Archives of Physical Medicine and Rehabilitation journal homepage: www.archives-pmr.org Archives of Physical Medicine and Rehabilitation 2016;97:61-6
ORIGINAL RESEARCH
Cognitive-Motor Related Brain Activity During Walking: Differences Between Men and Women With Multiple Sclerosis Jeffrey R. Hebert, PT, PhD,a,b John H. Kindred, MS,c Marco Bucci, PhD,d Jetro J. Tuulari, MD,d Lisa A. Brenner, PhD,a Jeri E. Forster, PhD,a Phillip J. Koo, MD,e Thorsten Rudroff, PhDc From the aDepartment of Physical Medicine and Rehabilitation, University of Colorado School of Medicine, Aurora, CO; bDepartment of Neurology, University of Colorado School of Medicine, Aurora, CO; cDepartment of Health and Exercise Science, Colorado State University, Fort Collins, CO; dTurku Positron Emission Tomography Centre, University of Turku and Turku University Hospital, Turku, Finland; and eDivision of Nuclear Medicine and Molecular Imaging, Department of Radiology, University of Colorado School of Medicine, Aurora, CO.
Abstract Objective: To determine if sex differences in glucose uptake, a marker of brain activity, are present in brain regions that facilitate walking performance in persons with multiple sclerosis (MS). Design: Cross-sectional, observational pilot. Setting: University laboratory. Participants: Positron emission tomography with fluorine-18-labeled deoxyglucose (FDG) was performed on persons with MS and healthy controls (4 men and 4 women per group; NZ16) after a 15-minute walking test. Interventions: Not applicable. Main Outcome Measure: Brain activity was quantified as the mean standardized uptake value (SUV). Results: The mean SUV was significantly lower in the thalamus (PZ.029) and cerebellum (PZ.029) for men with MS compared with women with MS, but not for the prefrontal (PZ.057) or frontal (PZ.057) cortices. Similar nonsignificant trends were found for healthy controls. No mean SUV group sex interaction effects were found between the MS and healthy control groups (all P>.05). Conclusions: To our knowledge, this is the first study of brain activity sex differences based on FDG uptake in persons with MS during walking. Significantly less FDG uptake in the thalamus and cerebellum brain regions important for walking performance was found in men with MS compared with women with MS; however, these comparisons were not significantly different in the healthy control group. No differences in FDG uptake were found between the MS and healthy control groups in any of the brain regions examined. Results from this study provide pilot data for larger studies aimed at identifying underlying mechanisms responsible for accelerated disability in men with MS. Archives of Physical Medicine and Rehabilitation 2016;97:61-6 ª 2016 by the American Congress of Rehabilitation Medicine
Presented as a poster to the Americas Committee for Treatment and Research in Multiple Sclerosis e European Committee for Treatment and Research in Multiple Sclerosis, September 12, 2014, Boston, MA. Supported by the National Multiple Sclerosis Society (grant no. PP1907) and in part by the National Institutes of Health/National Center for Advancing Translational Sciences Colorado Clinical and Translational Sciences Institute (grant no. UL1 TR000154). North American Research Consortium on Multiple Sclerosis is supported in part by the Consortium of Multiple Sclerosis Centers (CMSC) and the CMSC Foundation. Disclosures: none.
Multiple sclerosis (MS) is a chronic, demyelinating degenerative disease of the central nervous system. Although women present with greater disease activity at a younger age and during earlier phases of the disease, overall disability and disease progression are accelerated in men, advancing with age and disease duration.1 Secondary to their aggressive advancement of physical disability, men with MS are considerably less physically active2 and present with higher rates of falls.3,4
0003-9993/15/$36 - see front matter ª 2016 by the American Congress of Rehabilitation Medicine http://dx.doi.org/10.1016/j.apmr.2015.09.015
62
J.R. Hebert et al
Effective physical activity (eg, walking) is essential to daily living and requires cognitive and motor interaction to achieve coordinated and automated walking performance. Disability among those with MS has largely been evaluated on walking; however, cognition as it pertains to daily physical tasks, cognitivemotor function (eg, mental attention, processing), is paramount to safe and efficient walking. Cognitive impairment affects up to 70% of persons with MS, beginning early in the disease process,5 and worsening with disease duration and progression.6 Impaired cognition in MS leads to restricted work and social activities and participation, resulting in poorer quality of life.7 Persons with MS present with different aspects of cognitive dysfunction, most frequently observed as limitations in processing speed, sustained attention, and visuospatial perception.8 Multiple cortical and subcortical brain structures, including the thalamus, cerebellum, and prefrontal and frontal cortices are responsible for proper performance and long-term preservation of these cognitive-motor domains. Moreover, men with MS consistently present with greater cognitive impairments that are associated with altered functioning in multiple brain regions,9 including the thalamus.10 Previously, positron emission tomography (PET) neuroimaging has been implemented to quantify resting-state glucose uptake and metabolism in multiple cortical and subcortical brain structures among persons with MS.11,12 Recommendations have been made to implement neuroimaging to identify biomarkers that may play important roles in cognitive behavior.13 Recent studies have found functional attenuation of the thalamus, cerebellum, and prefrontal and frontal cortices in persons with MS during cognitive task performance and resting states.14-18 However, to our knowledge, no prior studies have compared brain activity in regions responsible for cognitive-motor function based on sex during or after a walking task, leaving the reasons for distinct sex differences among persons with MS poorly understood. The purpose of our study was to compare fluorine-18-labeled deoxyglucose (FDG), a glucose analogue PET tracer, uptake in brain regions that are important for sustained walking performance in men and women with MS and healthy controls after walking. Because men with MS present with greater disability in cognition and walking, we hypothesized that men with MS would present with significantly less FDG uptake in the thalamus, cerebellum, and prefrontal and frontal cortices brain regions compared with women with MS and that the sex differences in those with MS would be greater compared with healthy participants. Our efforts are further supported by a recent topical review on sex differences in MS, which concluded that the lack of sex-related neuroimaging comparisons on this topic is a significant gap in research.19
Methods Participants and procedures The pilot study was a cross-sectional, observational design. Eight participants with MS (4 men, 4 women) were recruited through
List of abbreviations: FDG MS PET SUV
fluorine-18-labeled deoxyglucose multiple sclerosis positron emission tomography standardized uptake value
