in multiple sclerosis (MS) has been challenged. Here we used hyperpolarized 13C MR spectroscopy (MRS) metabolic imaging in a MS model of inflammatory-mediated demyelinating disease with widespread demyelination of the central nervous system (CNS). We showed that hyperpolarized metabolic imaging could monitor immune cell activation by measuring hyperpolarized [1-13C]pyruvate conversion to lactate and demonstrated that this approach detected response to two existing treatments, fingolimod and dimethyl fumarate. We observed a reduction of pyruvate-to-lactate flux after treatment, that can be explained by increased pyruvate dehydrogenase activity and decrease of immune cells. In addition, we evaluated brain perfusion using hyperpolarized [13C]urea, but saw no therapy effect. In conclusion, hyperpolarized magnetic resonance spectroscopy of [1-1...

The Journal of Clinical Neurology, Sep 1, 2022

European Journal of Neurology

Background and purpose: Clinical outcomes of multiple sclerosis (MS) patients affected by coronav... more Background and purpose: Clinical outcomes of multiple sclerosis (MS) patients affected by coronavirus disease 2019 (COVID-19) have been thoroughly investigated, but a further analysis on main signs and symptoms and their risk factors still needs attention. The objective of this study was to group together and describe based on similarity the most common signs and symptoms of COVID-19 in MS patients and identify all factors associated with their manifestation. Method: Logistic and linear regression models were run to recognize factors associated with each pooled group of symptoms and their total number. Results: From March 2020 to November 2021, data were collected from 1354 MS patients with confirmed infection of COVID-19. Ageusia and anosmia was less frequent in older people (odds ratio [OR] 0.98; p = 0.005) and more in smoker patients (OR 1.39; p = 0.049). Smoke was also associated with an incremental number of symptoms (OR 1.24; p = 0.031), substance abuse (drugs or alcohol), conjunctivitis and rash (OR 5.20; p = 0.042) and the presence of at least one comorbidity with shortness of breath, tachycardia or chest pain (OR 1.24; p = 0.008). Some disease-modifying therapies were associated with greater frequencies of certain COVID-19 symptoms (association between anti-CD20 therapies and increment in the number of concomitant symptoms: OR 1.29; p = 0.05). Differences in frequencies between the three waves were found for flu-like symptoms (G1, p = 0.024), joint or muscle pain (G2, p = 0.013) and ageusia and anosmia (G5, p < 0.001). All cases should be referred to variants up to Delta. Conclusion: Several factors along with the choice of specific therapeutic approaches might have a different impact on the occurrence of some COVID-19 symptoms.

Neurology

Background and ObjectivesThe timing of neurodegeneration in multiple sclerosis (MS) remains uncle... more Background and ObjectivesThe timing of neurodegeneration in multiple sclerosis (MS) remains unclear. It is critical to understand the dynamics of neuroaxonal loss if we hope to prevent or forestall permanent disability in MS. We therefore used a deeply phenotyped longitudinal cohort to assess and compare rates of neurodegeneration in retina and brain throughout the MS disease course.MethodsWe analyzed 597 patients with MS who underwent longitudinal optical coherence tomography imaging annually for 4.5 ± 2.4 years and 432 patients who underwent longitudinal MRI scans for 10 ± 3.4 years, quantifying macular ganglion cell-inner plexiform layer (GCIPL) volume and cortical gray matter (CGM) volume. The association between the slope of decline in the anatomical structure and the age of entry in the cohort (categorized by the MRI cohort's age quartiles) was assessed by hierarchical linear models.ResultsThe rate of CGM volume loss declined with increasing age of study entry (1.3% per ye...

