**Unexplained Fatigue in the Elderly**

**An Exploratory Workshop sponsored by the National Institute on Aging**

**June 25-26, 2007**

**WORKSHOP SUMMARY**

**Purpose**

"Fatigue" or "exhaustion" is a common clinical complaint among older
adults for which multiple definitions and measurement instruments exist.
Fatigue is often a symptom of underlying medical or psychiatric illness.
Cancer, heart disease, chronic lung disease, hypothyroidism, multiple
sclerosis, and rheumatoid arthritis are just a few of the many diseases
or conditions that may present with fatigue; however, for many older
persons, no physiologic or psychological explanation is identified, and
fatigue becomes a diagnosis or a syndrome with which the elderly must
attempt to cope across all activities of daily living. In addition to
its direct effects on mood and function, persistent fatigue may also
elevate risk for later adverse outcomes \[1\]. In the absence of overt
medical conditions that could explain fatigue, it is likely that
multiple factors may play a role in its pathophysiology. Metabolic,
muscular, inflammatory, neurologic, and psychological factors may all
contribute to unexplained or idiopathic fatigue. Understanding these
factors may lead to identification of subtypes of fatigue, for which
specific interventions may be proposed. Furthermore, it is clear that
describing fatigue with qualifiers, such as cognitive fatigue or
muscular fatigue, can facilitate a better understanding of this broad
concept.

In June, 2007, the NIA convened this exploratory workshop to initiate a
broad-based scientific dialogue exploring the clinical problem of
"idiopathic" or "unexplained" fatigue in older adults. Participants
represented a diverse array of scientific and research fields, spanning
clinical, translational, and basic scientists from a variety of
biological, psychological, and social science backgrounds. The working
objectives of the program were to 1) describe the scope of the problem
of fatigue in older adults; 2) review current definitions, dimensions,
and correlates of fatigue; 3) describe diseases or conditions with which
fatigue is associated, exploring common characteristics,
pathophysiologic mechanisms, and interventions; 4) explore potential
pathophysiologic mechanisms underlying unexplained fatigue in older
adults; and 5) assess existing instruments for measuring fatigue and
related constructs such as functional measures and physiologic
variables.