advertisements through a local MS center, and 8 healthy control participants (4 men, 4 women) were recruited by advertisement on a local medical campus. A local scientific ethics committee, guided by the ethical principles for human subject research and in accordance with the U.S. Department of Health and Human Services policy and regulations (45 CFR 46), approved this study. All participants gave written informed consent prior to their participation in the study. Participants with MS had confirmed diagnosis of MS, no changes in disease status 3 months prior to the study, and no greater than mild spasticity in the legs; were between 18 to 55 years of age; and were able to walk 15 minutes without assistance. Participants with MS completed the Patient Determined Disease Steps Scalea to determine disability level. The healthy control participants were without neurologic or musculoskeletal disorders. All participants reported performing 2 to 4d/wk of no greater than moderate level of exercise. After completion of informed consent, all participants underwent the same experiment protocol to decrease variability and bias. The experiment began with each participant walking on a treadmill at a self-selected speed for 15 minutes. Two minutes after walking started, they were injected with approximately equal to 321.9MBq of FDG into an antecubital vein. On completion of treadmill walking, participants underwent PET imaging. PET images were subsequently converted into standardized uptake value (SUV) parametric images using a voxel by voxel calculation with the formula SUVmeanZactivity (Bq/mL3)/(injected activity [MBq]/body weight [kg]), where SUVmean is the mean SUV. SUV parametric images were then normalized to a tracer specific template into Montreal Neurological Institute space similar to Tuulari et al.20 Images were smoothed at 10-mm full width at half maximum. The mean SUV of regions of interest within the automatic anatomic labeling template21 were extracted from the SUV parametric images using the MarsBaR toolkitb within the Statistical Parametric Mapping 8 toolboxc for MATLAB R2014a.d Consent and all aspects of the experiment were performed in a university medical campus laboratory. Power and sample size estimates were not performed for this pilot study because no prior preliminary data or study results were available. The methodology of this study has been reported previously.22-25
Data analysis Data, including the regions of interest, analysis was conducted using the nonparametric Mann-Whitney U test for within-group characteristics and sex differences. To compare mean SUVs between the groups based on sex (group sex), an adjusted rank transformation was implemented as a nonparametric test of interaction.26 All tests were 2-tailed, using .05 as the level of statistical significance. Mean and SD, median and range, and nonparametric standard effect size index (Cohen r) were calculated. Cohen r interpretations are as follows: large effect was 0.5, medium effect was 0.3, and small effect was 0.1.27
Results Participant characteristics Participant demographics and characteristics for the MS group are detailed in table 1, where age, MS diagnosis duration, disability level, and self-selected speed walk were similar between men and
www.archives-pmr.org
Brain activity during walking in multiple sclerosis Table 1
63
Participant characteristics: MS group
Variable
Men (nZ4)
Age (y) MS diagnosis duration (y) Disability (PDDS) Walk test speed (km/h)
45.505.51, 9.505.07, 1.751.50, 3.981.19,
45.0 (40e52) 11.5 (2e13) 2.0 (0e3) 3.7 (2.9e5.6)
Women (nZ4)
P*
44.2511.87, 48.0 (27e54) 8.257.89, 6.5 (1e19) 0.831.63, 2.0 (0e4) 3.940.47, 3.9 (3.4e4.5)
.886 .686 .886 .686
NOTE. Values are mean SD, median (range). Abbreviation: PDDS, Patient Determined Disease Steps. * P values assessed by Mann-Whitney U test.
women. The healthy control group sex comparisons of age (men: 35.5y, women: 40.3y; PZ.486) and walk test speed (men: 5.1km/h, women: 4.8km/h; PZ.343) were also similar.
Brain region glucose uptake Differences in mean SUVs in brain regions were found for the MS group (fig 1). Men with MS had significantly lower mean SUVs compared with women with MS in the thalamus and cerebellum and had nonsignificant differences in the prefrontal and frontal cortices (table 2); however, MS group sex comparisons for the thalamus, cerebellum, and prefrontal and frontal cortices had large standard effect size indexes (see table 2). Sex differences in the mean SUVs for the healthy control group were nonsignificant in the thalamus, cerebellum, and prefrontal and frontal cortices (see table 2); however, large standard effect size indexes were found for the thalamus, cerebellum, and prefrontal and frontal cortices (see table 2). The inability to identify these large standard effect size indexes as statistically significant for the healthy control group is likely explained by the small sample size. No differences in the mean SUVs were found when comparing the MS group with the healthy control group based on sex. No interactions were found for the thalamus (FZ.35; PZ.563), cerebellum (FZ.04; PZ.852), prefrontal cortex (FZ.08; PZ.779), and frontal cortex (FZ.04; PZ.852).
more specifically men with MS. Our pilot study results laid the foundation for future PET brain imaging studies of sex differences in MS during cognitive-motor dual tasking, including walking. Furthermore, these studies would be expected to help determine if the male brain might be more susceptible to the effects of MS, pinpointing which brain region performances are most associated with accelerated disability found in men with MS. Our results for both the MS group and healthy control group seem in contrast with a prior FDG PET imaging study on healthy, young adults.29 In this study by Hu et al,29 it was found that women had significantly less FDG uptake in the cerebellum and frontal cortex and greater uptake in the thalamus at resting state. However, it must be considered that the designs of the studies are different and that the walking task in our study may have resulted in a reverse of effects on brain activity in these brain regions for both persons with MS and healthy people. Higher levels of physical activity are associated with better cognition across the life span30,31; however, worsening cognition and cognitive distraction during walking (cognitive-motor dual tasking) lead to greater walking impairments and falls in aging, older adults.32 Persons with MS often present with impaired cognitive-motor dual tasking.28 Dual tasking (eg, distracted
Discussion The main results of our study were that FDG uptake in the thalamus and cerebellum was significantly less in men with MS compared with women with MS during 15 minutes of self-paced walking and that the same comparison showed similar trends, but failed to achieve significance, in the healthy control group. Our findings are in line with prior reports of less FDG uptake in the thalamus and cerebellum in mildly disabled persons with MS during a resting state.12 Large standard effect sizes of FDG uptake in the thalamus, cerebellum, and prefrontal and frontal cortices were also found when comparing men and women with MS, which were also observed in the healthy control, but at relatively lower index levels and without achieving statistical significance. Additionally, differences in FDG uptake sex comparisons between the MS and healthy control groups were not found. Walking is a skilled, coordinated task that requires intact cognitive-motor function, and for persons with MS cognitivemotor function is a problem.28 Because the thalamus, cerebellum, and prefrontal and frontal cortices are primary brain regions for cognitive-motor function, the findings from this study provide early evidence that this is likely more concerning for men, and www.archives-pmr.org
Fig 1 Sagittal, coronal, and transverse views, respectively, of areas of lower metabolic activity in men with MS compared with women with MS. Threshold at T>3.0, extent threshold kZ3000, and cluster level uncorrected for visual inspection. The areas overlap those included in the statistical comparisons. Brighter yellow represents areas of greater differences as indicated by the colored T score bar. Image was generated from full brain volume comparison in Statistical Parametric Mapping.
J.R. Hebert et al
P*
.51 .61 .51 .51 (5.4e7.5) (4.1e5.5) (5.1e7.0) (5.2e7.2) 5.8 4.8 5.8 5.9 6.110.97, 4.820.80, 5.940.91, 6.070.95,
Women Men r P*
.029 .029 .057 .057 5.600.25, 4.390.35, 5.540.40, 5.640.41,
Study limitations
NOTE. Values are mean SD, median (range). Abbreviation: r, Cohen r standard effect size index.27 * P values assessed by Mann-Whitney U test.
