Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.

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.

Exploring experimental autoimmune optic neuritis using multimodal imaging.

BACKGROUND: Neuro-axonal injury is a key contributor to non-reversible long-term disability in multiple sclerosis (MS). However, the underlying mechanisms are not yet fully understood. Visual impairment is common among MS patients, in which episodes of optic neuritis (ON) are often followed by structural retinal damage and sustained functional impairment. Alterations in the optic nerve and retina have also been described in experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. Thus, investigating structural anterior visual pathway damage may constitute a unique model for assessing mechanisms and temporal sequence of neurodegeneration in MS. We used a multimodal imaging approach utilizing optical coherence tomography (OCT) and diffusion tensor imaging (DTI) to explore the mechanisms and temporal dynamics of visual pathway damage in the animal model of MS. METHODS: 7 EAE-MOG35-55 and 5 healthy female C57BL/6J mice were used in this study. Ganglion cell complex (GCC) thickness was derived from an OCT volume scan centred over the optic nerve head, while the structure of the optic nerve and tracts was assessed from DTI and co-registered T2-weighted sequences performed on a 7T MRI scanner. Data was acquired at baseline, disease onset, peak of disease and recovery. Linear mixed effect models were used to account for intra-subject, inter-eye dependencies, group and time point. Correlation analyses assessed the relationship between GCC thickness and DTI parameters. Immunofluorescence staining of retina and optic nerve sections was used to assess distribution of marker proteins for microglia and neurodegeneration (nerve filaments). RESULTS: In EAE mice, a significant increase in GCC thickness was observed at disease onset (p < 0.001) followed by a decrease at recovery (p < 0.001) compared to controls. The EAE group had significant GCC thinning at recovery compared to all other time points (p < 0.001 for each). Signal increase on T2-weighted images around the optic nerves indicative of inflammation was seen in most of the EAE mice but in none of the controls. A significant decrease in axial diffusivity (AD) and increase in radial diffusivity (RD) values in EAE optic nerves (AD: p = 0.02, RD: p = 0.01) and tract (AD: p = 0.02, RD: p = 0.006) was observed compared to controls. GCC at recovery was positively correlated with AD (optic nerve: rho = 0.74, p = 0.04, optic tract: rho = 0.74, p = 0.04) and negatively correlated with RD (optic nerve: rho = -0.80, p = 0.02, optic tract: rho = -0.75, p = 0.04). Immunofluorescence analysis indicated the presence of activated microglia in the retina and optic nerves in addition to astrocytosis and axonal degeneration in the optic nerve of EAE mice. CONCLUSION: OCT detected GCC changes in EAE may resemble what is observed in MS-related acute ON: an initial phase of swelling (indicative of inflammatory edema) followed by a decrease in thickness over time (representative of neuro-axonal degeneration). In line with OCT findings, DTI of the visual pathway identifies EAE induced pathology (decreased AD, and increased RD). Immunofluorescence analysis provides support for inflammatory pathology and axonal degeneration. OCT together with DTI can detect retinal and optic nerve damage and elucidate to the temporal sequence of neurodegeneration in this rodent model of MS in vivo.

Corticospinal tract integrity measured using transcranial magnetic stimulation and magnetic resonance imaging in neuromyelitis optica and multiple sclerosis.