**Speakers**

Neil Alexander, MD

University of Michigan

Kirsten Avlund, PhD

University of Copenhagen

Marcas Bamman, PhD

University of Alabama School of Medicine

Shalender Bhasin, MD, PhD

Boston Medical Center

Dedra Buchwald, MD

University of Washington

Paulo Chaves, MD, PhD

Johns Hopkins University

Christopher Christodoulou, PhD\
State University of New York Stony Brook

John DeLuca, PhD, ABPP

UMDNJ-New Jersey Medical School

Basil Eldadah, MD, PhD

National Institute on Aging

Bill Evans, PhD

University of Arkansas for Medical Sciences

Roger Fielding, PhD

Tufts University

Bret Goodpaster, PhD

University of Pittsburgh

Jack Guralnik, MD, PhD

National Institute on Aging

Evan Hadley, MD

National Institute on Aging

Susan Hardy, MD, PhD

University of Pittsburgh

Paul Jacobsen, PhD

Moffitt Cancer Center and Research Institute

Jane Kent-Braun, PhD

University of Massachusetts Amherst

Lauren Krupp, MD

State University of New York Stony Brook

Andrea Lacroix, PhD, MPH

University of Washington

Christiaan Leewenburgh, PhD

University of Florida College of Medicine

Jan Moynihan, PhD

University of Rochester

Susan Murphy, ScD, OTR

University of Michigan

Susan Nayfield, MD, MSc

National Institute on Aging

Anne Newman, MD, MPH

University of Pittsburgh

Barry Oken, MD

Oregon Health and Science University

Marco Pahor, MD

University of Florida College of Medicine

Denise Park, PhD

The University of Illinois

Catherine Sarkisian, MD, MSPH

University of California Los Angeles

Michael Sharpe, MA, MD

University of Edinburgh

Arthur Stone, PhD

State University of New York Stony Brook

Stephanie Studenski, MD, MPH

University of Pittsburgh School of Medicine

George Taffet, MD

Baylor College of Medicine

Joseph Verbalis, MD

Georgetown University Medical Center

Sonja Vestergaard, PhD

National Institute on Aging

Jeremy Walston, MD

Johns Hopkins University School of Medicine

Ellen Whyte, MD

University of Pittsburgh School of Medicine

Alex Zautra, PhD

Arizona State University

**SUMMARY**

**Introduction**

Several definitions of fatigue exist, ranging from broader definitions
that encompass subjective and objective dimensions, to narrower
definitions that consider discrete physiological mechanisms. Some
definitions are based on self-reported symptoms of tiredness or
exhaustion, while others are based on objective measurements of physical
or cognitive performance. Arguably, fatigue should result in some kind
of functional alteration.

The measurement of fatigue is complex. As articulated by Dittner et al.
\[2\], "No two scales measure exactly the same thing. Some measure
phenomenology and others measure fatigue severity or impact, while many
assess a mixture of all these." Fatigue results in functional impairment
and is also caused by functional impairments. When an individual has
less ability, it takes more energy to perform a task.

Fatigue can be studied in relation to level of activity, which is a
product of effort and time. Two individuals may report the same level of
fatigue in relation to different levels of activity; for example, one
individual may be fatigued after performance of an activity of daily
living (ADL), while another may be fatigued only after a full day's
work. This distinction is important for intervention studies, as
outcomes should consider fatigue in the context of function. For
example, consider an intervention that improves patients' function such
that they can perform more work before reporting the same level of
fatigue. If the outcome measure is function, the intervention appears
successful. If the outcome measure is fatigue level, the intervention
appears ineffective. Conversely, consider a subject who performs the
same amount of work after an intervention but reports a lower level of
fatigue. If the outcome measure is function, the intervention appears
ineffective; if the outcome measure is fatigue level, the intervention
appears successful. Therefore, a useful approach for evaluating efficacy
may be to assess fatigue per level of activity.

**Epidemiology of Fatigue**

Prevalence estimates of fatigue can be influenced by several factors,
including varying methods used to classify fatigue, arbitrary cutpoints
for scales, shifts over time in diagnostic conventions, population
characteristics (inclusion of special populations), and external events,
disasters, and major stressors. Without consideration of these factors,
asking what the prevalence of fatigue is may be like asking how long a
piece of string is \[3\].

Fatigue prevalence in published studies ranges from 5% to almost 50%.
Most studies of fatigue prevalence show a female preponderance, with
females reporting fatigue 1.2 to 2.3 times more frequently than males.
Age is a risk factor for chronic fatigue in some studies. Clark et al.
\[4\] demonstrated that the risk for persistent (\> 2.5 years) chronic
fatigue is associated with age greater than 38 years at initial
presentation. Cognitive impairment, anxiety, inflammation-related
chronic conditions (eg. cancer, rheumatoid arthritis), debilitating
symptoms (eg. dyspnea) and end-of-life scenarios can identify special
populations of older adults at high risk of fatigue. Depression, disease
burden, and functional status are likely to interact in the perception
and impact of fatigue in later life.

**A Brief Historical Overview of Fatigue Research**

Fatigue was generally unrecognized in the medical literature until the
mid-1800s with industrialization. George Beard coined the diagnostic
term "neurasthenia" as a *disease* characterized by general malaise,
debility, poor appetite, fugitive neuralgic pains, hysteria, insomnia,
hypochondriasis, disinclination for consecutive mental labor, and severe
and weakening attacks of headaches. It was viewed as a disease of the
nervous system resulting from "overexertion of the brain."

Around 1900, clinicians were already struggling with two issues still
confronting researchers today: the blurred distinction between fatigue
and depression, and the difficulty of differentiating between perceived
and observed exhaustion. At the same time, psychiatry was moving away
from the disease concepts of Kraepelin and more toward a symptom-based
nosology. As a result, fatigue became a *symptom* synonymous with
tiredness. Fatigue as a disease was included in the Diagnostic and
Statistical Manual (DSM) versions I and II, but was removed in the
DSM-III (1980). It remains in ICD-10 as neurasthenia.