(4.2e4.9) (3.1e3.7) (3.9e5.1) (4.0e5.2) Thalamus Cerebellum Prefrontal cortex Frontal cortex
4.5 3.5 4.8 4.9 Men
4.500.30, 3.440.30, 4.630.53, 4.730.54,
Brain Region
Table 2
Brain glucose uptake (mean SUV)
MS Group
5.6 4.3 5.5 5.6
(5.3e5.9) (4.1e4.9) (5.1e6.0) (5.2e6.2) Women
.82 .82 .71 .71
5.270.88, 4.110.87, 5.311.02, 5.401.05,
4.9 3.7 4.8 4.9
(4.6e6.5) (3.6e5.4) (4.7e6.8) (4.8e7.0)
Healthy Control Group
visuospatial attention,33 mental processing,34) adversely effects walking and has been linked to higher fall risk even in the early stages of MS.35 A possible reason for these outcomes is dysfunctional activity in brain regions responsible for cognitivemotor function (eg, thalamus, cerebellum). The reasons for the variability and limited treatment effectiveness for cognition-motor abilities in persons with MS are not well known; however, certain patient characteristics may play key roles. To this point, it is important for future studies to test changes in brain region FDG uptake from resting state to exerciserelated training states in persons with MS and healthy controls to identify important neural biomarkers responsible for differences in cognitive-motor performance and if variability in activity is sex dependent. Because it has been reported that men with MS benefit greater from neuropsychologic rehabilitation,36 and better aerobic fitness is associated with improved cognitive function37 and gray matter volume and white matter integrity38 in MS, it is important to know if outcomes from treatment approaches (eg, exercise, exercise cognitive dual-task training) follow similar sex-related influences. To date, no studies have investigated sex differences during these interventions; however, the results from our pilot study may provide early evidence that could lead to the development of new exercise and cognitive-motor dual-task treatment strategies. Additionally, it will be important to determine if metabolism and function of cognitive-motor brain structures are amiable to change after training or if they are irremediable and require compensation when structuring treatment approaches. Finally, reports are emerging suggesting that low levels of sexspecific hormones are associated with greater disability in women19 and men39 with MS and that higher levels may play an important role in neuroprotection.40 What is not known at this time is the underlying mechanisms of these effects.19 FDG PET imaging has been used to quantify brain activity in older adult men with Alzheimer disease, where changes in cerebral glucose metabolism were found in multiple brain regions after testosterone therapy.41 Although our study was not treatment based and we did not measure sex-specific hormone levels in our participants, we demonstrate the feasibility and utility of FDG PET imaging in similar hormone-based therapy studies in persons with MS.
.200 .114 .200 .200
r
64
There are limitations in this study. The most notable limitation is the small sample size, which resulted in low power and could explain the observed large effect sizes for the healthy control comparisons that did not achieve statistical significance. The sample size also necessitated the use of nonparametric tests, which have lower power, but by their use, decreased the chance of committing type I errors in this study. To our knowledge, there is no prior evidence of brain mean SUVs during or after exercise in persons with MS and healthy people, limiting our ability to compare effect sizes found in our study with prior study results. Although our study is unable to determine if the mean SUVs in the groups are clinically meaningful, our pilot study provides original preliminary data that future studies are able to apply to the development of larger studies to confirm and clarify our findings and determine what brain regions are most responsible for walking and cognitive-motor sex differences by implementing parametric multigroup comparisons, interaction effects, and covariate analyses. These larger studies will also help lead to establish clinically meaningful effect sizes of brain mean SUVs in persons with www.archives-pmr.org
Brain activity during walking in multiple sclerosis
65
MS and healthy people during exercise. Additionally, because of the cross-sectional design, our study was unable to determine cause and effect. Disability and other characteristics were similar between the sexes for the participants with MS; however, we did not qualify lesion involvement or quantify lesion load of the brain regions in this preliminary study. Although we are unable to report on lesion involvement, we did control to some extent for possible active lesion involvement globally by excluding prospective participants who had an MS-related relapse 3 months prior. Additionally, to the extent we could without concurrent magnetic resonance imaging data, we addressed this issue concurrently by performing weighted analysis of the brain regions of interest based on summative regional volume, controlling for volume variability that could be related to preexisting, chronic lesion involvement among the participants. Normalization to the tracer-specific template controls for volume variability between subjects. Although normalization through transformation matrices obtained from individual T1weighted magnetic resonance images might yield more precise results, we do not consider this a major confound. In future studies, the magnetic resonance imaging measurements would be important to quantify lesion load within individual brains because impaired white matter integrity might affect cortical glucose metabolism. Finally, we implemented a single valid measure of disability in the participants with MS, the Patient Determined Disease Steps Scale; however, this study could have been strengthened by including additional measures of function and disability for a more complete understanding of these factors in the MS group. Future studies will benefit from this approach so that the role of functional compensation in persons with MS can be considered in the determination of brain activity during functional task performance (eg, walking, cognitive-motor).
Suppliers
Conclusions
1. Tremlett H, Zhao Y, Joseph J, Devonshire V, UBCMS Clinic Neurologists. Relapses in multiple sclerosis are age- and time-dependent. J Neurol Neurosurg Psychiatry 2008;79:1368-74. 2. Anens E, Emtner M, Zetterberg L, Hellstro¨m K. Physical activity in subjects with multiple sclerosis with focus on gender differences: a survey. BMC Neurol 2014;14:47. 3. Gunn H, Creanor S, Haas B, Marsden J, Freeman J. Frequency, characteristics, and consequences of falls in multiple sclerosis: findings from a cohort study. Arch Phys Med Rehabil 2014;95: 538-45. 4. Nilsaga˚rd Y, Gunn H, Freeman J, et al. Falls in people with MSean individual data meta-analysis from studies from Australia, Sweden, United Kingdom and the United States. Mult Scler 2015;21:92-100. 5. Loitfelder M, Fazekas F, Koschutnig K, et al. Brain activity changes in cognitive networks in relapsing-remitting multiple sclerosis - insights from a longitudinal FMRI study. PLoS One 2014;9:e93715. 6. Chiaravalloti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurol 2008;7:1139-51. 7. Rao SM, Leo GJ, Ellington L, Nauertz T, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. II. Impact on employment and social functioning. Neurology 1991;41:692-6. 8. Rao SM, Leo GJ, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology 1991;41:685-91. 9. Koenig KA, Lowe MJ, Lin J, et al. Sex differences in resting-state functional connectivity in multiple sclerosis. AJNR Am J Neuroradiol 2013;34:2304-11. 10. Schoonheim MM, Vigeveno RM, Rueda Lopes FC, et al. Sex-specific extent and severity of white matter damage in multiple sclerosis: implications for cognitive decline. Hum Brain Mapp 2014;35:2348-58.
To our knowledge, this is the first study to identify sex differences in brain FDG uptake in persons with MS and healthy controls during a walking task. FDG uptake in the thalamus and cerebellum, brain regions vital to walking and cognitive-motor function, was significantly less in men with MS compared with women with MS. Moreover, less FDG uptake in the thalamus, cerebellum, and prefrontal and frontal cortices was found for men in both the MS and healthy control groups. The suggestion that men may possess inherent, preclinical vulnerability to the neuropathologic processes of MS is not supported by the actual results, but it deserves to be tested in a larger sample of healthy subjects. This study provides the feasibility and utility of FDG PET aimed at detecting brain region glucose uptake and activity during a physical performance task. Based on our approach and pilot results, larger studies should measure brain FDG uptake in persons with MS and healthy people during walking and cognitive-motor dual-task performance. Our study shows that this evidence may be more important for men with MS. Longitudinal mechanistic studies comparing brain FDG uptake with cognitive-motor performance may help identify biomarkers that are responsible for the disparate acceleration of disability in men with MS. Additionally, studies need to determine if brain FDG uptake has the potential to change as a result of exercise and cognitive-related interventions and if these changes are sex dependent.
www.archives-pmr.org
a. Patient Determined Disease Steps Scale; North American Research Consortium on Multiple Sclerosis. Available at: http://narcoms.org. b. MarsBaR. Available at: http://marsbar.sourceforge.net. c. Statistical Parametric Mapping 8; Wellcome Trust Centre. Available at: http://www.fil.ion.ucl.ac.uk/spm/. d. MATLAB R2014a; MathWorks.
