Can a serious game-based cognitive training attenuate cognitive decline related to Alzheimer's disease? Protocol for a randomized controlled trial

Esther Brill, Christine Krebs, Michael Falkner, Jessica Peter, Katharina Henke, Marc Züst, Lora Minkova, Anna-Katharine Brem, Stefan Klöppel, Esther Brill, Christine Krebs, Michael Falkner, Jessica Peter, Katharina Henke, Marc Züst, Lora Minkova, Anna-Katharine Brem, Stefan Klöppel

Abstract

Background: Alzheimer's disease (AD) is a major public health issue. Cognitive interventions such as computerized cognitive trainings (CCT) are effective in attenuating cognitive decline in AD. However, in those at risk of dementia related to AD, results are heterogeneous. Efficacy and feasibility of CCT needs to be explored in depth. Moreover, underlying mechanisms of CCT effects on the three cognitive domains typically affected by AD (episodic memory, semantic memory and spatial abilities) remain poorly understood.

Methods: In this bi-centric, randomized controlled trial (RCT) with parallel groups, participants (planned N = 162, aged 60-85 years) at risk for AD and with at least subjective cognitive decline will be randomized to one of three groups. We will compare serious game-based CCT against a passive wait list control condition and an active control condition (watching documentaries). Training will consist of daily at-home sessions for 10 weeks (50 sessions) and weekly on-site group meetings. Subsequently, the CCT group will continue at-home training for an additional twenty-weeks including monthly on-site booster sessions. Investigators conducting the cognitive assessments will be blinded. Group leaders will be aware of participants' group allocations. Primarily, we will evaluate change using a compound value derived from the comprehensive cognitive assessment for each of three cognitive domains. Secondary, longitudinal functional and structural magnetic resonance imaging (MRI) and evaluation of blood-based biomarkers will serve to investigate neuronal underpinnings of expected training benefits.

Discussion: The present study will address several shortcomings of previous CCT studies. This entails a comparison of serious game-based CCT with both a passive and an active control condition while including social elements crucial for training success and adherence, the combination of at-home and on-site training, inclusion of booster sessions and assessment of physiological markers. Study outcomes will provide information on feasibility and efficacy of serious game-based CCT in older adults at risk for AD and will potentially generalize to treatment guidelines. Moreover, we set out to investigate physiological underpinnings of CCT induced neuronal changes to form the grounds for future individually tailored interventions and neuro-biologically informed trainings.

Trial registration: This RCT was registered 1st of July 2020 at clinicaltrials.gov (Identifier NCT04452864).

Keywords: Alzheimer’s disease; Cognitive training; Computerized cognitive training; Magnetic resonance imaging; Mild cognitive impairment; Serious games; Subjective cognitive decline; Training adherence.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
a Study Design: In the three study arms participants perform a cognitive assessment four times with an interval of 3 months in-between. Neuroimaging is performed at baseline and after 3 months in all study arms. After 6 months neuroimaging is performed in the cognitive training and the waitlist control group and after 9 months in the waitlist control group only. Blood samples are collected once, in the first group appointment. b Assessment: Each assessment has a duration of approximately 3 hours if neuroimaging is included. Abbreviations Figure a: CCT = Computerized cognitive training, CG = Control group, A = Assessment, o = Neuroimaging. Abbreviations Figure b: MoCA = Montreal Cognitive Assessment, AVLT = Auditory verbal learning test, GNT = Graded naming test, fMRI = Functional magnetic resonance Imaging, ASL = Arterial spin labelling