BACKGROUND: Both multiple sclerosis (MS) and neuromyelitis optica (NMO) can present with transverse myelitis; however, NMO symptoms are usually more severe and may present with more extensive axonal loss. Transcranial magnetic stimulation (TMS)-based input-output recruitment curves can quantitatively assess the excitability of corticospinal tract pathways and myelin water imaging can quantify the amount of myelin within this same pathway. OBJECTIVE: To compare differential effects of MS and NMO on TMS recruitment curves and myelin water imaging. METHODS: Ten healthy controls, 10 individuals with MS and 10 individuals with NMO completed clinical assessments, a TMS assessment and magnetic resonance imaging scan to measure recruitment curves and myelin water fraction in the corticospinal tract. RESULTS: Individuals with NMO had lower recruitment curve slopes (mean 13.6±6 µV/%) than MS (23.6±11 µV/%) and controls (21.9±9 µV/%, analysis of variance (ANOVA) P=0.05). Corticospinal tract myelin water fraction was lower in individuals with NMO (mean 0.17±0.02) compared to MS (0.19±0.02) and controls (0.20±0.02, ANOVA P=0.0006). CONCLUSION: Corticospinal pathway damage in individuals with NMO was evident by reduced recruitment curve slope and lower myelin water fraction. These specific measures of corticospinal function and structure may be used to obtain a better understanding and monitor brain injury caused by inflammatory central nervous system disorders.

Longitudinal Study of Retinal Nerve Fiber Layer Thickness and Macular Volume in Patients With Neuromyelitis Optica Spectrum Disorder.

BACKGROUND: Neuromyelitis spectrum disorder (NMOSD) is a rare autoimmune disorder previously thought to be a subtype of multiple sclerosis (MS). NMOSD is characterized by episodes of inflammation and damage to astrocytes that primarily results in damage to optic nerve and spinal cord. The objective of this exploratory study was to use optical coherence tomography (OCT) to measure axonal and neuronal health in NMOSD eyes over time. METHODS: Nine patients with definite NMOSD were assessed at baseline and follow-up visits (time between visits: 35-55 months). OCT assessment involved a macular volume protocol and a retinal nerve fiber layer (RNFL) thickness scan. RESULTS: The temporal, inferior, nasal, or superior quadrant and the mean global RNFL thickness, macular thickness, and volume of each NMOSD patient was unchanged compared with baseline for each eye separately and both together. There also was no change between the 2 time points for the OCT measures for eyes affected and unaffected by optic neuritis and all eyes together except for a significant change in the temporal RNFL quadrant when all NMOSD eyes were pooled together (mean = 2.88 µm, SD = 3.7, P = 0.021). CONCLUSIONS: Unlike in MS eyes, ongoing RNFL and macular thinning secondary to brain and optic nerve atrophy could not be observed in NMOSD eyes during an observation period of 4 years. This might be an additional marker to distinguish these 2 diseases. However, to confirm this finding, more long-term data are needed to compare these 2 diseases longitudinally.

Optical Coherence Tomography and Magnetic Resonance Imaging in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder.

Irreversible disability in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is largely attributed to neuronal and axonal degeneration, which, along with inflammation, is one of the major pathological hallmarks of these diseases. Optical coherence tomography (OCT) is a non-invasive imaging tool that has been used in MS, NMOSD, and other diseases to quantify damage to the retina, including the ganglion cells and their axons. The fact that these are the only unmyelinated axons within the central nervous system (CNS) renders the afferent visual pathway an ideal model for studying axonal and neuronal degeneration in neurodegenerative diseases. Structural magnetic resonance imaging (MRI) can be used to obtain anatomical information about the CNS and to quantify evolving pathology in MS and NMOSD, both globally and in specific regions of the visual pathway including the optic nerve, optic radiations and visual cortex. Therefore, correlations between brain or optic nerve abnormalities on MRI, and retinal pathology using OCT, may shed light on how damage to one part of the CNS can affect others. In addition, these imaging techniques can help identify important differences between MS and NMOSD such as disease-specific damage to the visual pathway, trans-synaptic degeneration, or pathological changes independent of the underlying disease process. This review focuses on the current knowledge of the role of the visual pathway using OCT and MRI in patients with MS and NMOSD. Emphasis is placed on studies that employ both MRI and OCT to investigate damage to the visual system in these diseases.

T-Cell Specificity Influences Disease Heterogeneity in Multiple Sclerosis.

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.

Bilateral retinal pathology following a first-ever clinical episode of autoimmune optic neuritis.

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.