Journal of Neurology, Neurosurgery & Psychiatry

BackgroundChronic demyelination is a major contributor to axonal vulnerability in multiple sclero... more BackgroundChronic demyelination is a major contributor to axonal vulnerability in multiple sclerosis (MS). Therefore, remyelination could provide a potent neuroprotective strategy. The ReBUILD trial was the first study showing evidence for successful remyelination following treatment with clemastine in people with MS (pwMS) with no evidence of disease activity or progression (NEDAP). Whether remyelination was associated with neuroprotection remains unexplored.MethodsPlasma neurofilament light chain (NfL) levels were measured from ReBUILD trial’s participants. Mixed linear effect models were fit for individual patients, epoch and longitudinal measurements to compare NfL concentrations between samples collected during the active and placebo treatment period.ResultsNfL concentrations were 9.6% lower in samples collected during the active treatment with clemastine (n=53, geometric mean=6.33 pg/mL) compared to samples collected during treatment with placebo (n=73, 7.00 pg/mL) (B=−0.035 [...

PLOS ONE, 2020

No single neuroimaging technique or sequence is capable of reflecting the functional deficits man... more No single neuroimaging technique or sequence is capable of reflecting the functional deficits manifest in MS. Given the interest in imaging biomarkers for short-to medium-term studies, we aimed to assess which imaging metrics might best represent functional impairment for monitoring in clinical trials. Given the complexity of functional impairment in MS, however, it is useful to isolate a particular functionally relevant pathway to understand the relationship between imaging and neurological function. We therefore analyzed existing data, combining multiparametric MRI and OCT to describe MS associated visual impairment. We assessed baseline data from fifty MS patients enrolled in ReBUILD, a prospective trial assessing the effect of a remyelinating drug (clemastine). Subjects underwent 3T MRI imaging, including Neurite Orientation Dispersion and Density Imaging (NODDI), myelin content quantification, and retinal imaging, using OCT. Visual function was assessed, using low-contrast letter acuity. MRI and OCT data were studied to model visual function in MS, using a partial, leastsquares, regression analysis. Measures of neurodegeneration along the entire visual pathway, described most of the observed variance in visual disability, measured by low contrast letter acuity. In those patients with an identified history of ON, however, putative myelin measures also showed correlation with visual performance. In the absence of clinically identifiable inflammatory episodes, residual disability correlates with neurodegeneration, whereas after an identifiable exacerbation, putative measures of myelin content are additionally informative.

Neuroimmunology and Neuroinflammation, 2020

A provocative and overly reductive mantra is that "the back of the eye is the front of the brain"... more A provocative and overly reductive mantra is that "the back of the eye is the front of the brain". Retinal imaging techniques that take advantage of this "window" to the central nervous system can provide valuable information regarding injury to the nervous system with relative ease and with a limited burden to patients. The retina develops embryonically as part of the neuroectoderm, is made up principally of neurons and their supporting cells, and is synaptically tied to the central nervous system (CNS). This has led to significant interest in using retinal health as a biomarker for brain health-given the relatively limited accessibility of brain tissue in chronic neurodegenerative diseases that progress over decades. The retina is not truly part of the CNS, and as with much of brain imagingthe grounds for asserting the pathological specificity of retinal imaging is limited. Biophotonics-based methods such as optical coherence tomography indirectly provide an opportunity to evaluate retinal neurodegeneration, while autopsy studies, histology and immunohistochemistry predominate as the methods that collect direct pathological data. Our understanding of pathological retinal lesions characteristic of demyelinating diseases, specifically diseases showing anterior visual pathway involvement, has grown significantly in recent years.

Journal of Neuroimaging, 2020

Background and Purpose: Neurological and neurodegenerative diseases can affect the spinal cord (S... more Background and Purpose: Neurological and neurodegenerative diseases can affect the spinal cord (SC) of pediatric patients. MRI allows for in-vivo quantification of SC atrophy via crosssectional area (CSA). The study of CSA values in the general population is important to disentangle disease-related changes from inter-subject variability. This study aimed at providing normative values for cervical CSA in children, extending our previous work performed with adults. Methods: Seventy-eight children (age 7-17 years) were selected from a Developmental Dyslexia study. All subjects underwent a 3T brain MRI session and any incidental findings were reported on the scans. A sagittal 1 mm 3 3D T 1-weighted brain acquisition extended to the upper cervical cord was used to measure CSA at C2-C3, as well as spinal canal area and skull volume (V-scale). These three metrics were linearly fitted as a function of age to extract trends and percentage annual changes. Sex differences of CSA were assessed using least squares regression analyses, adjusting for age. We tested normalization strategies proven to be effective in reducing the inter-subject variability of adults' CSA. Results: CSA changed as a function of age at a faster rate when compared with skull volume (CSA: 1.82% increase, V-scale: 0.60% reduction). Sex had a statistically significant effect on CSA. Normalization methods based on canal area and skull volume reduced the CSA inter-subject variability up to 16.84%. Conclusions: We present CSA normative values in a large cohort of children, reporting on sources of inter-subject variability and how to reduce them applying normalization methods previously developed.

