Publications by authors named "Michael G Dwyer"

157 Publications

Quantifying disease pathology and predicting disease progression in multiple sclerosis with only clinical routine T2-FLAIR MRI.

Neuroimage Clin 2021 May 24;31:102705. Epub 2021 May 24.

Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA; IRCCS, Fondazione Don Carlo Gnocchi ONLUS, Milan, Italy. Electronic address:

Background: Although quantitative measures from research-quality MRI provide a means to study multiple sclerosis (MS) pathology in vivo, these metrics are often unavailable in legacy clinical datasets.

Objective: To determine how well an automatically-generated quantitative snapshot of brain pathology, measured only on clinical routine T2-FLAIR MRI, can substitute for more conventional measures on research MRI in terms of capturing multi-factorial disease pathology and providing similar clinical relevance.

Methods: MRI with both research-quality sequences and conventional clinical T2-FLAIR was acquired for 172 MS patients at baseline, and neurologic disability was assessed at baseline and five-years later. Five measures (thalamus volume, lateral ventricle volume, medulla oblongata volume, lesion volume, and network efficiency) for quantifying disparate aspects of neuropathology from low-resolution T2-FLAIR were applied to predict standard research-quality MRI measures. They were compared in regard to association with future neurologic disability and disease progression over five years.

Results: The combination of the five T2-FLAIR measures explained most of the variance in standard research-quality MRI. T2-FLAIR measures were associated with neurologic disability and cognitive function five-years later (R = 0.279, p < 0.001; R = 0.382, p < 0.001), similar to standard research-quality MRI (R = 0.279, p < 0.001; R = 0.366, p < 0.001). They also similarly predicted disability progression over five years (%-correctly-classified = 69.8, p = 0.034), compared to standard research-quality MRI (%-correctly-classified = 72.4%, p = 0.022) in relapsing-remitting MS.

Conclusion: A set of five T2-FLAIR-only measures can substitute for standard research-quality MRI, especially in relapsing-remitting MS. When only clinical T2-FLAIR is available, it can be used to obtain substantially more quantitative information about brain pathology and disability than is currently standard practice.
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http://dx.doi.org/10.1016/j.nicl.2021.102705DOI Listing
May 2021

Diffusion tensor imaging reveals greater microstructure damage in lesional tissue that shrinks into cerebrospinal fluid in multiple sclerosis.

J Neuroimaging 2021 Jun 3. Epub 2021 Jun 3.

Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, New York, USA.

Background And Purpose: Atrophied T2 lesion volume (LV), reflecting the complete transformation of lesions into cerebrospinal fluid (CSF), has been associated with disease progression in multiple sclerosis (MS). The underlying damage leading to lesion destruction remains poorly understood. The objective of this study was to use diffusion tensor imaging (DTI) to investigate the extent of microstructural tissue damage at baseline in lesions that subsequently transform into CSF.

Methods: Ninety-nine MS patients (67 relapsing-remitting MS [RRMS] and 32 progressive PMS [PMS]) were imaged at baseline and after an average of 5.3 ± 0.6 years of follow-up. Assessments included T2 LV and DTI at baseline and atrophied T2 LV over follow-up. Lesioned areas that became atrophied T2 LV were compared to those that did not. Baseline lesional DTI metrics were compared between RRMS versus PMS patients and between patients with disability progression (DP, n = 35) versus non-DP (n = 64), using ANCOVA models.

Results: Lesion tissue that developed into atrophied T2 LV had significantly different baseline DTI parameters compared to nonatrophied T2-LV tissue (p<0.001), with the largest effect for free-water (d = 2.739). Baseline tissue characteristics of future atrophied T2 LV were not significantly different between groups. However, DP patients developed greater atrophied T2 LV (377 vs. 83 mm , p < 0.001).

Conclusions: Extensive microstructural damage characterizes lesions replaced by CSF, independently of disease phenotype or future DP. Greater atrophied T2 LV predicts DP.
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http://dx.doi.org/10.1111/jon.12891DOI Listing
June 2021

A randomized evaluation of the TriGuard™ HDH cerebral embolic protection device to Reduce the Impact of Cerebral Embolic LEsions after TransCatheter Aortic Valve ImplanTation: the REFLECT I trial.

Eur Heart J 2021 May 17. Epub 2021 May 17.

College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Aims : The REFLECT I trial investigated the safety and effectiveness of the TriGuard™ HDH (TG) cerebral embolic deflection device in patients undergoing transcatheter aortic valve replacement (TAVR).

Methods And Results : This prospective, multicentre, single-blind, 2:1 randomized (TG vs. no TG) study aimed to enrol up to 375 patients, including up to 90 roll-in patients. The primary combined safety endpoint (VARC-2 defined early safety) at 30 days was compared with a performance goal. The primary efficacy endpoint was a hierarchical composite of (i) all-cause mortality or any stroke at 30 days, (ii) National Institutes of Health Stroke Scale (NIHSS) worsening at 2-5 days or Montreal Cognitive Assessment worsening at 30 days, and (iii) total volume of cerebral ischaemic lesions detected by diffusion-weighted magnetic resonance imaging at 2-5 days. Cumulative scores were compared between treatment groups using the Finkelstein-Schoenfeld method. A total of 258 of the planned, 375 patients (68.8%) were enrolled (54 roll-in and 204 randomized). The primary safety outcome was met compared with the performance goal (21.8% vs. 35%, P < 0.0001). The primary hierarchical efficacy endpoint was not met (mean efficacy score, higher is better: -5.3 ± 99.8 TG vs. 11.8 ± 96.4 control, P = 0.31). Covert central nervous system injury was numerically lower with TG both in-hospital (46.1% vs. 60.3%, P = 0.0698) and at 5 days (61.7 vs. 76.2%, P = 0.054) compared with controls.

Conclusion : REFLECT I demonstrated that TG cerebral protection during TAVR was safe in comparison with historical TAVR data but did not meet the predefined effectiveness endpoint compared with unprotected TAVR controls.
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http://dx.doi.org/10.1093/eurheartj/ehab213DOI Listing
May 2021

Nucleus basalis of Meynert damage and cognition in patients with multiple sclerosis.

J Neurol 2021 May 16. Epub 2021 May 16.

Department of Neurology, Buffalo Neuroimaging Analysis Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, 100 High St., Buffalo, NY, 14203, USA.

Background: The nucleus basalis of Meynert (NBM), representing the major source of cerebral cholinergic innervations, is vulnerable to neurodegeneration in Alzheimer's and Parkinson's disease.

Objective: To determine associations between NBM properties and cognitive outcomes in patients with multiple sclerosis (PwMS).

Methods: 84 PwMS and 19 controls underwent 3T MRI, the Paced Auditory Serial Addition Test (PASAT) and subtests of the Brief International Cognitive Assessment for MS (BICAMS). NBM volume, fractional anisotropy, mean diffusivity (MD), axial diffusivity and radial diffusivity (D) were calculated. Analyses assessed relationships between cognition and NBM measures. Linear regressions evaluated the prognostic value of baseline measures in predicting cognitive change over 3 years of follow-up (n = 67).

