Generic placeholder image

Endocrine, Metabolic & Immune Disorders - Drug Targets

Author(s): Guven Toprak, Lutfu Hanoglu, Tansel Cakir, Bahar Guntekin, Halil Aziz Velioglu and Burak Yulug*

DOI: 10.2174/1871530322666220131120349

DownloadDownload PDF Flyer Cite As
DLPF Targeted Repetitive Transcranial Magnetic Stimulation Improves Brain Glucose Metabolism Along with the Clinical and Electrophysiological Parameters in CBD Patients

Page: [415 - 424] Pages: 10

  • * (Excluding Mailing and Handling)

Abstract

Background: Corticobasal Degeneration (CBD) is a rare neurological disease caused by the pathological accumulation of tau protein. The primary pathological features of CBD include progressive neurodegenerative processes resulting in remarkable frontoparietal and basal ganglia atrophy.

Objective: Like in many other neurodegenerative disorders, there is still no effective disease-modifying drug therapy in CBD. Therefore, the development of new treatment methods is of great importance. In this study, we aimed to assess the stimulating effects of high-frequency DLPFC rTMS on the motor, cognitive and behavioral disturbances in four CBD patients.

Methods: Four (three females, one male) CBD patients who had been diagnosed as CBD were enrolled in this study. Patients were evaluated before and after the rTMS procedure regarding the motor, neuropsychometric and behavioral tests. The results of statistical analysis of behavioral and neuropsychometric evaluation were assessed via SPSS 18.0 package program. Data are expressed as mean, standard deviation. Before and after values of the groups were compared with the Wilcoxon sign rank test, and p<0.05 was considered significant.

Results: We have provided strong preliminary evidence that the improvement in clinical parameters was associated with the normalizations of the theta activity and glucose metabolism.

Conclusion: Our current results are consistent with some previous trials showing a strong association between DLPFC targeted rTMS and electrophysiological normalizations in the left DLPFC.

Keywords: rTMS, CBD, cognitive scores, behavioral scores, FDG-PET, QEEG.