JCI Insight, 2021

Figure 7. CSLO image processing for the morphological analysis of innate immune cells. The image ... more Figure 7. CSLO image processing for the morphological analysis of innate immune cells. The image preparation on ImageJ includes background subtraction (-50 px), contrast enhancement (saturated pixels 1%), and Z-stacking after image alignment. Then, a sample area of 350 px (red circle) in the vicinity of the optic nerve head is selected, and the number of cells are measured (somata areas are not shown).

Annals of Clinical and Translational Neurology, 2021

Artificial intelligence (AI)-based diagnostic algorithms have achieved ambitious aims through aut... more Artificial intelligence (AI)-based diagnostic algorithms have achieved ambitious aims through automated image pattern recognition. For neurological disorders, this includes neurodegeneration and inflammation. Scalable imaging technology for big data in neurology is optical coherence tomography (OCT). We highlight that OCT changes observed in the retina, as a window to the brain, are small, requiring rigorous quality control pipelines. There are existing tools for this purpose. Firstly, there are human-led validated consensus quality control criteria (OSCAR-IB) for OCT. Secondly, these criteria are embedded into OCT reporting guidelines (APOSTEL). The use of the described annotation of failed OCT scans advances machine learning. This is illustrated through the present review of the advantages and disadvantages of AI-based applications to OCT data. The neurological conditions reviewed here for the use of big data include Alzheimer disease, stroke, multiple sclerosis (MS), Parkinson disease, and epilepsy. It is noted that while big data is relevant for AI, ownership is complex. For this reason, we also reached out to involve representatives from patient organizations and the public domain in addition to clinical and research centers. The evidence reviewed can be grouped in a five-point expansion of the OSCAR-IB criteria to embrace AI (OSCAR-AI). The review concludes by specific recommendations on how this can be achieved practically and in compliance with existing guidelines.

Annals of Neurology, 2020

Journal of Neurology, 2020

We have read with interest the recent paper published in this journal by Maghzi et al. [1] report... more We have read with interest the recent paper published in this journal by Maghzi et al. [1] reporting a case series of five teriflunomide-treated multiple sclerosis (MS) patients who developed active COVID-19 infection and continued their therapy with a self-limiting infection, without any relapse. The authors hypothesized that, in these cases, COVID-19 infection could have had a better outcome because of the immune-biologic mechanisms pertaining to teriflunomide. In line with this hypothesis, Möhn and colleagues [2] reported another case of a 42-year-old male MS patient that, despite treatment with teriflunomide and high-dose methylprednisolone pulse therapy, developed a mild course of COVID-19. To date, no other cases of COVID-19 teriflunomidetreated patients were reported. We present here a case series of six patients treated with teriflunomide that developed a self-limiting COVID-19 infection. Diagnosis was confirmed in three of them with PCR from nasopharyngeal swabs and/or serology, while in the other three patients the diagnosis was based on typical symptomatology after a contact with COVID-19 patients during the epidemic peak in Lombardy between March and May 2020. All patients continued their therapy, and none of them experienced an MS relapse during the COVID-19 symptoms. Clinical characteristics and hematological

Annals of Neurology, 2021

15,16 and the Musc-19 Study Group Objective: This study was undertaken to assess the impact of im... more 15,16 and the Musc-19 Study Group Objective: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). Methods: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. Results: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses. Interpretation: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists.