Keywords Brain; Multiple Rehabilitation
sclerosis;
Positron-emission
tomography;
Corresponding author Jeffrey R. Hebert, PT, PhD, Departments of Physical Medicine and Rehabilitation and Neurology, University of Colorado School of Medicine, 12631 E 17th Ave, Mail Stop F493, Aurora, CO 80045. E-mail address: [email protected].
Acknowledgment We thank Ramesh Karki, MS, for his help with data collection, image acquisition, and image analysis.
References
66 11. Sorensen PS, Jonsson A, Mathiesen HK, et al. The relationship between MRI and PET changes and cognitive disturbances in MS. J Neurol Sci 2006;245:99-102. 12. Derache N, Marie RM, Constans JM, Defer GL. Reduced thalamic and cerebellar rest metabolism in relapsing-remitting multiple sclerosis, a positron emission tomography study: correlations to lesion load. J Neurol Sci 2006;245:103-9. 13. Basford J, Malec J. A brief overview and assessment of the role and benefits of cognitive rehabilitation. Arch Phys Med Rehabil 2015;96: 977-80. 14. Wojtowicz M, Mazerolle EL, Bhan V, Fisk JD. Altered functional connectivity and performance variability in relapsing-remitting multiple sclerosis. Mult Scler 2014;20:1453-63. 15. Kollndorfer K, Krajnik J, Woitek R, Freiherr J, Prayer D, Schopf V. Altered likelihood of brain activation in attention and working memory networks in patients with multiple sclerosis: an ALE metaanalysis. Neurosci Biobehav Rev 2013;37:2699-708. 16. Rocca MA, Mesaros S, Pagani E, Sormani MP, Comi G, Filippi M. Thalamic damage and long-term progression of disability in multiple sclerosis. Radiology 2010;257:463-9. 17. Rocca MA, Valsasina P, Hulst HE, et al. Functional correlates of cognitive dysfunction in multiple sclerosis: a multicenter fMRI study. Hum Brain Mapp 2014;35:5799-814. 18. Ruet A, Hamel D, Deloire MS, Charre-Morin J, Saubusse A, Brochet B. Information processing speed impairment and cerebellar dysfunction in relapsing-remitting multiple sclerosis. J Neurol Sci 2014;347:246-50. 19. Bove R, Chitnis T. The role of gender and sex hormones in determining the onset and outcome of multiple sclerosis. Mult Scler 2014; 20:520-6. 20. Tuulari JJ, Karlsson HK, Hirvonen J, et al. Weight loss after bariatric surgery reverses insulin-induced increases in brain glucose metabolism of the morbidly obese. Diabetes 2013;62:2747-51. 21. Tzourio-Mazoyer N, Landeau B, Papathanassiou D, et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 2002;15:273-89. 22. Rudroff T, Kindred JH, Koo PJ, Karki R, Hebert JR. Asymmetric glucose uptake in leg muslces of patients with multiple sclerosis during walking detected by [18F]-FDG PET/CT. NeuroRehabilitation 2014;35:813-23. 23. Kindred JH, Tuulari JJ, Bucci M, Kalliokoski KK, Rudroff T. Walking speed and brain glucose uptake are uncoupled in patients with multiple sclerosis. Front Hum Neurosci 2014;9:84. 24. Kindred JH, Ketelhut NB, Rudroff T. Glucose uptake heterogeneity of the leg muscles is similar between patients with multiple sclerosis and healthy controls during walking. Clin Biomech (Bristol, Avon) 2015; 30:159-65.
J.R. Hebert et al 25. Kindred JH, Koo PJ, Rudroff T. Case report: glucose uptake in spinal cord in patients with multiple sclerosis detected by 18F-fluorodeoxyglucose PET/CT after walking. Spinal Cord 2014; 52(Suppl 3):S11-3. 26. Sawilowsky S. Nonparametric tests of interaction in experimental design. Rev Educ Res 1990;60:91-126. 27. Fritz C, Morris P, Richler J. Effect size estimates: current use, calculations, and interpretation. J Exp Psychol Gen 2012;141:2-18. 28. Leone C, Patti F, Feys P. Measuring the cost of cognitive-motor dual tasking during walking in multiple sclerosis. Mult Scler 2015;21:123-31. 29. Hu Y, Xu Q, Li K, et al. Gender differences of brain glucose metabolic networks revealed by FDG-PET: evidence from a large cohort of 400 young adults. PLoS One 2013;8:e83821. 30. Lees C, Hopkins J. Effect of aerobic exercise on cognition, academic achievement, and psychosocial function in children: a systematic review of randomized control trials. Prev Chronic Dis 2013;10:E174. 31. Carvalho A, Rea IM, Parimon T, Cusack BJ. Physical activity and cognitive function in individuals over 60 years of age: a systematic review. Clin Interv Aging 2014;9:661-82. 32. Bridenbaugh SA, Kressig RW. Motor cognitive dual tasking: Early detection of gait impairment, fall risk and cognitive decline. Z Gerontol Geriatr 2015;48:15-21. 33. Lo OY, van Donkelaar P, Chou LS. Distracting visuospatial attention while approaching an obstacle reduces the toe-obstacle clearance. Exp Brain Res 2015;233:1137-44. 34. Learmonth YC, Sandroff BM, Pilutti LA, et al. Cognitive motor interference during walking in multiple sclerosis using an alternateletter alphabet task. Arch Phys Med Rehabil 2014;95:1498-503. 35. Kalron A, Dvir Z, Achiron A. Walking while talkingedifficulties incurred during the initial stages of multiple sclerosis disease process. Gait Posture 2010;32:332-5. 36. Rosti-Otajarvi E, Mantynen A, Koivisto K, Huhtala H, Hamalainen P. Patient-related factors may affect the outcome of neuropysychological rehabilitation in multiple sclerosis. J Neurol Sci 2013;334:106-11. 37. Prakash RS, Snook EM, Erickson KI, et al. Cardiorespiratory fitness: a predictor of cortical plasticity in multiple sclerosis. Neuroimage 2007; 34:1238-44. 38. Prakash RS, Snook EM, Motl RW, Kramer AF. Aerobic fitness is associated with gray matter volume and white matter integrity in multiple sclerosis. Brain Res 2010;1341:41-51. 39. Bove R, Musallam A, Healy BC, et al. Low testosterone is associated with disability in men with multiple sclerosis. Mult Scler 2014;20:1584-92. 40. Kurth F, Luders E, Sicotte NL, et al. Neuroprotective effects of testosterone treatment in men with multiple sclerosis. Neuroimage Clin 2014;4:454-60. 41. Tan RS. Testosterone effect on brain metabolism in elderly patients with Alzheimer’s disease: comparing two cases at different disease stages. Aging Clin Exp Res 2013;25:343-7.
www.archives-pmr.org
ORIGINAL RESEARCH
Cognitive-Motor Related Brain Activity During Walking: Differences Between Men and Women With Multiple Sclerosis Jeffrey R. Hebert, PT, PhD,a,b John H. Kindred, MS,c Marco Bucci, PhD,d Jetro J. Tuulari, MD,d Lisa A. Brenner, PhD,a Jeri E. Forster, PhD,a Phillip J. Koo, MD,e Thorsten Rudroff, PhDc From the aDepartment of Physical Medicine and Rehabilitation, University of Colorado School of Medicine, Aurora, CO; bDepartment of Neurology, University of Colorado School of Medicine, Aurora, CO; cDepartment of Health and Exercise Science, Colorado State University, Fort Collins, CO; dTurku Positron Emission Tomography Centre, University of Turku and Turku University Hospital, Turku, Finland; and eDivision of Nuclear Medicine and Molecular Imaging, Department of Radiology, University of Colorado School of Medicine, Aurora, CO.