[1]
Wilfong, L.; Edwards, N.E.; Yehle, K.S.; Faha, K.R. Frontotemporal dementia: Identification and management. J. Nurse Pract., 2016, 155(5), 277-282.
[http://dx.doi.org/10.1016/j.nurpra.2015.08.006]
[2]
Pasquier, F. New behavioural variant FTD criteria and clinical practice. Rev. Neurol. (Paris), 2013, 169(10), 799-805.
[http://dx.doi.org/10.1016/j.neurol.2013.08.002] [PMID: 24034691]
[3]
Marsili, L.; Suppa, A.; Berardelli, A.; Colosimo, C. Therapeutic interventions in parkinsonism: Corticobasal degeneration. Parkinsonism Relat. Disord., 2016, 22(Suppl. 1), S96-S100.
[http://dx.doi.org/10.1016/j.parkreldis.2015.09.023] [PMID: 26382843]
[4]
Armstrong, MJ.; Litvan, I.; Lang, AE.; Bak, TH.; Bhatia, KP.; Borroni, B. Criteria for the diagnosis of corticobasal degeneration. Neurology, 2013, 80(5), 496-503.
[http://dx.doi.org/10.1212/WNL.0b013e31827f0fd1] [PMID: 23359374]
[5]
Alexander, S.K.; Rittman, T.; Xuereb, J.H.; Bak, T.H.; Hodges, J.R.; Rowe, J.B. Validation of the new consensus criteria for the diagnosis of corticobasal degeneration. J. Neurol. Neurosurg. Psychiatry, 2014, 85(8), 925-929.
[http://dx.doi.org/10.1136/jnnp-2013-307035] [PMID: 24521567]
[6]
Mokaberi, P.; Babayan-Mashhadi, F.; Amiri Tehrani Zadeh, Z.; Saberi, M.R.; Chamani, J. Analysis of the interaction behavior between Nano-Curcumin and two human serum proteins: Combining spectroscopy and molecular stimulation to understand protein-protein interaction. J. Biomol. Struct. Dyn., 2021, 39(9), 3358-3377.
[http://dx.doi.org/10.1080/07391102.2020.1766570] [PMID: 32397834]
[7]
Sadeghzadeh, F.; Entezari, A.A.; Behzadian, K.; Habibi, K.; Amiri-Tehranizadeh, Z.; Asoodeh, A.; Saberi, M.R.; Chamani, J. Characterizing the binding of angiotensin converting Enzyme I inhibitory peptide to human hemoglobin: Influence of electromagnetic fields. Protein Pept. Lett., 2020, 27(10), 1007-1021.
[http://dx.doi.org/10.2174/1871530320666200425203636] [PMID: 32334494]
[8]
Sohrabi, T.; Hosseinzadeh, M.; Beigoli, S.; Saberi, M.R.; Chamani, J. Probing the binding of lomefloxacin to a calf thymus DNA-histone H1 complex by multi-spectroscopic and molecular modeling techniques. J. Mol. Liq., 2018, 256, 127-138.
[http://dx.doi.org/10.1016/j.molliq.2018.02.031]
[9]
Sani, F.D.; Shakibapour, N.; Beigoli, S.; Sadeghian, H.; Hosainzadeh, M.; Chamani, J. Changes in binding affinity between ofloxacin and calf thymus DNA in the presence of histone H1: Spectroscopic and molecular modeling investigations. J. Lumin., 2018, 203, 599-608.
[http://dx.doi.org/10.1016/j.jlumin.2018.06.083]
[10]
Chamani, J. Energetic domains analysis of bovine α-lactalbumin upon interaction with copper and dodecyl trimethylammonium bromide. J. Mol. Struct., 2010, 979(1-3), 227-234.
[http://dx.doi.org/10.1016/j.molstruc.2010.06.035]
[11]
Kamshad, M.; Jahanshah Talab, M.; Beigoli, S.; Sharifirad, A.; Chamani, J. Use of spectroscopic and zeta potential techniques to study the interaction between lysozyme and curcumin in the presence of silver nanoparticles at different sizes. J. Biomol. Struct. Dyn., 2019, 37(8), 2030-2040.
[http://dx.doi.org/10.1080/07391102.2018.1475258] [PMID: 29757090]
[12]
Mokaberi, P.; Reyhani, V.; Tehranizadeh, Z.A.; Saberi, M.R.; Beigoli, S.; Samandar, F.; Chamani, J. New insights into the binding behavior of lomefloxacin and human hemoglobin using biophysical techniques: Binary and ternary approaches. New J. Chem., 2019, 43(21), 8132-8145.
[http://dx.doi.org/10.1039/C9NJ01048C]
[13]
