Advertisement

A Multi-Dimensional Model of Fatigue in Old Age: Implications for Brain Aging

  • Feng V. Lin
    Correspondence
    Send correspondence and reprint requests to Feng V. Lin, Ph.D., 1070 Arastradero road, Palo Alto, CA, 94304.
    Affiliations
    Department of Psychiatry and Behavioral Sciences(FVL), Stanford University, Palo Alto, CA, 94304

    Wu Tsai Neuroscience Institute, Stanford University(FVL), Palo Alto, CA, 94304
    Search for articles by this author
Published:November 04, 2022DOI:https://doi.org/10.1016/j.jagp.2022.10.007

      ABSTRACT

      As the most reported symptom in old age, fatigue is understudied in terms of both mechanisms and measures. Population heterogeneity and methodological inconsistency makes understanding the relationship between fatigue and brain aging challenging. The present article comprehensively reviews existing conceptual and operational frameworks of fatigue, as well as mechanistic heterogeneities of fatigue that exist in the aging literature. Then, I propose a Multi-Dimensional Model of fatigue to provide theoretical cohesion to the study of fatigue in old age, along with a “fatigue circuit” addressing brain profiles across dimensions of fatigue. The potential relationships between fatigue dimensions, the fatigue circuit, and brain aging are discussed to inform the direction of future research.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The American Journal of Geriatric Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Penner IK
        • Paul F
        Fatigue as a symptom or comorbidity of neurological diseases.
        Nat Rev Neurol. 2017; 13: 662-675
        • Alexander NB
        • Taffet GE
        • Horne FM
        • et al.
        Bedside-to-Bench conference: research agenda for idiopathic fatigue and aging.
        J Am Geriatr Soc. 2011; 58: 967-975
        • Meng H
        • Hale L
        • Friedberg F
        Prevalence and predictors of fatigue in middle-aged and older adults: evidence from the health and retirement study.
        J Am Geriatr Soc. 2010; 58: 2033-2034
        • Kluger BM
        • Krupp LB
        • Enoka RM
        Fatigue and fatigability in neurologic illnesses: proposal for a unified taxonomy.
        Neurology. 2013; 80: 409-416
        • Klimas NG
        • Broderick G
        • Fletcher MA
        Biomarkers for chronic fatigue.
        Brain Behav Immun. 2012; 26: 1202-1210
        • Chaudhuri A
        • Behan PO
        Fatigue in neurological disorders.
        Lancet. 2004; 363: 978-988
        • Banerjee N
        • Slugh M
        • Kaur S
        • et al.
        Neuropsychological correlates of subjective fatigue in non-demented older adults and the moderating effect of physical activity.
        Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2020; 27: 254-269
        • Lin F
        • Chen DG
        • Vance DE
        • et al.
        Longitudinal relationships between subjective fatigue, cognitive function, and everyday functioning in old age.
        Int Psychogeriatr. 2013; 25: 275-285
        • Jaremka LM
        • Andridge RR
        • Fagundes CP
        • et al.
        Pain, depression, and fatigue: loneliness as a longitudinal risk factor.
        Health Psychol. 2014; 33: 948-957
        • Hardy SE
        • Studenski SA
        Fatigue predicts mortality in older adults.
        J Am Geriatr Soc. 2008; 56: 1910-1914
        • Moreh E
        • Jacobs JM
        • Stessman J
        Feeling tired predicts functional status, physical activity, and mortality in elderly people.
        J Am Geriatr Soc. 2009; 57: 742-743
        • Avlund K
        • Rantanen T
        • Schroll M
        Tiredness and subsequent disability in older adults: The role of walking limitations.
        J Gerontol A Biol Sci Med Sci. 2006; 61: 1201-1205
        • Renner SW
        • Cauley JA
        • Brown PJ
        • et al.
        Higher fatigue prospectively increases the risk of falls in older men.
        Innov Aging. 2021; 5: igaa061
        • Kukla B
        • Anthony M
        • Chen S
        • et al.
        Brain small-worldness properties and perceived fatigue in mild cognitive impairment.