References

    1. Peter J, Abdulkadir A, Kaller C, Kümmerer D, Hüll M, Vach W, et al. Subgroups of Alzheimer’s disease: stability of empirical clusters over time. J Alzheimers Dis. 2014;42(2):651–661. doi: 10.3233/JAD-140261.
    1. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):263–269. doi: 10.1016/j.jalz.2011.03.005.
    1. Alzheimer’s Association Alzheimer’s disease: facts and figures special report race, ethnicity and Alzheimer’s in America. Alzheimers Dement. 2021;17(3):327–406. doi: 10.1002/alz.12328.
    1. Pike KE, Cavuoto MG, Li L, Wright BJ, Kinsella GJ. Subjective cognitive decline: level of risk for future dementia and mild cognitive impairment, a meta-analysis of longitudinal studies. neuropsychology review. Springer US; 2021.
    1. Koppara A, Wagner M, Lange C, Ernst A, Wiese B, König HH, et al. Cognitive performance before and after the onset of subjective cognitivedecline in old age. Alzheimer’s Dement Diagnosis, Assess Dis Monit. 2015;1(2):194–205.
    1. Hao L, Xing Y, Li X, Mu B, Zhao W, Wang G, et al. Risk factors and neuropsychological assessments of subjective cognitive decline (plus) in Chinese memory clinic. Front Neurosci. 2019;13(August):1–11.
    1. Barnett JH, Lewis L, Blackwell AD, Taylor M. Early intervention in Alzheimer’s disease: a health economic study of the effects of diagnostic timing. BMC Neurol. 2014;14(1):1–9. doi: 10.1186/1471-2377-14-101.
    1. Savulich G, Piercy T, Fox C, Suckling J, Rowe JB, O’brien JT, et al. Cognitive training using a novel memory game on an iPad in patients with amnestic mild cognitive impairment (aMCI) Int J Neuropsychopharmacol. 2017;20(8):624–633. doi: 10.1093/ijnp/pyx040.
    1. Gates NJ, Vernooij RWM, Di Nisio M, Karim S, March E, Martínez G, et al. Computerised cognitive training for preventing dementia in people with mild cognitive impairment. Cochrane Database Syst Rev. 2019;(3). Art. No.: CD012279.
    1. Ten Brinke LF, Davis JC, Barha CK, Liu-Ambrose T. Effects of computerized cognitive training on neuroimaging outcomes in older adults: a systematic review. BMC Geriatr. 2017;17(1):1–20. doi: 10.1186/s12877-016-0400-5.
    1. Hill NTM, Mowszowski L, Naismith SL, Chadwick VL, Valenzuela M, Lampit A. Computerized cognitive training in older adults with mild cognitive impairment or dementia: a systematic review and meta-analysis. Am J Psychiatry. 2017;174(4):329–340. doi: 10.1176/appi.ajp.2016.16030360.
    1. Rodella C, Bernini S, Panzarasa S, Sinforiani E, Picascia M, Quaglini S, et al. A double-blind randomized controlled trial combining cognitive training (CoRe) and neurostimulation (tDCS) in the early stages of cognitive impairment. Aging Clin Exp Res. 2022;34(1):73–83. doi: 10.1007/s40520-021-01912-0.
    1. Nousia A, Martzoukou M, Siokas V, Aretouli E, Aloizou AM, Folia V, et al. Beneficial effect of computer-based multidomain cognitive training in patients with mild cognitive impairment. Appl Neuropsychol. 2021;28(6):717–726. doi: 10.1080/23279095.2019.1692842.
    1. Dudas RB, Clague F, Thompson SA, Graham KS, Hodges JR. Episodic and semantic memory in mild cognitive impairment. Neuropsychologia. 2005;43(9):1266–1276. doi: 10.1016/j.neuropsychologia.2004.12.005.
    1. Quental NBM, Brucki SMD, Bueno OFA. Funções visoespaciais na doença de alzheimer de intensidade leve: Estudo preliminar. Dement e Neuropsychol. 2009;3(3):234–240. doi: 10.1590/S1980-57642009DN30300010.
    1. Rubiño J, Andrés P. The face-name associative memory test as a tool for early diagnosis of alzheimer’s disease. Front Psychol. 2018;9(AUG):1–5.
    1. Karbach J, Verhaeghen P. Making working memory work: a Meta-analysis of executive-control and working memory training in older adults. Psychol Sci. 2014;25(11):2027–2037. doi: 10.1177/0956797614548725.
