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. 2023 Jun 8:14:1188124.
doi: 10.3389/fneur.2023.1188124. eCollection 2023.

Processing speed and memory test performance are associated with different brain region volumes in Veterans and others with progressive multiple sclerosis

Rebecca I Spain  1   2 , Andrea Hildebrand  3 , Carin S Waslo  1 , William D Rooney  4 , Joshua Emmons  4 , Daniel L Schwartz  2   4 , Mark S Freedman  5 , M Mateo Paz Soldan  6   7 , Pavle Repovic  8 , Andrew J Solomon  9 , John Rinker 2nd  10 , Mitchell Wallin  11   12 , Jodie K Haselkorn  13   14 , Olaf Stuve  15   16   17 , Robert H Gross  18 , Aaron P Turner  13   14
Affiliations

Processing speed and memory test performance are associated with different brain region volumes in Veterans and others with progressive multiple sclerosis

Rebecca I Spain et al. Front Neurol. .

Abstract

Background: Cognitive dysfunction and brain atrophy are both common in progressive multiple sclerosis (MS) but are seldom examined comprehensively in clinical trials. Antioxidant treatment may affect the neurodegeneration characteristic of progressive MS and slow its symptomatic and radiographic correlates.

Objectives: This study aims to evaluate cross-sectional associations between cognitive battery components of the Brief International Cognitive Assessment for Multiple Sclerosis with whole and segmented brain volumes and to determine if associations differ between secondary progressive (SPMS) and primary progressive (PPMS) MS subtypes.

Design: The study was based on a baseline analysis from a multi-site randomized controlled trial of the antioxidant lipoic acid in veterans and other people with progressive MS (NCT03161028).

Methods: Cognitive batteries were conducted by trained research personnel. MRIs were processed at a central processing site for maximum harmonization. Semi-partial Pearson's adjustments evaluated associations between cognitive tests and MRI volumes. Regression analyses evaluated differences in association patterns between SPMS and PPMS cohorts.

Results: Of the 114 participants, 70% had SPMS. Veterans with MS made up 26% (n = 30) of the total sample and 73% had SPMS. Participants had a mean age of 59.2 and sd 8.5 years, and 54% of them were women, had a disease duration of 22.4 (sd 11.3) years, and had a median Expanded Disability Status Scale of 6.0 (with an interquartile range of 4.0-6.0, moderate disability). The Symbol Digit Modalities Test (processing speed) correlated with whole brain volume (R = 0.29, p = 0.01) and total white matter volume (R = 0.33, p < 0.01). Both the California Verbal Learning Test (verbal memory) and Brief Visuospatial Memory Test-Revised (visual memory) correlated with mean cortical thickness (R = 0.27, p = 0.02 and R = 0.35, p < 0.01, respectively). Correlation patterns were similar in subgroup analyses.

Conclusion: Brain volumes showed differing patterns of correlation across cognitive tasks in progressive MS. Similar results between SPMS and PPMS cohorts suggest combining progressive MS subtypes in studies involving cognition and brain atrophy in these populations. Longitudinal assessment will determine the therapeutic effects of lipoic acid on cognitive tasks, brain atrophy, and their associations.

Keywords: brain atrophy; brain volume changes; clinical trials; processing speed; progressive multiple sclerosis; verbal memory; veterans; visual memory.

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Conflict of interest statement

AS contracted Research with Sanofi, Biogen, Novartis, Actelion, Genentech/Roche. Consulting fees from Octave Bioscience. Research support from Bristol Myers Squibb. Personal compensation for consulting for Genentech, Biogen, Alexion, Celgene, Greenwich Biosciences, TG Therapeutics and OctavemBioscience. Personal compensation non-promotional speaking for EMD Serono. Participationin ma Data Safety and Monitoring Board for NCT03073603, and NCT04877457. MF received a grant from Sanofi-Genzyme Canada. Honoraria or consultation fees from Alexion/Astra Zeneca, BiogenIdec, EMD Inc./EMD Serono/Merck Serono, Find Therapeutics, Hoffman La-Roche, Novartis, Quanterix, Sanofi-Genzyme, Teva Canada Innovation. Member of a company advisory board or board of directors for Alexion/Astra Zeneca, Atara Biotherapeutics, Bayer Healthcare, Celestra Health, EMD Inc./Merck Serono, Find Therapeutics, Hoffman La-Roche, Actelion/Janssen (J&J), Novartis, Sanofi-Genzyme, Setpoint Medical. Participation in a company sponsored speaker's bureau: Sanofi-Genzyme, EMD Serono. PR contracted research with Biogen, Genentech, Novartis, Sanofi. Consulting honoraria: Banner, BristolMyersSquibb, EMD Serono, Genentech, Novartis, Sanofi, TG therapeutics. Speaker honoraria: Biogen, BristolMyersSquibb, Genentech, Novartis, Sanofi, TG therapeutics. OS serves on the editorial boards of Therapeutic Advances in Neurological Disorders, has served on data monitoring committees for Genentech-Roche, Pfizer, Novartis, and TG Therapeutics without monetary compensation, has advised EMD Serono, Novartis, and VYNE, receives grant support from EMD Serono, is a 2021 recipient of a Grant for Multiple Sclerosis Innovation (GMSI), Merck KGaA, is funded by a Merit Review grant (federal award document number (FAIN) BX005664-01 from the United States (U.S.) Department of Veterans Affairs, Biomedical Laboratory Research and Development, is funded by RFA-2203-39314 (PI) and RFA-2203-39305 (co-PI) grants from the National Multiple Sclerosis Society (NMSS). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Semi-partial Pearson's correlations between the cognitive processing speed test Symbol Digit Modalities Test (SDMT) Z-scores and whole brain volume, deep gray matter volume, total white matter volume, and mean cortical thickness. MRI measures have been adjusted for age and sex, so what is presented here are the residuals (distance each participant is from the age- and sex-adjusted mean). Correlations are for combined secondary progressive (SPMS, filled circles) and primary progressive (PPMS, unfilled circles) multiple sclerosis cohorts. Statistical significance was set at a p-value of ≤ 0.05.
Figure 2
Figure 2
Semi-partial Pearson's correlations between the California Verbal Learning Test, second edition (CVLT) T-scores and whole brain volume, deep gray matter volume, total white matter volume, and mean cortical thickness. MRI measures have been adjusted for age and sex, so what is presented here are the residuals (distance each participant is from the age- and sex-adjusted mean). Correlations are for combined secondary progressive (SPMS, filled circles) and primary progressive (PPMS, unfilled circles) multiple sclerosis cohorts. Statistical significance was set at a p-value of ≤ 0.05.
Figure 3
Figure 3
Pearson's correlations between the Brief Visuospatial Memory Test-Revised (BVMT-R) T-scores and whole brain volume, deep gray matter volume, total white matter volume, and mean cortical thickness. MRI measures have been adjusted for age and sex, so what is presented here are the residuals (distance each participant is from the age- and sex-adjusted mean). Correlations are for combined secondary progressive (SPMS, filled circles) and primary progressive (PPMS, unfilled circles) multiple sclerosis cohorts. Statistical significance was set at a p-value of ≤ 0.05.
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