        J Gerontol A Biol Sci Med Sci. 2021;
        • Cho SS
        • Aminian K
        • Li C
        • et al.
        Fatigue in Parkinson's disease: the contribution of cerebral metabolic changes.
        Hum Brain Mapp. 2017; 38: 283-292
        • Hooper C
        • De Souto Barreto P
        • Coley N
        • et al.
        Cross-sectional associations of fatigue with cerebral β-amyloid in older adults at risk of dementia.
        Frontiers in medicine. 2017; 4: 173
        • Kluger BM
        • Zhao Q
        • Tanner JJ
        • et al.
        Structural brain correlates of fatigue in older adults with and without Parkinson's disease.
        Neuroimage Clin. 2019; 22101730
        • Anderson AJ
        • Ren P
        • Baran TM
        • et al.
        Insula and putamen centered functional connectivity networks reflect healthy agers' subjective experience of cognitive fatigue in multiple tasks.
        Cortex. 2019; 119: 428-440
        • Syndrome IoMCotDCfMECF
        Beyond Myalgic Encephalomyelitis/chronic Fatigue Syndrome: Redefining an Illness.
        National Academies Press, 2015
        • Goni M
        • Basu N
        • Murray AD
        • et al.
        Neural indicators of fatigue in chronic diseases: a systematic review of MRI STUDIES.
        Diagnostics (Basel, Switzerland). 2018; 8
        • Lacourt TE
        • Vichaya EG
        • Chiu GS
        • et al.
        The high costs of low-grade inflammation: persistent fatigue as a consequence of reduced cellular-energy availability and non-adaptive energy expenditure.
        Front Behav Neurosci. 2018; 12: 78
        • Kanungo S
        • Morton J
        • Neelakantan M
        • et al.
        Mitochondrial disorders.
        Ann Transl Med. 2018; 6: 475
        • Holtzer R
        • Shuman M
        • Mahoney JR
        • et al.
        Cognitive fatigue defined in the context of attention networks. Neuropsychology, development, and cognition.
        Section B, Aging, Neuropsychol Cogn. 2011; 18: 108-128
        • Proske U
        • Allen T
        The neural basis of the senses of effort, force and heaviness.
        Exp Brain Res. 2019; 237: 589-599
        • Muller T
        • Apps MAJ
        Motivational fatigue: a neurocognitive framework for the impact of effortful exertion on subsequent motivation.
        Neuropsychologia. 2018;
        • Chaudhuri A
        • Behan PO
        Fatigue in neurological disorders.
        Lancet North Am Ed. 2004; 363: 978-988
        • Eldadah BA
        Fatigue and fatigability in older adults.
        PM R. 2011; 2: 406-413
        • Klein I-L
        • van de Loo KFE
        • Smeitink JAM
        • et al.
        Cognitive functioning and mental health in mitochondrial disease: a systematic scoping review.
        Neurosci Biobehav Rev. 2021; 125: 57-77
        • Silverman MN
        • Heim CM
        • Nater UM
        • et al.
        Neuroendocrine and immune contributors to fatigue.
        Pm r. 2010; 2: 338-346
        • Lin F
        • Ren P
        • Cotton K
        • et al.
        Mental fatigability and heart rate variability in mild cognitive impairment.
        Am J Geriatr Psychiatry. 2016; 24: 374-378
        • Kavanagh JJ
        • Taylor JL
        Voluntary activation of muscle in humans: does serotonergic neuromodulation matter?.
        J Physiol. 2022; 600: 3657-3670
        • Shan ZY
        • Barnden LR
        • Kwiatek RA
        • et al.
        Neuroimaging characteristics of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review.
        J Transl Med. 2020; 18: 335
        • Dobryakova E
        • Genova HM
        • DeLuca J
        • et al.
        The dopamine imbalance hypothesis of fatigue in multiple sclerosis and other neurological disorders.
        Front Neurol. 2015; 6: 52
        • Pavese N
        • Metta V
        • Bose SK
        • et al.
        Fatigue in Parkinson's disease is linked to striatal and limbic serotonergic dysfunction.