Results: Cognitive tests correlated with NBM diffusivity in PwMS (range r = - 0.29 to r = - 0.40, p < 0.05). After accounting for NBM volume, NBM MD and D explained additional variance (adjusted R range 0.08-0.20, p < 0.05). Correlations between NBM imaging metrics and cognitive tests remained significant when including imaging parameters of other cognitive key brain regions in the models. After controlling for age, education, and baseline cognitive test score, NBM measures predicted change in cognition over follow-up in 5 of 10 and 2 of 10 assessments in the relapsing-remitting sample (n = 43) (adjusted R range from 0.23 to 0.38, p < 0.05) and secondary progressive sample (adjusted R of 0.280 and 0.183), respectively.

Conclusions: NBM damage is linked to cognitive impairment in PwMS.
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http://dx.doi.org/10.1007/s00415-021-10594-7DOI Listing
May 2021

Staging and stratifying cognitive dysfunction in multiple sclerosis.

Mult Scler 2021 May 6:13524585211011390. Epub 2021 May 6.

Jacobs Multiple Sclerosis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA.

Background: The sequence in which cognitive domains become impaired in multiple sclerosis (MS) is yet to be formally demonstrated. It is unclear whether processing speed dysfunction temporally precedes other cognitive impairments, such as memory and executive function.

Objective: Determine the order in which different cognitive domains become impaired in MS and validate these findings using clinical and vocational outcomes.

Methods: In a longitudinal sample of 1073 MS patients and 306 healthy controls, we measured performance on multiple, consensus-standard, neurocognitive tests. We used an event-based staging approach to model the sequence in which cognitive domains become impaired. Linear and logistic mixed-effects models were used to explore associations between stages of impairment, neurological disability, and employment status.

Results: Our model suggested that the order of impairments was as follows: processing speed, visual learning, verbal learning, working memory/attention, and executive function. Stage of cognitive impairment predicted greater neurological disability, β = 0.16, = 0.02, < 0.001, and probability of unemployment, β = 1.14, = 0.001, < 0.001.

Conclusion: This is the first study to introduce a cognitive staging and stratification system for MS. Findings underscore the importance of using the Symbol Digit Modalities Test in routine screening for cognitive impairment and memory testing to assess patients later in disease evolution.
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http://dx.doi.org/10.1177/13524585211011390DOI Listing
May 2021

Deep grey matter injury in multiple sclerosis: A NAIMS consensus statement.

Brain 2021 Mar 23. Epub 2021 Mar 23.

Department of Neurology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.

Although multiple sclerosis (MS) has traditionally been considered a white matter disease, extensive research documents the presence and importance of gray matter injury including cortical and deep regions. The deep gray matter (DGM) exhibits a broad range of pathology and is uniquely suited to study the mechanisms and clinical relevance of tissue injury in MS using magnetic resonance techniques. DGM injury has been associated with clinical and cognitive disability. Recently, MRI characterization of DGM properties, such as thalamic volume, have been tested as potential clinical trial endpoints associated with neurodegenerative aspects of MS. Given this emerging area of interest and its potential clinical trial relevance, the North American Imaging in MS (NAIMS) Cooperative held a workshop and reached consensus on imaging topics related to the DGM. Herein, we review current knowledge regarding DGM injury in MS from an imaging perspective, including insights from histopathology, image acquisition and post-processing for DGM. We discuss the clinical relevance of DGM injury and specific regions of interest within the DGM. We highlight unanswered questions and propose future directions, with the aim of focusing research priorities towards better methods, analysis, and interpretation of results.
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http://dx.doi.org/10.1093/brain/awab132DOI Listing
March 2021

Evolution of Brain Volume Loss Rates in Early Stages of Multiple Sclerosis.

Neurol Neuroimmunol Neuroinflamm 2021 05 16;8(3). Epub 2021 Mar 16.

From the CORe (T.U., C.M., T.K.), Department of Medicine, the University of Melbourne, VIC, Australia; Department of Neurology and Center of Clinical Neuroscience (T.U., E.K.H., D.H.), Charles University in Prague, 1st Faculty of Medicine and General University Hospital; Department of Radiology (J.K., M.V.), Charles University in Prague, First Faculty of Medicine and General University Hospital in Prague, Czech Republic; Buffalo Neuroimaging Analysis Center (N.B., M.G.D., R.Z.), Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York; IRCCS (N.B.), Fondazione Don Carlo Gnocchi, Milan, Italy; Center for Biomedical Imaging at Clinical Translational Science Institute (R.Z.), University at Buffalo, State University of New York; and Melbourne MS Centre (T.K.), Department of Neurology, the Royal Melbourne Hospital, VIC, Australia.

Objective: To describe the dynamics of brain volume loss (BVL) at different stages of relapsing-remitting multiple sclerosis (RRMS), to describe the association between BVL and clinical measures, and to investigate an effect of treatment escalation on the rate of BVL.

Methods: Together, 1903 patients predominantly with RRMS from the Avonex-Steroids-Azathioprine cohort (N = 166), the study of early IFN-β1a treatment cohort (N = 180), and the quantitative MRI cohort (N = 1,557) with ≥2 MRI scans and ≥1-year of follow-up were included. Brain MRI scans (N = 7,203) were performed using a single 1.5-T machine. Relationships between age or disease duration and global and tissue-specific BVL rates were analyzed using mixed models.

Results: Age was not associated with the rate of BVL (β = -0.003; Cohen f2 = 0.0005; adjusted = 0.39). Although disease duration was associated with the rate of BVL, its effect on the BVL rate was minimal (β = -0.012; Cohen f2 = 0.004; adjusted = 4 × 10). Analysis of association between tissue-specific brain volume changes and age (β = -0.019 to -0.011; adjusted = 0.028-1.00) or disease duration (β = -0.028 to -0.008; adjusted = 0.16-0.96) confirmed these results. Although increase in the relapse rate (β = 0.10; adjusted = 9 × 10), Expanded Disability Status Scale (EDSS; β = 0.17; adjusted = 8 × 10), and EDSS change (β = 0.15; adjusted = 2 × 10) were associated with accelerated rate of BVL, their effect on the rate of BVL was minimal (all Cohen f2 ≤ 0.007). In 94 patients who escalated therapy, the rate of BVL decreased following treatment escalation by 0.29% (β = -0.29; Cohen f2 = 0.133; = 5.5 × 10).

Conclusions: The rate of BVL is relatively stable throughout the course of RRMS. The accelerated BVL is weakly associated with concurrent higher disease activity, and timely escalation to high-efficacy immunotherapy helps decrease the rate of BVL.
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http://dx.doi.org/10.1212/NXI.0000000000000979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984675PMC
May 2021

Measuring Aqueduct of Sylvius Cerebrospinal Fluid Flow in Multiple Sclerosis Using Different Software.

Diagnostics (Basel) 2021 Feb 17;11(2). Epub 2021 Feb 17.

Buffalo Neuroimaging Analysis Center (BNAC), Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA.

Aqueduct of Sylvius (AoS) cerebrospinal fluid flow can be quantified using phase-contrast (PC) Magnetic Resonance Imaging. The software used for AoS segmentation might affect the PC-derived measures. We analyzed AoS PC data of 30 people with multiple sclerosis and 19 normal controls using three software packages, and estimated cross-sectional area (CSA), average and highest AoS velocity (Vmean and Vmax), flow rate and volume. Our aims were to assess the repeatability and reproducibility of each PC-derived measure obtained with the various software packages, including in terms of group differentiation. All the variables had good repeatability, except the average Vmean, flow rate and volume obtained with one software package. Substantial to perfect agreement was seen when evaluating the overlap between the AoS segmentations obtained with different software packages. No variable was significantly different between software packages, with the exception of Vmean diastolic peak and CSA. Vmax diastolic peak differentiated groups, regardless of the software package. In conclusion, a clinical study should preliminarily evaluate the repeatability in order to interpret its findings. Vmax seemed to be a repeatable and reproducible measure, since the pixel with its value is usually located in the center of the AoS, and is thus unlikely be affected by ROI size.
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http://dx.doi.org/10.3390/diagnostics11020325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923004PMC
February 2021

Randomized Evaluation of TriGuard 3 Cerebral Embolic Protection After Transcatheter Aortic Valve Replacement: REFLECT II.

