Exploring Unexplained Fatigue in the Elderly: Pathophysiology and Measurement

1. Unexplained Fatigue in the ElderlyA summary from the NIA exploratory workshop Basil Eldadah Division of Geriatrics & Clinical Gerontology NIA Bedside-to-Bench Conference: Idiopathic Fatigue of Aging 3 September 2008

2. Objectives and Outcomes • Describe the scope of the problem of fatigue in the elderly. • Review current definitions, dimensions, and correlates of fatigue. • Describe diseases or conditions with which fatigue is associated, exploring common characteristics, pathophysiologic mechanisms, and interventions. • Explore potential pathophysiologic mechanisms underlying unexplained fatigue in the elderly. • Assess existing instruments for measuring fatigue and related constructs such as functional measures and physiologic variables. Unexplained Fatigue in the Elderly An Exploratory Workshop sponsored by the National Institute on Aging June 25-26, 2007 Bethesda, MD

3. Overview of the Workshop Epidemiology Fatigue as a Symptom of Disease Fatigue as Part of a Syndrome or Geriatric Condition Potential Pathophysiologic Mechanisms of Fatigue Measurement of Fatigue Cognitive and Psychosocial Aspects of Fatigue Interventions for Fatigue

4. Epidemiology of Fatigue Prevalence rates of fatigue in older adults range widely – from 5% to almost 50%. Females report fatigue up to twice as often as men. In some analyses, fatigue prevalence remained constant or even decreased with age.

5. Fatigue as a Symptom of Disease • Cancer • Symptom at presentation or with advancing disease • Acute side effect of treatment • Persistent symptom after completion of treatment

6. Fatigue as a Symptom of Disease • Cancer • Multiple sclerosis • Poor correlation between self-reported fatigue and physical or cognitive function • Treatment with interferon β-1a is a potential clinical model of acute, reversible fatigue

7. Fatigue as a Symptom of Disease • Cancer • Multiple sclerosis • Major depression • Depression (and anxiety) are highly associated with the presence of self-reported fatigue • Fatigue may persist with treatment of depression

8. Criteria for Major Depressive Episode (DSM-IV-TR, 2000) A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. (1) depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). (2) markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others) (3) significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. (4) insomnia or hypersomnia nearly every day (5) psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) (6) fatigue or loss of energy nearly every day (7) feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick) (8) diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others) (9) recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide . . .

9. Fatigue as a Symptom of Disease Cancer Multiple sclerosis Major depression Sleep disorders Chronic pain

10. Strober & Arnett Arch Clin Neuropsych 2005;20:631-646

11. Fatigue as Part of a Syndrome or Geriatric Condition Chronic fatigue syndrome Sarcopenia Frailty

12. Tiredness and Risk of Disability • Self-reported tiredness during daily activities predict • Mobility disability • Use of health services • Restricted activity • Death

13. Potential Pathophysiologic Mechanisms of Fatigue Mitochondrial dysfunction Cardiovascular physiology Electrolyte disturbances / dehydration Inflammatory processes Central processes

14. Capacity to produce energy (ATP) is reduced in skeletal muscle Drew, B., Phaneuf, S., Dirks, A., Selman, C., Gredilla, R., Lezza, A., Barja, G., and Leeuwenburgh, C. 2003. Effects of aging and caloric restriction on mitochondrial energy production in gastrocnemius muscle and heart. Am J PhysiolRegulIntegr Comp Physiol 284:R474-R480. Slide courtesy of Christiaan Leeuwenburgh

15. ErgoReceptor May Be HyperActive in Heart Failure Piepoli et al. Circulation 1996 Slide courtesy of George Taffet

16. Is there Clinical Utility to Blocking Inflammation? • Aggregate measures to predict outcomes • Identify specific triggers that are most likely to cause or aggravate chronic disease states • Target those for interventions • Identify ‘at risk’ genotypes/phenotypes and target individuals for interventions Slide courtesy of Jeremy Walston

17. General sites of pathology in central fatigue Chaudhuri & Behan Lancet 2004;363:978-988

18. Approaches to Measuring Fatigue How you define it determines how you measure it. Feeling of tiredness vs. Decrement in performance

19. Approaches to Measuring Fatigue • Self-report measures • Functional measures • Physical • Cognitive • Physiologic measures

20. Cognitive Fatigue • Cognitive function characterized by: • Speed of cognitive processes • Capacity (working memory) • Durability of memory traces • Accrued effects of experience (world knowledge) • Cognitive function decreases with age, but neural activity increases with age

21. Frontal Cortex Reuter-Lorenz, et al., Journal of Cognitive Neuroscience, 2001 Slide courtesy of Denise Park

22. Daily Life Processes Zautra et al. Pain 128:128-135 • A comprehensive understanding of fatigue requires study of biological, psychological, and social factors. • Greater fatigue is predicted by: • Greater physical illness • Greater negative affect • Greater negative interpersonal interactions

23. Interventions for Fatigue • Pharmacologic • Centrally acting drugs • Promyogenic agents • Agents to improve aerobic capacity or endurance • Immune modulators / anti-inflammatory agents • Others • Exercise • Cognitive Behavioral Therapy • Complementary/Alternative Medicine

24. Oken et al, Neurology 2004, 62:2058-2064

25. Summary of Main Ideas Multiple potential mechanisms may underlie fatigue in older adults with or without overt disease. Diseases in which fatigue is a prominent symptom and acutely-induced fatigue can be useful models for understanding pathophysiologic mechanisms. The choice of fatigue measurement instrument should be consistent with the questions asked, population studied, and outcomes sought.

26. Summary of Main Ideascontinued Fatigability (fatigue related to activity) may be a more meaningful outcome than fatigue alone. Fatigue can be understood from biological, psychological, and social perspectives—a transdisciplinary approach is important to achieve a comprehensive understanding of fatigue. Fatigue as a disorder of energy balance is a promising perspective through which to understand fatigue in older adults.

27. Workshop Summary www.nia.nih.gov/ResearchInformation/ConferencesAndMeetings/UnexplainedFatigue.htm

28. Program Announcements Transdisciplinary Research on Fatigue and Fatigability in Aging (R01 & R21) grants.nih.gov/grants/guide/pa-files/PA-08-161.html grants.nih.gov/grants/guide/pa-files/PA-08-162.html

29. Contact Information Basil A. Eldadah, MD, PhD Program Officer, Geriatrics Branch Division of Geriatrics and Clinical Gerontology National Institute on Aging Gateway Building, Suite 3C-307 7201 Wisconsin Avenue Bethesda, MD 20892-9205 (for FedEx use 20814) Phone: 301-496-6761 Fax: 301-402-1784 email: eldadahb@nia.nih.gov