Praveena Manogaran

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Manogaran

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Praveena

ORCID

0000-0003-0829-7171

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Publications 1 - 10 of 13

Exploring experimental autoimmune optic neuritis using multimodal imaging
Manogaran, Praveena; Walker-Egger, Christine; Samardzija, Marijana; et al. (2018)
NeuroImage
Estimates of age-dependent cutoffs for pathological brain volume loss using SIENA/FSL—a longitudinal brain volumetry study in healthy adults
Opfer, Roland; Ostwaldt, Ann-Christin; Sormani, Maria P.; et al. (2018)
Neurobiology of Aging
Bilateral retinal pathology following a first-ever clinical episode of autoimmune optic neuritis
Wicki, Carla A.; Manogaran, Praveena; Simic, Tanja; et al. (2020)
Neurology: Neuroimmunology & Neuroinflammation
Objective This longitudinal study aimed to assess changes in retinal structure and visual function following a first-ever episode of acute optic neuritis (ON). Methods Clinical and optical coherence tomography (OCT) data obtained over a period of 12 months were retrospectively analyzed in 41 patients with a first-ever clinical episode of acute ON. OCT scans, high-contrast visual acuity (HCVA), and low-contrast visual acuity (LCVA) were acquired at baseline and at 1, 3, 6, and 12 months thereafter. Macular ganglion cell and inner plexiform layer (GCIP), peripapillary retinal nerve fiber layer (pRNFL), and macular inner nuclear layer (INL) thicknesses were assessed by OCT. Linear mixed-effects models were used to analyze OCT variables of ipsilateral ON and contralateral non-ON (NON) eyes over time. Results The mean change of GCIP thickness in ON eyes was significant at all follow-up time points, with nearly 75% of the total reduction having occurred by month 1. In ON eyes, thinner GCIP thickness at month 1 correlated with lower LCVA at month 3. Mean pRNFL thickness in ON eyes differed significantly from NON eyes at all postbaseline time points. INL thickness was significantly increased in ON eyes (month 1) but also in contralateral NON eyes (month 12). Conclusions Retinal structural damage develops rapidly following acute ON and is associated with subsequent functional visual deficits. Our results also suggest bilateral retinal pathology following unilateral ON, possibly caused by subclinical involvement of the contralateral NON eyes. Moreover, our data may assist in clinical trial planning in studies targeting tissue damage in acute ON.
Optical coherence tomography of patients with Parkinson’s disease and progressive supranuclear palsy
Alkabie, Samir; Lange, Alex; Manogaran, Praveena; et al. (2020)
Clinical Neurology and Neurosurgery
Fully automated longitudinal segmentation of new or enlarged multiple sclerosis lesions using 3D convolutional neural networks
Krüger, Julia; Opfer, Roland; Gessert, Nils; et al. (2020)
NeuroImage: Clinical
The quantification of new or enlarged lesions from follow-up MRI scans is an important surrogate of clinical disease activity in patients with multiple sclerosis (MS). Not only is manual segmentation time consuming, but inter-rater variability is high. Currently, only a few fully automated methods are available. We address this gap in the field by employing a 3D convolutional neural network (CNN) with encoder-decoder architecture for fully automatic longitudinal lesion segmentation. Input data consist of two fluid attenuated inversion recovery (FLAIR) images (baseline and follow-up) per patient. Each image is entered into the encoder and the feature maps are concatenated and then fed into the decoder. The output is a 3D mask indicating new or enlarged lesions (compared to the baseline scan). The proposed method was trained on 1809 single point and 1444 longitudinal patient data sets and then validated on 185 independent longitudinal data sets from two different scanners. From the two validation data sets, manual segmentations were available from three experienced raters, respectively. The performance of the proposed method was compared to the open source Lesion Segmentation Toolbox (LST), which is a current state-of-art longitudinal lesion segmentation method. The mean lesion-wise inter-rater sensitivity was 62%, while the mean inter-rater number of false positive (FP) findings was 0.41 lesions per case. The two validated algorithms showed a mean sensitivity of 60% (CNN), 46% (LST) and a mean FP of 0.48 (CNN), 1.86 (LST) per case. Sensitivity and number of FP were not significantly different (p < 0.05) between the CNN and manual raters. New or enlarged lesions counted by the CNN algorithm appeared to be comparable with manual expert ratings. The proposed algorithm seems to outperform currently available approaches, particularly LST. The high inter-rater variability in case of manual segmentation indicates the complexity of identifying new or enlarged lesions. An automated CNN-based approach can quickly provide an independent and deterministic assessment of new or enlarged lesions from baseline to follow-up scans with acceptable reliability.
Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis
Dietrich, Michael; Koska, Valeria; Hecker, Christina; et al. (2020)
Brain: A Journal of Neurology
Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters.
Outer retinal dysfunction in the absence of structural abnormalities in multiple sclerosis
Hanson, James V.M.; Hediger, Michael; Manogaran, Praveena; et al. (2018)
Investigative Ophthalmology & Visual Science
Purpose: Recent evidence suggests structural changes distal to the inner retina in multiple sclerosis (MS) patients. The functional correlates of these proposed structural abnormalities remain unclear. We investigated outer retinal function and structure in MS patients, and quantified to what extent outer retinal structure influenced function in these patients. Methods: Outer retinal function was assessed using the full-field and multifocal electroretinogram (ERG/MF-ERG), whereas retinal structure was assessed using spectral-domain optical coherence tomography (OCT). Results were compared with preexisting normative data. The relationships between electrophysiology parameters and the OCT values corresponding to the proposed cellular origins of the ERG and MF-ERG were analyzed. Results: Most electrophysiological responses were delayed in MS patients, independently of optic neuritis (ON). Inner retinal thickness and volumes were reduced, and inner nuclear layer volume marginally increased, in eyes with previous ON; all other OCT parameters were normal. OCT results correlated with ERG amplitudes, but not with ERG peak times or any MF-ERG parameters. Conclusions: We recorded outer retinal dysfunction without detectable abnormalities of the corresponding retinal layers in MS patients, not ascribable to retrograde degeneration following ON. The findings complement a growing body of literature reporting primary retinal abnormalities distal to the ganglion cell–inner plexiform layer complex in MS patients, with our data suggesting that this may be a more widespread phenomenon than previously thought. ERG may be of more utility in detecting retinal dysfunction in MS patients than MF-ERG. Analysis of peak times, rather than response amplitudes, is recommended.
The afferent visual pathway as a model for assessing neurodegeneration in experimental autoimmune encephalomyelitis – a translational optical coherence tomography (OCT) approach
Manogaran, Praveena (2020)
Multiple sclerosis is an inflammatory and neurodegenerative autoimmune disease of the central nervous system that presents with perivenous lymphocytic infiltration, focal demyelination and neuro-axonal degeneration. Neuro-axonal injury is a key contributor to non-reversible long-term disability in multiple sclerosis, however, the exact mechanisms underlying neurodegeneration as well as the sequence of events leading to structural and functional impairment are not yet fully understood. Visual impairment, including optic neuritis, is a common and early clinical feature of multiple sclerosis, with up to 75% of patients experiencing some form of visual disability during their disease course. Frequently, episodes of multiple sclerosis related acute optic neuritis are followed by structural retinal damage that can be quantified in vivo using optical coherence tomography (OCT). Reduced retinal peripapillary nerve fibre layer and macular ganglion cell layer thickness assessed by OCT have been shown to correlate strongly with functional visual impairment and- on a broader level - brain atrophy among multiple sclerosis patients. Similar to findings in human studies, alterations in the retina including the retinal ganglion cells and optic nerve have been reported in a mouse model of multiple sclerosis called experimental autoimmune encephalomyelitis (EAE). However, the exact biological basis and temporal dynamics behind the retinal abnormalities observed clinically and in OCT studies, including the complex interplay between inflammatory and degenerative mechanisms