JACC Cardiovasc Interv 2021 Mar 1;14(5):515-527. Epub 2021 Mar 1.

Division of Cardiology, Yale School of Medicine, New Haven, Connecticut, USA; Barts Heart Centre, London and Queen Mary University of London, London, United Kingdom. Electronic address:

Objectives: The REFLECT II (Randomized Evaluation of TriGuard 3 Cerebral Embolic Protection After Transcatheter Aortic Valve Implantation) trial was designed to investigate the safety and efficacy of the TriGUARD 3 (TG3) cerebral embolic protection in patients undergoing transcatheter aortic valve replacement.

Background: Cerebral embolization occurs frequently following transcatheter aortic valve replacement and procedure-related ischemic stroke occurs in 2% to 6% of patients at 30 days. Whether cerebral protection with TriGuard 3 is safe and effective in reducing procedure-related cerebral injury is not known.

Methods: This prospective, multicenter, single-blind, 2:1 randomized (TG3 vs. no TG3) study was designed to enroll up to 345 patients. The primary 30-day safety endpoint (Valve Academic Research Consortium-2 defined) was compared with a performance goal (PG). The primary hierarchical composite efficacy endpoint (including death or stroke at 30 days, National Institutes of Health Stroke Scale score worsening in hospital, and cerebral ischemic lesions on diffusion-weighted magnetic resonance imaging at 2 to 5 days) was compared using the Finkelstein-Schoenfeld method.

Results: REFLECT II enrolled 220 of the planned 345 patients (63.8%), including 41 roll-in and 179 randomized patients (121 TG3 and 58 control subjects) at 18 US sites. The sponsor closed the study early after the U.S. Food and Drug Administration recommended enrollment suspension for unblinded safety data review. The trial met its primary safety endpoint compared with the PG (15.9% vs. 34.4% (p < 0.0001). The primary hierarchal efficacy endpoint at 30 days was not met (mean scores [higher is better]: -8.58 TG3 vs. 8.08 control; p = 0.857). A post hoc diffusion-weighted magnetic resonance imaging analysis of per-patient total lesion volume above incremental thresholds showed numeric reductions in total lesion volume >500 mm (-9.7%) and >1,000 mm (-44.5%) in the TG3 group, which were more pronounced among patients with full TG3 coverage: -51.1% (>500 mm) and -82.9% (>1,000 mm).

Conclusions: The REFLECT II trial demonstrated that the TG3 was safe compared with a historical PG but did not meet its pre-specified primary superiority efficacy endpoint.
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http://dx.doi.org/10.1016/j.jcin.2020.11.011DOI Listing
March 2021

Visual deficits and cognitive assessment of multiple sclerosis: confounder, correlate, or both?

J Neurol 2021 Feb 15. Epub 2021 Feb 15.

Department of Neurology, Buffalo Neuroimaging Analysis Center (BNAC), Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, 100 High Street, Buffalo, NY, 14203, USA.

Background: The relationship between visual impairment and cognitive performance in multiple sclerosis (MS) remains poorly understood.

Objective: To determine associations between visual acuity and optical coherence tomography (OCT) measures with cognitive performance of MS patients and healthy controls (HCs).

Methods: 141 MS patients (with and without MS optic neuritis; MSON) and 50 HCs underwent neuropsychological, visual, and OCT testing. California Verbal Learning Test (CVLT-II), Brief Visuospatial Memory Test (BVMT-R), and Symbol Digit Modalities Test (SDMT) were used. Patients with test performance below - 1.5 standard deviations of the mean HCs scores were labeled as cognitive impairment. Visual ability was assessed with 100%, 2.5%, and 1.25% low-contrast letter acuity (LCLA) charts. OCT-derived peripapillary retinal nerve fiber layer (pRNFL) thickness, macular volume (MV), macular ganglion cell inner plexiform (mGCIP) thickness (as a sum of GC and IP layers), and macular inner nuclear layer (mINL) were computed.

Results: 100% and 2.5% LCLA associated with SDMT in MS and HCs (p < 0.001; and p < 0.012, respectively). In MSON patients, visually demanding tests were explained by pRNFL and macular volume for SDMT (β = 0.172, p = 0.039 and β = 0.27, p = 0.001) and MV for BVMT-R (β = 0.21, p = 0.012). In non-MSON, only mINL was predictor of CVLT-II. pRNFL and MV predicted cognitive impairment with an accuracy of 72.2% (Negelkerke R = 0.234). These findings were driven by associations within the progressive MS subgroup. HC's SDMT performance was explained by mGCIP (β = 0.316, p = 0.001).

Conclusions: Both LCLA and OCT-based measures (pRNFL and macular volume) were associated with MS cognitive performance. OCT-based measures were also significant predictors of cognitive status in MS patients. mGCIP associated with cognitive performance in HCs.
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http://dx.doi.org/10.1007/s00415-021-10437-5DOI Listing
February 2021

Clinical feasibility of longitudinal lateral ventricular volume measurements on T2-FLAIR across MRI scanner changes.

Neuroimage Clin 2021 4;29:102554. Epub 2021 Jan 4.

Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA; Center for Biomedical Imaging at Clinical Translational Science Institute, University at Buffalo, State University of New York, Buffalo, NY, USA. Electronic address:

Background: Greater brain atrophy is associated with disability progression (DP) in patients with multiple sclerosis (PwMS). However, methodological challenges limit its routine clinical use.

Objective: To determine the feasibility of atrophy measures as markers of DP in PwMS scanned across different MRI field strengths.

Methods: A total of 980 PwMS were scanned on either 1.5 T or 3.0 T MRI scanners. Demographic and clinical data were retrospectively collected, and the presence of DP was determined according to standard clinical trial criteria. Lateral ventricular volume (LVV) change was measured with the NeuroSTREAM technique on clinical routine T2-FLAIR images. Percent brain volume change (PBVC) was measured using SIENA and ventricular cerebrospinal fluid (vCSF) % change was measured using VIENA and SIENAX algorithms on 3D T1-weighted images (WI). Stable vs. DP PwMS were compared using analysis of covariance (ANCOVA). Mixed modeling determined the effect of MRI scanner change on MRI-derived atrophy measures.

Results: Longitudinal LVV analysis was successful in all PwMS. SIENA-based PBVC and VIENA-based changes failed in 37.6% of cases, while SIENAX-based vCSF failed in 12.9% of cases. PwMS with DP (n = 241) had significantly greater absolute (20.9% vs. 8.7%, d = 0.66, p < 0.001) and annualized LVV % change (4.1% vs. 2.3%, d = 0.27, p < 0.001) when compared to stable PwMS (n = 739). In subjects with both analyses available, both 3D-T1 and T2-FLAIR-based analyses differentiated PwMS with DP (n = 149). However, only NeuroSTREAM and VIENA-based LVV/vCSF were able to show greater atrophy in PwMS that were scanned on different scanners. PBVC and SIENAX-based vCSF % changes were significantly affected by scanner change (Beta = -0.16, t-statistics = -2.133, p = 0.033 and Beta = -2.08, t-statistics = -4.084, p < 0.001), whereas no MRI scanner change effects on NeuroSTREAM-based PLVVC and VIENA-based vCSF % change were noted.