    1. Chandler MJ, Parks AC, Marsiske M, Rotblatt LJ, Smith GE. Everyday impact of cognitive interventions in mild cognitive impairment: a systematic review and Meta-analysis. Neuropsychol Rev. 2016;26(3):225–251. doi: 10.1007/s11065-016-9330-4.
    1. Bahar-Fuchs A, Martyr A, Goh A, Sabates CL. Cognitive rehabilitation for people with mild to moderate dementia. Cochrane Database Syst Rev. 2019;2019(8):1–116.
    1. Noack H, Lövdén M, Schmiedek F. On the validity and generality of transfer effects in cognitive training research. Psychol Res. 2014;78(6):773–789. doi: 10.1007/s00426-014-0564-6.
    1. Zinke K, Zeintl M, Rose NS, Putzmann J, Pydde A, Kliegel M. Working memory training and transfer in older adults: effects of age, baseline performance, and training gains. Dev Psychol. 2014;50(1):304–315. doi: 10.1037/a0032982.
    1. Anderson-Hanley C, Barcelos NM, Zimmerman EA, Gillen RW, Dunnam M, Cohen BD, et al. The aerobic and cognitive exercise study (ACES) for community-dwelling older adults with or at-risk for mild cognitive impairment (MCI): neuropsychological, neurobiological and neuroimaging outcomes of a randomized clinical trial. Front Aging Neurosci. 2018;10(76):1–25.
    1. Chiu H-L, Chu H, Tsai J-C, Liu D, Chen Y-R, Yang H-L, et al. The effect of cognitive-based training for the healthy older people: a meta-analysis of randomized controlled trials. PLoS One. 2017;12(5):e0176742. doi: 10.1371/journal.pone.0176742.
    1. Miotto EC, Batista AX, Simon SS, Hampstead BM. Neurophysiologic and cognitive changes arising from cognitive training interventions in persons with mild cognitive impairment: a systematic review. Neural Plast. 2018;2018(1):1–14. doi: 10.1155/2018/7301530.
    1. Hosseini SMH, Kramer JH, Kesler SR. Neural correlates of cognitive intervention in persons at risk of developing alzheimer’s disease. Front Aging Neurosci. 2014;6(AUG):1–9.
    1. Vemuri P, Fields J, Peter J, Klöppel S. Cognitive interventions in Alzheimer’s and Parkinson’s diseases: emerging mechanisms and role of imaging. Curr Opin Neurol. 2016;29(4):405–411. doi: 10.1097/WCO.0000000000000346.
    1. Nguyen L, Murphy K, Andrews G. Cognitive and neural plasticity in old age: A systematic review of evidence from executive functions cognitive training. Ageing Res Rev. 2019;53(November 2018):100912. doi: 10.1016/j.arr.2019.100912.
    1. Stern Y. Cognitive reserve. Neuropsychologia. 2009;47(10):2015–2028. doi: 10.1016/j.neuropsychologia.2009.03.004.
    1. Hafkemeijer A, van der Grond J, Rombouts SARB. Imaging the default mode network in aging and dementia. Biochim Biophys Acta Mol basis Dis. 2012;1822(3):431–441. doi: 10.1016/j.bbadis.2011.07.008.
    1. Cao W, Cao X, Hou C, Li T, Cheng Y, Jiang L, et al. Effects of cognitive training on resting-state functional connectivity of default mode, salience, and central executive networks. Front Aging Neurosci. 2016;8(70):1–11.
    1. Thomas B, Sheelakumari R, Kannath S, Sarma S, Menon RN. Regional cerebral blood flow in the posterior cingulate and precuneus and the entorhinal cortical atrophy score differentiate mild cognitive impairment and dementia due to Alzheimer disease. Am J Neuroradiol. 2019;40(10):1658–1664.
    1. Tosun D, Schuff N, Mathis CA, Jagust W, Weiner MW. Spatial patterns of brain amyloid-β burden and atrophy rate associations in mild cognitive impairment. Brain. 2011;134(4):1077–1088. doi: 10.1093/brain/awr044.
    1. Catasús CAS, Willemsen A, Boellaard R, Juarez-Orozco LE, Samper-Noa J, Aguila-Ruiz A, et al. Episodic memory in mild cognitive impairment inversely correlates with the global modularity of the cerebral blood flow network. Psychiatry Res Neuroimaging. 2018;282(September):73–81. doi: 10.1016/j.pscychresns.2018.11.003.