Multiple sclerosis lesion activity segmentation with attention-guided two-path CNNs.

Multiple sclerosis is an inflammatory autoimmune demyelinating disease that is characterized by lesions in the central nervous system. Typically, magnetic resonance imaging (MRI) is used for tracking disease progression. Automatic image processing methods can be used to segment lesions and derive quantitative lesion parameters. So far, methods have focused on lesion segmentation for individual MRI scans. However, for monitoring disease progression, lesion activity in terms of new and enlarging lesions between two time points is a crucial biomarker. For this problem, several classic methods have been proposed, e.g., using difference volumes. Despite their success for single-volume lesion segmentation, deep learning approaches are still rare for lesion activity segmentation. In this work, convolutional neural networks (CNNs) are studied for lesion activity segmentation from two time points. For this task, CNNs are designed and evaluated that combine the information from two points in different ways. In particular, two-path architectures with attention-guided interactions are proposed that enable effective information exchange between the two time point's processing paths. It is demonstrated that deep learning-based methods outperform classic approaches and it is shown that attention-guided interactions significantly improve performance. Furthermore, the attention modules produce plausible attention maps that have a masking effect that suppresses old, irrelevant lesions. A lesion-wise false positive rate of 26.4% is achieved at a true positive rate of 74.2%, which is not significantly different from the interrater performance.

Fully automated longitudinal segmentation of new or enlarged multiple sclerosis lesions using 3D convolutional neural networks.

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.

Optical coherence tomography of patients with Parkinson's disease and progressive supranuclear palsy.

OBJECTIVES: To determine if Parkinson's disease (PD) and progressive supranuclear palsy (PSP) differed on retinal measurements using optical coherence tomography (OCT). PATIENTS AND METHODS: In a prospective, controlled, cross-sectional cohort study, we recruited patients with PD or PSP for more than three years, as well as control subjects. We measured peripapillary retinal nerve fiber layer (RNFL) thickness and macular volume using spectral-domain OCT. The association between these OCT measures and the disease characteristics of duration and disability were examined using a linear mixed effect model. RESULTS: We analyzed eyes from n = 12 PD patients, n = 11 PSP patients, and n = 12 control subjects. RNFL thickness was reduced in eyes from patients with PSP, but there were no differences in macular volume between groups. RNFL thickness and macular volume were not significantly different between eyes from patients with PD and controls. Worse disability was associated with reduced macular volumes. CONCLUSION: PSP but not PD is associated with thinning of the peripapillary RNFL when symptoms have been present for more than three years.

Correction to: Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis.

In the original publication of this article [1], Fig. 10 contained two panels "C" as panel "F" was accidentally omitted. The incorrect (Fig. 1) and correct (Fig. 2) versions are published in this correction article.

Retinal pathology in experimental optic neuritis is characterized by retrograde degeneration and gliosis.

The exact mechanisms and temporal sequence of neurodegeneration in multiple sclerosis are still unresolved. The visual pathway including its unmyelinated retinal axons, can serve as a prototypic model of neurodegeneration in experimental optic neuritis. We conducted a longitudinal study combining retinal imaging through optical coherence tomography (OCT) with immunohistochemical analyses of retinal and optic nerve tissue at various time points in experimental autoimmune encephalomyelitis (EAE).Inner retinal layer (IRL) thickness was measured in 30 EAE and 14 healthy control C57BL/6 J mice using OCT. Distribution of marker proteins was assessed by immunofluorescence staining and retinal mRNA levels were assayed using real-time PCR. Histological morphology was evaluated on light and electron microscopy images.Signs of inflammatory edema 11 days post immunisation coincided with IRL thickening, while neuro-axonal degeneration throughout the disease course contributed to IRL thinning observed after 20 days post immunisation. Retinal pathology, including axonal transport impairment, was observed early, prior to cellular infiltration (i.e. T-cells) in the optic nerve 11 days post immunisation. Yet, the effects of early retinal damage on OCT-derived readouts were outweighed by the initial inflammatory edema. Early microglial activation and astrocytosis was detected in the retina prior to retinal ganglion cell loss and persisted until 33 days post immunisation. Müller cell reactivity (i.e. aquaporin-4 and glutamine synthetase decrease) presented after 11 days post immunisation in the IRL. Severe neuro-axonal degeneration was observed in the optic nerve and retina until 33 days post immunisation.Initial signs of retinal pathology subsequent to early glial activity, suggests a need for prophylactic treatment of optic neuritis. Following early inflammation, Müller cells possibly respond to retinal pathology with compensatory mechanisms. Although the majority of the IRL damage observed is likely due to retrograde degeneration following optic neuritis, initial pathology, possibly due to gliosis, may contribute further to IRL thinning. These results add morphological substrate to our OCT findings. The extent and rapid onset of axonal and neuronal damage in this model appears relevant for testing interventions scaled to human optic neuritis.

