Publications by authors named "Tobias Granberg"

47 Publications

COVID-19 pathophysiology may be driven by an imbalance in the renin-angiotensin-aldosterone system.

Nat Commun 2021 04 23;12(1):2417. Epub 2021 Apr 23.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

SARS-CoV-2 uses ACE2, an inhibitor of the Renin-Angiotensin-Aldosterone System (RAAS), for cellular entry. Studies indicate that RAAS imbalance worsens the prognosis in COVID-19. We present a consecutive retrospective COVID-19 cohort with findings of frequent pulmonary thromboembolism (17%), high pulmonary artery pressure (60%) and lung MRI perfusion disturbances. We demonstrate, in swine, that infusing angiotensin II or blocking ACE2 induces increased pulmonary artery pressure, reduces blood oxygenation, increases coagulation, disturbs lung perfusion, induces diffuse alveolar damage, and acute tubular necrosis compared to control animals. We further demonstrate that this imbalanced state can be ameliorated by infusion of an angiotensin receptor blocker and low-molecular-weight heparin. In this work, we show that a pathophysiological state in swine induced by RAAS imbalance shares several features with the clinical COVID-19 presentation. Therefore, we propose that severe COVID-19 could partially be driven by a RAAS imbalance.
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http://dx.doi.org/10.1038/s41467-021-22713-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065208PMC
April 2021

Brain Atrophy Subtypes and the ATN Classification Scheme in Alzheimer's Disease.

Neurodegener Dis 2020 31;20(4):153-164. Epub 2021 Mar 31.

Division of Clinical Geriatrics, Department of Neurobiology, Karolinska Institutet, Center for Alzheimer Research, Care Sciences, and Society, Stockholm, Sweden.

Introduction: We investigated the association between atrophy subtypes of Alzheimer's disease (AD), the ATN classification scheme, and key demographic and clinical factors in 2 cohorts with different source characteristics (a highly selective research-oriented cohort, the Alzheimer's Disease Neuroimaging Initiative [ADNI]; and a naturalistic heterogeneous clinically oriented cohort, Karolinska Imaging Dementia Study [KIDS]).

Methods: A total of 382 AD patients were included. Factorial analysis of mixed data was used to investigate associations between AD subtypes based on brain atrophy patterns, ATN profiles based on cerebrospinal fluid biomarkers, and age, sex, Mini Mental State Examination (MMSE), cerebrovascular disease (burden of white matter signal abnormalities, WMSAs), and APOE genotype.

Results: Older patients with high WMSA burden, belonging to the typical AD subtype and showing A+T+N+ or A+T+N- profiles clustered together and were mainly from ADNI. Younger patients with low WMSA burden, limbic-predominant or minimal atrophy AD subtypes, and A+T-N- or A+T-N+ profiles clustered together and were mainly from KIDS. APOE ε4 carriers more frequently showed the A+T-N- and A+T+N- profiles.

Conclusions: Our findings align with the recent framework for biological subtypes of AD: the combination of risk factors, protective factors, and brain pathologies determines belonging of AD patients to distinct subtypes.
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http://dx.doi.org/10.1159/000515322DOI Listing
March 2021

Deep Learning Corpus Callosum Segmentation as a Neurodegenerative Marker in Multiple Sclerosis.

J Neuroimaging 2021 05 15;31(3):493-500. Epub 2021 Feb 15.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Background And Purpose: Corpus callosum atrophy is a sensitive biomarker of multiple sclerosis (MS) neurodegeneration but typically requires manual 2D or volumetric 3D-based segmentations. We developed a supervised machine learning algorithm, DeepnCCA, for corpus callosum segmentation and relate callosal morphology to clinical disability using conventional MRI scans collected in clinical routine.

Methods: In a prospective study of 553 MS patients with 704 acquisitions, 200 unique 2D T -weighted MRI scans were delineated to develop, train, and validate DeepnCCA. Comparative FreeSurfer segmentations were obtained in 504 3D T -weighted scans. Both FreeSurfer and DeepnCCA outputs were correlated with clinical disability. Using principal component analysis of the DeepnCCA output, the morphological changes were explored in relation to clinical disease burden.

Results: DeepnCCA and manual segmentations had high similarity (Dice coefficients 98.1 .11%, 89.3 .76%, for intracranial and corpus callosum area, respectively through 10-fold cross-validation). DeepnCCA had numerically stronger correlations with cognitive and physical disability as compared to FreeSurfer: Expanded disability status scale (EDSS) ±6 months (r = -.22 P = .002; r = -.17, P = .013), future EDSS (r = -.26, P<.001; r = -.17, P = .012), and future symbol digit modalities test (r = .26, P = .001; r = .24, P = .003). The corpus callosum became thinner with increasing cognitive and physical disability. Increasing physical disability, additionally, significantly correlated with a more angled corpus callosum.

Conclusions: DeepnCCA (https://github.com/plattenmichael/DeepnCCA/) is an openly available tool that can provide fast and accurate corpus callosum measurements applicable to large MS cohorts, potentially suitable for monitoring disease progression and therapy response.
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http://dx.doi.org/10.1111/jon.12838DOI Listing
May 2021

Heterozygous variants in : Beyond congenital mirror movements.

Neurol Genet 2020 Dec 20;6(6):e526. Epub 2020 Oct 20.

Department of Clinical Neuroscience (S.T., T.G., M.P.), Karolinska Institutet; Department of Neurology (S.T., M.P.), Karolinska University Hospital; Department of Neurophysiology (M.I.), Karolinska University Hospital; Department of Pediatric Neurology (M.L.), Astrid Lindgren's Hospital; Department of Clinical Genetics (A.N., B.T., G.B.), Karolinska University Hospital; Department of Molecular Medicine and Surgery (A.N., B.T., G.B., D.N.), Karolinska Institutet; and Department of Neuroradiology (T.G.), Karolinska University Hospital, Stockholm, Sweden.

Objective: To perform a comprehensive characterization of a cohort of patients with congenital mirror movements (CMMs) in Sweden.

Methods: Clinical examination with the Woods and Teuber scale for mirror movements (MMs), neuroimaging, navigated transcranial magnetic stimulation (nTMS), and massive parallel sequencing (MPS) were applied.

Results: The cohort is ethnically diverse and includes a total of 7 patients distributed in 2 families and 2 sporadic cases. The degree of MMs was variable in this cohort. MPS revealed 2 novel heterozygous frameshift variants in DCC netrin 1 receptor (). Two siblings harboring the pathogenic variant in c.1466_1476del display a complex syndrome featuring MMs and in 1 case receptive-expressive language disorder, chorea, epilepsy, and agenesis of the corpus callosum. The second variant, c.1729delG, was associated with a typical benign CMM phenotype. No variants in , , , or were found for the 2 sporadic CMM cases. However, one of these sporadic cases had concomitant high-risk myelodysplastic syndrome and a homozygous variant in ERCC excision repair like 2 (). Reorganized corticospinal projection patterns to upper extremities were demonstrated with nTMS.

Conclusions: The presence of chorea expands the clinical spectrum of syndromes associated with variants in . Biallelic pathogenic variants in cause bone marrow failure, but a potential association with CMM remains to be studied in larger cohorts.
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http://dx.doi.org/10.1212/NXG.0000000000000526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670573PMC
December 2020

Cerebrospinal Fluid Metals and the Association with Cerebral Small Vessel Disease.