Other fatigue-based illnesses have also been described throughout modern
history. Irritable heart, effort syndrome, and neurocirculatory asthenia
were recognized during wartime and were also attributed to psychiatric
etiology. Others include myalgic encephalomyelitis, epidemic
neuromyasthenia, Iceland disease, atypical poliomyelitis, and chronic
fatigue syndrome (formally recognized in 1988 in the US).

The multidimensional nature of fatigue has been appreciated for a long
time. Mosso \[5\] described four components of fatigue---behavior
(decrement in performance), feeling state (perception), mechanism, and
context. He found that perception does not correlate with performance.
The dichotomy of central vs. peripheral fatigue dates to least the turn
of the 19^th^ century. According to a current description \[6\]
peripheral fatigue involves an end organ (muscle), while central fatigue
is a "failure to initiate and/or sustain attentional tasks ('mental
fatigue') and physical activities ('physical fatigue') requiring self
motivation (as opposed to external stimulation)." The distinction may
not always be clear.

**FATIGUE AS A SYMPTOM OF DISEASE**

Fatigue can be a symptom of underlying medical disease. Commonly cited
conditions include cancer, multiple sclerosis, rheumatoid arthritis,
lupus, sleep disorders, HIV/AIDS, depression, heart failure, chronic
pain conditions, and following stroke or traumatic brain injury. The
manifestations and mechanisms of fatigue in each of these conditions are
probably diverse; however, many conditions may share common
pathophysiologic processes. For this workshop, only a few of many
conditions could be explored.

**Cancer**

Fatigue associated with cancer can present as a disease symptom, as an
acute side effect of treatment, or as a persistent symptom after
completion of treatment. Cancer-related fatigue (CRF) syndrome is a more
recently defined entity consisting of clinically significant fatigue of
2 weeks' duration associated with 5 additional symptoms (including
non-restorative sleep and active disruption of daily activities by
fatigue), and is not a consequence of cancer, cancer treatment, or
psychiatric disorder according to clinical judgment \[7\]. Among 40
studies of cancer-related fatigue, the majority found no relationship
between age and fatigue \[8\]. Possible explanations are that 1) older
patients are not more susceptible to fatigue; 2) older patients are more
susceptible to fatigue but they may not report it because they have
different expectations for it (e.g., they expect to feel tired or they
ascribe it to aging); or 3) older patients are more susceptible to
fatigue, but they may be less bothered by it because they have fewer
competing demands for their energy (self-pacing).

Possible causes of cancer-related fatigue include anemia \[9\], physical
inactivity/deconditioning \[10\], central nervous system toxicity of
cancer treatment ("chemobrain") \[11\]; altered immune function \[12\];
or cancer-related symptoms themselves (for example, menopausal symptoms
in breast cancer \[13\].)

Different chemotherapeutic agents may be associated with different
levels of fatigue, but the challenge is to separate concomitant side
effects from specific properties of the chemotherapeutic agent. The most
reliable finding in chemotherapy-associated fatigue is a dose-response
relationship---if a drug is associated with fatigue in a particular
individual, a greater dose is associated with greater fatigue in that
individual.

Future questions:

-   What are the mechanisms underlying the multiple putative causes of
    cancer-related fatigue?

-   What factors predict development of persistent fatigue in cancer
    survivors? Is family history of depression or fatigue one such
    factor? Do physician-patient interactions play a role?

-   Can genetic variability explain differences between individuals in
    susceptibility to treatment-related fatigue?

-   How can we develop empirically-based approaches to treatment
    selection for management of cancer-related fatigue?