Sharifi-Rad, A.; Mehrzad, J.; Darroudi, M.; Saberi, M.R.; Chamani, J. Oil-in-water nanoemulsions comprising Berberine in olive oil: Biological activities, binding mechanisms to human serum albumin or holo-transferrin and QMMD simulations. J. Biomol. Struct. Dyn., 2021, 39(3), 1029-1043.
[http://dx.doi.org/10.1080/07391102.2020.1724568] [PMID: 32000592]
[14]
Lamb, R.; Rohrer, J.D.; Lees, A.J.; Morris, H.R. Progressive supranuclear palsy and corticobasal degeneration: Pathophysiology and treatment options. Curr. Treat. Options Neurol., 2016, 18(9), 42.
[http://dx.doi.org/10.1007/s11940-016-0422-5] [PMID: 27526039]
[15]
Berardelli, I.; Belvisi, D.; Pasquini, M.; Fabbrini, A.; Petrini, F.; Fabbrini, G. Treatment of psychiatric disturbances in hypokinetic movement disorders. Expert Rev. Neurother., 2019, 19(10), 965-981.
[http://dx.doi.org/10.1080/14737175.2019.1636648] [PMID: 31241368]
[16]
Moretti, D.V. Available and future treatments for atypical parkinsonism. A systematic review. CNS Neurosci. Ther., 2019, 25(2), 159-174.
[http://dx.doi.org/10.1111/cns.13068] [PMID: 30294976]
[17]
Turaga, S.P.; Mridula, R.; Borgohain, R. Cerebral glucose metabolism, clinical, neuropsychological, and radiological profile in patients with corticobasal syndrome. Neurol. India, 2013, 61(1), 7-11.
[http://dx.doi.org/10.4103/0028-3886.107916] [PMID: 23466832]
[18]
O’Reardon, J.P.; Solvason, H.B.; Janicak, P.G.; Sampson, S.; Isenberg, K.E.; Nahas, Z.; McDonald, W.M.; Avery, D.; Fitzgerald, P.B.; Loo, C.; Demitrack, M.A.; George, M.S.; Sackeim, H.A. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: A multisite randomized controlled trial. Biol. Psychiatry, 2007, 62(11), 1208-1216.
[http://dx.doi.org/10.1016/j.biopsych.2007.01.018] [PMID: 17573044]
[19]
Civardi, C.; Pisano, F.; Delconte, C.; Collini, A.; Monaco, F. Effects of slow repetitive transcranial magnetic stimulation in patients with corticobasal syndrome. Neurol. Sci., 2015, 36(6), 1007-1009.
[http://dx.doi.org/10.1007/s10072-015-2115-3] [PMID: 25693871]
[20]
Hu, W.T.; Rippon, G.W.; Boeve, B.F.; Knopman, D.S.; Petersen, R.C.; Parisi, J.E.; Josephs, K.A. Alzheimer’s disease and corticobasal degeneration presenting as corticobasal syndrome. Mov. Disord., 2009, 24(9), 1375-1379.
[http://dx.doi.org/10.1002/mds.22574] [PMID: 19425061]
[21]
Zheng, Y.; Zhong, D.; Huang, Y.; He, M.; Xiao, Q.; Jin, R.; Li, J. Effectiveness and safety of repetitive transcranial magnetic stimulation (rTMS) on aphasia in cerebrovascular accident patients: Protocol of a systematic review and meta-analysis. Medicine (Baltimore), 2019, 98(52), e18561.
[http://dx.doi.org/10.1097/MD.0000000000018561] [PMID: 31876757]
[22]
Amassian, V.E.; Maccabee, P.J. Transcranial magnetic stimulation. Conf. Proc. IEEE Eng. Med. Biol. Soc., 2006, 2006, 1620-1623.
[http://dx.doi.org/10.1109/IEMBS.2006.259398] [PMID: 17946912]
[23]
Yuluğ, B.; Ozan, E.; Kilic, E. Brain-derived neurotrophic factor polymorphism as a genetic risk for depression? A short review of the literatüre. J Neuropsychiatry Clin Neurosci, 2010, 22(1), 123.E5-123.E6.
[http://dx.doi.org/10.1176/jnp.2010.22.1.123.e5] [PMID: 20160224]
[24]
Caglayan, A.B.; Beker, M.C.; Caglayan, B.; Yalcin, E.; Caglayan, A.; Yulug, B.; Hanoglu, L.; Kutlu, S.; Doeppner, T.R.; Hermann, D.M.; Kilic, E. Acute and post-acute neuromodulation induces stroke recovery by promoting survival signaling, neurogenesis, and pyramidal tract plasticity. Front. Cell. Neurosci., 2019, 12, 13-144.
[http://dx.doi.org/10.3389/fncel.2019.00144] [PMID: 31031599]
[25]
Cankaya, S.; Cankaya, B.; Kilic, U.; Kilic, E.; Yulug, B. The therapeutic role of minocycline in Parkinson’s disease. Drugs Context, 2019, 8(8), 212553.
[http://dx.doi.org/10.7573/dic.212553] [PMID: 30873213]
[26]
Çağlayan, B.; Kılıç, E.; Dalay, A.; Altunay, S.; Tuzcu, M.; Erten, F.; Orhan, C.; Gunal, M.Y.; Yulug, B.; Juturu, V.; Sahin, K. Allyl isothiocyanate attenuates oxidative stress and inflammation by modulating Nrf2/HO-1 and NF-κB pathways in traumatic brain injury in mice. Mol. Biol. Rep., 2019, 46(1), 241-250.
[http://dx.doi.org/10.1007/s11033-018-4465-4] [PMID: 30406889]
[27]
Lapchak, P.A.; Zhang, J.H. Neuroprotective therapy for stroke and ischemic disease. Springer Series in Translational Stroke Research book series, 2017, 123-131.
[28]
Shehata, H.S.; Shalaby, N.M.; Esmail, E.H.; Fahmy, E. Corticobasal degeneration: Clinical characteristics and multidisciplinary therapeutic approach in 26 patients. Neurol. Sci., 2015, 36(9), 1651-1657.
[http://dx.doi.org/10.1007/s10072-015-2226-x] [PMID: 25917399]
[29]
Lomarev, M.P.; Kanchana, S.; Bara-Jimenez, W.; Iyer, M.; Wassermann, E.M.; Hallett, M. Placebo-controlled study of rTMS for the treatment of Parkinson’s disease. Mov. Disord., 2006, 21(3), 325-331.
[http://dx.doi.org/10.1002/mds.20713] [PMID: 16211618]
[30]
Nakamura, M.; Bekki, M.; Miura, Y.; Itatani, M.; Jie, L.X.; Cerebellar Transcranial Magnetic Stimulation Improves Ataxia, X. Cerebellar transcranial magnetic stimulation improves ataxia in minamata disease. Case Rep. Neurol., 2019, 11(2), 167-172.
[http://dx.doi.org/10.1159/000500241] [PMID: 31543798]
[31]
Kaneko, F.; Shibata, E.; Okawada, M.; Nagamine, T. Region-dependent bidirectional plasticity in M1 following quadripulse transcranial magnetic stimulation in the inferior parietal cortex. Brain Stimul., 2020, 13(2), 310-317.
[http://dx.doi.org/10.1016/j.brs.2019.10.016] [PMID: 31711881]
[32]
Hamada, M.; Ugawa, Y.; Tsuji, S. High-frequency rTMS over the supplementary motor area for treatment of Parkinson’s disease. Mov. Disord., 2008, 23(11), 1524-1531.
[http://dx.doi.org/10.1002/mds.22168] [PMID: 18548577]
[33]
Bede, P.; Omer, T.; Finegan, E.; Chipika, R.H.; Iyer, P.M.; Doherty, M.A.; Vajda, A.; Pender, N.; McLaughlin, R.L.; Hutchinson, S.; Hardiman, O. Connectivity-based characterisation of subcortical grey matter pathology in frontotemporal dementia and ALS: A multimodal neuroimaging study. Brain Imaging Behav., 2018, 12(6), 1696-1707.
[http://dx.doi.org/10.1007/s11682-018-9837-9] [PMID: 29423814]
[34]
Pal, E.; Nagy, F.; Aschermann, Z.; Balazs, E.; Kovacs, N. The impact of left prefrontal repetitive transcranial magnetic stimulation on depression in Parkinson’s disease: A randomized, double-blind, placebo-controlled study. Mov. Disord., 2010, 25(14), 2311-2317.
[http://dx.doi.org/10.1002/mds.23270] [PMID: 20740485]
[35]
Benninger, D.H.; Hallett, M. Non-invasive brain stimulation for Parkinson’s disease: Current concepts and outlook 2015. NeuroRehabilitation, 2015, 37(1), 11-24.
[http://dx.doi.org/10.3233/NRE-151237] [PMID: 26409690]
[36]
Chou, Y.H.; Hickey, P.T.; Sundman, M.; Song, A.W.; Chen, N.K. Effects of repetitive transcranial magnetic stimulation on motor symptoms in Parkinson disease: A systematic review and meta-analysis. JAMA Neurol., 2015, 72(4), 432-440.
[http://dx.doi.org/10.1001/jamaneurol.2014.4380] [PMID: 25686212]
[37]
Bergmann, T.O.; Karabanov, A.; Hartwigsen, G.; Thielscher, A.; Siebner, H.R. Combining non-invasive transcranial brain stimulation with neuroimaging and electrophysiology: Current approaches and future perspectives. Neuroimage, 2016, 140(140), 4-19.
[http://dx.doi.org/10.1016/j.neuroimage.2016.02.012] [PMID: 26883069]
[38]
Yang, C.; Guo, Z.; Peng, H.; Xing, G.; Chen, H.; McClure, M.A.; He, B.; He, L.; Du, F.; Xiong, L.; Mu, Q. Repetitive transcranial magnetic stimulation therapy for motor recovery in Parkinson’s disease: A Meta-analysis. Brain Behav., 2018, 8(11), e01132.
[http://dx.doi.org/10.1002/brb3.1132] [PMID: 30264518]
[39]
Chung, C.L.; Mak, M.K. Effect of repetitive transcranial magnetic stimulation on physical function and motor signs in Parkinson’s disease: A systematic review and meta- analysis. Brain Stimul., 2016, 9(4), 475-487.
[http://dx.doi.org/10.1016/j.brs.2016.03.017] [PMID: 27117282]
[40]
Sabatini, U.; Boulanouar, K.; Fabre, N.; Martin, F.; Carel, C.; Colonnese, C.; Bozzao, L.; Berry, I.; Montastruc, J.L.; Chollet, F.; Rascol, O. Cortical motor reorganization in akinetic patients with Parkinson’s disease: A functional MRI study. Brain, 2000, 123(Pt 2), 394-403.
[http://dx.doi.org/10.1093/brain/123.2.394] [PMID: 10648446]
[41]
Dinkelbach, L.; Brambilla, M.; Manenti, R.; Brem, A.K. Non-invasive brain stimulation in Parkinson’s disease: Exploiting crossroads of cognition and mood. Neurosci. Biobehav. Rev., 2017, 75, 407-418.
[http://dx.doi.org/10.1016/j.neubiorev.2017.01.021] [PMID: 28119070]
[42]
Guse, B.; Falkai, P.; Wobrock, T. Cognitive effects of high-frequency repetitive transcranial magnetic stimulation: A systematic review. J. Neural Transm. (Vienna), 2010, 117(1), 105-122.
[http://dx.doi.org/10.1007/s00702-009-0333-7] [PMID: 19859782]
[43]
Borroni, A.B.; Cotelli, M. Anodal transcranial direct current stimulation of parietal cortex enhances action naming in Corticobasal Syndrome. Front. Aging Neurosci., 2015, 14, 7-49.
[http://dx.doi.org/10.3389/fnagi.2015.00049]
[44]
Chou, Y.H.; Ton That, V.; Sundman, M. A systematic review and meta-analysis of rTMS effects on cognitive enhancement in mild cognitive impairment and Alzheimer’s disease. Neurobiol. Aging, 2020, 86, 1-10.
[http://dx.doi.org/10.1016/j.neurobiolaging.2019.08.020] [PMID: 31783330]
[45]
Reza, K.; Reza, R.; Sanaz, K.; Golnaz, B.; Mehdi, R.; Masahiro, H.; Yasunori, A.; Ryouhei, I.; Masao, I.; Paul, B.F. Bilateral transcranial magnetic stimulation on DLPFC changes resting state networks and cognitive function in patients with bipolar depression. Front. Hum. Neurosci., 2018, 5, 12-356.
[http://dx.doi.org/10.3389/fnhum.2018.00356]
[46]
Zanjani, A.; Zakzanis, K.K.; Daskalakis, Z.J.; Chen, R. Repetitive transcranial magnetic stimulation of the primary motor cortex in the treatment of motor signs in Parkinson’s disease: A quantitative review of the literature. Mov. Disord., 2015, 30(6), 750-758.
[http://dx.doi.org/10.1002/mds.26206] [PMID: 25786995]
[47]
Shulman, L.M.; Gruber-Baldini, A.L.; Anderson, K.E.; Fishman, P.S.; Reich, S.G.; Weiner, W.J. The clinically important difference on the unified Parkinson’s disease rating scale. Arch. Neurol., 2010, 67(1), 64-70.
[http://dx.doi.org/10.1001/archneurol.2009.295] [PMID: 20065131]
[48]
Bosboom, J.L.; Stoffers, D.; Stam, C.J.; Berendse, H.W.; Wolters, E.Ch. Cholinergic modulation of MEG resting-state oscillatory activity in Parkinson’s disease related dementia. Clin. Neurophysiol., 2009, 120(5), 910-915.
[http://dx.doi.org/10.1016/j.clinph.2009.03.004] [PMID: 19386543]
[49]