J Alzheimers Dis 2020 ;78(3):1229-1236

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Department of Radiology, Karolinska University Hospital, Stockholm, Sweden.

Background: Brain metal homeostasis is essential for brain health, and deregulation can result in oxidative stress on the brain parenchyma.

Objective: Our objective in this study was to focus on two hemorrhagic MRI manifestations of small vessel disease [cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS)] and associations with cerebrospinal fluid (CSF) iron levels. In addition, we aimed to analyze CSF biomarkers for dementia and associations with CSF metal levels.

Methods: This is a cross-sectional study of 196 patients who underwent memory clinic investigation, including brain MRI. CSF was collected and analyzed for metals, amyloid-β (Aβ) 42, total tau (T-tau), and phosphorylated tau (P-tau), and CSF/serum albumin ratios. Statistical analyses were performed using generalized linear models.

Results: No significant difference was found between CSF metal levels across diagnostic groups. Higher iron and copper levels were associated with higher CSF levels of Aβ42, T-tau, P-tau, and CSF/serum albumin ratios (p < 0.05). Zinc was associated with higher CSF/serum albumin ratios. There was no significant association between CMBs or cSS and CSF iron levels. An increase in CSF iron with the number of CMBs was seen in APOEɛ4 carriers.

Conclusion: CSF iron levels are elevated with cerebral microbleeds in APOEɛ4 carriers, with no other association seen with hemorrhagic markers of small vessel disease. The association of elevated CSF iron and copper with tau could represent findings of increased neurodegeneration in these patients.
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http://dx.doi.org/10.3233/JAD-200656DOI Listing
January 2020

The reliability of a deep learning model in clinical out-of-distribution MRI data: A multicohort study.

Med Image Anal 2020 12 1;66:101714. Epub 2020 May 1.

Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; Department of Neuroimaging, Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Deep learning (DL) methods have in recent years yielded impressive results in medical imaging, with the potential to function as clinical aid to radiologists. However, DL models in medical imaging are often trained on public research cohorts with images acquired with a single scanner or with strict protocol harmonization, which is not representative of a clinical setting. The aim of this study was to investigate how well a DL model performs in unseen clinical datasets-collected with different scanners, protocols and disease populations-and whether more heterogeneous training data improves generalization. In total, 3117 MRI scans of brains from multiple dementia research cohorts and memory clinics, that had been visually rated by a neuroradiologist according to Scheltens' scale of medial temporal atrophy (MTA), were included in this study. By training multiple versions of a convolutional neural network on different subsets of this data to predict MTA ratings, we assessed the impact of including images from a wider distribution during training had on performance in external memory clinic data. Our results showed that our model generalized well to datasets acquired with similar protocols as the training data, but substantially worse in clinical cohorts with visibly different tissue contrasts in the images. This implies that future DL studies investigating performance in out-of-distribution (OOD) MRI data need to assess multiple external cohorts for reliable results. Further, by including data from a wider range of scanners and protocols the performance improved in OOD data, which suggests that more heterogeneous training data makes the model generalize better. To conclude, this is the most comprehensive study to date investigating the domain shift in deep learning on MRI data, and we advocate rigorous evaluation of DL models on clinical data prior to being certified for deployment.
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http://dx.doi.org/10.1016/j.media.2020.101714DOI Listing
December 2020

7 T imaging reveals a gradient in spinal cord lesion distribution in multiple sclerosis.

Brain 2020 10;143(10):2973-2987

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.

We used 7 T MRI to: (i) characterize the grey and white matter pathology in the cervical spinal cord of patients with early relapsing-remitting and secondary progressive multiple sclerosis; (ii) assess the spinal cord lesion spatial distribution and the hypothesis of an outside-in pathological process possibly driven by CSF-mediated immune cytotoxic factors; and (iii) evaluate the association of spinal cord pathology with brain burden and its contribution to neurological disability. We prospectively recruited 20 relapsing-remitting, 15 secondary progressive multiple sclerosis participants and 11 age-matched healthy control subjects to undergo 7 T imaging of the cervical spinal cord and brain as well as conventional 3 T brain acquisition. Cervical spinal cord imaging at 7 T was used to segment grey and white matter, including lesions therein. Brain imaging at 7 T was used to segment cortical and white matter lesions and 3 T imaging for cortical thickness estimation. Cervical spinal cord lesions were mapped voxel-wise as a function of distance from the inner central canal CSF pool to the outer subpial surface. Similarly, brain white matter lesions were mapped voxel-wise as a function of distance from the ventricular system. Subjects with relapsing-remitting multiple sclerosis showed a greater predominance of spinal cord lesions nearer the outer subpial surface compared to secondary progressive cases. Inversely, secondary progressive participants presented with more centrally located lesions. Within the brain, there was a strong gradient of lesion formation nearest the ventricular system that was most evident in participants with secondary progressive multiple sclerosis. Lesion fractions within the spinal cord grey and white matter were related to the lesion fraction in cerebral white matter. Cortical thinning was the primary determinant of the Expanded Disability Status Scale, white matter lesion fractions in the spinal cord and brain of the 9-Hole Peg Test and cortical thickness and spinal cord grey matter cross-sectional area of the Timed 25-Foot Walk. Spinal cord lesions were localized nearest the subpial surfaces for those with relapsing-remitting and the central canal CSF surface in progressive disease, possibly implying CSF-mediated pathogenic mechanisms in lesion development that may differ between multiple sclerosis subtypes. These findings show that spinal cord lesions involve both grey and white matter from the early multiple sclerosis stages and occur mostly independent from brain pathology. Despite the prevalence of cervical spinal cord lesions and atrophy, brain pathology seems more strongly related to physical disability as measured by the Expanded Disability Status Scale.
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http://dx.doi.org/10.1093/brain/awaa249DOI Listing
October 2020

Automated brainstem volumetry can aid in the diagnostics of parkinsonian disorders.

Parkinsonism Relat Disord 2020 Aug 13;79:18-25. Epub 2020 Aug 13.

Department of Clinical Neuroscience, Karolinska Institutet, 171 77, Stockholm, Sweden; Center for Neurology, Academic Specialist Center, 113 65, Stockholm, Sweden; Department of Neurology, Karolinska University Hospital, 141 86, Stockholm, Sweden.

Introduction: Separating progressive supranuclear palsy (PSP) from Parkinson's disease (PD) and multiple system atrophy (MSA) is often challenging in early disease but is important for appropriate management. Magnetic resonance imaging (MRI) can aid the diagnostics and manual 2D measurements are often used. However, new fully automatic brainstem volumetry could potentially be more accurate and increase availability of brainstem metrics.

Methods: Clinical 3D T1-weighted MRI were obtained from 196 consecutive patients; 29 PSP, 27 MSA, 140 PD. Midbrain-pons ratio and magnetic resonance parkinsonism index (MRPI) 1.0 and 2.0 were manually calculated, and intra-rater and inter-rater reliability was assessed. FreeSurfer was used to automatically segment brainstem substructures, normalized to the intracranial volume. The robustness of the automated analysis was evaluated in 3 healthy controls. The diagnostic accuracy of the brainstem biomarkers was assessed using receiver operating characteristic curves.

Results: Automatic brainstem volumetry had good repeatability/reproducibility with intra-scanner coefficient of variation 0.3-5.5% and inter-scanner coefficient of variation 0.9-8.4% in the different brainstem regions. Midbrain volume performs better than planimetric measurements in separating PSP from PD (Area under the curve (AUC) 0.90 compared with 0.81 for midbrain-pons ratio (p = 0.019), 0.77 for MRPI 1.0 (p = 0.007) and 0.81 for MRPI 2.0 (p = 0.021)). Midbrain volume performed on par with planimetry for separation between PSP and MSA.

Conclusion: Automatic brainstem segmentation is robust and shows promising diagnostic performance in separating PSP from PD and MSA. If further developed, it could play a role in diagnosing PSP and could potentially be used as an outcome in clinical trials.
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http://dx.doi.org/10.1016/j.parkreldis.2020.08.004DOI Listing
August 2020

Neurological manifestations of coronavirus infections - a systematic review.

Ann Clin Transl Neurol 2020 10 27;7(10):2057-2071. Epub 2020 Aug 27.

Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden.

To optimize diagnostic workup of the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, we systematically reviewed neurological and neuroradiological manifestations of SARS-CoV-2 and all other known human coronavirus species (HCoV). Which lessons can we learn? We identified relevant publications (until 26 July 2020) using systematic searches in PubMed, Web of Science, and Ovid EMBASE with predefined search strings. A total of 4571 unique publications were retrieved, out of which 378 publications were selected for in-depth analysis by two raters, including a total of 17549 (out of which were 14418 SARS-CoV-2) patients. Neurological complications and associated neuroradiological manifestations are prevalent for all HCoVs (HCoV-229E, HKU1, NL63, OC43, Middle East respiratory syndrome (MERS)-CoV, SARS-CoV-1, and SARS-CoV-2). Moreover there are similarities in symptomatology across different HCoVs, particularly between SARS-CoV-1 and SARS-CoV-2. Common neurological manifestations include fatigue, headache, and smell/taste disorders. Additionally, clinicians need to be attentive for at least five classes of neurological complications: (1) Cerebrovascular disorders including ischemic stroke and macro/micro-hemorrhages, (2) encephalopathies, (3) para-/postinfectious immune-mediated complications such as Guillain-Barré syndrome and acute disseminated encephalomyelitis, (4) (meningo-)encephalitis, potentially with concomitant seizures, and (5) neuropsychiatric complications such as psychosis and mood disorders. Our systematic review highlights the need for vigilance regarding neurological complications in patients infected by SARS-CoV-2 and other HCoVs, especially since some complications may result in chronic disability. Neuroimaging protocols should be designed to specifically screen for these complications. Therefore, we propose practical imaging guidelines to facilitate the diagnostic workup and monitoring of patients infected with HCoVs.
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http://dx.doi.org/10.1002/acn3.51166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461163PMC
October 2020

Magnetic resonance imaging in multiple sclerosis animal models: A systematic review, meta-analysis, and white paper.

Neuroimage Clin 2020 2;28:102371. Epub 2020 Aug 2.

Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, United States.

Magnetic resonance imaging (MRI) is the most important paraclinical tool for assessing drug response in multiple sclerosis (MS) clinical trials. As such, MRI has also been widely used in preclinical research to investigate drug efficacy and pathogenic aspects in MS animal models. Keeping track of all published preclinical imaging studies, and possible new therapeutic approaches, has become difficult considering the abundance of studies. Moreover, comparisons between studies are hampered by methodological differences, especially since small differences in an MRI protocol can lead to large differences in tissue contrast. We therefore provide a comprehensive qualitative overview of preclinical MRI studies in the field of neuroinflammatory and demyelinating diseases, aiming to summarize experimental setup, MRI methodology, and risk of bias. We also provide estimates of the effects of tested therapeutic interventions by a meta-analysis. Finally, to improve the standardization of preclinical experiments, we propose guidelines on technical aspects of MRI and reporting that can serve as a framework for future preclinical studies using MRI in MS animal models. By implementing these guidelines, clinical translation of findings will be facilitated, and could possibly reduce experimental animal numbers.
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http://dx.doi.org/10.1016/j.nicl.2020.102371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451445PMC
June 2021

variant associated with hemiplegic migraine and acetazolamide-responsive MRS changes.

Neurol Genet 2020 Aug 7;6(4):e474. Epub 2020 Jul 7.

Department of Neurology (M.P., E.W., P.S.), Karolinska University Hospital; Department of Clinical Neuroscience (M.P., T.G., E.W., P.S.), Karolinska Institutet; Department of Neuroradiology (T.G.), Karolinska University Hospital; Department of Molecular Medicine and Surgery (K.L.-R.), Karolinska Institutet; Department of Clinical Genetics (K.L.-R.); Medical Radiation Physics and Nuclear Medicine (S.P., L.N.), Karolinska University Hospital; and Division of Clinical Geriatrics (L.N.), Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

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http://dx.doi.org/10.1212/NXG.0000000000000474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357413PMC
August 2020

Nervous System Involvement in Coronavirus Disease 2019: Results from a Retrospective Consecutive Neuroimaging Cohort.

Radiology 2020 12 30;297(3):E324-E334. Epub 2020 Jul 30.

From the Department of Neuroradiology (S.K., A.T., A.K., C.Ö., E.K., H.A., Å.A., H.M., R.O., M. Hasselberg, M. Haghgou, M.P., J.F., J.L., A.F.D., T.G.), Department of Neurology (A.A.), and Department of Medical Radiation Physics and Nuclear Medicine (S.P.), Karolinska University Hospital, 141 86, Stockholm, Sweden; Department of Clinical Neuroscience (S.K., A.K., C.Ö., H.A., Å.A., R.O., J.A.S., M. Hasselberg., J.F., J.L., A.F.D., T.G.) and Department of Department of Clinical Science, Intervention and Technology (A.T., S.P.), Karolinska Institutet, Stockholm, Sweden.

Background Neurologic complications in coronavirus disease 2019 (COVID-19) have been described, but the understanding of their pathophysiologic causes and neuroanatomical correlates remains limited. Purpose To report on the frequency and type of neuroradiological findings in COVID-19. Materials and Methods In this retrospective study, all consecutive adult hospitalized patients with polymerase chain reaction positivity for severe acute respiratory syndrome coronavirus 2 and who underwent neuroimaging at Karolinska University Hospital between March 2 and May 24, 2020, were included. All examinations were systematically re-evaluated by 12 readers. Summary descriptive statistics were calculated. Results A total of 185 patients with COVID-19 (62 years ± 14 [standard deviation]; 138 men) underwent neuroimaging. In total, 222 brain CT, 47 brain MRI, and seven spinal MRI examinations were performed. Intra-axial susceptibility abnormalities were the most common finding (29 of 39; 74%, 95% CI: 58, 87) in patients who underwent brain MRI, often with an ovoid shape suggestive of microvascular pathology and with a predilection for the corpus callosum (23 of 39; 59%; 95% CI: 42, 74) and juxtacortical areas (14 of 39; 36%; 95% CI: 21, 53). Ischemic and macrohemorrhagic manifestations were also observed, but vascular imaging did not demonstrate overt abnormalities. Dynamic susceptibility contrast perfusion MRI in 19 patients did not reveal consistent asymmetries between hemispheres or regions. Many patients (18 of 41; 44%; 95% CI: 28, 60) had leukoencephalopathy and one patient had a cytotoxic lesion of the corpus callosum. Other findings included olfactory bulb signal abnormalities (seven of 37; 19%), prominent optic nerve subarachnoid spaces (20 of 36; 56%), and enhancement of the parenchyma (three of 20; 15%), leptomeninges (three of 20; 15%), cranial nerves (two of 20; 10%), and spinal nerves (two of four; 50%). At MRI follow-up, regression of leukoencephalopathy and progressive leptomeningeal enhancement was observed in one patient each, respectively, which is suggestive of dynamic processes. Conclusion Patients with coronavirus disease 2019 had a wide spectrum of vascular and inflammatory involvement of both the central and peripheral nervous system. © RSNA, 2020
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http://dx.doi.org/10.1148/radiol.2020202791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393954PMC
December 2020

Multiple sclerosis lesions in motor tracts from brain to cervical cord: spatial distribution and correlation with disability.

Brain 2020 07;143(7):2089-2105

Aix-Marseille Univ, CNRS, CRMBM, Marseille, France.

Despite important efforts to solve the clinico-radiological paradox, correlation between lesion load and physical disability in patients with multiple sclerosis remains modest. One hypothesis could be that lesion location in corticospinal tracts plays a key role in explaining motor impairment. In this study, we describe the distribution of lesions along the corticospinal tracts from the cortex to the cervical spinal cord in patients with various disease phenotypes and disability status. We also assess the link between lesion load and location within corticospinal tracts, and disability at baseline and 2-year follow-up. We retrospectively included 290 patients (22 clinically isolated syndrome, 198 relapsing remitting, 39 secondary progressive, 31 primary progressive multiple sclerosis) from eight sites. Lesions were segmented on both brain (T2-FLAIR or T2-weighted) and cervical (axial T2- or T2*-weighted) MRI scans. Data were processed using an automated and publicly available pipeline. Brain, brainstem and spinal cord portions of the corticospinal tracts were identified using probabilistic atlases to measure the lesion volume fraction. Lesion frequency maps were produced for each phenotype and disability scores assessed with Expanded Disability Status Scale score and pyramidal functional system score. Results show that lesions were not homogeneously distributed along the corticospinal tracts, with the highest lesion frequency in the corona radiata and between C2 and C4 vertebral levels. The lesion volume fraction in the corticospinal tracts was higher in secondary and primary progressive patients (mean = 3.6 ± 2.7% and 2.9 ± 2.4%), compared to relapsing-remitting patients (1.6 ± 2.1%, both P < 0.0001). Voxel-wise analyses confirmed that lesion frequency was higher in progressive compared to relapsing-remitting patients, with significant bilateral clusters in the spinal cord corticospinal tracts (P < 0.01). The baseline Expanded Disability Status Scale score was associated with lesion volume fraction within the brain (r = 0.31, P < 0.0001), brainstem (r = 0.45, P < 0.0001) and spinal cord (r = 0.57, P < 0.0001) corticospinal tracts. The spinal cord corticospinal tracts lesion volume fraction remained the strongest factor in the multiple linear regression model, independently from cord atrophy. Baseline spinal cord corticospinal tracts lesion volume fraction was also associated with disability progression at 2-year follow-up (P = 0.003). Our results suggest a cumulative effect of lesions within the corticospinal tracts along the brain, brainstem and spinal cord portions to explain physical disability in multiple sclerosis patients, with a predominant impact of intramedullary lesions.
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http://dx.doi.org/10.1093/brain/awaa162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364770PMC
July 2020

Enlarged perivascular spaces in multiple sclerosis on magnetic resonance imaging: a systematic review and meta-analysis.

J Neurol 2020 Nov 13;267(11):3199-3212. Epub 2020 Jun 13.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Background: Perivascular spaces can become detectable on magnetic resonance imaging (MRI) upon enlargement, referred to as enlarged perivascular spaces (EPVS) or Virchow-Robin spaces. EPVS have been linked to small vessel disease. Some studies have also indicated an association of EPVS to neuroinflammation and/or neurodegeneration. However, there is conflicting evidence with regards to their potential as a clinically relevant imaging biomarker in multiple sclerosis (MS).

Methods: To perform a systematic review and meta-analysis of EPVS as visualized by MRI in MS. Nine out of 299 original studies addressing EPVS in humans using MRI were eligible for the systematic review and meta-analysis including a total of 457 MS patients and 352 control subjects.

Results: In MS, EPVS have been associated with cognitive decline, contrast-enhancing MRI lesions, and brain atrophy. Yet, these associations were not consistent between studies. The meta-analysis revealed that MS patients have greater EPVS prevalence (odds ratio = 4.61, 95% CI = [1.84; 11.60], p = 0.001) as well as higher EPVS counts (standardized mean difference [SMD] = 0.46, 95% CI = [0.26; 0.67], p < 0.001) and larger volumes (SMD = 0.88, 95% CI = [0.19; 1.56], p = 0.01) compared to controls.

Conclusions: Available literature suggests a higher EPVS burden in MS patients compared to controls. The association of EPVS to neuroinflammatory or -degenerative pathology in MS remains inconsistent. Thus, there is currently insufficient evidence supporting EPVS as diagnostic and/or prognostic marker in MS. In order to benefit future comparisons of studies, we propose recommendations on EPVS assessment standardization in MS. PROSPERO No: CRD42019133946.
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http://dx.doi.org/10.1007/s00415-020-09971-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577911PMC
November 2020

Phenotypic variability in chorea-acanthocytosis associated with novel mutations.

Neurol Genet 2020 Jun 27;6(3):e426. Epub 2020 Apr 27.

Department of Neurology (V.N.), Uppsala University Hospital; Department of Neurology (A.S.), Västerås Hospital, Sweden; Department of Neurology (D.S.), Gävle Hospital; Department of Neurology (B.L.), University Hospital in Örebro; Department of Neurology (J.W., M.P.), Karolinska University Hospital, Stockholm, Sweden; Department of Neurology (G.M.), Ludwig-Maximilians-Universität München, Munich, Germany; Department of Clinical Neuroscience (T.G., M.P.), Karolinska Institutet, Stockholm; Department of Radiology (T.G., A.T.), Karolinska University Hospital, Stockholm; Department of Diagnostic Medical Physics (L.N.), Karolinska University Hospital Solna, Stockholm; Division of Clinical Geriatrics (L.N.), Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm; Department of Surgical Sciences (T.D.), Section for Nuclear Medicine and PET, Uppsala University Hospital; Department of Medical Radiation Physics and Nuclear Medicine (I.S.), Karolinska University Hospital, Stockholm; and Department of Immunology, Genetics and Pathology (N.D.), Science for Life Laboratory, Uppsala University, Sweden.

Objective: To perform a comprehensive characterization of a cohort of patients with chorea-acanthocytosis (ChAc) in Sweden.

Methods: Clinical assessments, targeted genetic studies, neuroimaging with MRI, [F]-fluorodeoxyglucose (FDG) PET, and dopamine transporter with I FP-CIT (DaTscan) SPECT. One patient underwent magnetic resonance spectroscopy (MRS).

Results: Four patients living in Sweden but with different ethnical backgrounds were included. Their clinical features were variable. Biallelic mutations were confirmed in all patients, including 3 novel mutations. All tested patients had either low or absent chorein levels. One patient had progressive caudate atrophy. Investigation using FDG-PET revealed severe bilateral striatal hypometabolism, and DaTscan SPECT displayed presynaptic dopaminergic deficiency in 3 patients. MRS demonstrated reduced N-acetylaspartate/creatine (Cr) ratio and mild elevation of both choline/Cr and combined glutamate and glutamine/Cr in the striatum in 1 case. One patient died during sleep, and another was treated with deep brain stimulation, which transiently attenuated feeding dystonia but not his gait disorder or chorea.

Conclusions: Larger longitudinal neuroimaging studies with different modalities, particularly MRS, are needed to determine their potential role as biomarkers for ChAc.
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http://dx.doi.org/10.1212/NXG.0000000000000426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217656PMC
June 2020

Machine Learning and Multiparametric Brain MRI to Differentiate Hereditary Diffuse Leukodystrophy with Spheroids from Multiple Sclerosis.

J Neuroimaging 2020 09 26;30(5):674-682. Epub 2020 May 26.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Background And Purpose: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) and multiple sclerosis (MS) are demyelinating and neurodegenerative disorders that can be hard to distinguish clinically and radiologically. HDLS is a rare disorder compared to MS, which has led to occurrent misdiagnosis of HDLS as MS. That is problematic since their prognosis and treatment differ. Both disorders are investigated by MRI, which could help to identify patients with high probability of having HDLS, which could guide targeted genetic testing to confirm the HDLS diagnosis.

Methods: Here, we present a machine learning method based on quantitative MRI that can achieve a robust classification of HDLS versus MS. Four HDLS and 14 age-matched MS patients underwent a quantitative brain MRI protocol (synthetic MRI) at 3 Tesla (T) (scan time <7 minutes). We also performed a repeatability analysis of the predicting features to assess their generalizability by scanning a healthy control with five scan-rescans at 3T and 1.5T.

Results: Our predicting features were measured with an average confidence interval of 1.7% (P = .01), at 3T and 2.3% (P = .01) at 1.5T. The model gave a 100% correct classification of the cross-validation data when using 5-11 predicting features. When the maximum measurement noise was inserted in the model, the true positive rate of HDLS was 97.2%, while the true positive rate of MS was 99.6%.

Conclusions: This study suggests that computer-assistance in combination with quantitative MRI may be helpful in aiding the challenging differential diagnosis of HDLS versus MS.
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http://dx.doi.org/10.1111/jon.12725DOI Listing
September 2020

Rare variants in dynein heavy chain genes in two individuals with situs inversus and developmental dyslexia: a case report.

BMC Med Genet 2020 05 1;21(1):87. Epub 2020 May 1.

Department of Medicine, Solna, Karolinska Institutet, Solnavägen 30, 171 76 Solna, Stockholm, Sweden.

Background: Developmental dyslexia (DD) is a neurodevelopmental learning disorder with high heritability. A number of candidate susceptibility genes have been identified, some of which are linked to the function of the cilium, an organelle regulating left-right asymmetry development in the embryo. Furthermore, it has been suggested that disrupted left-right asymmetry of the brain may play a role in neurodevelopmental disorders such as DD. However, it is unknown whether there is a common genetic cause to DD and laterality defects or ciliopathies.

Case Presentation: Here, we studied two individuals with co-occurring situs inversus (SI) and DD using whole genome sequencing to identify genetic variants of importance for DD and SI. Individual 1 had primary ciliary dyskinesia (PCD), a rare, autosomal recessive disorder with oto-sino-pulmonary phenotype and SI. We identified two rare nonsynonymous variants in the dynein axonemal heavy chain 5 gene (DNAH5): a previously reported variant c.7502G > C; p.(R2501P), and a novel variant c.12043 T > G; p.(Y4015D). Both variants are predicted to be damaging. Ultrastructural analysis of the cilia revealed a lack of outer dynein arms and normal inner dynein arms. MRI of the brain revealed no significant abnormalities. Individual 2 had non-syndromic SI and DD. In individual 2, one rare variant (c.9110A > G;p.(H3037R)) in the dynein axonemal heavy chain 11 gene (DNAH11), coding for another component of the outer dynein arm, was identified.

Conclusions: We identified the likely genetic cause of SI and PCD in one individual, and a possibly significant heterozygosity in the other, both involving dynein genes. Given the present evidence, it is unclear if the identified variants also predispose to DD and further studies into the association between laterality, ciliopathies and DD are needed.
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http://dx.doi.org/10.1186/s12881-020-01020-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193346PMC
May 2020

Validation of Rapid Magnetic Resonance Myelin Imaging in Multiple Sclerosis.

Ann Neurol 2020 05 2;87(5):710-724. Epub 2020 Mar 2.

Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.

Objective: Magnetic resonance imaging (MRI) is essential for multiple sclerosis diagnostics but is conventionally not specific to demyelination. Myelin imaging is often hampered by long scanning times, complex postprocessing, or lack of clinical approval. This study aimed to assess the specificity, robustness, and clinical value of Rapid Estimation of Myelin for Diagnostic Imaging, a new myelin imaging technique based on time-efficient simultaneous T /T relaxometry and proton density mapping in multiple sclerosis.

Methods: Rapid myelin imaging was applied using 3T MRI ex vivo in 3 multiple sclerosis brain samples and in vivo in a prospective cohort of 71 multiple sclerosis patients and 21 age/sex-matched healthy controls, with scan-rescan repeatability in a subcohort. Disability in patients was assessed by the Expanded Disability Status Scale and the Symbol Digit Modalities Test at baseline and 2-year follow-up.

Results: Rapid myelin imaging correlated with myelin-related stains (proteolipid protein immunostaining and Luxol fast blue) and demonstrated good precision. Multiple sclerosis patients had, relative to controls, lower normalized whole-brain and normal-appearing white matter myelin fractions, which correlated with baseline cognitive and physical disability. Longitudinally, these myelin fractions correlated with follow-up physical disability, even with correction for baseline disability.

Interpretation: Rapid Estimation of Myelin for Diagnostic Imaging provides robust myelin quantification that detects diffuse demyelination in normal-appearing tissue in multiple sclerosis, which is associated with both cognitive and clinical disability. Because the technique is fast, with automatic postprocessing and US Food and Drug Administration/CE clinical approval, it can be a clinically feasible biomarker that may be suitable to monitor myelin dynamics and evaluate treatments aiming at remyelination. ANN NEUROL 2020;87:710-724.
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http://dx.doi.org/10.1002/ana.25705DOI Listing
May 2020

MRI-Based Manual versus Automated Corpus Callosum Volumetric Measurements in Multiple Sclerosis.

J Neuroimaging 2020 03 20;30(2):198-204. Epub 2019 Nov 20.

Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.