**Multiple sclerosis and other neurological disorders**

Fatigue is a major symptom of many neurological disorders of both the
central nervous system (e.g., multiple sclerosis, Parkinson's disease)
and peripheral nervous system (e.g., muscular dystrophy,
post-poliomyelitis syndrome). Fatigue associated with neurological
disorders is challenging to study because its presence and severity are
under-recognized, it is difficult to measure, its pathophysiology is
unclear, and its treatments are incomplete.

Self-report measures of fatigue are easy to administer and readily
available, but they are entirely subjective. In addition, patients often
have limited insight to distinguish different types of fatigue (mental,
physical, social, etc.) Performance measures are objective, but
invariably, in the field of multiple sclerosis, performance-based
measures do not correlate with self-reported fatigue. This is
particularly true with regard to cognitive performance. Patients with
multiple sclerosis demonstrate impaired sustained motor force
generation, impaired recruitment of motor pathways, metabolic changes in
skeletal muscle, and cognitive fatigability, but none of these correlate
well with self-reported fatigue.

Independent cross-sectional predictors of fatigue include depression,
pain, quality of life, disrupted sleep, sense of loss of control over
one's environment, and lower education level \[14-16\]. Longitudinal
predictors of fatigue after one year include baseline fatigue, pain,
mood, and neurologic impairment. All together, these account for only
36% of fatigue variance, so a large amount of fatigue variance is due to
unidentified factors.

Proposed mechanisms underlying fatigue in multiple sclerosis include
cytokine disturbances (particularly, α-interferon, β-interferon,
γ-interferon, interleukin-6, interleukin-1, and tumor necrosis
factor-α); hypothalamic-pituitary-adrenal axis abnormalities; axonal
injury; and brain atrophy. Neuroimaging studies of patients with MS show
differences in brain metabolism between fatigued and non-fatigued
individuals as assessed by glucose utilization and functional MRI.

Management of fatigue includes education (encouraging exercise,
practicing energy conservation, avoiding isolation, counseling);
addressing co-morbidities (e.g., depression, anxiety, sleep disturbance,
pain); and medication: modafinil, amantadine, pemoline, and aspirin have
all been shown to have modest, though inconsistent, benefit.

Future questions:

-   On which bases can a typology of fatigue be established? For
    example, according to measurement (self-report vs. performance,
    unidimensional vs. multidimensional)? Locus (motor vs. cognitive)?
    Etiology (primary vs. secondary)?

-   Can clinical situations where fatigue occurs predictably, acutely,
    and reversibly be used to study underlying mechanisms of fatigue?

**Depression and sleep disorders**

Fatigue is a common complaint among patients with major depression.
Fatigue is most strongly associated with deficits in social functioning
and work productivity. Pathophysiologic studies of major depression in
chronic fatigue syndrome have shown increased perfusion in the right
thalamus (suggestive of increased vigilance to cognitive and motor
tasks), increased frontal subcortical white matter hyperintensity,
limbic dysfunction, lower levels of corticotropin releasing hormone
(CRH), and increased levels of interleukin-1, interleukin-2,
interleukin-6, and tumor necrosis factor \[17;18\]. Modafinil improves
fatigue acutely in late life major depression, but this effect
disappears after 6-8 weeks of treatment.

Fatigue, depression, and sleep disturbances are intimately connected.
Depression may lead to deconditioning and sleep disturbance, which in
turn can lead to fatigue; however, sleep disturbance can also lead to
further depression, possibly via inflammatory mediators. Alternatively,
depression and fatigue may feed each other, with both arising from a
common third factor. One group examined four models describing the
relationships among disease severity, sleep disturbance, depression, and
fatigue in multiple sclerosis \[19\]. The best-fitting model showed
depression, sleep disturbance, and disease severity leading
independently to fatigue.

**Stroke**

Fatigue is common in stroke survivors and is separable from post-stroke
depression. It is rated as one of the worst residual symptoms in up to
half of adult stroke survivors \[20\] and predicts dependency in
activities of daily living (ADLs) and death \[21\]. Possible mechanisms
of post-stroke fatigue include lesions in basal ganglia, thalamus, or
brainstem, diffuse neuronal injury, inflammation, abnormalities of the
hypothalamic-pituitary-adrenal axis, and physical deconditioning.

**Chronic pain conditions**

Chronic pain affects half of community living older adults and
three-fourths of long term care residents. Pain associated with
osteoarthritis is the leading cause of disability among older adults
\[22\]. Contributors to functional decline in osteoarthritis also ADL
disability \[23\], depression and sleep disturbance \[24\], and physical
inactivity and anxiety \[25\]. All of these factors are also associated
with fatigue. Retrospective self-report of fatigue can be influenced by
peak or recent symptoms, so real-time assessment may be more
accurate---what has been called ecological momentary assessment \[26\].
Most interventions for chronic pain conditions tend to focus exclusively
on pain, but more attention should be given to treating associated
symptoms such as fatigue.

Future questions:

-   What are the main predictors of fatigue in older adults with chronic
    pain with or without co-morbidities?

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-   What is the relationship between sleep quality and daytime momentary
    pain and fatigue?

**FATIGUE AS PART OF A SYNDROME**

**Chronic Fatigue Syndrome (CFS)**

Chronic fatigue syndrome is often defined according to the case
definition of Fukuda et al. \[27\] CFS affects 1-2 million in the US;
60-70% are female; patients are usually between 20-50 years old. Risk
factors include female gender, less education, lower social class and
income, ethnic minority group membership. Most symptoms reported in CFS
are, in fact, complex symptoms requiring more exploration than simply
noting their presence. For example, poor sleep can be associated with
defined sleep disorders such as restless leg syndrome or sleep state
misperception (a discordance between actual sleep measured by
polysomnography and a subject's perception of that sleep), as well as
other entities, such as pain, environmental sensitivity (e.g., noise),
mental health problems, and polypharmacy. Psychiatric disorders are
\~3-5 times more prevalent in CFS than in the general population.
Predictors of resolution of CFS are younger age, shorter duration of
fatigue, and absence of psychiatric co-morbidity.

Patients with CFS are often misdiagnosed. Psychiatric disorders and
sleep disorders are the most common misdiagnoses. In addition,
drowsiness and true muscle weakness must be distinguished from fatigue.
It is challenging to distinguish performance declines due to fatigue
from declines from other aging-related conditions. Physicians are often
reluctant to diagnose CFS because many believe that doing so could be
disabling and self-fulfilling to patients; however, the majority of
patients feel that a diagnosis is enabling.

It is important to consider the context in which fatigue occurs. For
example, environmental, family, social, occupational, and personal
factors and stressors may all contribute to an individual's fatigue.

The population with CFS comprises a small portion of a much larger
population of individuals affected by prolonged fatigue. CFS overlaps
with several other disorders including fibromyalgia, irritable bowel
syndrome, temperomandibular disorder, interstitial cystitis, multiple
chemical sensitivity, tension headache, chronic low back pain, chronic
pelvic pain, post-concussion syndrome, and chronic Lyme disease. Each
entity tends to fall under the purview of a particular medical
specialty. All of these entities encompass varying degrees of fatigue,
sleep disorder, pain, and disability.

Studies attempting to find biomarkers of CFS have inconsistently shown
higher antibody titers, natural killer cell dysfunction, or HPA axis
abnormalities in CFS. Recent neuroimaging studies point to possible
structural or functional differences compared to controls, such as
decreased density of serotonin transporters in anterior cingulated
gyrus, decreased volume of gray matter which may be linked to reduced
physical activity, and more extensive activation of brain regions to
process challenging auditory information.

Many factors have been proposed to explain CFS, including amplification
or perceptional disturbance, atypical psychiatric disorder,
stress-distress disorder, autonomic hyperactivity, neuroendocrine
disorder, genetic vulnerability, central nervous system disorder, viral
infection, and immune dysfunction. No theory explains all or even most
cases.

Among randomized controlled trials for CFS, the only interventions
demonstrated consistently to have clear benefit are exercise, cognitive
behavioral therapy, and possibly steroids.

Future questions:

-   What are the effects of aging on outcomes in CFS?

-   Can highly active or energetic individuals serve as a clinical model
    for studying fatigue?

**Frailty**

Frailty refers to a clinical syndrome whose hallmark is increased
vulnerability to stressors secondary to decreased physiologic reserve.
Frail older adults are at high risk for major outcomes, including
disability, morbidity, and mortality.

Fatigue has been regarded as an integral part of the phenotype of
frailty in older adults. Operational definitions of frailty have
included a component of self-reported exhaustion or, more broadly,
fatigue. In the Cardiovascular Health Study \[28\], the fatigue
component of the phenotype was measured according to two items from the
Center for Epidemiological Studies---Depression scale \[29\]:
"everything I did was an effort" and "I could not get going." In the
Women's Health and Aging Studies \[30\], the fatigue component was
considered present based on the presence of low usual energy level
(score 3 in an visual analog scale ranging from 0--10), self-report of
"I felt unusually tired in last month" (most or all the time), or "I
could not get going in the last week" (most or all the time).

There may be synergy of risk factors for frailty; for example,
cardiovascular disease or anemia alone are moderate risk factors for
frailty, but both combined they substantially enhance the likelihood of
frailty. Community-dwelling older subjects with anemia report being
exhausted with equal frequency as those without anemia; however,
however, they are significantly more likely to report other components
of frailty, including decreased physical activity and weakness \[29\].
This lack of association between non-severe anemia and fatigue may be
due an effect modification by physical activity; i.e., anemia may
promote behavioral modifications, including reduction in spontaneous
physical activity levels, which in turn may lead to resolution of
fatigue although while simultaneously promoting further deconditioning
and acceleration of the frailty process. This gradual pathway, which
remains to be more fully studied, is consistent with recent data showing
that in the frailty process hierarchy, exhaustion is often preceded by
reduction in physical activity and weakness \[31\].

**Disability**

Self-reported tiredness in response to specific daily activities can be
assessed by the Mobility-Tiredness scale and Lower Limb-Tiredness Scale
\[32-34\]. These measures are qualitative and do not include information
about severity of each disability. Self-reported tiredness in daily
activities is predictive of onset of disability, walking limitations,
use of health and social services, decline in physical activity, and
mortality. This is true in both young-old and old-old populations, and
in different geographic localities \[33;35\]. Factors related to
tiredness, but that do not explain the association between tiredness and
above outcomes, include social position, comorbidity (specific diseases,
depressed mood, medications), and physiologic and functional impairment
(muscle strength, pain, cognitive performance, aerobic capacity, walking
limitations) \[36\].

An intervention study evaluated interdisciplinary education of general
practitioners and other community figures and of health care
professionals involved in preventative home visits for 75+ year old
individuals. The intervention consisted of education focused on
recognizing tiredness in daily activities and intervening when possible,
a multidimensional geriatric assessment, and referral to general
practitioner when appropriate. There was less functional decline, less
self-reported tiredness, and less use of nursing homes. The effect was
greater in 80 year-olds vs. 75 year-olds, and in women more than men
\[37\].

Future questions:

-   Which social, psychological, physiological, or health factors
    explain the association between tiredness and functional decline?

-   Is tiredness related to other indicators of aging, such as
    biological indicators?

-   Is tiredness in midlife related to functional decline in old age?

-   Is the predictive power of measures of function and fatigue the same
    among different ages or between sexes?

**MECHANISMS AND MODIFIERS OF FATIGUE**

Multiple biological and psychosocial factors may contribute to or
influence fatigue. Biological mechanisms include changes in skeletal
muscle function, cardiovascular impairment, anemia, dehydration and
electrolyte disorders, inflammatory mediators, and nutritional
deficiencies. Psychosocial mediators include depression, pain, positive
and negative affect, and interpersonal processes. A few of these factors
were considered for further exploration.

**Skeletal muscle changes**

Skeletal muscle is the single largest organ in the body, comprising 45%
of body mass. Skeletal muscle is also a significant reserve of energy,
comprised by amino acids stored as protein. Therefore, it is possible
that a reduction in skeletal muscle mass could influence the
availability of energy, the ability to perform work, and the feeling of
fatigue with effort.

The functional unit of muscles is the sarcomere, a series of actin and
myosin filaments where contraction takes place in response to cytosolic
levels of calcium. Three isoforms of myosin determine speed of
contraction: type I (slowest), type IIa (intermediate) and type IIx
(fastest). The maximum capacity to generate force is dependent on muscle
cross-sectional area, intrinsic force-generating ability of the muscle
fiber, and ability of the nervous system to recruit motor units.

Sarcopenia is defined simply as age-associated loss in muscle mass, but
it is operationalized by different researchers in different ways. One
such definition is appendicular skeletal muscle mass, normalized to
height, less than 2 standard deviations below the mean of a younger
sex-matched reference group \[38\]. Sarcopenia begins around the 5^th^
or 6^th^ decade, but functional precursors of sarcopenia begin much
earlier. Factors contributing to diminished muscle mass include
malnutrition, anorexia, cachexia in disease states, deconditioning, low
testosterone, and growth hormone.

In longitudinal and cross-sectional studies, muscle strength decreases
with age, but sarcopenia does not represent the entire spectrum of
age-related muscle pathophysiology. Loss in strength does not parallel
loss in muscle mass---strength declines later than does skeletal muscle
mass. Furthermore, sarcopenia does not address qualitative changes in
muscle; eg. specific force, attenuation associated with increased
accumulation of intramyocellular lipid, velocity components that occur
with age, or phenotypic changes in muscle (e.g.,. loss of type II units
with preservation of type I units). There is debate over whether
strength or power is the most appropriate measure of muscle function.
Age-related declines in muscle strength (force) occur later in life than
do declines in muscle power (force times velocity). In older adults, leg
power is more closely associated with gait speed and self-reported
physical disability than leg strength.

Aerobic capacity represents the rate of oxygen consumption during
activity, and is determined predominantly by skeletal muscle function.
With aging, the oxygen cost of activities becomes a greater percentage
of an individual's maximum aerobic capacity (VO~2~max). For example, a
sedentary 75 year-old healthy woman has a VO~2~max of approximately 1.2
L/min, but the oxygen cost of climbing a flight of stairs is
approximately 1.5 L/min. Both younger and older subjects self-pace
activity to about 50% of their VO~2~max. Therefore, reduced aerobic
capacity should translate to reduced spontaneous activity with age.
However, peak VO~2~ is only modestly related to level of daily physical
activity \[39\].

Future questions:

-   What is the relationship between muscle mass (sarcopenia) and
    fatigue?

-   What is the relationship between adiposity and fatigue? To what
    extent is the effect of adiposity on fatigue mediated by fat mass
    alone vs. metabolic mediators; for example, adipokines?

**Mitochondria**

Mitochondria are the major source of energy production in the body. ATP
generated by mitochondria is the biological currency of energy used
ultimately to power all metabolic activities. Mitochondrial dysfunction
can lead to reduced energy production, which could result in fatigue. In
addition, decreased oxidative metabolism in mitochondria leads to
increased anaerobic metabolism and lactic acid production. Acidosis in
skeletal muscle can be perceived as muscular fatigue.

The mitochondrial theory of aging proposes that oxidants or free
radicals produced in mitochondria lead to mitochondrial DNA damage,
leading to mutations, defective encoded proteins, and impaired
mitochondrial function. A mutant mouse devoid of DNA replication
proofreading ability, which led to increased mitochondrial DNA mutation
frequency, exhibited an aging phenotype including sarcopenia,
osteoporosis, and reduced aerobic capacity at older age.

There are two populations of mitochondria in skeletal muscle:
subsarcolemmal (near muscle cell membrane) and intrafibrillar (embedded
deep within myofibrils); the latter are located near fat stores, have
higher oxygen consumption, but also higher free radical production and
DNA damage and greater antioxidative adaptations to counteract damage.
Previous literature did not make the distinction between these two
populations, which may explain discrepancies in findings.