have not yet been fully elucidated. EAE can be used to investigate structural damage in the afferent visual pathway, providing a unique model for assessing neurodegenerative changes and their functional consequences. In addition, it has the potential to generate deeper insight into basic mechanisms underlying structural tissue damage in multiple sclerosis. To assess visual pathway damage in EAE, an OCT and magnetic resonance imaging platform was developed and established. OCT detected inner retinal layer thickness changes in EAE mice, resembles what is observed in human multiple sclerosis related acute papillitis. Where an initial phase of swelling was associated with inner retinal layer thickening, followed by a significant decrease in thickness over time, once the swelling had subsided, likely representative of neuro-axonal pathology. Diffusion tensor imaging measurements of the optic nerve and tract provided complementary results suggestive of demyelination and axonal damage in the visual pathway. OCT retinal thickness also correlated significantly with diffusion tensor imaging measurements providing support for retrograde and anterograde degeneration in the visual pathway following optic neuritis. Immunofluorescence analysis contributed further evidence for a strong inflammatory response in the retina and optic nerve in EAE mice at the final observational time point. A combination of both OCT and magnetic resonance imaging provided a reliable and sensitive quantitative tool to assess structural damage in the visual pathway and the temporal sequence of neurodegeneration in EAE. To further characterize the biological mechanisms of visual pathway impairment in EAE and to unravel the morphological correlates of retinal thickness changes, a longitudinal OCT study including a systematic assessment of retinal and optic nerve immunohistochemical analysis was performed. Signs of inflammatory edema 11 days post immunisation coincided with inner retinal layer thickening, while neuro-axonal degeneration throughout the disease course contributed to inner retinal layer thinning observed at later time points. Early retinal pathology, including axonal transport impairment, was observed prior to cellular infiltration (i.e. T-cells) in the optic nerve 11 days post immunisation. However, the consequences of early retinal damage on OCT-derived measurements were offset by the initial inflammatory edema. Microgliosis and astrocytosis was detected in the retina prior to optic neuritis and persisted until the final observational time point. Early glial activity likely contributed to initial signs of retinal pathology that appeared in the absence of cellular infiltration, suggesting a need for early intervention of optic neuritis. Subsequent to inflammation, Müller cells responded to retinal pathology with possible neuroprotective behaviour. Müller cell reactivity (i.e. aquaporin-4 and glutamine synthetase decrease) occurred after 11 days post immunisation in the inner retinal layer. Future studies should explore Müller cell reactivity and its potentially neuroprotective role. Severe neuro-axonal degeneration was observed in the optic nerve and retina until 33 days post immunisation. Although, retrograde degeneration likely promoted the majority of observed inner retinal layer damage following optic neuritis, primary pathology – possibly due to gliosis – also contributed to inner retinal layer thinning. These results added morphological substrate to the OCT findings, further solidifying this tool as a valuable method to assess visual pathway damage in EAE and multiple sclerosis. Although, retinal ganglion cell pathology had been observed using immunohistochemical analysis and corroborated inner retinal layer thickness findings, it is still unclear to what extent retinal ganglion cell loss plays a role in OCT observed thinning of the retina. In vivo measurements of retinal ganglion cells can provide additional information on the time-course of neuro-axonal pathology within the same mouse, which histology is not capable of. A transgenic mouse line with yellow fluorescent proteins expressed in the Thy1 sequence (a marker for neurons including retinal ganglion cells) was used in conjunction with green autofluorescence imaging to examine neuro-axonal damage in the retina longitudinally. Feasibility and longitudinal reliability of green autofluorescence imaging to assess yellow fluorescent protein expressing cells was confirmed in healthy transgenic mice. To measure the number of yellow fluorescent