        Brain. 2010; 133: 3434-3443
        • Conio B
        • Martino M
        • Magioncalda P
        • et al.
        Opposite effects of dopamine and serotonin on resting-state networks: review and implications for psychiatric disorders.
        Mol Psychiatry. 2020; 25: 82-93
        • DeLuca J
        • Genova HM
        • Capili EJ
        • et al.
        Functional neuroimaging of fatigue.
        Phys Med Rehabil Clin N Am. 2009; 20: 325-337
        • Babulal GM
        • Chen L
        • Doherty JM
        • et al.
        Longitudinal changes in anger, anxiety, and fatigue are associated with cerebrospinal fluid biomarkers of Alzheimer's disease.
        J Alzheimers Dis. 2022; 87: 141-148
        • Clancy U
        • Gilmartin D
        • Jochems ACC
        • et al.
        Neuropsychiatric symptoms associated with cerebral small vessel disease: a systematic review and meta-analysis.
        Lancet Psychiatry. 2021; 8: 225-236
        • Carvalho DZ
        • St Louis EK
        • Boeve BF
        • et al.
        Excessive daytime sleepiness and fatigue may indicate accelerated brain aging in cognitively normal late middle-aged and older adults.
        Sleep Med. 2017; 32: 236-243
        • Lin C
        • Glynn NW
        • Gmelin T
        • et al.
        Validation of the traditional chinese version of the pittsburgh fatigability scale for older adults.
        Clin Gerontol. 2021; : 1-13
        • Di Vico IA
        • Cirillo G
        • Tessitore A
        • et al.
        Fatigue in hypokinetic, hyperkinetic, and functional movement disorders.
        Parkinsonism Relat Disord. 2021; 86: 114-123
        • Chen WG
        • Schloesser D
        • Arensdorf AM
        • et al.
        The emerging science of interoception: sensing, integrating, interpreting, and regulating signals within the self.
        Trends Neurosci. 2021; 44: 3-16
        • Gonzalez Campo C
        • Salamone PC
        • Rodríguez-Arriagada N
        • et al.
        Fatigue in multiple sclerosis is associated with multimodal interoceptive abnormalities.
        Mult Scler. 2020; 26: 1845-1853
        • Lin F
        • Roiland R
        • Polesskaya O
        • et al.
        Fatigability disrupts cognitive processes' regulation of inflammatory reactivity in old age.
        Am J Geriatr Psychiatry. 2013;
        • Lin F
        • Roiland R
        • Heffner K
        • et al.
        Evaluation of objective and perceived mental fatigability in older adults with vascular risk.
        J Psychosom Res. 2014; 76: 458-464
        • Baran TM
        • Zhang Z
        • Anderson AJ
        • et al.
        Brain structural connectomes indicate shared neural circuitry involved in subjective experience of cognitive and physical fatigue in older adults.
        Brain Imaging Behav. 2019;
        • Phillips KM
        • Faul LA
        • Small BJ
        • et al.
        Comparing the retrospective reports of fatigue using the fatigue symptom index with daily diary ratings in women receiving chemotherapy for gynecologic cancer.
        J Pain Symptom Manage. 2013; 46: 282-288
        • Anderson AJ
        • Lin F
        How pattern information analyses of semantic brain activity elicited in language comprehension could contribute to the early identification of Alzheimer's Disease.
        Neuroimage Clin. 2019; 22101788
        • Anderson AJ
        • McDermott K
        • Dodell-Feder D
        • et al.
        Decoding individual identity from brain activity elicited in imagining personal experiences of common scenarios.
        Nat Commun. 2020;
        • Chen Q
        • Yang H
        • Rooks B
        • et al.
        Autonomic flexibility reflects learning and associated neuroplasticity in old age.
        Hum Brain Mapp. 2020; 41: 3608-3619
        • Craig AD
        How do you feel–now? The anterior insula and human awareness.
        Nat Rev Neurosci. 2009; 10: 59-70
        • Dantzer R
        • Heijnen CJ
        • Kavelaars A
        • et al.
        The neuroimmune basis of fatigue.