Background And Purpose: Corpus callosum atrophy is a neurodegenerative biomarker in multiple sclerosis (MS). Manual delineations are gold standard but subjective and labor intensive. Novel automated methods are promising but require validation. We aimed to compare the robustness of manual versus automatic corpus callosum segmentations based on FreeSurfer.

Methods: Nine MS patients (6 females, age 38 ± 13 years, disease duration 7.3 ± 5.2 years) were scanned twice with repositioning using 3-dimensional T -weighted magnetic resonance imaging on three scanners (two 1.5 T and one 3.0 T), that is, six scans/patient, on the same day. Normalized corpus callosum areas were measured independently by a junior doctor and neuroradiologist. The cross-sectional and longitudinal streams of FreeSurfer were used to segment the corpus callosum volume.

Results: Manual measurements had high intrarater (junior doctor .96 and neuroradiologist .96) and interrater agreement (.94), by intraclass correlation coefficient (P < .001). The coefficient of variation was lowest for longitudinal FreeSurfer (.96% within scanners; 2.0% between scanners) compared to cross-sectional FreeSurfer (3.7%, P = .001; 3.8%, P = .058) and the neuroradiologist (2.3%, P = .005; 2.4%, P = .33). Longitudinal FreeSurfer was also more accurate than cross-sectional (Dice scores 83.9 ± 7.5% vs. 78.9 ± 8.4%, P < .01 relative to manual segmentations). The corpus callosum measures correlated with physical disability (longitudinal FreeSurfer r = -.36, P < .01; neuroradiologist r = -.32, P < .01) and cognitive disability (longitudinal FreeSurfer r = .68, P < .001; neuroradiologist r = .64, P < .001).

Conclusions: FreeSurfer's longitudinal stream provides corpus callosum measures with better repeatability than current manual methods and with similar clinical correlations. However, due to some limitations in accuracy, caution is warranted when using FreeSurfer with clinical data.
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http://dx.doi.org/10.1111/jon.12676DOI Listing
March 2020

Using optimization to provide decision support for strategic emergency medical service planning - Three case studies.

Int J Med Inform 2020 01 9;133:103975. Epub 2019 Oct 9.

Department of Industrial Economics and Technology Management, Norwegian University of Science and Technology, Trondheim, Norway.

To achieve high performing emergency medical services (EMS), planning is of vital importance. EMS planners face several challenges when managing ambulance stations and the fleet of ambulances. In this paper, three strategic cases for EMS planners are presented together with potential solutions. In the first case, the effects of closing down a local emergency room (ER) are analyzed together with how adding an ambulance station and an ambulance to the area affected by the closing of the ER can be used to mitigate the negative consequences from the closing. The second case investigates a change in the organization of EMS. Currently, many non-urgent transport assignments are performed by ambulances which make them unavailable for more urgent calls. The potential for a more effective utilization of the ambulances is explored through transferring these assignments to designated transport vehicles. The third case is more technical and challenges the common practice regarding how time dependent demand is handled. Looking at the busiest hour or the average daily demand, is compared with taking time varying demand into account. The cases and solutions are studied using a recently developed strategic ambulance station location and ambulance allocation model for the Maximum Expected Performance Location Problem with Heterogeneous Regions (MEPLP-HR). The model has been extended to also include multiple time periods. This article demonstrates an innovative use of the model and how it can be applied to find and evaluate solutions to real cases within the field of strategic planning of EMS. The model is found to be a useful decision support tool when analyzing the cases and the expected performance of potential solutions.
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http://dx.doi.org/10.1016/j.ijmedinf.2019.103975DOI Listing
January 2020

Sustained remission in multiple sclerosis after hematopoietic stem cell transplantation.

Acta Neurol Scand 2019 Nov 5;140(5):320-327. Epub 2019 Aug 5.

Department of Neuroscience, Uppsala University, Uppsala, Sweden.

Objectives: To determine whether treatment with autologous hematopoietic stem cell transplantation (HSCT) can induce sustained complete remission in patients with multiple sclerosis (MS).

Material And Methods: Case series of patients with relapsing-remitting MS (n = 10) treated at a single center between 2004 and 2007 and followed up for 10 years. The patients were treated with a BEAM/ATG conditioning regimen (n = 9) or a cyclophosphamide/ATG conditioning regimen (n = 1) followed by infusion of unmanipulated autologous hematopoietic stem cells. The primary endpoint was sustained complete remission. Sustained complete remission was defined as "no evidence of disease activity-4," sustained for a period of at least 5 years without any ongoing disease-modifying treatment. Furthermore, MS was considered as "resolved" if intrathecal IgG production and cerebrospinal fluid neurofilament light levels were normalized as well.

Results: Five out of 10 patients were in sustained complete remission at the end of the study. In three of them, MS was resolved.

Conclusions: Our data demonstrate that sustained complete remission after autologous HSCT for MS is possible.
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http://dx.doi.org/10.1111/ane.13147DOI Listing
November 2019

Rituximab treatment for multiple sclerosis.

Mult Scler 2020 02 25;26(2):137-152. Epub 2019 Jun 25.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden Center for Neurology, Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden.

Rituximab, a chimeric anti-CD20-antibody, attracts increasing attention as a treatment option for multiple sclerosis (MS). Apart from smaller controlled trials, an increasing number of studies in real-world populations indicate high efficacy based on clinical and neuroradiological outcomes for rituximab in relapsing-remitting MS patients. Additional evidence also demonstrates efficacy of rituximab with treatment of progressive MS phenotypes. In this topical review, we summarize and discuss current evidence on mechanisms of action, efficacy, safety, tolerance and other clinical aspects of rituximab in the treatment of MS. Finally, we will highlight current knowledge gaps and the need for comparative studies with other disease-modifying therapies in MS.
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http://dx.doi.org/10.1177/1352458519858604DOI Listing
February 2020

Mapping of apparent susceptibility yields promising diagnostic separation of progressive supranuclear palsy from other causes of parkinsonism.

Sci Rep 2019 04 15;9(1):6079. Epub 2019 Apr 15.

Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, 212 24, Malmö, Sweden.

There is a need for methods that distinguish Parkinson's disease (PD) from progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), which have similar characteristics in the early stages of the disease. In this prospective study, we evaluate mapping of apparent susceptibility based on susceptibility weighted imaging (SWI) for differential diagnosis. We included 134 patients with PD, 11 with PSP, 10 with MSA and 44 healthy controls. SWI data were processed into maps of apparent susceptibility. In PSP, apparent susceptibility was increased in the red nucleus compared to all other groups, and in globus pallidus, putamen, substantia nigra and the dentate nucleus compared to PD and controls. In MSA, putaminal susceptibility was increased compared to PD and controls. Including all studied regions and using discriminant analysis between PSP and PD, 100% sensitivity and 97% specificity was achieved, and 91% sensitivity and 90% specificity in separating PSP from MSA. Correlations between putaminal susceptibility and disease severity in PD could warrant further research into using susceptibility mapping for monitoring disease progression and in clinical trials. Our study indicates that susceptibility in deep nuclei could play a role in the diagnosis of atypical parkinsonism, especially in PSP.
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http://dx.doi.org/10.1038/s41598-019-42565-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465307PMC
April 2019

Longitudinal Characterization of Cortical Lesion Development and Evolution in Multiple Sclerosis with 7.0-T MRI.