Conclusions: LVV-based atrophy on T2-FLAIR is a clinically relevant measure in spite of MRI scanner changes and mild disability levels.
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http://dx.doi.org/10.1016/j.nicl.2020.102554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816007PMC
January 2021

Decreasing brain iron in multiple sclerosis: The difference between concentration and content in iron MRI.

Hum Brain Mapp 2021 Apr 30;42(5):1463-1474. Epub 2020 Dec 30.

Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, New York, USA.

Increased brain iron concentration is often reported concurrently with disease development in multiple sclerosis (MS) and other neurodegenerative diseases. However, it is unclear whether the higher iron concentration in patients stems from an influx of iron into the tissue or a relative reduction in tissue compartments without much iron. By taking into account structural volume, we investigated tissue iron content in the deep gray matter (DGM) over 2 years, and compared findings to previously reported changes in iron concentration. 120 MS patients and 40 age- and sex-matched healthy controls were included. Clinical testing and MRI were performed both at baseline and after 2 years. Overall, iron content was calculated from structural MRI and quantitative susceptibility mapping in the thalamus, caudate, putamen, and globus pallidus. MS patients had significantly lower iron content than controls in the thalamus, with progressive MS patients demonstrating lower iron content than relapsing-remitting patients. Over 2 years, iron content decreased in the DGM of patients with MS, while it tended to increase or remain stable among controls. In the thalamus, decreasing iron content over 2 years was associated with disability progression. Our study showed that temporally increasing magnetic susceptibility in MS should not be considered as evidence for iron influx because it may be explained, at least partially, by disease-related atrophy. Declining DGM iron content suggests that, contrary to the current understanding, iron is being removed from the DGM in patients with MS.
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http://dx.doi.org/10.1002/hbm.25306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927296PMC
April 2021

Leptomeningeal, dura mater and meningeal vessel wall enhancements in multiple sclerosis.

Mult Scler Relat Disord 2021 Jan 4;47:102653. Epub 2020 Dec 4.

Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA; Center for Biomedical Imaging at Clinical Translational Science Institute, University at Buffalo, State University of New York, Buffalo, NY, USA. Electronic address:

Background: Leptomeningeal contrast enhancement (LMCE) has previously shown potential to be an indirect marker for leptomeningeal inflammation in multiple sclerosis (MS). Dura mater (DME), inclusive falx cerebri (FCE) enhancement and meningeal vessel wall enhancement (VWE) represent two other meningeal enhancement patterns in MS that have not been extensively studied.

Objectives: To investigate the frequency of LMCE, DME/FCE and VWE in patients with MS and their associations with demographic, clinical and MRI characteristics in a longitudinal retrospective study.

Methods: 217 MS patients (193 relapsing-remitting MS, 24 progressive MS) were assessed at baseline and over 18 months follow-up using 3T 3D FLAIR pre- and post-contrast and subtraction images. Lesion and brain volume outcomes were additionally calculated. Analyses were adjusted for age, and corrected for multiple comparisons.

Results: LMCE and VWE frequency was associated with higher age (p<0.02), but the presence of DME/FCE was not (p=0.402). 24% of MS patients revealed LMCE and VWE, respectively, and 47% showed DME/FCE. Presence of LMCE, VWE and DME/FCE was not significantly associated with clinical or imaging markers of disease severity. All three patterns of meningeal enhancement showed a high persistence in shape and size at follow-up.

Conclusions: LMCE, DME/FCE and VWE can be identified by gadolinium-enhanced 3D FLAIR MR imaging. Meningeal enhancement is associated with higher age. DME/FCE is the most frequent meningeal enhancement pattern in MS, however further case-control studies should determine whether this represents abnormal lymphatic drainage in these patients or is an age-dependent physiologic phenomenon.
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http://dx.doi.org/10.1016/j.msard.2020.102653DOI Listing
January 2021

Interpretation of Brain Volume Increase in Multiple Sclerosis.

J Neuroimaging 2021 03 13;31(2):401-407. Epub 2020 Dec 13.

Department of Radiology, First Faculty of Medicine, Charles University and General, University Hospital in Prague, Prague, Czech Republic.

Background And Purpose: A high variability of brain MRI volume change measurement renders challenging its interpretation in multiple sclerosis (MS). Occurrence and clinical relevance of observed apparent brain volume increase (BVI) in MS patients have not been investigated yet. The objective was to quantify the prevalence and factors associated with BVI.

Methods: We examined 366 MS patients (2,317 scans) and 44 controls (132 scans). Volumetric analysis of brain volume changes was performed by SIENA and ScanView. BVI was defined as brain volume change >0%. We compared characteristics of patients with and without BVI.

Results: BVI was found in 26.3% (from 1,951) longitudinal scans (SIENA). If BVI occurred, a probability that BVI will be repeated consecutively more than or equal to two times was 15.9%. The repeated BVI was associated with clinical disease activity in 50% of cases. BVI was associated with shorter time and lower T2 lesion volume increase between two MRI scans, and higher normalized brain volume (all P < .0001). A proportion of scans with BVI was higher when analyzed by ScanView (35.3%) and in controls (36.4% by SIENA).

Conclusions: BVI occurs in a great proportion of MR scans over short-term follow-up and is not associated with disease stabilization. Although BVI can be caused by several factors, the results indicate that measurement error may contribute to BVI in the majority of cases. Clinicians should be aware of the frequent occurrence of apparent BVI, interpret brain volume changes in MS patients with great caution, and use methods with precise quantification of brain volume changes.
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http://dx.doi.org/10.1111/jon.12816DOI Listing
March 2021

Late onset multiple sclerosis is associated with more severe ventricle expansion.

Mult Scler Relat Disord 2020 Nov 17;46:102588. Epub 2020 Oct 17.

Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA; Center for Biomedical Imaging at Clinical Translational Science Institute, University at Buffalo, State University of New York, Buffalo, NY, USA. Electronic address:

Background: Late-onset multiple sclerosis (LOMS) is associated with faster disability progression than persons with adult-onset MS (PwAOMS). The differences in brain atrophy are currently unknown.

Objectives: To determine MRI-derived atrophy rates in persons with late-onset MS (PwLOMS) and compare them to an age-matched and disease duration-matched sample of PwAOMS.

Methods: 870 persons with MS (290 PwLOMS, 290 age-matched PwAOMS, and 290 disease duration-matched PwAOMS), and 150 healthy controls (HCs), were followed for 5 years and 3 years, respectively. Cross-sectional and longitudinal measures of T2-lesion volume (LV), lateral ventricular volume (LVV) and whole brain volume (WBV) were derived. Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) were calculated. Both analyses were corrected for false discovery rate.

Results: Persons with MS exhibited significantly greater annualized WBV loss (-0.88% vs. -0.38%, p<0.001) and annualized LVV expansion (3.1% vs. 1.7%, p=0.002) when compared to HCs. PwLOMS had significantly higher baseline and follow-up median MSSS when compared to both age-matched and disease duration-matched PwAOMS (p<0.026). PwLOMS showed significantly greater percent LVV change (14.3% vs. 9.3% p=0.001) and greater annualized percent LVV change (4.1% vs. 1.6%, p<0.001) compared to age-matched PwAOMS.