Journal of Clinical Neuroscience, 2020

To evaluate density and morphology of corneal epithelial dendritic cells (DCs) in patients with m... more To evaluate density and morphology of corneal epithelial dendritic cells (DCs) in patients with multiple sclerosis (MS) using in vivo confocal microscopy (IVCM). Methods: This was a single-center cross-sectional comparative study. All MS patients were clinically scored using the Expanded Disability Status Scale (EDSS) score. Patients underwent ophthalmological examination and then cornea was analyzed by IVCM Heidelberg Retina Tomograph (HRT 3) in combination with Rostock Cornea Module and CCD camera. Five sectors (central, nasal, temporal, inferior, superior and central area) were analyzed in both patient eyes, then for each sector one image was selected and analyzed by using the manual cell counting system offered with the software and ImageJ program. DCs density (cell/mm 2) and DCs size (mm 2) were considered for the analyses. Difference between the two groups and correlation between DCs, MS type, EDSS score, optic neuritis and ongoing therapy were analyzed. Results: We enrolled 46 consecutive patients: 23 with MS (age 47.87 ± 7.22 years (mean ± standard deviation) and 21 healthy subjects (age 46.0 ± 12.6 years) from July 2017 to July 2018. MS patients showed a lower DCs density when compared with healthy subjects (p < 0.05). Moreover, we found a direct correlation (r:0.48, p < 0.05) between DCs density and ongoing disease-modifying therapy. Conclusion: IVCM was able to show a difference in corneal DCs density between MS patients and healthy subjects, providing an insight to the underlying changes of the clinical manifestations of MS. Further studies are needed to provide evidence of possible clinical implications.

Dementia & Neuropsychologia, 2020

ABSTRACT. Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are neurodegenerative disord... more ABSTRACT. Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are neurodegenerative disorders that result in a significant burden to both patients and caregivers. By 2050, the number of people with dementia in Latin America will increase 4-fold. A deep understanding of the relevant genetic factors of AD and FTD is fundamental to tackle this reality through prevention. A review of different genetic variants that cause AD or FTD in Latin America was conducted. We searched Medline and PubMed databases using the keywords “Alzheimer’s disease,” “frontotemporal dementia,” “mutation,” “America,” and “Latin America,” besides specific Latin American countries. Forty-five items were chosen and analyzed. PSEN1 mutations are the commonest cause of genetic early-onset Alzheimer’s disease (EOAD), followed by PSEN2 and APP mutations. Genetic FTD can be mainly explained by GRN and MAPT mutations, as well as C9orf72 G4C2 repeat expansion. APOE ε4 can modify the prevalence and incidence of lat...

The Lancet Neurology, 2020

Background-Methylphenidate, modafinil, and amantadine are commonly prescribed medications for all... more Background-Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis (MS); however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications against each other and placebo in patients with MS-related fatigue. Methods-In this randomized, double-blind, placebo-controlled, four-sequence, four-period crossover trial, patients with MS who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic MS centers in the US.

Neurological Sciences, 2020

Introduction Contrast-induced encephalopathy is a rare and usually reversible entity due to the a... more Introduction Contrast-induced encephalopathy is a rare and usually reversible entity due to the administration of iodinated contrast. Clinical manifestations include cortical blindness, encephalopathy, seizures and focal neurological deficits. Methods We report the case of a 56-year-old woman who developed global aphasia and right hemiplegia after a cerebral angiography performed for a subarachnoid haemorrhage. A prompt brain MRI resulted negative, while CT scan revealed left cerebral oedema with the cerebral sulci effacement. Complete recovery was observed in 10 days. Discussion Diagnosis of contrast-induced encephalopathy requires a temporal correlation between neurological dysfunction and administration of iodinated contrast. Usually, the symptomatology is transient with a full recovery within 48-72 h. The most common symptom is cortical blindness, while other symptoms have been rarely reported. Only 20 cases previously reported global aphasia and/or hemiplegia or mimed anterior circulation strokes. Prompt brain neuroimaging is essential in order to exclude an alternative diagnosis that requires a distinct therapeutic approach.