Within-patient fluctuation of brain volume estimates from short-term repeated MRI measurements using SIENA/FSL.

BACKGROUND: Measurements of brain volume loss (BVL) in individual patients are currently discussed controversially. One concern is the impact of short-term biological noise, like hydration status. METHODS: Three publicly available reliability MRI datasets with scan intervals of days to weeks were used. An additional cohort of 60 early relapsing multiple sclerosis (MS) patients with MRI follow-ups was analyzed to test whether after 1 year pathological BVL is detectable in a relevant fraction of MS patients. BVL was determined using SIENA/FSL. Results deviating from zero in the reliability datasets were considered as within-patient fluctuation (WPF) consisting of the intrinsic measurement error as well as the short-term biological fluctuations of brain volumes. We provide an approach to interpret BVL measurements in individual patients taking the WPF into account. RESULTS: The estimated standard deviation of BVL measurements from the pooled reliability datasets was 0.28%. For a BVL measurement of x% per year in an individual patient, the true BVL lies with an error probability of 5% in the interval x% ± (1.96 × 0.28)/(scan interval in years)%. To allow a BVL per year of at least 0.4% to be identified after 1 year, the measured BVL needs to exceed 0.94%. The median BVL per year in the MS patient cohort was 0.44%. In 11 out of 60 MS patients (18%) we found a BVL per year equal or greater than 0.94%. CONCLUSION: The estimated WPF may be helpful when interpreting BVL results on an individual patient level in diseases such as MS.

Outer Retinal Dysfunction in the Absence of Structural Abnormalities in Multiple Sclerosis.

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.

Outer Retinal Dysfunction in the Absence of Structural Abnormalities in Multiple Sclerosis.

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.

Estimates of age-dependent cutoffs for pathological brain volume loss using SIENA/FSL-a longitudinal brain volumetry study in healthy adults.

Brain volume loss (BVL) has gained increasing interest for monitoring tissue damage in neurodegenerative diseases including multiple sclerosis (MS). In this longitudinal study, 117 healthy participants (age range 37.3-82.6 years) received at least 2 magnetic resonance imaging examinations. BVL (in %) was determined with the Structural Image Evaluation using Normalisation of Atrophy/FMRIB Software Library and annualized. Mean BVL per year was 0.15%, 0.30%, 0.46%, and 0.61% at ages 45, 55, 65, and 75 years, respectively. The corresponding BVL per year values of the age-dependent 95th percentiles were 0.52%, 0.77%, 1.05% and 1.45%. Pathological BVL can be assumed if an individual BVL per year exceeds these thresholds for a given age. The mean BVL per year determined in this longitudinal study was consistent with results from a cross-sectional study that was published recently. The cut-off for a pathological BVL per year at the age of 45 years (0.52%) was consistent with the cut-off suggested previously to distinguish between physiological and pathological BVL in MS patients. Different cut-off values, however, need to be considered when interpreting BVL assessed in cohorts of higher ages.