Conclusion: PwLOMS had higher MSSS and greater ventricle expansion when compared to PwAOMS.
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http://dx.doi.org/10.1016/j.msard.2020.102588DOI Listing
November 2020

Slowing of brain atrophy with teriflunomide and delayed conversion to clinically definite MS.

Ther Adv Neurol Disord 2020 11;13:1756286420970754. Epub 2020 Nov 11.

The Buffalo Neuroimaging Analysis Center Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.

Background: We explored the effect of teriflunomide on cortical gray matter (CGM) and whole brain (WB) atrophy in patients with clinically isolated syndrome (CIS) from the phase III TOPIC study and assessed the relationship between atrophy and risk of conversion to clinically definite MS (CDMS).

Methods: Patients (per McDonald 2005 criteria) were randomized 1:1:1 to placebo, teriflunomide 7 mg, or teriflunomide 14 mg for ⩽108 weeks (core study). In the extension, teriflunomide-treated patients maintained their original dose; placebo-treated patients were re-randomized 1:1 to teriflunomide 7 mg or 14 mg. Brain volume was assessed during years 1-2.

Results: Teriflunomide 14 mg significantly slowed annualized CGM and WB atrophy placebo during years 1-2 [percent reduction: month 12, 61.4% (CGM; = 0.0359) and 28.6% (WB;  = 0.0286); month 24, 40.2% (CGM; = 0.0416) and 43.0% (WB; < 0.0001)]. For every 1% decrease in CGM or WB volume during years 1-2, risk of CDMS conversion increased by 14.5% (=0.0004) and 47.3% (< 0.0001) during years 1-2, respectively, and 6.6% (=0.0570) and 35.9% (= 0.0250) during years 1-5. In patients with the least (bottom quartile) most (top quartile) atrophy during years 1-2, risk of CDMS conversion was reduced by 58% (CGM; = 0.0024) and 58% (WB; = 0.0028) during years 1-2, and 42% (CGM; = 0.0138) and 29% (WB; = 0.1912) during years 1-5.

Conclusion: These findings support the clinical relevance of CGM and WB atrophy and early intervention with teriflunomide in CIS.
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http://dx.doi.org/10.1177/1756286420970754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672760PMC
November 2020

Thalamic Nuclei Volumes and Their Relationships to Neuroperformance in Multiple Sclerosis: A Cross-Sectional Structural MRI Study.

J Magn Reson Imaging 2021 03 12;53(3):731-739. Epub 2020 Oct 12.

Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, New York, USA.

Background: Although reduced thalamic volume is associated with multiple sclerosis (MS)-related clinical impairment, the role of individual thalamic nuclei remains poorly understood.

Purpose/hypothesis: To test whether individual thalamic nuclei volumes are more strongly associated with clinical disability than the whole thalamic volume.

Study Type: Retrospective analysis of a prospective dataset.

Subjects: A total of 108 MS patients and 48 age- and sex-matched healthy controls (HCs) FIELD STRENGTH: 3T.

Sequences: 3D T -weighted inversion recovery spoiled gradient echo; 2D T -weighted fluid-attenuated inversion recovery spin echo; 2D dual-echo proton density-weighted/T -weighted spin echo.

Assessments: Clinical assessments included the Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25FW), Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMTR), and the California Verbal Learning Test (CVLT2). FreeSurfer provided anterior, intralaminar, lateral, medial, ventral, posterior, and total volumes.

Statistical Tests: False discovery rate-corrected partial correlations (controlling for age, sex, and education) to assess the relationships between volumes and neuroperformance.

Results: Compared to HCs, MS patients presented with lower thalamic nuclei volumes (P < 0.05) except for the intralaminar nucleus (P = 0.279) and scored worse on all neuroperformance scales (P ≤ 0.05) except for CVLT2 (P = 0.151). All nuclei except intralaminar were associated with EDSS (correlation coefficient range: -0.233 to -0.395), SDMT (range: 0.247-0.423), and 9HPT (range: -0.232 to -0.303) (all P < 0.05). BVMTR was associated with anterior (r = 0.319), lateral (r = 0.31), and medial (r = 0.304) volumes (all P < 0.05). T25FW correlated with ventral (r = -0.392) and total (r = -0.309) volumes (both P < 0.05), with the latter being significantly greater (P < 0.05).

Data Conclusion: Assessing individual nuclei volume can aid in unraveling the relationship between thalamic pathology and disparate aspects of MS-related disability.

Level Of Evidence: 2 TECHNICAL EFFICACY STAGE: 2.
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http://dx.doi.org/10.1002/jmri.27389DOI Listing
March 2021

Subcutaneous anti-CD20 antibody treatment delays gray matter atrophy in human myelin oligodendrocyte glycoprotein-induced EAE mice.

Exp Neurol 2021 01 28;335:113488. Epub 2020 Sep 28.

Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA; Center for Biomedical Imaging at Clinical Translational Science Institute, University at Buffalo, State University of New York, NY, USA. Electronic address:

Background: The human myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (huMOG-EAE) model, generates B-cell driven demyelination in mice, making it a suitable multiple sclerosis model to study B cell depletion.

Objectives: We investigated the effect of subcutaneous anti-CD20 antibody treatment on huMOG-EAE gray matter (GM) pathology.

Methods: C57Bl/6, 8-week old mice were immunized with 200 huMOG and treated with 50 μg/mouse of anti-CD20 antibody (n = 16) or isotype control (n = 16). Serial brain volumetric 9.4 T MRI scans was performed at baseline, 1 and 5 wkPI. Disease severity was measured by clinical disability score (CDS) and performance on rotarod test.

Results: Anti-CD20 antibody significantly reduced brain volume loss compared with the isotype control across all timepoints longitudinally in the basal ganglia (p = 0.01), isocortex (p = 0.025) and thalamus (p = 0.023). The CDS was reduced significantly with anti-CD20 antibody vs. the isotype control at 3 (p = 0.003) and 4 (p = 0.03) wkPI, while a trend was observed at 5 (p = 0.057) and 6 (p = 0.086) wkPI. Performance on rotarod was also improved significantly at 3 (p = 0.007) and 5 (p = 0.01) wkPI compared with the isotype control. At cellular level, anti-CD20 therapy suppressed the percentage of proliferative nuclear antigen positive microglia in huMOG-EAE isocortex (p = 0.016). Flow cytometry confirmed that anti-CD20 antibody strongly depleted the CD19-expressing B cell fraction in peripheral blood mononuclear cells, reducing it from 39.7% measured in isotype control to 1.59% in anti-CD20 treated mice (p < 0.001).

Conclusions: Anti-CD20 antibody treatment delayed brain tissue neurodegeneration in GM, and showed clinical benefit on measures of disease severity in huMOG-EAE mice.
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http://dx.doi.org/10.1016/j.expneurol.2020.113488DOI Listing
January 2021

High density lipoprotein cholesterol and apolipoprotein A-I are associated with greater cerebral perfusion in multiple sclerosis.

J Neurol Sci 2020 Nov 8;418:117120. Epub 2020 Sep 8.

Department of Pharmaceutical Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA. Electronic address:

Background: The pathophysiological mechanisms underlying the associations of multiple sclerosis (MS) neurodegeneration serum cholesterol profiles is currently unknown.

Objective: To determine associations between lipid profile measures and cerebral perfusion-based indices in MS patients.