Radiology 2019 06 9;291(3):740-749. Epub 2019 Apr 9.

From the A. A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Bldg 149, 13th St, Charleston, MA 02129 (C.A.T., T.E.G., E.H., R.A.O., C.L., C.M.); Harvard Medical School, Boston, MA (C.A.T., T.E.G., E.H., C.L., C.M.); Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (T.E.G.); Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy (M.P.S.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (J.A.S.); and Department of Neurosciences, University of California San Diego, San Diego, CA (R.P.K.).

Background Cortical lesions develop early in multiple sclerosis (MS) and play a major role in disease progression. MRI at 7.0 T shows high sensitivity for detection of cortical lesions as well as better spatial resolution and signal-to-noise ratio compared with lower field strengths. Purpose To longitudinally characterize the development and evolution of cortical lesions in multiple sclerosis across the cortical width, sulci, and gyri; their relation with white matter lesion accrual; and the contribution of 7.0-T cortical and white matter lesion load and cortical thickness to neurologic disability. Materials and Methods Twenty participants with relapsing-remitting MS and 13 with secondary progressive MS, along with 10 age-matched healthy controls, were prospectively recruited from 2010 to 2016 to acquire, in two imaging sessions (mean interval, 1.5 years), 7.0-T MRI T2*-weighted gradient-echo images (0.33 × 0.33 × 1.0 mm) for cortical and white matter lesion segmentation and 3.0-T T1-weighted images for cortical surface reconstruction and cortical thickness estimation. Cortical lesions were sampled through the cortex to quantify cortical lesion distribution. The Expanded Disability Status Scale (EDSS) was used to assess neurologic disability. Nonparametric statistics assessed differences between and within groups in MRI metrics of cortical and white matter lesion burden; regression analysis explored associations of disability with MRI metrics. Results Twenty-five of 31 (81%) participants developed new cortical lesions per year (intracortical, 1.3 ± 1.7 vs leukocortical, 0.7 ± 1.9; = .04), surpassing white matter lesion accrual (cortical, 2.0 ± 2.8 vs white matter, 0.7 ± 0.6; = .01). In contrast to white matter lesions, cortical lesion accrual was greater in participants with secondary progressive MS than with relapsing-remitting MS (3.6 lesions/year ± 4.2 vs 1.1 lesions/year ± 0.9, respectively; = .03) and preferentially localized in sulci. Total cortical lesion volume independently predicted baseline EDSS (β = 1.5, < .001) and EDSS changes at follow-up (β = 0.5, = .003). Conclusion Cortical lesions predominantly develop intracortically and within sulci, suggesting an inflammatory cerebrospinal fluid-mediated lesion pathogenesis. Cortical lesion accumulation was prominent at 7.0 T and independently predicted neurologic disability progression. © RSNA, 2019 See also the editorial by Filippi and Rocca in this issue.
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http://dx.doi.org/10.1148/radiol.2019181719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543899PMC
June 2019

Evidence of early microstructural white matter abnormalities in multiple sclerosis from multi-shell diffusion MRI.

Neuroimage Clin 2019 30;22:101699. Epub 2019 Jan 30.

Athinoula A. Martinos Center for Biomedical Imaging and Harvard Medical School, Boston, MA, USA.; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy. Electronic address:

Irreversible white matter (WM) damage, including severe demyelination and axonal loss, is a main determinant of long-term disability in multiple sclerosis (MS). Non-invasive detection of changes in microstructural WM integrity in the disease is challenging since commonly used imaging metrics lack the necessary sensitivity, especially in the early phase of the disease. This study aims at assessing microstructural WM abnormalities in early-stage MS by using ultra-high gradient strength multi-shell diffusion MRI and the restricted signal fraction (FR) from the Composite Hindered and Restricted Model of Diffusion (CHARMED), a metric sensitive to the volume fraction of axons. In 22 early MS subjects (disease duration ≤5 years) and 15 age-matched healthy controls, restricted fraction estimates were obtained through the CHARMED model along with conventional Diffusion Tensor Imaging (DTI) metrics. All imaging parameters were compared cross-sectionally between the MS subjects and controls both in WM lesions and normal-appearing white matter (NAWM). We found a significant reduction in FR focally in WM lesions and widespread in the NAWM in MS patients relative to controls (corrected p < .05). Signal fraction changes in NAWM were not driven by perilesional tissue, nor were they influenced by proximity to the ventricles, challenging the hypothesis of an outside-in pathological process driven by CSF-mediated immune cytotoxic factors. No significant differences were found in conventional DTI parameters. In a cross-validated classification task, FR showed the largest effect size and outperformed all other diffusion imaging metrics in discerning lesions from contralateral NAWM. Taken together, our data provide evidence for the presence of widespread microstructural changes in the NAWM in early MS stages that are, at least in part, unrelated to focal demyelinating lesions. Interestingly, these pathological changes were not yet detectable by conventional diffusion imaging at this early disease stage, highlighting the sensitivity and value of multi-shell diffusion imaging for better characterizing axonal microstructure in MS.
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http://dx.doi.org/10.1016/j.nicl.2019.101699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370560PMC
January 2020

Spatial distribution of multiple sclerosis lesions in the cervical spinal cord.

Brain 2019 03;142(3):633-646

Queen Square MS Centre, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, London,UK.

Spinal cord lesions detected on MRI hold important diagnostic and prognostic value for multiple sclerosis. Previous attempts to correlate lesion burden with clinical status have had limited success, however, suggesting that lesion location may be a contributor. Our aim was to explore the spatial distribution of multiple sclerosis lesions in the cervical spinal cord, with respect to clinical status. We included 642 suspected or confirmed multiple sclerosis patients (31 clinically isolated syndrome, and 416 relapsing-remitting, 84 secondary progressive, and 73 primary progressive multiple sclerosis) from 13 clinical sites. Cervical spine lesions were manually delineated on T2- and T2*-weighted axial and sagittal MRI scans acquired at 3 or 7 T. With an automatic publicly-available analysis pipeline we produced voxelwise lesion frequency maps to identify predilection sites in various patient groups characterized by clinical subtype, Expanded Disability Status Scale score and disease duration. We also measured absolute and normalized lesion volumes in several regions of interest using an atlas-based approach, and evaluated differences within and between groups. The lateral funiculi were more frequently affected by lesions in progressive subtypes than in relapsing in voxelwise analysis (P < 0.001), which was further confirmed by absolute and normalized lesion volumes (P < 0.01). The central cord area was more often affected by lesions in primary progressive than relapse-remitting patients (P < 0.001). Between white and grey matter, the absolute lesion volume in the white matter was greater than in the grey matter in all phenotypes (P < 0.001); however when normalizing by each region, normalized lesion volumes were comparable between white and grey matter in primary progressive patients. Lesions appearing in the lateral funiculi and central cord area were significantly correlated with Expanded Disability Status Scale score (P < 0.001). High lesion frequencies were observed in patients with a more aggressive disease course, rather than long disease duration. Lesions located in the lateral funiculi and central cord area of the cervical spine may influence clinical status in multiple sclerosis. This work shows the added value of cervical spine lesions, and provides an avenue for evaluating the distribution of spinal cord lesions in various patient groups.
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http://dx.doi.org/10.1093/brain/awy352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391605PMC
March 2019

Evidence for Progressive Microstructural Damage in Early Multiple Sclerosis by Multi-Shell Diffusion Magnetic Resonance Imaging.