Global and regional annual brain volume loss rates in physiological aging.

The objective is to estimate average global and regional percentage brain volume loss per year (BVL/year) of the physiologically ageing brain. Two independent, cross-sectional single scanner cohorts of healthy subjects were included. The first cohort (n = 248) was acquired at the Medical Prevention Center (MPCH) in Hamburg, Germany. The second cohort (n = 316) was taken from the Open Access Series of Imaging Studies (OASIS). Brain parenchyma (BP), grey matter (GM), white matter (WM), corpus callosum (CC), and thalamus volumes were calculated. A non-parametric technique was applied to fit the resulting age-volume data. For each age, the BVL/year was derived from the age-volume curves. The resulting BVL/year curves were compared between the two cohorts. For the MPCH cohort, the BVL/year curve of the BP was an increasing function starting from 0.20% at the age of 35 years increasing to 0.52% at 70 years (corresponding values for GM ranged from 0.32 to 0.55%, WM from 0.02 to 0.47%, CC from 0.07 to 0.48%, and thalamus from 0.25 to 0.54%). Mean absolute difference between BVL/year trajectories across the age range of 35-70 years was 0.02% for BP, 0.04% for GM, 0.04% for WM, 0.11% for CC, and 0.02% for the thalamus. Physiological BVL/year rates were remarkably consistent between the two cohorts and independent from the scanner applied. Average BVL/year was clearly age and compartment dependent. These results need to be taken into account when defining cut-off values for pathological annual brain volume loss in disease models, such as multiple sclerosis.

Quantifying visual pathway axonal and myelin loss in multiple sclerosis and neuromyelitis optica.

BACKGROUND: The optic nerve is frequently injured in multiple sclerosis and neuromyelitis optica, resulting in visual dysfunction, which may be reflected by measures distant from the site of injury. OBJECTIVE: To determine how retinal nerve fiber layer as a measure of axonal health, and macular volume as a measure of neuronal health are related to changes in myelin water fraction in the optic radiations of multiple sclerosis and neuromyelitis optica participants with and without optic neuritis and compared to healthy controls. METHODS: 12 healthy controls, 42 multiple sclerosis (16 with optic neuritis), and 10 neuromyelitis optica participants (8 with optic neuritis) were included in this study. Optical coherence tomography assessment involved measurements of the segmented macular layers (total macular, ganglion cell layer, inner plexiform layer, and inner nuclear layer volume) and paripapillary retinal nerve fiber layer thickness. The MRI protocol included a 32-echo T2-relaxation GRASE sequence. Average myelin water fraction values were calculated within the optic radiations as a measure of myelin density. RESULTS: Multiple sclerosis and neuromyelitis optica eyes with optic neuritis history had lower retinal nerve fiber layer thickness, total macular, ganglion cell and inner plexiform layer volumes compared to eyes without optic neuritis history and controls. Inner nuclear layer volume increased in multiple sclerosis with optic neuritis history (mean = 0.99 mm(3), SD = 0.06) compared to those without (mean = 0.97 mm(3), SD = 0.06; p = 0.003). Mean myelin water fraction in the optic radiations was significantly lower in demyelinating diseases (neuromyelitis optica: mean = 0.098, SD = 0.01, multiple sclerosis with optic neuritis history: mean = 0.096, SD = 0.01, multiple sclerosis without optic neuritis history: mean = 0.098, SD = 0.02; F3,55 = 3.35, p = 0.03) compared to controls. Positive correlations between MRI and optical coherence tomography measures were also apparent (retinal nerve fiber layer thickness and ganglion cell layer thickness: r = 0.25, p = 0.05, total macular volume and inner plexiform layer volume: r = 0.27, p = 0.04). CONCLUSIONS: The relationship between reductions in OCT measures of neuro-axonal health in the anterior visual pathway and MRI-based measures of myelin health in the posterior visual pathway suggests that these measures may be linked through bidirectional axonal degeneration.