Methods: Seventy-seven MS patients underwent 3 T MRI. Cerebral blood volume (CBV), time-to-peak (TTP) and mean transit time (MTT) measures were computed from dynamic susceptibility contrast (DSC) perfusion-weighted imaging (PWI) for normal-appearing brain tissue (NABT), GM, cortex, deep gray matter (DGM) and thalamus. Total cholesterol, low and high-density lipoprotein cholesterol (LDL-C and HDL-C) and the apolipoproteins (Apo), ApoA-I, ApoA-II, ApoB, ApoC-II and ApoE levels were measured in plasma. Age and body mass index (BMI)-adjusted correlations were used to assess the associations between PWI and lipid profile measures.

Results: Higher HDL-C levels were associated with shorter MTT, which are indicative of greater perfusion, in NABT (p = 0.012), NAWM (p = 0.021), GM (p = 0.009), cortex (p = 0.014), DGM p = 0.015; and thalamus p = 0.015). The HDL-C-associated apolipoproteins, ApoA-I and ApoA-II, were associated with shorter MTT of the same brain regions (all p < 0.028). HDL-C and ApoA-I levels were also associated with shorter TTP, indicative of faster cerebral blood delivery. ApoC-II was associated with lower nCBV of the GM and cortex (p = 0.035 and p = 0.014, respectively).

Conclusion: The HDL pathway is associated with better global brain perfusion and faster cerebral blood delivery as measured by shorter MTT and TTP, respectively. ApoC-II may be associated with lower cortical and DGM perfusion.
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http://dx.doi.org/10.1016/j.jns.2020.117120DOI Listing
November 2020

Serum Neurofilament Light Chain Levels are Associated with Lower Thalamic Perfusion in Multiple Sclerosis.

Diagnostics (Basel) 2020 Sep 11;10(9). Epub 2020 Sep 11.

Buffalo Neuroimaging Analysis Center (BNAC), Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA.

Both perfusion-weighted imaging (PWI) measures and serum neurofilament light (sNfL) chain levels have been independently associated with disability in multiple sclerosis (MS) patients. This study aimed to determine whether these measures are correlated to each other or independently describe different MS processes. For this purpose, 3T MRI dynamic susceptibility contrast (DSC)-PWI and single-molecule assay (Simoa)-based sNfL methods were utilized when investigating 86 MS patients. The perfusion measures of mean transit time (MTT), cerebral blood volume (CBV), and cerebral blood flow (CBF) were derived for the normal-appearing whole brain (NAWB), the normal-appearing white matter (NAWM), the gray matter (GM), the deep GM (DGM), and the thalamus. The normalized CBV and CBF (nCBV and nCBV) were calculated by dividing by the corresponding NAWM measure. Age- and sex-adjusted linear regression models were used to determine associations between the DSC-PWI and sNfL results. False discovery rate (FDR)-adjusted -values < 0.05 were considered statistically significant. A greater age and thalamic MTT were independently associated with higher sNfL levels ( < 0.001 and = 0.011) and explained 36.9% of sNfL level variance. NAWM MTT association with sNfL levels did not survive the FDR correction. In similar models, a lower thalamic nCBF and nCBV were both associated with greater sNfL levels ( < 0.001 and = 0.022), explaining 37.8% and 44.7% of the variance, respectively. In conclusion, higher sNfL levels were associated with lower thalamic perfusion.
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http://dx.doi.org/10.3390/diagnostics10090685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554722PMC
September 2020

Detection of Monocyte/Macrophage and Microglia Activation in the TMEV Model of Chronic Demyelination Using USPIO-Enhanced Ultrahigh-Field Imaging.

J Neuroimaging 2020 11 31;30(6):769-778. Epub 2020 Aug 31.

Buffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY.

Background And Purpose: Blood-derived monocytes/macrophages can be labeled with ultrasmall superparamagnetic iron oxides (USPIO) at periphery and subsequently migrate into areas of inflammation in the brain. We investigated temporal pattern of migration of peripheral immune cells in Theiler's murine encephalomyelitis virus (TMEV) model of chronic demyelination by USPIO-enhanced imaging.

Methods: Fifteen SJL mice (Envigo, Indianapolis, IN) were injected with TMEV (n = 12) or saline (n = 3) at 7 weeks of age. Brain MRI of 9.4 T was performed at 3 months postinfection (mpi) (the peak of inflammatory phase), at 4, 5, and 7 mpi (throughout neurodegenerative phase) using T2*-weighted gradient echo MRI, and performed 24 hours after USPIO injection. Contrast enhancing lesion (CEL) number and volume were measured and development of brain atrophy was assessed across serial time points. Clinical disability scale and rotarod score assessed disease progression.

Results: CEL was detected in a total of eight (66.7%) TMEV-infected animals and none of the Controls. The CEL was present in four (33.3%) TMEV-infected animals at 3 mpi, two (16.7%) at 4 mpi, six (54.5%) at 5 mpi, and four (44.4%) at 7 mpi, respectively. In TMEV-infected animals, the CEL number and volume increased significantly from 3 to 7 mpi (P < .01 for both). The correlation between total CEL number and volume with clinical and MRI outcomes was trending (P < .05). On histopathology analysis, CEL showed increased density of Iba1 staining for microglia activity.

Conclusions: Serial USPIO imaging is a promising biomarker for investigating the effect of therapeutic interventions on monocytes/macrophages and microglia activation and neurodegeneration in TMEV-infected animals.
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http://dx.doi.org/10.1111/jon.12768DOI Listing
November 2020

Cortical and Deep Gray Matter Perfusion Associations With Physical and Cognitive Performance in Multiple Sclerosis Patients.

Front Neurol 2020 17;11:700. Epub 2020 Jul 17.

Department of Neurology, Buffalo Neuroimaging Analysis Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States.

Reports suggest presence of cerebral hypoperfusion in multiple sclerosis (MS). Currently there are no studies that examine if the cerebral MS perfusion is affected by presence of cardiovascular comorbidities. To investigate associations between cerebral perfusion and disease outcomes in MS patients with and without comorbid cardiovascular diseases (CVD). One hundred three MS patients (75.7% female) with average age of 54.4 years and 21.1 years of disease duration underwent 3T MRI dynamic susceptibility contrast (DSC) imaging and were tested with Expanded Disability Status Scale, Multiple Sclerosis Severity Score (MSSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT) and Symbol Digit Modalities Test (SDMT). Structural and perfusion-based normalized measures of cerebral blood flow (nCBF), cerebral blood volume (nCBV) and mean transit time (MTT) of global, tissue-specific and deep gray matter (DGM) areas were derived. CBV and CBF were normalized by the normal-appearing white matter counterpart. In linear step-wise regression analysis, age- and sex-adjusted, MSSS ( = 0.186) was associated with whole brain volume (WBV) (β = -0.244, = 0.046) and gray matter (GM) nCBF (β = -0.22, = 0.035). T25FW ( = 0.278) was associated with WBV (β = -0.289, = 0.012) and hippocampus nCBV (β = -0.225, = 0.03). 9HPT ( = 0.401) was associated with WBV (β = 0.195, = 0.049) and thalamus MTT (β = -0.198, =0.032). After adjustment for years of education, SDMT ( = 0.412) was explained by T2-lesion volume (β = -0.305, = 0.001), and GM nCBV (β = 0.236, = 0.013). No differences in MTT, nCBF nor nCBV measures between patients with ( = 42) and without CVD ( = 61) were found. Perfusion-measures were also not able to distinguish CVD status in a logistic regression model. Decreased GM and deep GM perfusion is associated with poorer MS outcomes, but not with presence of CVD.
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http://dx.doi.org/10.3389/fneur.2020.00700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380109PMC
July 2020

Conscientiousness and deterioration in employment status in multiple sclerosis over 3 years.