Neuroscience 2019 04 29;403:27-34. Epub 2019 Jan 29.

Athinoula A. Martinos Center for Biomedical Imaging and Harvard Medical School, Boston, MA, USA.

In multiple sclerosis (MS), it would be of clinical value to be able to track the progression of axonal pathology, especially before the manifestation of clinical disability. However, non-invasive evaluation of short-term longitudinal progression of white matter integrity is challenging. This study aims at assessing longitudinal changes in the restricted (i.e. intracellular) diffusion signal fraction (FR) in early-stage MS by using ultra-high gradient strength multi-shell diffusion magnetic resonance imaging. In 11 early MS subjects (disease duration ≤5 years), FR was obtained at two timepoints (one year apart) through the Composite Hindered and Restricted Model of Diffusion, along with conventional Diffusion Tensor Imaging metrics. At follow-up, no statistically significant change was detected in clinical variables, while all imaging metrics showed statistically significant longitudinal changes (p < 0.01, corrected for multiple comparisons) in widespread regions in normal-appearing white matter (NAWM). The most extensive longitudinal changes were observed in FR, including areas known to include a large fraction of crossing fibers. Furthermore, FR was also the only metric showing significant longitudinal changes in lesions that were present at both time points (p = 0.007), with no significant differences found for conventional diffusion metrics. Finally, FR was the only diffusion metric (as compared to Diffusion Tensor Imaging) that revealed pre-lesional changes already present at baseline. Taken together, our data provide evidence for progressive microstructural damage in the NAWM of early MS cases detectable already at 1-year follow-up. Our study highlights the value of multi-shell diffusion imaging for sensitive tracking of disease evolution in MS before any clinical changes are observed. This article is part of a Special Issue entitled: SI: MRI and Neuroinflammation.
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http://dx.doi.org/10.1016/j.neuroscience.2019.01.022DOI Listing
April 2019

Automatic segmentation of the spinal cord and intramedullary multiple sclerosis lesions with convolutional neural networks.

Neuroimage 2019 01 6;184:901-915. Epub 2018 Oct 6.

Brigham and Women's Hospital, Harvard Medical School, Boston, USA.

The spinal cord is frequently affected by atrophy and/or lesions in multiple sclerosis (MS) patients. Segmentation of the spinal cord and lesions from MRI data provides measures of damage, which are key criteria for the diagnosis, prognosis, and longitudinal monitoring in MS. Automating this operation eliminates inter-rater variability and increases the efficiency of large-throughput analysis pipelines. Robust and reliable segmentation across multi-site spinal cord data is challenging because of the large variability related to acquisition parameters and image artifacts. In particular, a precise delineation of lesions is hindered by a broad heterogeneity of lesion contrast, size, location, and shape. The goal of this study was to develop a fully-automatic framework - robust to variability in both image parameters and clinical condition - for segmentation of the spinal cord and intramedullary MS lesions from conventional MRI data of MS and non-MS cases. Scans of 1042 subjects (459 healthy controls, 471 MS patients, and 112 with other spinal pathologies) were included in this multi-site study (n = 30). Data spanned three contrasts (T-, T-, and T-weighted) for a total of 1943 vol and featured large heterogeneity in terms of resolution, orientation, coverage, and clinical conditions. The proposed cord and lesion automatic segmentation approach is based on a sequence of two Convolutional Neural Networks (CNNs). To deal with the very small proportion of spinal cord and/or lesion voxels compared to the rest of the volume, a first CNN with 2D dilated convolutions detects the spinal cord centerline, followed by a second CNN with 3D convolutions that segments the spinal cord and/or lesions. CNNs were trained independently with the Dice loss. When compared against manual segmentation, our CNN-based approach showed a median Dice of 95% vs. 88% for PropSeg (p ≤ 0.05), a state-of-the-art spinal cord segmentation method. Regarding lesion segmentation on MS data, our framework provided a Dice of 60%, a relative volume difference of -15%, and a lesion-wise detection sensitivity and precision of 83% and 77%, respectively. In this study, we introduce a robust method to segment the spinal cord and intramedullary MS lesions on a variety of MRI contrasts. The proposed framework is open-source and readily available in the Spinal Cord Toolbox.
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http://dx.doi.org/10.1016/j.neuroimage.2018.09.081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759925PMC
January 2019

Repeatability and reproducibility of FreeSurfer, FSL-SIENAX and SPM brain volumetric measurements and the effect of lesion filling in multiple sclerosis.

Eur Radiol 2019 Mar 21;29(3):1355-1364. Epub 2018 Sep 21.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Objectives: To compare the cross-sectional robustness of commonly used volumetric software and effects of lesion filling in multiple sclerosis (MS).

Methods: Nine MS patients (six females; age 38±13 years, disease duration 7.3±5.2 years) were scanned twice with repositioning on three MRI scanners (Siemens Aera 1.5T, Avanto 1.5T, Trio 3.0T) the same day. Volumetric T-weighted images were processed with FreeSurfer, FSL-SIENAX, SPM and SPM-CAT before and after 3D FLAIR lesion filling with LST. The whole-brain, grey matter (GM) and white matter (WM) volumes were calculated with and without normalisation to the intracranial volume or FSL-SIENAX scaling factor. Robustness was assessed using the coefficient of variation (CoV).

Results: Variability in volumetrics was lower within than between scanners (CoV 0.17-0.96% vs. 0.65-5.0%, p<0.001). All software provided similarly robust segmentations of the brain volume on the same scanner (CoV 0.17-0.28%, p=0.076). Normalisation improved inter-scanner reproducibility in FreeSurfer and SPM-based methods, but the FSL-SIENAX scaling factor did not improve robustness. Generally, SPM-based methods produced the most consistent volumetrics, while FreeSurfer was more robust for WM volumes on different scanners. FreeSurfer had more robust normalised brain and GM volumes on different scanners than FSL-SIENAX (p=0.004). MS lesion filling changed the output of FSL-SIENAX, SPM and SPM-CAT but not FreeSurfer.

Conclusions: Consistent use of the same scanner is essential and normalisation to the intracranial volume is recommended for multiple scanners. Based on robustness, SPM-based methods are particularly suitable for cross-sectional volumetry. FreeSurfer poses a suitable alternative with WM segmentations less sensitive to MS lesions.

Key Points: • The same scanner should be used for brain volumetry. If different scanners are used, the intracranial volume normalisation improves the FreeSurfer and SPM robustness (but not the FSL scaling factor). • FreeSurfer, FSL and SPM all provide robust measures of the whole brain volume on the same MRI scanner. SPM-based methods overall provide the most robust segmentations (except white matter segmentations on different scanners where FreeSurfer is more robust). • MS lesion filling with Lesion Segmentation Toolbox changes the output of FSL-SIENAX and SPM. FreeSurfer output is not affected by MS lesion filling since it already takes white matter hypointensities into account and is therefore particularly suitable for MS brain volumetry.
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http://dx.doi.org/10.1007/s00330-018-5710-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510869PMC
March 2019
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