    1. Chapman SB, Aslan S, Spence JS, Hart JJ, Bartz EK, Didehbani N, et al. Neural mechanisms of brain plasticity with complex cognitive training in healthy seniors. Cereb Cortex. 2015;25(2):396–405. doi: 10.1093/cercor/bht234.
    1. Bueller JA, Aftab M, Sen S, Gomez-Hassan D, Burmeister M, Zubieta JK. BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry. 2006;59(9):812–815. doi: 10.1016/j.biopsych.2005.09.022.
    1. Boots EA, Schultz SA, Clark LR, Racine AM, Darst BF, Koscik RL, et al. BDNF Val66Met predicts cognitive decline in the Wisconsin registry for Alzheimer’s prevention. Neurology. 2017;88(22):2098–2106. doi: 10.1212/WNL.0000000000003980.
    1. Roheger M, Meyer J, Kessler J, Kalbe E. Predicting short- and long-term cognitive training success in healthy older adults: who benefits? Aging Neuropsychol Cogn. 2020;27(3):351–369. doi: 10.1080/13825585.2019.1617396.
    1. Thijssen EH, La Joie R, Wolf A, Strom A, Wang P, Iaccarino L, et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med. 2020;26(3):387–397. doi: 10.1038/s41591-020-0762-2.
    1. Verberk IMW, Thijssen E, Koelewijn J, Mauroo K, Vanbrabant J, De Wilde A, et al. Combination of plasma amyloid beta (1-42/1-40) and glial fibrillary acidic protein strongly associates with cerebral amyloid pathology. Alzheimers Res Ther. 2020;12(1):1–14. doi: 10.1186/s13195-020-00682-7.
    1. Verberk IMW, Slot RE, Verfaillie SCJ, Heijst H, Prins ND, van Berckel BNM, et al. Plasma amyloid as Prescreener for the earliest Alzheimer pathological changes. Ann Neurol. 2018;84(5):648–658. doi: 10.1002/ana.25334.
    1. Krebs C, Peter J, Wyss P, Brem A-K, Klöppel S. Transcranial electrical stimulation improves cognitive training effects in healthy elderly adults with low cognitive performance. Clin Neurophysiol. 2021;(xxxx). 10.1016/j.clinph.2021.01.034.
    1. Alexopoulos P, Skondra M, Kontogianni E, Vratsista A, Frounta M, Konstantopoulou G, et al. Validation of the cognitive telephone screening instruments COGTEL and COGTEL+ in identifying clinically diagnosed neurocognitive disorder due to Alzheimer’s disease in a naturalistic clinical setting. J Alzheimers Dis. 2021;83(1):259–268. doi: 10.3233/JAD-210477.
    1. Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695–699. doi: 10.1111/j.1532-5415.2005.53221.x.
    1. RStudio Team. RStudio Team. RStudio: Integrated Development for R; RStudio, PBC, Boston, MA; 2020. Available from: .
    1. Chesham A, Gerber SM, Schütz N, Saner H, Gutbrod K, Müri RM, et al. Search and match task: development of a taskified match-3 puzzle game to assess and practice visual search. JMIR Serious Games. 2019;7(2).
    1. Boot WR, Champion M, Blakely DP, Wright T, Souders DJ, Charness N. Video games as a means to reduce age-related cognitive decline: attitudes, compliance, and effectiveness. Front Psychol. 2013;4(31):1–9.
    1. Calvillo-gámez EH, Cairns P, Cox AL. Evaluating user experience in games. 2010.
    1. Belleville S, Clément F, Mellah S, Gilbert B, Fontaine F, Gauthier S. Training-related brain plasticity in subjects at risk of developing Alzheimer’s disease. Brain. 2011;134(6):1623–1634. doi: 10.1093/brain/awr037.
    1. Diaz-Orueta U, Facal D, Nap HH, Ranga M-M. What is the key for older people to show interest in playing digital learning games? Initial qualitative findings from the LEAGE project on a multicultural European sample. Games Health J. 2012;1(2):115–123. doi: 10.1089/g4h.2011.0024.
    1. De Schutter B. Never too old to play: the appeal of digital games to an older audience. Games Cult. 2011;6(2):155–170. doi: 10.1177/1555412010364978.
    1. Scheller E, Minkova L, Leitner M, Klöppel S. Attempted and successful compensation in preclinical and early manifest neurodegeneration - a review of task fMRI studies. Front. Psychiatry. 2014;5(SEP):1–16.