        Trends Neurosci. 2014; 37: 39-46
        • Ren P
        • Anderson AJ
        • McDermott K
        • et al.
        Cognitive fatigue and cortical-striatal network in old age.
        Aging. 2019; 11: 2312-2326
        • Davis SW
        • Dennis NA
        • Daselaar SM
        • et al.
        Que PASA? The posterior-anterior shift in aging.
        Cereb Cortex. 2008; 18: 1201-1209
        • Babu Henry Samuel I
        • Wang C
        • Burke SE
        • et al.
        Compensatory neural responses to cognitive fatigue in young and older adults.
        Front Neural Circuits. 2019; 13: 12
        • Zhou Y
        • Yu F
        • Duong TQ
        White matter lesion load is associated with resting state functional MRI activity and amyloid PET but not FDG in mild cognitive impairment and early Alzheimer's disease patients.
        J Magn Reson Imaging. 2015; 41: 102-109
        • Mueller SG
        • Weiner MW
        Amyloid associated intermittent network disruptions in cognitively intact older subjects: Structural connectivity matters.
        Front Aging Neurosci. 2017; 9: 418
        • Klaassen EB
        • Plukaard S
        • Evers EAT
        • et al.
        Young and middle-aged schoolteachers differ in the neural correlates of memory encoding and cognitive fatigue: a functional MRI study.
        Front Hum Neurosci. 2016; 10: 148
        • Dobryakova E
        • DeLuca J
        • Genova HM
        • et al.
        Neural correlates of cognitive fatigue: cortico-striatal circuitry and effort-reward imbalance.
        J Int Neuropsychol Soc. 2013; 19: 583-849
        • Prescott JW
        • Guidon A
        • Doraiswamy PM
        • et al.
        The Alzheimer structural connectome: Changes in cortical network topology with increased amyloid plaque burden.
        Radiology. 2014; 273: 175-184
        • Racine AM
        • Adluru N
        • Alexander AL
        • et al.
        Associations between white matter microstructure and amyloid burden in preclinical Alzheimer's disease: a multimodal imaging investigation.
        Neuroimage Clin. 2014; 4: 604-614
        • Rieckmann A
        • Dijk KRAV
        • Sperling RA
        • et al.
        Accelerated decline in white matter integrity in clinically normal individuals at risk for Alzheimer's disease.
        Neurobiol Aging. 2016; 42: 177-188
        • Gold BT
        • Johnson NF
        • Powell DK
        • et al.
        White matter integrity and vulnerability to Alzheimer's disease: preliminary findings and future directions.
        Biochim Biophys Acta Mol Basis Dis. 2012; 1822: 416-422
        • Molinuevo JL
        • Ripolles P
        • Simó M
        • et al.
        White matter changes in preclinical Alzheimer's disease: a magnetic resonance imaging-diffusion tensor imaging study on cognitively normal older people with positive amyloid β protein 42 levels.
        Neurobiol Aging. 2014; 35: 2671-2680
        • Chen Q
        • Baran TM
        • Rooks B
        • et al.
        Cognitively supernormal older adults maintain a unique structural connectome that is resistant to Alzheimer's pathology.
        Neuroimage Clin. 2020; 28102413
        • Grothe MJ
        • Barthel H
        • Sepulcre J
        • et al.
        In vivo staging of regional amyloid deposition.
        Neurology. 2017;
        • Lowsky DJ
        • Olshansky SJ
        • Bhattacharya J
        • et al.
        Heterogeneity in healthy aging.
        J Gerontol A Biol Sci Med Sci. 2014; 69: 640-649
        • Thayer JF
        • Hansen AL
        • Saus-Rose E
        • et al.
        Heart rate variability, prefrontal neural function, and cognitive performance: the neurovisceral integration perspective on self-regulation, adaptation, and health.
        Ann Behav Med. 2009; 37: 141-153
        • Hardoon DR
        • Szedmak S
        • Shawe-Taylor J
        Canonical correlation analysis: an overview with application to learning methods.
        Neural Comput. 2004; 16: 2639-2664