Babiloni, C.; Del Percio, C.; Bordet, R.; Bourriez, J.L.; Bentivoglio, M.; Payoux, P.; Derambure, P.; Dix, S.; Infarinato, F.; Lizio, R.; Triggiani, A.I.; Richardson, J.C.; Rossini, P.M. Effects of acetylcholinesterase inhibitors and memantine on resting-state electroencephalographic rhythms in Alzheimer’s disease patients. Clin. Neurophysiol., 2013, 124(5), 837-850.
[http://dx.doi.org/10.1016/j.clinph.2012.09.017] [PMID: 23098644]
[50]
Strafella, A.P.; Paus, T.; Barrett, J.; Dagher, A. Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus. J. Neurosci., 2001, 21(15), RC157.
[http://dx.doi.org/10.1523/JNEUROSCI.21-15-j0003.2001] [PMID: 11459878]
[51]
Cho, S.S.; Strafella, A.P. rTMS of the left dorsolateral prefrontal cortex modulates dopamine release in the ipsilateral anterior cingulate cortex and orbitofrontal cortex. PLoS One, 2009, 4(8), e6725.
[http://dx.doi.org/10.1371/journal.pone.0006725] [PMID: 19696930]
[52]
Cozac, V.V.; Gschwandtner, U.; Hatz, F.; Hardmeier, M.; Rüegg, S.; Fuhr, P. Quantitative EEG and cognitive decline in Parkinson’s disease. Parkinsons Dis., 2016, 2016, 9060649.
[http://dx.doi.org/10.1155/2016/9060649] [PMID: 27148466]
[53]
Musaeus, C.S.; Engedal, K.; Høgh, P.; Jelic, V.; Mørup, M.; Naik, M.; Oeksengaard, A.R.; Snaedal, J.; Wahlund, L.O.; Waldemar, G.; Andersen, B.B. EEG theta power is an early marker of cognitive decline in dementia due to Alzheimer’s disease. J. Alzheimers Dis., 2018, 64(4), 1359-1371.
[http://dx.doi.org/10.3233/JAD-180300] [PMID: 29991135]
[54]
Pizzagalli, D.A.; Oakes, T.R.; Davidson, R.J. Coupling of theta activity and glucose metabolism in the human rostral anterior cingulate cortex: An EEG/PET study of normal and depressed subjects. Psychophysiology, 2003, 40(6), 939-949.
[http://dx.doi.org/10.1111/1469-8986.00112] [PMID: 14986847]
[55]
Guze, B.H.; Baxter, L.R., Jr; Schwartz, J.M.; Szuba, M.P.; Mazziotta, J.C.; Phelps, M.E. Changes in glucose metabolism in dementia of the Alzheimer type compared with depression: A preliminary report. Psychiatry Res., 1991, 40(3), 195-202.
[http://dx.doi.org/10.1016/0925-4927(91)90010-N] [PMID: 1780392]
[56]
Chamani, J. Comparison of the conformational stability of the non-native α-helical intermediate of thiol-modified β-lactoglobulin upon interaction with sodium n-alkyl sulfates at two different pH. J. Colloid Interface Sci., 2006, 299(2), 636-646.
[http://dx.doi.org/10.1016/j.jcis.2006.02.049] [PMID: 16554059]
[57]
Chamani, J.; Heshmati, M. Mechanism for stabilization of the molten globule state of papain by sodium n-alkyl sulfates: Spectroscopic and calorimetric approaches. J. Colloid Interface Sci., 2008, 322(1), 119-127.
[http://dx.doi.org/10.1016/j.jcis.2008.03.001] [PMID: 18405913]
[58]
Wilson, H.; Pagano, G.; Politis, M. Dementia spectrum disorders: Lessons learnt from decades with PET research. J. Neural Transm. (Vienna), 2019, 126(3), 233-251.
[http://dx.doi.org/10.1007/s00702-019-01975-4] [PMID: 30762136]
[59]
Huang, Z.; Tan, T.; Du, Y.; Chen, L.; Fu, M.; Yu, Y.; Zhang, L.; Song, W.; Dong, Z. Low-frequency repetitive transcranial magnetic stimulation ameliorates cognitive function and synaptic plasticity in APP23/PS45 mouse model of Alzheimer’s disease. Front. Aging Neurosci., 2017, 9, 292.
[http://dx.doi.org/10.3389/fnagi.2017.00292] [PMID: 28955219]
[60]
Woźniak-Kwaśniewska, A.; Szekely, D.; Aussedat, P.; Bougerol, T.; David, O. Changes of oscillatory brain activity induced by repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex in healthy subjects. Neuroimage, 2014, 88, 91-99.
[http://dx.doi.org/10.1016/j.neuroimage.2013.11.029] [PMID: 24269574]