Abstract Objective: To determine if sex differences in glucose uptake, a marker of brain activity, are present in brain regions that facilitate walking performance in persons with multiple sclerosis (MS). Design: Cross-sectional, observational pilot. Setting: University laboratory. Participants: Positron emission tomography with fluorine-18-labeled deoxyglucose (FDG) was performed on persons with MS and healthy controls (4 men and 4 women per group; NZ16) after a 15-minute walking test. Interventions: Not applicable. Main Outcome Measure: Brain activity was quantified as the mean standardized uptake value (SUV). Results: The mean SUV was significantly lower in the thalamus (PZ.029) and cerebellum (PZ.029) for men with MS compared with women with MS, but not for the prefrontal (PZ.057) or frontal (PZ.057) cortices. Similar nonsignificant trends were found for healthy controls. No mean SUV group sex interaction effects were found between the MS and healthy control groups (all P>.05). Conclusions: To our knowledge, this is the first study of brain activity sex differences based on FDG uptake in persons with MS during walking. Significantly less FDG uptake in the thalamus and cerebellum brain regions important for walking performance was found in men with MS compared with women with MS; however, these comparisons were not significantly different in the healthy control group. No differences in FDG uptake were found between the MS and healthy control groups in any of the brain regions examined. Results from this study provide pilot data for larger studies aimed at identifying underlying mechanisms responsible for accelerated disability in men with MS. Archives of Physical Medicine and Rehabilitation 2016;97:61-6 ª 2016 by the American Congress of Rehabilitation Medicine
Presented as a poster to the Americas Committee for Treatment and Research in Multiple Sclerosis e European Committee for Treatment and Research in Multiple Sclerosis, September 12, 2014, Boston, MA. Supported by the National Multiple Sclerosis Society (grant no. PP1907) and in part by the National Institutes of Health/National Center for Advancing Translational Sciences Colorado Clinical and Translational Sciences Institute (grant no. UL1 TR000154). North American Research Consortium on Multiple Sclerosis is supported in part by the Consortium of Multiple Sclerosis Centers (CMSC) and the CMSC Foundation. Disclosures: none.
Multiple sclerosis (MS) is a chronic, demyelinating degenerative disease of the central nervous system. Although women present with greater disease activity at a younger age and during earlier phases of the disease, overall disability and disease progression are accelerated in men, advancing with age and disease duration.1 Secondary to their aggressive advancement of physical disability, men with MS are considerably less physically active2 and present with higher rates of falls.3,4
0003-9993/15/$36 - see front matter ª 2016 by the American Congress of Rehabilitation Medicine http://dx.doi.org/10.1016/j.apmr.2015.09.015
62
J.R. Hebert et al
Effective physical activity (eg, walking) is essential to daily living and requires cognitive and motor interaction to achieve coordinated and automated walking performance. Disability among those with MS has largely been evaluated on walking; however, cognition as it pertains to daily physical tasks, cognitivemotor function (eg, mental attention, processing), is paramount to safe and efficient walking. Cognitive impairment affects up to 70% of persons with MS, beginning early in the disease process,5 and worsening with disease duration and progression.6 Impaired cognition in MS leads to restricted work and social activities and participation, resulting in poorer quality of life.7 Persons with MS present with different aspects of cognitive dysfunction, most frequently observed as limitations in processing speed, sustained attention, and visuospatial perception.8 Multiple cortical and subcortical brain structures, including the thalamus, cerebellum, and prefrontal and frontal cortices are responsible for proper performance and long-term preservation of these cognitive-motor domains. Moreover, men with MS consistently present with greater cognitive impairments that are associated with altered functioning in multiple brain regions,9 including the thalamus.10 Previously, positron emission tomography (PET) neuroimaging has been implemented to quantify resting-state glucose uptake and metabolism in multiple cortical and subcortical brain structures among persons with MS.11,12 Recommendations have been made to implement neuroimaging to identify biomarkers that may play important roles in cognitive behavior.13 Recent studies have found functional attenuation of the thalamus, cerebellum, and prefrontal and frontal cortices in persons with MS during cognitive task performance and resting states.14-18 However, to our knowledge, no prior studies have compared brain activity in regions responsible for cognitive-motor function based on sex during or after a walking task, leaving the reasons for distinct sex differences among persons with MS poorly understood. The purpose of our study was to compare fluorine-18-labeled deoxyglucose (FDG), a glucose analogue PET tracer, uptake in brain regions that are important for sustained walking performance in men and women with MS and healthy controls after walking. Because men with MS present with greater disability in cognition and walking, we hypothesized that men with MS would present with significantly less FDG uptake in the thalamus, cerebellum, and prefrontal and frontal cortices brain regions compared with women with MS and that the sex differences in those with MS would be greater compared with healthy participants. Our efforts are further supported by a recent topical review on sex differences in MS, which concluded that the lack of sex-related neuroimaging comparisons on this topic is a significant gap in research.19
Methods Participants and procedures The pilot study was a cross-sectional, observational design. Eight participants with MS (4 men, 4 women) were recruited through
List of abbreviations: FDG MS PET SUV
fluorine-18-labeled deoxyglucose multiple sclerosis positron emission tomography standardized uptake value
advertisements through a local MS center, and 8 healthy control participants (4 men, 4 women) were recruited by advertisement on a local medical campus. A local scientific ethics committee, guided by the ethical principles for human subject research and in accordance with the U.S. Department of Health and Human Services policy and regulations (45 CFR 46), approved this study. All participants gave written informed consent prior to their participation in the study. Participants with MS had confirmed diagnosis of MS, no changes in disease status 3 months prior to the study, and no greater than mild spasticity in the legs; were between 18 to 55 years of age; and were able to walk 15 minutes without assistance. Participants with MS completed the Patient Determined Disease Steps Scalea to determine disability level. The healthy control participants were without neurologic or musculoskeletal disorders. All participants reported performing 2 to 4d/wk of no greater than moderate level of exercise. After completion of informed consent, all participants underwent the same experiment protocol to decrease variability and bias. The experiment began with each participant walking on a treadmill at a self-selected speed for 15 minutes. Two minutes after walking started, they were injected with approximately equal to 321.9MBq of FDG into an antecubital vein. On completion of treadmill walking, participants underwent PET imaging. PET images were subsequently converted into standardized uptake value (SUV) parametric images using a voxel by voxel calculation with the formula SUVmeanZactivity (Bq/mL3)/(injected activity [MBq]/body weight [kg]), where SUVmean is the mean SUV. SUV parametric images were then normalized to a tracer specific template into Montreal Neurological Institute space similar to Tuulari et al.20 Images were smoothed at 10-mm full width at half maximum. The mean SUV of regions of interest within the automatic anatomic labeling template21 were extracted from the SUV parametric images using the MarsBaR toolkitb within the Statistical Parametric Mapping 8 toolboxc for MATLAB R2014a.d Consent and all aspects of the experiment were performed in a university medical campus laboratory. Power and sample size estimates were not performed for this pilot study because no prior preliminary data or study results were available. The methodology of this study has been reported previously.22-25
Data analysis Data, including the regions of interest, analysis was conducted using the nonparametric Mann-Whitney U test for within-group characteristics and sex differences. To compare mean SUVs between the groups based on sex (group sex), an adjusted rank transformation was implemented as a nonparametric test of interaction.26 All tests were 2-tailed, using .05 as the level of statistical significance. Mean and SD, median and range, and nonparametric standard effect size index (Cohen r) were calculated. Cohen r interpretations are as follows: large effect was 0.5, medium effect was 0.3, and small effect was 0.1.27
Results Participant characteristics Participant demographics and characteristics for the MS group are detailed in table 1, where age, MS diagnosis duration, disability level, and self-selected speed walk were similar between men and
www.archives-pmr.org
Brain activity during walking in multiple sclerosis Table 1
63
Participant characteristics: MS group
Variable
Men (nZ4)
Age (y) MS diagnosis duration (y) Disability (PDDS) Walk test speed (km/h)
45.505.51, 9.505.07, 1.751.50, 3.981.19,
45.0 (40e52) 11.5 (2e13) 2.0 (0e3) 3.7 (2.9e5.6)
Women (nZ4)
P*
44.2511.87, 48.0 (27e54) 8.257.89, 6.5 (1e19) 0.831.63, 2.0 (0e4) 3.940.47, 3.9 (3.4e4.5)
.886 .686 .886 .686
NOTE. Values are mean SD, median (range). Abbreviation: PDDS, Patient Determined Disease Steps. * P values assessed by Mann-Whitney U test.
women. The healthy control group sex comparisons of age (men: 35.5y, women: 40.3y; PZ.486) and walk test speed (men: 5.1km/h, women: 4.8km/h; PZ.343) were also similar.
Brain region glucose uptake Differences in mean SUVs in brain regions were found for the MS group (fig 1). Men with MS had significantly lower mean SUVs compared with women with MS in the thalamus and cerebellum and had nonsignificant differences in the prefrontal and frontal cortices (table 2); however, MS group sex comparisons for the thalamus, cerebellum, and prefrontal and frontal cortices had large standard effect size indexes (see table 2). Sex differences in the mean SUVs for the healthy control group were nonsignificant in the thalamus, cerebellum, and prefrontal and frontal cortices (see table 2); however, large standard effect size indexes were found for the thalamus, cerebellum, and prefrontal and frontal cortices (see table 2). The inability to identify these large standard effect size indexes as statistically significant for the healthy control group is likely explained by the small sample size. No differences in the mean SUVs were found when comparing the MS group with the healthy control group based on sex. No interactions were found for the thalamus (FZ.35; PZ.563), cerebellum (FZ.04; PZ.852), prefrontal cortex (FZ.08; PZ.779), and frontal cortex (FZ.04; PZ.852).
more specifically men with MS. Our pilot study results laid the foundation for future PET brain imaging studies of sex differences in MS during cognitive-motor dual tasking, including walking. Furthermore, these studies would be expected to help determine if the male brain might be more susceptible to the effects of MS, pinpointing which brain region performances are most associated with accelerated disability found in men with MS. Our results for both the MS group and healthy control group seem in contrast with a prior FDG PET imaging study on healthy, young adults.29 In this study by Hu et al,29 it was found that women had significantly less FDG uptake in the cerebellum and frontal cortex and greater uptake in the thalamus at resting state. However, it must be considered that the designs of the studies are different and that the walking task in our study may have resulted in a reverse of effects on brain activity in these brain regions for both persons with MS and healthy people. Higher levels of physical activity are associated with better cognition across the life span30,31; however, worsening cognition and cognitive distraction during walking (cognitive-motor dual tasking) lead to greater walking impairments and falls in aging, older adults.32 Persons with MS often present with impaired cognitive-motor dual tasking.28 Dual tasking (eg, distracted
Discussion The main results of our study were that FDG uptake in the thalamus and cerebellum was significantly less in men with MS compared with women with MS during 15 minutes of self-paced walking and that the same comparison showed similar trends, but failed to achieve significance, in the healthy control group. Our findings are in line with prior reports of less FDG uptake in the thalamus and cerebellum in mildly disabled persons with MS during a resting state.12 Large standard effect sizes of FDG uptake in the thalamus, cerebellum, and prefrontal and frontal cortices were also found when comparing men and women with MS, which were also observed in the healthy control, but at relatively lower index levels and without achieving statistical significance. Additionally, differences in FDG uptake sex comparisons between the MS and healthy control groups were not found. Walking is a skilled, coordinated task that requires intact cognitive-motor function, and for persons with MS cognitivemotor function is a problem.28 Because the thalamus, cerebellum, and prefrontal and frontal cortices are primary brain regions for cognitive-motor function, the findings from this study provide early evidence that this is likely more concerning for men, and www.archives-pmr.org
Fig 1 Sagittal, coronal, and transverse views, respectively, of areas of lower metabolic activity in men with MS compared with women with MS. Threshold at T>3.0, extent threshold kZ3000, and cluster level uncorrected for visual inspection. The areas overlap those included in the statistical comparisons. Brighter yellow represents areas of greater differences as indicated by the colored T score bar. Image was generated from full brain volume comparison in Statistical Parametric Mapping.
J.R. Hebert et al
P*
.51 .61 .51 .51 (5.4e7.5) (4.1e5.5) (5.1e7.0) (5.2e7.2) 5.8 4.8 5.8 5.9 6.110.97, 4.820.80, 5.940.91, 6.070.95,
Women Men r P*
.029 .029 .057 .057 5.600.25, 4.390.35, 5.540.40, 5.640.41,
Study limitations
NOTE. Values are mean SD, median (range). Abbreviation: r, Cohen r standard effect size index.27 * P values assessed by Mann-Whitney U test.
(4.2e4.9) (3.1e3.7) (3.9e5.1) (4.0e5.2) Thalamus Cerebellum Prefrontal cortex Frontal cortex
4.5 3.5 4.8 4.9 Men
4.500.30, 3.440.30, 4.630.53, 4.730.54,
Brain Region
Table 2
Brain glucose uptake (mean SUV)
MS Group
5.6 4.3 5.5 5.6
(5.3e5.9) (4.1e4.9) (5.1e6.0) (5.2e6.2) Women
.82 .82 .71 .71
5.270.88, 4.110.87, 5.311.02, 5.401.05,
4.9 3.7 4.8 4.9
(4.6e6.5) (3.6e5.4) (4.7e6.8) (4.8e7.0)
Healthy Control Group
visuospatial attention,33 mental processing,34) adversely effects walking and has been linked to higher fall risk even in the early stages of MS.35 A possible reason for these outcomes is dysfunctional activity in brain regions responsible for cognitivemotor function (eg, thalamus, cerebellum). The reasons for the variability and limited treatment effectiveness for cognition-motor abilities in persons with MS are not well known; however, certain patient characteristics may play key roles. To this point, it is important for future studies to test changes in brain region FDG uptake from resting state to exerciserelated training states in persons with MS and healthy controls to identify important neural biomarkers responsible for differences in cognitive-motor performance and if variability in activity is sex dependent. Because it has been reported that men with MS benefit greater from neuropsychologic rehabilitation,36 and better aerobic fitness is associated with improved cognitive function37 and gray matter volume and white matter integrity38 in MS, it is important to know if outcomes from treatment approaches (eg, exercise, exercise cognitive dual-task training) follow similar sex-related influences. To date, no studies have investigated sex differences during these interventions; however, the results from our pilot study may provide early evidence that could lead to the development of new exercise and cognitive-motor dual-task treatment strategies. Additionally, it will be important to determine if metabolism and function of cognitive-motor brain structures are amiable to change after training or if they are irremediable and require compensation when structuring treatment approaches. Finally, reports are emerging suggesting that low levels of sexspecific hormones are associated with greater disability in women19 and men39 with MS and that higher levels may play an important role in neuroprotection.40 What is not known at this time is the underlying mechanisms of these effects.19 FDG PET imaging has been used to quantify brain activity in older adult men with Alzheimer disease, where changes in cerebral glucose metabolism were found in multiple brain regions after testosterone therapy.41 Although our study was not treatment based and we did not measure sex-specific hormone levels in our participants, we demonstrate the feasibility and utility of FDG PET imaging in similar hormone-based therapy studies in persons with MS.
.200 .114 .200 .200
r
64
There are limitations in this study. The most notable limitation is the small sample size, which resulted in low power and could explain the observed large effect sizes for the healthy control comparisons that did not achieve statistical significance. The sample size also necessitated the use of nonparametric tests, which have lower power, but by their use, decreased the chance of committing type I errors in this study. To our knowledge, there is no prior evidence of brain mean SUVs during or after exercise in persons with MS and healthy people, limiting our ability to compare effect sizes found in our study with prior study results. Although our study is unable to determine if the mean SUVs in the groups are clinically meaningful, our pilot study provides original preliminary data that future studies are able to apply to the development of larger studies to confirm and clarify our findings and determine what brain regions are most responsible for walking and cognitive-motor sex differences by implementing parametric multigroup comparisons, interaction effects, and covariate analyses. These larger studies will also help lead to establish clinically meaningful effect sizes of brain mean SUVs in persons with www.archives-pmr.org
Brain activity during walking in multiple sclerosis
65
MS and healthy people during exercise. Additionally, because of the cross-sectional design, our study was unable to determine cause and effect. Disability and other characteristics were similar between the sexes for the participants with MS; however, we did not qualify lesion involvement or quantify lesion load of the brain regions in this preliminary study. Although we are unable to report on lesion involvement, we did control to some extent for possible active lesion involvement globally by excluding prospective participants who had an MS-related relapse 3 months prior. Additionally, to the extent we could without concurrent magnetic resonance imaging data, we addressed this issue concurrently by performing weighted analysis of the brain regions of interest based on summative regional volume, controlling for volume variability that could be related to preexisting, chronic lesion involvement among the participants. Normalization to the tracer-specific template controls for volume variability between subjects. Although normalization through transformation matrices obtained from individual T1weighted magnetic resonance images might yield more precise results, we do not consider this a major confound. In future studies, the magnetic resonance imaging measurements would be important to quantify lesion load within individual brains because impaired white matter integrity might affect cortical glucose metabolism. Finally, we implemented a single valid measure of disability in the participants with MS, the Patient Determined Disease Steps Scale; however, this study could have been strengthened by including additional measures of function and disability for a more complete understanding of these factors in the MS group. Future studies will benefit from this approach so that the role of functional compensation in persons with MS can be considered in the determination of brain activity during functional task performance (eg, walking, cognitive-motor).
Suppliers
Conclusions
1. Tremlett H, Zhao Y, Joseph J, Devonshire V, UBCMS Clinic Neurologists. Relapses in multiple sclerosis are age- and time-dependent. J Neurol Neurosurg Psychiatry 2008;79:1368-74. 2. Anens E, Emtner M, Zetterberg L, Hellstro¨m K. Physical activity in subjects with multiple sclerosis with focus on gender differences: a survey. BMC Neurol 2014;14:47. 3. Gunn H, Creanor S, Haas B, Marsden J, Freeman J. Frequency, characteristics, and consequences of falls in multiple sclerosis: findings from a cohort study. Arch Phys Med Rehabil 2014;95: 538-45. 4. Nilsaga˚rd Y, Gunn H, Freeman J, et al. Falls in people with MSean individual data meta-analysis from studies from Australia, Sweden, United Kingdom and the United States. Mult Scler 2015;21:92-100. 5. Loitfelder M, Fazekas F, Koschutnig K, et al. Brain activity changes in cognitive networks in relapsing-remitting multiple sclerosis - insights from a longitudinal FMRI study. PLoS One 2014;9:e93715. 6. Chiaravalloti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurol 2008;7:1139-51. 7. Rao SM, Leo GJ, Ellington L, Nauertz T, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. II. Impact on employment and social functioning. Neurology 1991;41:692-6. 8. Rao SM, Leo GJ, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology 1991;41:685-91. 9. Koenig KA, Lowe MJ, Lin J, et al. Sex differences in resting-state functional connectivity in multiple sclerosis. AJNR Am J Neuroradiol 2013;34:2304-11. 10. Schoonheim MM, Vigeveno RM, Rueda Lopes FC, et al. Sex-specific extent and severity of white matter damage in multiple sclerosis: implications for cognitive decline. Hum Brain Mapp 2014;35:2348-58.
To our knowledge, this is the first study to identify sex differences in brain FDG uptake in persons with MS and healthy controls during a walking task. FDG uptake in the thalamus and cerebellum, brain regions vital to walking and cognitive-motor function, was significantly less in men with MS compared with women with MS. Moreover, less FDG uptake in the thalamus, cerebellum, and prefrontal and frontal cortices was found for men in both the MS and healthy control groups. The suggestion that men may possess inherent, preclinical vulnerability to the neuropathologic processes of MS is not supported by the actual results, but it deserves to be tested in a larger sample of healthy subjects. This study provides the feasibility and utility of FDG PET aimed at detecting brain region glucose uptake and activity during a physical performance task. Based on our approach and pilot results, larger studies should measure brain FDG uptake in persons with MS and healthy people during walking and cognitive-motor dual-task performance. Our study shows that this evidence may be more important for men with MS. Longitudinal mechanistic studies comparing brain FDG uptake with cognitive-motor performance may help identify biomarkers that are responsible for the disparate acceleration of disability in men with MS. Additionally, studies need to determine if brain FDG uptake has the potential to change as a result of exercise and cognitive-related interventions and if these changes are sex dependent.
www.archives-pmr.org
a. Patient Determined Disease Steps Scale; North American Research Consortium on Multiple Sclerosis. Available at: http://narcoms.org. b. MarsBaR. Available at: http://marsbar.sourceforge.net. c. Statistical Parametric Mapping 8; Wellcome Trust Centre. Available at: http://www.fil.ion.ucl.ac.uk/spm/. d. MATLAB R2014a; MathWorks.
Keywords Brain; Multiple Rehabilitation
sclerosis;
Positron-emission
tomography;
Corresponding author Jeffrey R. Hebert, PT, PhD, Departments of Physical Medicine and Rehabilitation and Neurology, University of Colorado School of Medicine, 12631 E 17th Ave, Mail Stop F493, Aurora, CO 80045. E-mail address: [email protected].
Acknowledgment We thank Ramesh Karki, MS, for his help with data collection, image acquisition, and image analysis.
References
66 11. Sorensen PS, Jonsson A, Mathiesen HK, et al. The relationship between MRI and PET changes and cognitive disturbances in MS. J Neurol Sci 2006;245:99-102. 12. Derache N, Marie RM, Constans JM, Defer GL. Reduced thalamic and cerebellar rest metabolism in relapsing-remitting multiple sclerosis, a positron emission tomography study: correlations to lesion load. J Neurol Sci 2006;245:103-9. 13. Basford J, Malec J. A brief overview and assessment of the role and benefits of cognitive rehabilitation. Arch Phys Med Rehabil 2015;96: 977-80. 14. Wojtowicz M, Mazerolle EL, Bhan V, Fisk JD. Altered functional connectivity and performance variability in relapsing-remitting multiple sclerosis. Mult Scler 2014;20:1453-63. 15. Kollndorfer K, Krajnik J, Woitek R, Freiherr J, Prayer D, Schopf V. Altered likelihood of brain activation in attention and working memory networks in patients with multiple sclerosis: an ALE metaanalysis. Neurosci Biobehav Rev 2013;37:2699-708. 16. Rocca MA, Mesaros S, Pagani E, Sormani MP, Comi G, Filippi M. Thalamic damage and long-term progression of disability in multiple sclerosis. Radiology 2010;257:463-9. 17. Rocca MA, Valsasina P, Hulst HE, et al. Functional correlates of cognitive dysfunction in multiple sclerosis: a multicenter fMRI study. Hum Brain Mapp 2014;35:5799-814. 18. Ruet A, Hamel D, Deloire MS, Charre-Morin J, Saubusse A, Brochet B. Information processing speed impairment and cerebellar dysfunction in relapsing-remitting multiple sclerosis. J Neurol Sci 2014;347:246-50. 19. Bove R, Chitnis T. The role of gender and sex hormones in determining the onset and outcome of multiple sclerosis. Mult Scler 2014; 20:520-6. 20. Tuulari JJ, Karlsson HK, Hirvonen J, et al. Weight loss after bariatric surgery reverses insulin-induced increases in brain glucose metabolism of the morbidly obese. Diabetes 2013;62:2747-51. 21. Tzourio-Mazoyer N, Landeau B, Papathanassiou D, et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 2002;15:273-89. 22. Rudroff T, Kindred JH, Koo PJ, Karki R, Hebert JR. Asymmetric glucose uptake in leg muslces of patients with multiple sclerosis during walking detected by [18F]-FDG PET/CT. NeuroRehabilitation 2014;35:813-23. 23. Kindred JH, Tuulari JJ, Bucci M, Kalliokoski KK, Rudroff T. Walking speed and brain glucose uptake are uncoupled in patients with multiple sclerosis. Front Hum Neurosci 2014;9:84. 24. Kindred JH, Ketelhut NB, Rudroff T. Glucose uptake heterogeneity of the leg muscles is similar between patients with multiple sclerosis and healthy controls during walking. Clin Biomech (Bristol, Avon) 2015; 30:159-65.
J.R. Hebert et al 25. Kindred JH, Koo PJ, Rudroff T. Case report: glucose uptake in spinal cord in patients with multiple sclerosis detected by 18F-fluorodeoxyglucose PET/CT after walking. Spinal Cord 2014; 52(Suppl 3):S11-3. 26. Sawilowsky S. Nonparametric tests of interaction in experimental design. Rev Educ Res 1990;60:91-126. 27. Fritz C, Morris P, Richler J. Effect size estimates: current use, calculations, and interpretation. J Exp Psychol Gen 2012;141:2-18. 28. Leone C, Patti F, Feys P. Measuring the cost of cognitive-motor dual tasking during walking in multiple sclerosis. Mult Scler 2015;21:123-31. 29. Hu Y, Xu Q, Li K, et al. Gender differences of brain glucose metabolic networks revealed by FDG-PET: evidence from a large cohort of 400 young adults. PLoS One 2013;8:e83821. 30. Lees C, Hopkins J. Effect of aerobic exercise on cognition, academic achievement, and psychosocial function in children: a systematic review of randomized control trials. Prev Chronic Dis 2013;10:E174. 31. Carvalho A, Rea IM, Parimon T, Cusack BJ. Physical activity and cognitive function in individuals over 60 years of age: a systematic review. Clin Interv Aging 2014;9:661-82. 32. Bridenbaugh SA, Kressig RW. Motor cognitive dual tasking: Early detection of gait impairment, fall risk and cognitive decline. Z Gerontol Geriatr 2015;48:15-21. 33. Lo OY, van Donkelaar P, Chou LS. Distracting visuospatial attention while approaching an obstacle reduces the toe-obstacle clearance. Exp Brain Res 2015;233:1137-44. 34. Learmonth YC, Sandroff BM, Pilutti LA, et al. Cognitive motor interference during walking in multiple sclerosis using an alternateletter alphabet task. Arch Phys Med Rehabil 2014;95:1498-503. 35. Kalron A, Dvir Z, Achiron A. Walking while talkingedifficulties incurred during the initial stages of multiple sclerosis disease process. Gait Posture 2010;32:332-5. 36. Rosti-Otajarvi E, Mantynen A, Koivisto K, Huhtala H, Hamalainen P. Patient-related factors may affect the outcome of neuropysychological rehabilitation in multiple sclerosis. J Neurol Sci 2013;334:106-11. 37. Prakash RS, Snook EM, Erickson KI, et al. Cardiorespiratory fitness: a predictor of cortical plasticity in multiple sclerosis. Neuroimage 2007; 34:1238-44. 38. Prakash RS, Snook EM, Motl RW, Kramer AF. Aerobic fitness is associated with gray matter volume and white matter integrity in multiple sclerosis. Brain Res 2010;1341:41-51. 39. Bove R, Musallam A, Healy BC, et al. Low testosterone is associated with disability in men with multiple sclerosis. Mult Scler 2014;20:1584-92. 40. Kurth F, Luders E, Sicotte NL, et al. Neuroprotective effects of testosterone treatment in men with multiple sclerosis. Neuroimage Clin 2014;4:454-60. 41. Tan RS. Testosterone effect on brain metabolism in elderly patients with Alzheimer’s disease: comparing two cases at different disease stages. Aging Clin Exp Res 2013;25:343-7.
www.archives-pmr.org