    1. Krebs C, Peter J, Klöppel S. Wissenschaftlich begründetes Gedächtnistraining bei kognitiver Störung. Swiss Arch Neurol Psychiatry Psychother. 2018;169(04):114–120. doi: 10.4414/sanp.2018.00576.
    1. Klink K, Peter J, Wyss P, Klöppel S. Transcranial electric current stimulation during associative memory encoding: comparing tACS and tDCS effects in healthy aging. Front Aging Neurosci. 2020;12(March):1–12.
    1. Seydell-Greenwald A, Ferrara K, Chambers CE, Newport EL, Landau B. Bilateral parietal activations for complex visual-spatial functions: evidence from a visual-spatial construction task. Neuropsychologia. 2017;106(September):194–206. doi: 10.1016/j.neuropsychologia.2017.10.005.
    1. De Quervain DJF, Papassotiropoulos A. Identification of a genetic cluster influencing memory performance and hippocampal activity in humans. Proc Natl Acad Sci U S A. 2006;103(11):4270–4274. doi: 10.1073/pnas.0510212103.
    1. Bean J. Rey Auditory Verbal Learning Test, Rey AVLT. In: Kreutzer JS, DeLuca J, Caplan B, editors. Encyclopedia of clinical neuropsychology. New York, NY: Springer New York; 2011. pp. 2174–2175.
    1. Osterrieth PA. Le test de copie d’une figure complexe; contribution à l’étude de la perception et de la mémoire. [Test of copying a complex figure; contribution to the study of perception and memory.] Arch Psychol (Geneve) 1944;30:206–356.
    1. Williams BW, Mack W, Henderson VW. Boston naming test in Alzheimer’s disease. Neuropsychologia. 1989;27(8):1073–1079. doi: 10.1016/0028-3932(89)90186-3.
    1. Zelazo PD, Anderson JE, Richler J, Wallner-Allen K, Beaumont JL, Conway KP, et al. NIH toolbox cognition battery (CB): validation of executive function measures in adults. J Int Neuropsychol Soc. 2014;20(6):620–629. doi: 10.1017/S1355617714000472.
    1. Guay F, Vallerand RJ, Blanchard C. On the assessment of situational intrinsic and extrinsic motivation: the situational motivation scale (SIMS) Motiv Emot. 2000;24(3):175–213. doi: 10.1023/A:1005614228250.
    1. Stevanovic D. Quality of life enjoyment and satisfaction questionnaire - short form for quality of life assessments in clinical practice: a psychometric study. J Psychiatr Ment Health Nurs. 2011;18(8):744–750. doi: 10.1111/j.1365-2850.2011.01735.x.
    1. Yesavage JA, Brink TL, Rose TL, Virwnia H, Adfy M, Leirer VO. Development and validation of a geriatric depression screening scale: Preliminary report. Vol. 17, J. psychial. Rex. 1983.
    1. Devilly GJ, Borkovec TD. Psychometric properties of the credibility/expectancy questionnaire. J Behav Ther Exp Psychiatry. 2000;31(2):73–86.
    1. Graf C. Instrumental activities of daily living scale. Am J Nurs. 2008;108(4):1–62. doi: 10.1097/01.NAJ.0000314810.46029.74.
    1. Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia. 1971;9(1):97–113. doi: 10.1016/0028-3932(71)90067-4.
    1. Faul F, Erdfelder E, Lang A-G, Buchner A. G*power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical. Behav Res Methods. 2007;39(2):175–191. doi: 10.3758/BF03193146.
    1. Whitfield-Gabrieli S, Nieto-Castanon A. Conn: a functional connectivity toolbox for correlated and Anticorrelated brain networks. Brain Connect. 2012;2(3):125–141. doi: 10.1089/brain.2012.0073.
    1. Arevalo-Rodriguez I, Smailagic N, Roquéi Figuls M, Ciapponi A, Sanchez-Perez E, Giannakou A, et al. Mini-mental state examination (MMSE) for the detection of Alzheimer’s disease and other dementias in people with mild cognitive impairment (MCI) Cochrane Database Syst Rev. 2015;2015(3):1–76.
    1. Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, et al. Spirit 2013 statement: defining standard protocol items for clinical trials. Chinese J Evidence-Based Med. 2013;13(12):1501–1507.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner