Spinocerebellar ataxia (SCA) is a degenerative cerebellar disease, causing progressive impairment of gait and balance in adults. To identify the ideal subjects for disease-modifying therapies it is critical to identify biomarkers for the earliest stages of SCA.
Objective
We investigated whether prefrontal cortex activity is increased during walking in in early SCA or in pre-manifest SCA compared to healthy control subjects.
Methods
Sixteen participants with genetically determined SCA and 15 age-matched healthy controls participated in the study. The SARA was administered by a movement disorders specialist before the gait assessment. An 8-channel, mobile, fNIRS, with 2 reference channels, was used to record changes in oxygenated hemoglobin (HbO2) and deoxygenated hemoglobin within the PFC. Participants walked for 2-minutes at a comfortable pace while wearing wireless, inertial sensors to derive gait characteristics.
Results
Of the 16 individuals with SCA, 9 were classified as pre-manifest (SARA < 3) and 7 as early SCA (SARA < 10). PFC activity (HbO2) while walking was greater than controls of similar age in people with SCA. Increased PFC activity was also present even in the pre-manifest stage of SCA. Increase in PFC activity was related to worse gait (double-support time and toe-out angle).
Conclusions
PFC activity is increased in pre-manifest SCA, even when clinical scores are normal in the pre-manifest stage of the disease, and may serve as a biomarker that precedes onset of clinical disease. Increased PFC activity is consistent less automatic, cortical control of gait to compensate for impaired automatic, cerebellar control, even in early stages of ataxia.
GlobasCdu MontcelSTBalikoL, et al. Early symptoms in spinocerebellar ataxia type 1, 2, 3, and 6. Mov Disord. 2008;23(15):2232-2238. doi:10.1002/mds.22288
2.
LuoLWangJLoRY, et al. The initial symptom and motor progression in spinocerebellar ataxias. Cerebellum. 2017;16(3):615-622. doi:10.1007/s12311-016-0836-3
PilottoFDel BondioAPuccioH.Hereditary ataxias: from bench to clinic, where do we stand?Cells. 2024;13(4):319. doi:10.3390/cells13040319
5.
JacobiHdu MontcelSTBauerP, et al. Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: a longitudinal cohort study. Lancet Neurol. 2015;14(11):1101-1108. doi:10.1016/s1474-4422(15)00202-1
6.
AshizawaTÖzGPaulsonHL.Spinocerebellar ataxias: prospects and challenges for therapy development. Nat Rev Neurol. 2018;14(10):590-605. doi:10.1038/s41582-018-0051-6
7.
BuijsenRAMToonenLJAGardinerSLvan Roon-MomWMC. Genetics, mechanisms, and therapeutic progress in polyglutamine spinocerebellar ataxias. Neurotherapeutics. 2019;16(2):263-286. doi:10.1007/s13311-018-00696-y
8.
LinCCAshizawaTKuoSH.Collaborative efforts for spinocerebellar ataxia research in the United States: CRC-SCA and READISCA. Front Neurol. 2020;11:902. doi:10.3389/fneur.2020.00902
9.
KlockgetherTAshizawaTBraisB, et al. Paving the way toward meaningful trials in ataxias: an ataxia global initiative perspective. Mov Disord. 2022;37(6):1125-1130. doi:10.1002/mds.29032
10.
RubinszteinDCOrrHT.Diminishing return for mechanistic therapeutics with neurodegenerative disease duration?: there may be a point in the course of a neurodegenerative condition where therapeutics targeting disease-causing mechanisms are futile. Bioessays. 2016;38(10):977-980. doi:10.1002/bies.201600048
11.
ShahVVRodriguez-LabradaRHorakFB, et al. Gait variability in spinocerebellar ataxia assessed using wearable inertial sensors. Mov Disord. 2021;36(12):2922-2931. doi:10.1002/mds.28740
12.
Velázquez-PérezLRodriguez-LabradaRGonzález-GarcésY, et al. Prodromal spinocerebellar ataxia type 2 subjects have quantifiable gait and postural sway deficits. Mov Disord. 2021;36(2):471-480. doi:10.1002/mds.28343
13.
Velázquez-PérezLSeifriedCAbeleM, et al. Saccade velocity is reduced in presymptomatic spinocerebellar ataxia type 2. Clin Neurophysiol. 2009;120(3):632-635. doi:10.1016/j.clinph.2008.12.040
14.
MaasRPvan GaalenJKlockgetherTvan de WarrenburgBP.The preclinical stage of spinocerebellar ataxias. Neurology. 2015;85(1):96-103. doi:10.1212/wnl.0000000000001711
15.
SobanskaACzerwoszLSulekARolaRStepniakIRakowiczM.Quantitative evaluation of stance as a sensitive biomarker of postural ataxia development in preclinical SCA1 mutation carriers. Cerebellum. 2024;23(5):1882-1891. doi:10.1007/s12311-024-01679-w
16.
ChristovaPAndersonJHGomezCM.Impaired eye movements in presymptomatic spinocerebellar ataxia type 6. Arch Neurol. 2008;65(4):530-536. doi:10.1001/archneur.65.4.530
17.
KimDHKimRLeeJYLeeKM.Clinical, imaging, and laboratory markers of premanifest spinocerebellar ataxia 1, 2, 3, and 6: a systematic review. J Clin Neurol. 2021;17(2):187-199. doi:10.3988/jcn.2021.17.2.187
18.
JoersJMDeelchandDKLyuT, et al. Neurochemical abnormalities in premanifest and early spinocerebellar ataxias. Ann Neurol. 2018;83(4):816-829. doi:10.1002/ana.25212
19.
ParkYWJoersJMGuoB, et al. Assessment of cerebral and cerebellar white matter microstructure in spinocerebellar ataxias 1, 2, 3, and 6 using diffusion MRI. Front Neurol. 2020;11:411. doi:10.3389/fneur.2020.00411
20.
TakakusakiK.Functional neuroanatomy for posture and gait control. J Mov Disord. 2017;10(1):1-17. doi:10.14802/jmd.16062
21.
TakakusakiKTomitaNYanoM.Substrates for normal gait and pathophysiology of gait disturbances with respect to the basal ganglia dysfunction. J Neurol. 2008;255(Suppl 4):19-29. doi:10.1007/s00415-008-4004-7
22.
BaekCYKimHDYooDYKangKYLeeJW.Change in activity patterns in the prefrontal cortex in different phases during the dual-task walking in older adults. J Neuroeng Rehabil. 2023;20(1):86. doi:10.1186/s12984-023-01211-x
23.
CaliandroPMasciulloMPaduaL, et al. Prefrontal cortex controls human balance during overground ataxic gait. Restor Neurol Neurosci. 2012;30(5):397-405. doi:10.3233/rnn-2012-120239
24.
CaliandroPSerraoMPaduaL, et al. Prefrontal cortex as a compensatory network in ataxic gait: a correlation study between cortical activity and gait parameters. Restor Neurol Neurosci. 2015;33(2):177-187. doi:10.3233/rnn-140449
25.
MiharaMMiyaiIHatakenakaMKubotaKSakodaS.Role of the prefrontal cortex in human balance control. NeuroImage. 2008;43(2):329-336. doi:10.1016/j.neuroimage.2008.07.029
26.
Schmitz-HübschTdu MontcelSTBalikoL, et al. Scale for the assessment and rating of ataxia. Neurology. 2006;66(11):1717-1720. doi:10.1212/01.wnl.0000219042.60538.92
27.
RiccioCAReynoldsCRLowePMooreJJ.The continuous performance test: a window on the neural substrates for attention?Arch Clin Neuropsychol. 2002;17(3):235-272.
28.
HeroldFWiegelPScholkmannFThiersAHamacherDSchegaL.Functional near-infrared spectroscopy in movement science: a systematic review on cortical activity in postural and walking tasks. Neurophotonics. 2017;4(4):041403. doi:10.1117/1.NPh.4.4.041403
29.
VitorioRStuartSRochesterLAlcockLPantallA.fNIRS response during walking – artefact or cortical activity? A systematic review. Neurosci Biobehav Rev. 2017;83:160–172. doi:10.1016/j.neubiorev.2017.10.002
30.
TsuzukiDDanI.Spatial registration for functional near-infrared spectroscopy: from channel position on the scalp to cortical location in individual and group analyses. Neuroimage. 2014;85(Pt 1):92-103. doi:10.1016/j.neuroimage.2013.07.025
CuiXBraySReissAL.Functional near infrared spectroscopy (NIRS) signal improvement based on negative correlation between oxygenated and deoxygenated hemoglobin dynamics. Neuroimage. 2010;49(4):3039-3046. doi:10.1016/j.neuroimage.2009.11.050
33.
VitorioRStuartSManciniM.Executive control of walking in people with Parkinson’s disease with freezing of gait. Neurorehabil Neural Repair. 2020;34(12):1138-1149. doi:10.1177/1545968320969940
34.
MorrisRStuartSMcBarronGFinoPCManciniMCurtzeC.Validity of Mobility Lab (version 2) for gait assessment in young adults, older adults and Parkinson’s disease. Physiol Meas. 2019;40(9):095003. doi:10.1088/1361-6579/ab4023
35.
BuckleyEMazzaCMcNeillA.A systematic review of the gait characteristics associated with cerebellar ataxia. Gait Posture. 2018;60:154-163. doi:10.1016/j.gaitpost.2017.11.024
36.
ClarkDJ.Automaticity of walking: functional significance, mechanisms, measurement and rehabilitation strategies. Front Hum Neurosci. 2015;9:246. doi:10.3389/fnhum.2015.00246
37.
RiemannBLLephartSM.The sensorimotor system, part I: the physiologic basis of functional joint stability. J Athl Train. 2002;37(1):71-79.
38.
MortonSMBastianAJ.Mechanisms of cerebellar gait ataxia. Cerebellum. 2007;6(1):79-86. doi:10.1080/14734220601187741
39.
MantoMSerraoMFilippo CastigliaS, et al. Neurophysiology of cerebellar ataxias and gait disorders. Clin Neurophysiol Pract. 2023;8:143-160. doi:10.1016/j.cnp.2023.07.002
40.
WalterJTAlviñaKWomackMDChevezCKhodakhahK.Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. Nat Neurosci. 2006;9(3):389-397. doi:10.1038/nn1648
41.
IlgWMilneSSchmitz-HübschT, et al. Quantitative gait and balance outcomes for ataxia trials: consensus recommendations by the ataxia global initiative working group on digital-motor biomarkers. Cerebellum. 2024;23(4):1566-1592. doi:10.1007/s12311-023-01625-2
42.
CollinsSHKuoAD.Two independent contributions to step variability during over-ground human walking. PloS One. 2013;8(8):e73597. doi:10.1371/journal.pone.0073597
43.
Frenkel-ToledoSGiladiNPeretzCHermanTGruendlingerLHausdorffJM.Effect of gait speed on gait rhythmicity in Parkinson’s disease: variability of stride time and swing time respond differently. J Neuroeng Rehabil. 2005;2:23. doi:10.1186/1743-0003-2-23
44.
GilatMBellPTEhgoetz MartensKA, et al. Dopamine depletion impairs gait automaticity by altering cortico-striatal and cerebellar processing in Parkinson’s disease. Neuroimage. 2017;152:207-220. doi:10.1016/j.neuroimage.2017.02.073
45.
PetersonDSHorakFB.Neural control of walking in people with Parkinsonism. Physiology. 2016;31(2):95-107. doi:10.1152/physiol.00034.2015
46.
YogevGGiladiNPeretzCSpringerSSimonESHausdorffJM.Dual tasking, gait rhythmicity, and Parkinson’s disease: which aspects of gait are attention demanding?Eur J Neurosci. 2005;22(5):1248-1256. doi:10.1111/j.1460-9568.2005.04298.x
47.
CallisayaMLBlizzardLSchmidtMDMcGinleyJLSrikanthVK.Ageing and gait variability—a population-based study of older people. Age Ageing. 2010;39(2):191-197. doi:10.1093/ageing/afp250
48.
WuehrMSchnieppRSchlickC, et al. Sensory loss and walking speed related factors for gait alterations in patients with peripheral neuropathy. Gait Posture. 2014;39(3):852-858. doi:10.1016/j.gaitpost.2013.11.013
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