Mult Scler 2021 Jun 6;27(7):1125-1135. Epub 2020 Aug 6.

Department of Neurology, Jacobs Multiple Sclerosis Center for Treatment and Research, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York (SUNY), Buffalo, NY, USA.

Background: Physical and cognitive symptoms of multiple sclerosis (MS) correlate with unemployment cross-sectionally. Prospective studies, rarely published, have not accounted for personality traits such as Conscientiousness.

Methods: In a 3-year study of 70 people with MS (PwMS) and 25 healthy controls (HCs), we evaluated employment status using online interviews capturing hours worked, negative work events, employee relations, and accommodations. Deteriorating employment status (DES) was defined as reduced employment (full-time to part-time or negative work events). In PwMS, we explored workplace accommodations, disclosure of disease status, and physical/psychological predictors of DES (e.g. Conscientiousness).

Results: At follow-up, DES was 0% in HCs and 25.7% in MS, and 62.7% of work-stable PwMS used at least one work accommodation, most frequently, flexible hours. At baseline, DES-PwMS had lower education ( = 0.009), lower Conscientiousness ( < 0.001), more fatigue ( = 0.033), and performed worse on Symbol Digit Modalities Test ( = 0.013), Brief Visuospatial Memory Test-Revised ( = 0.041), and Nine-Hole Peg Test ( = 0.046) relative to work-stable. The model predicting DES was significant (χ(7) = 30.936,  < 0.001) and baseline Conscientiousness accounted for more variance in DES ( = 0.004) than other factors. Higher Conscientiousness PwMS were more likely to disclose their condition at work ( = 0.038).

Conclusion: Accommodations for low Conscientiousness, flexible hours, and physical/cognitive rehabilitation may prevent DES.
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http://dx.doi.org/10.1177/1352458520946019DOI Listing
June 2021

Diagnosis of depression in multiple sclerosis is predicted by frontal-parietal white matter tract disruption.

J Neurol 2021 Jan 4;268(1):169-177. Epub 2020 Aug 4.

Department of Neurology, Buffalo Neuroimaging Analysis Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York (SUNY), 100 High St., Buffalo, NY, 14226, USA.

Background: Persons with multiple sclerosis (PwMS) are at an elevated risk of depression. Decreased Conscientiousness may affect patient outcomes in PwMS. Low Conscientiousness has a strong correlation with depression. Previous work has also reported that white matter (WM) tract disruption in frontal-parietal networks explains reduced Conscientiousness in PwMS.

Objective: We hypothesized that Conscientiousness-associated WM tract disruption predicts new-onset depression over 5 years in PwMS and evaluated this by assessing the predictive power of mean Conscientiousness associated frontal-parietal network (CFPN) disruption in PwMS for clinically diagnosed depression over 5 years.

Methods: This longitudinal retrospective analysis included 53 PwMS who were not previously diagnosed as depressed. All participants underwent structural MRI. Medical records were reviewed to evaluate diagnosis of depression for these patients over 5 years. WM tract damage between pairs of gray matter regions in the CFPN was measured using diffusion imaging. The relationship between CFPN disruption and depression was analyzed using logistic regression.

Results: Participants with MS had a mean age of 46.0 years (SD = 11.2). 22.6% (n = 12) acquired a diagnosis of clinical depression over the 5-year period. Baseline disruption in the CFPN was a significant predictor (ROC AUC = 61.8%). of new-onset clinical depression, accounting for age, sex, lateral ventricular volume, disease modifying treatment, and lesion volume.

Conclusion: Baseline CFPN disruption is associated with progression to clinical depression over 5 years in PwMS. Development of new WM pathology within this network may be a risk factor for depression.
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http://dx.doi.org/10.1007/s00415-020-10110-3DOI Listing
January 2021

Serum neurofilament light chain and optical coherence tomography measures in MS: A longitudinal study.

Neurol Neuroimmunol Neuroinflamm 2020 07 18;7(4). Epub 2020 May 18.

From the Buffalo Neuroimaging Analysis Center (E.T., D.J., J.H., O.O., N.B., M.G.D., R.Z.), Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York; IRCCS (N.B.), Fondazione Don Carlo Gnocchi, Milan, Italy; Neurologic Clinic and Policlinic (J.K., C.B., Z.M., N.L.), Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland; Department of Pharmaceutical Sciences (M.R.), Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York; Novartis Pharma AG (D.T., H.K., D.L.), Basel, Switzerland; Jacobs MS Center (R.H.B.B., B.W.-G.), Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, and Center for Biomedical Imaging at Clinical Translational Science Institute (R.Z.), University at Buffalo, State University of New York.

Objective: To study the association between serum neurofilament light chain (sNfL) and multiple optical coherence tomography (OCT) measures in patients with MS and healthy controls (HCs).

Methods: In this prospective study, 110 patients with MS were recruited, together with 52 age- and sex-matched HCs. Clinical evaluation and spectral domain OCT and sNfL were obtained at baseline and after 5.5 years of follow-up. Nested linear mixed models were used to assess differences between MS vs HC and associations between sNfL and OCT measures. Partial correlation coefficients are reported, and values were adjusted for the false discovery rate.

Results: At baseline, peripapillary retinal nerve fiber layer thickness (pRNFLT) and macular ganglion cell and inner plexiform layer thickness (mGCIP) were significantly lower in MS than HC both in MS-associated optic neuritis (MSON) ( = 0.007, = 0.001) and nonaffected MSON (n-MSON) eyes ( = 0.003, = 0.018), along with total macular volume (TMV) in n-MSON eyes ( = 0.011). At follow-up, MS showed significantly lower pRNFLT, mGCIP, and TMV both in MSON and n-MSON eyes ( < 0.001) compared with HC. In MS n-MSON eyes, sNfL was significantly associated with baseline pRNFLT and mGCIP ( = 0.019). No significant associations were found in MSON eyes.

Conclusions: This study confirms the ability of sNfL to detect neurodegeneration in MS and advocates for the inclusion of sNfL and OCT measures in clinical trials.

Classification Of Evidence: This study provides Class III evidence that sNfL levels were associated with MS neurodegeneration measured by OCT.
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http://dx.doi.org/10.1212/NXI.0000000000000737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251512PMC
July 2020

Sex-Specific Differences in Life Span Brain Volumes in Multiple Sclerosis.

J Neuroimaging 2020 05 11;30(3):342-350. Epub 2020 May 11.

Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY.

Background And Purpose: Numerous sex-specific differences in multiple sclerosis (MS) susceptibility, disease manifestation, disability progression, inflammation, and neurodegeneration have been previously reported. Previous magnetic resonance imaging (MRI) studies have shown structural differences between female and male MS brain volumes. To determine sex-specific global and tissue-specific brain volume throughout the MS life span in a real-world large MRI database.

Methods: A total of 2,199 MS patients (female/male ratio of 1,651/548) underwent structural MRI imaging on either a 1.5-T or 3-T scanner. Global and tissue-specific volumes of whole brain (WBV), white matter, and gray matter (GMV) were determined by utilizing Structural Image Evaluation using Normalisation of Atrophy Cross-sectional (SIENAX). Lateral ventricular volume (LVV) was determined with the Neurological Software Tool for REliable Atrophy Measurement (NeuroSTREAM). General linear models investigated sex and age interactions, and post hoc comparative sex analyses were performed.

Results: Despite being age-matched with female MS patents, a greater proportion of male MS patients were diagnosed with progressive MS and had lower normalized WBV (P < .001), GMV (P < .001), and greater LVV (P < .001). In addition to significant stand-alone main effects, an interaction between sex and age had an additional effect on the LVV (F-statistics = 4.53, P = .033) and GMV (F-statistics = 4.59, P = .032). The sex and age interaction was retained in both models of LVV (F-statistics = 3.31, P = .069) and GMV (F-statistics = 6.1, P = .003) when disease subtype and disease-modifying treatment (DMT) were also included. Although male MS patients presented with significantly greater LVV and lower GMV during the early and midlife period when compared to their female counterparts (P < .001 for LVV and P < .019 for GMV), these differences were nullified in 60+ years old patients. Similar findings were seen within a subanalysis of MS patients that were not on any DMT at the time of enrollment.

Conclusion: There are sex-specific differences in the LVV and GMV over the MS life span.
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http://dx.doi.org/10.1111/jon.12709DOI Listing
May 2020

Functional Connectivity and Structural Disruption in the Default-Mode Network Predicts Cognitive Rehabilitation Outcomes in Multiple Sclerosis.

J Neuroimaging 2020 07 11;30(4):523-530. Epub 2020 May 11.

Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY.

Background And Purpose: Efficacy of restorative cognitive rehabilitation can be predicted from baseline patient factors. In addition, patient profiles of functional connectivity are associated with cognitive reserve and moderate the structure-cognition relationship in people with multiple sclerosis (PwMS). Such interactions may help predict which PwMS will benefit most from cognitive rehabilitation. Our objective was to determine whether patient response to restorative cognitive rehabilitation is predictable from baseline structural network disruption and whether this relationship is moderated by functional connectivity.

Methods: For this single-arm repeated measures study, we recruited 25 PwMS for a 12-week program. Following magnetic resonance imaging, participants were tested using the Symbol Digit Modalities Test (SDMT) pre- and postrehabilitation. Baseline patterns of structural and functional connectivity were characterized relative to healthy controls.

Results: Lower white matter tract disruption in a network of region-pairs centered on the precuneus and posterior cingulate (default-mode network regions) predicted greater postrehabilitation SDMT improvement (P = .048). This relationship was moderated by profiles of functional connectivity within the network (R = .385, P = .017, Interaction β = -.415).

Conclusion: Patient response to restorative cognitive rehabilitation is predictable from the interaction between structural network disruption and functional connectivity in the default-mode network. This effect may be related to cognitive reserve.
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http://dx.doi.org/10.1111/jon.12723DOI Listing
July 2020

A preliminary investigation of cognitive intolerance and neuroimaging among adolescents returning to school after concussion.

Brain Inj 2020 05 23;34(6):818-827. Epub 2020 Apr 23.

Department of Orthopaedics and Sports Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York, USA.

Primary Objective: To introduce the concept of cognitive intolerance. A test is proposed to measure this concept and pilot data are presented to support this measure and future research to develop this concept into a construct. : Three-group comparison to protect larger study blinding. : Two groups of student athletes (n = 13, n = 13) between 13 and 17 (mean 15.1 ± 1.1 years; 58% male) who sustained a sport-related concussion within 10 days and one group (n = 13) of age-matched healthy controls were recruited for a comparison of correlations between self and observer ratings of cognitive difficulties and DTI fractional anisotropy (FA) using tract-based spatial statistics (TBSS) analysis at two time points. : Significant negative only associations (higher cognitive difficulty and lower FA) with DTI FA were found in white matter tracts. These included the anterior corpus callosum, frontal-parietal longitudinal fasciculi, and cortical-subcortical pathways at only the second time point. Several working memory networks would likely involve connections using the above-identified white matter tracts. : Cognitive intolerance can be defined as symptom exacerbation from prolonged cognitive activity. Cognitive intolerance could be measured by the n-back working memory task and time to symptom exacerbation.
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http://dx.doi.org/10.1080/02699052.2020.1749932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540225PMC
May 2020

MRI biomarkers of disease progression and conversion to secondary-progressive multiple sclerosis.

Expert Rev Neurother 2020 08 3;20(8):821-834. Epub 2020 May 3.

Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York , Buffalo, NY, USA.

Introduction: Conventional imaging measures remain a key clinical tool for the diagnosis multiple sclerosis (MS) and monitoring of patients. However, most measures used in the clinic show unsatisfactory performance in predicting disease progression and conversion to secondary progressive MS.

Areas Covered: Sophisticated imaging techniques have facilitated the identification of imaging biomarkers associated with disease progression, such as global and regional brain volume measures, and with conversion to secondary progressive MS, such as leptomeningeal contrast enhancement and chronic inflammation. The relevance of emerging imaging approaches partially overcoming intrinsic limitations of traditional techniques is also discussed.

Expert Opinion: Imaging biomarkers capable of detecting tissue damage early on in the disease, with the potential to be applied in multicenter trials and at an individual level in clinical settings, are strongly needed. Several measures have been proposed, which exploit advanced imaging acquisitions and/or incorporate sophisticated post-processing, can quantify irreversible tissue damage. The progressively wider use of high-strength field MRI and the development of more advanced imaging techniques will help capture the missing pieces of the MS puzzle. The ability to more reliably identify those at risk for disability progression will allow for earlier intervention with the aim to favorably alter the disease course.
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http://dx.doi.org/10.1080/14737175.2020.1757435DOI Listing
August 2020

Long-standing multiple sclerosis neurodegeneration: volumetric magnetic resonance imaging comparison to Parkinson's disease, mild cognitive impairment, Alzheimer's disease, and elderly healthy controls.

Neurobiol Aging 2020 06 8;90:84-92. Epub 2020 Feb 8.

Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA; Jacobs Multiple Sclerosis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA; Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA; Center for Biomedical Imaging at Clinical Translational Science Institute, University at Buffalo, State University of New York, Buffalo, NY, USA. Electronic address:

Multiple sclerosis (MS) exhibits neurodegeneration driven disability progression. We compared the extent of neurodegeneration among 112 long-standing MS patients, 37 Parkinson's disease (PD) patients, 34 amnestic mild cognitive impairment (aMCI) patients, 37 Alzheimer's disease (AD) patients, and 184 healthy controls. 3T MRI volumes of whole brain (WBV), white matter (WMV), gray matter (GMV), cortical (CV), deep gray matter (DGM), and nuclei-specific volumes of thalamus, caudate, putamen, globus pallidus, and hippocampus were derived with SIENAX and FIRST software. Аge and sex-adjusted analysis of covariance was used. WBV was not significantly different between diseases. MS had significantly lower WMV compared to other disease groups (p < 0.021). Only AD had smaller GMV and CV when compared to MS (both p < 0.001). MS had smaller DGM volume than PD and aMCI (p < 0.001 and p = 0.026, respectively) and lower thalamic volume when compared to all other neurodegenerative diseases (p < 0.008). Long-standing MS exhibits comparable global atrophy with lower WMV and thalamic volume when compared to other classical neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166193PMC
June 2020