protein expressing cells in the retina both a manual and automated cell counting method was employed. Although the automated cell counting method had high variance compared to the manual cell count, it was significantly faster and allowed for a greater area on the fundus image to be examined, giving a more unbiased representative read-out of neurodegeneration and allowing for spatial statistics. In EAE mice, hyperintensity of the yellow fluorescent signal was observed around the optic nerve head at onset of clinical symptoms, likely coinciding with the occurrence of optic neuritis in this model. Interestingly, this phenomenon dissipated at peak of symptoms in almost all the EAE mice. Green autofluorescence imaging may be a useful way to identify the occurrence of optic neuritis in EAE through the hyperintensity observed at clinical onset of symptoms, especially compared to standard magnetic resonance imaging or ex-vivo methods of confirming optic neuritis. Future studies should evaluate the value of this model for assessing retinal ganglion cell death or neuropathology at later stages of experimental optic neuritis. The EAE induced Thy1 transgenic mouse model would be valuable in future pre-clinical trials that want to target retinal ganglion cells. Overall, investigating structural anterior visual pathway damage may constitute a unique model for assessing mechanism and temporal sequence of neurodegeneration in multiple sclerosis. The extent and rapid onset of axonal and neuronal damage in this model appears relevant for pre-clinical trials and for testing interventions scaled to multiple sclerosis.
T-Cell Specificity Influences Disease Heterogeneity in Multiple Sclerosis
Cruciani, Carolina; Puthenparampil, Marco; Tomas-Ojer, Paula; et al. (2021)
Neurology: Neuroimmunology & Neuroinflammation
Background and Objectives Encouraged by the enormous progress that the identification of specific autoantigens added to the understanding of neurologic autoimmune diseases, we undertook here an in-depth study of T-cell specificities in the autoimmune disease multiple sclerosis (MS), for which the spectrum of responsible autoantigens is not fully defined yet. The identification of target antigens in MS is crucial for therapeutic strategies aimed to induce antigen-specific tolerance. In addition, knowledge of relevant T-cell targets can improve our understanding of disease heterogeneity, a hallmark of MS that complicates clinical management. Methods The proliferative response and interferon gamma (IFN-γ) release of CSF-infiltrating CD4+ T cells from patients with MS against several autoantigens was used to identify patients with different intrathecal T-cell specificities. Fresh CSF-infiltrating and paired circulating lymphocytes in these patients were characterized in depth by ex vivo immunophenotyping and transcriptome analysis of relevant T-cell subsets. Further examination of these patients included CSF markers of inflammation and neurodegeneration and a detailed characterization with respect to demographic, clinical, and MRI features. Results By testing CSF-infiltrating CD4+ T cells from 105 patients with MS against seven long-known myelin and five recently described GDP-l-fucose synthase peptides, we identified GDP-l-fucose synthase and myelin oligodendrocyte glycoprotein (35-55) responder patients. Immunophenotyping of CSF and paired blood samples in these patients revealed a significant expansion of an effector memory (CCR7− CD45RA−) CD27− Th1 CD4+ cell subset in GDP-l-fucose synthase responders. Subsequent transcriptome analysis of this subset demonstrated expression of Th1 and cytotoxicity-associated genes. Patients with different intrathecal T-cell specificities also differ regarding inflammation- and neurodegeneration-associated biomarkers, imaging findings, expression of HLA class II alleles, and seasonal distribution of the time of the lumbar puncture. Discussion Our observations reveal an association between autoantigen reactivity and features of disease heterogeneity that strongly supports an important role of T-cell specificity in MS pathogenesis. These data have the potential to improve patient classification in clinical practice and to guide the development of antigen-specific tolerization strategies.
Within-patient fluctuation of brain volume estimates from short-term repeated MRI measurements using SIENA/FSL
Opfer, Roland; Ostwaldt, Ann-Christin; Walker-Egger, Christine; et al. (2018)
Journal of Neurology

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