Mitochondria under oxidative stress release cytochrome-C and
apoptosis-inducing factor leading to apoptosis of cells. This process
may be affected by upregulation of antiapoptotic proteins or expression
of inflammatory mediators. Damaged mitochondria are removed from
otherwise healthy cells through autophagy; however, the efficiency of
this process decreases with age.

Exercise leads to increased mitochondrial size and number. Different
components of mitochondrial structure or electron transport chain have
different responses to exercise. In \~70 year old subjects after 16
weeks of moderate exercise, there was a \~50% increase in electron
transport chain activity, which was thought to be due to increased
proliferation of mitochondria \[40\].

Future questions:

-   Does aging lead to mitochondrial dysfunction? How should
    "dysfunction" be defined?

-   Does exercise-induced proliferation of mitochondria propagate
    damaged mitochondrial DNA?

-   How can we develop standardized methods for assessing mitochondrial
    function *in vivo?*

-   What is the relationship between mitochondria and acute or chronic
    skeletal muscle fatigue?

**Neuromuscular mechanisms**

Neuromuscular fatigue is a focused conceptualization of fatigue based on
skeletal muscle performance. Neuromuscular fatigue can be defined as a
decline in skeletal muscle function with repeated effort. Muscle
function can be characterized in terms of strength, power, activation
(central vs. peripheral), contractile properties (fast vs. slow),
energetics (oxidative vs. glycolytic), fatigue resistance (fall of
maximal force), and endurance (time to task failure).

Changes in muscle function with old age include decreased number of
motor units, decreased maximum motor unit discharge rate, no changes in
ability to fully activate muscle; decreased muscle size, decreased
muscle strength, increased intramuscular fat (both intramyocellular and
fat deposits outside muscle cell), equivocal changes in specific
strength (force per cross-sectional area); no change in peripheral
activation (excitability of neuromuscular junction in muscle membrane),
decreased type II:type I fiber area, decreased contractile speed,
equivocal change in oxidative capacity (matched for health and physical
activity level), and unclear changes in blood flow.

Central activation is assessed by measuring the difference in force
generated between maximum voluntary contraction and electrically
stimulated contraction. Peripheral activation is assessed by the
electrical signal in response to a single stimulus across the belly of a
muscle. Energetics is assessed by phosphorous magnetic resonance
spectroscopy (MRS). Contractile function is assessed by the amount of
force produced by muscle in response to single or multiple stimuli,
which provides information indirectly about excitation/contraction
coupling and calcium handling. Phosphorus MRS can assess pH,
concentrations of α-, β-, and γ-ATP, phosphocreatine, inorganic
phosphate, ADP, AMP, and diprotonated inorganic phosphate
(H~2~PO~4~^-^), a metabolite reputed to cause fatigue.

There is disagreement among multiple studies on muscle fatigue
resistance and endurance in older vs. younger subjects. Across studies,
fatigue resistance has been shown to be poorer, better, or the same in
older subjects; endurance has been shown to be better or the same but
not worse in older subjects. More recent literature suggests greater
fatigue in older muscle under conditions of high velocity. Differences
are probably attributable to variation in subjects, muscle group, and
type of contraction. In older adults who show relatively less fatigue,
there is less acidosis in muscle and less concentration of other
metabolites associated with fatigue.

Therefore, central activation and peripheral activation are not the
source of age-related fatigue differences; also there is no evidence for
impairment of electrochemical coupling or calcium kinetics *in vivo* as
an explanation. What is left, then, is energetics. There is a similar
V~max~ for oxidative phosphorylation in older vs. younger subjects, but
a much lower peak glycolytic rate in older subjects. Therefore, it
appears that older adults rely on oxidative metabolism more than
anaerobic metabolism, which is consistent with pH data.

Neuromuscular fatigue has been associated with symptomatic fatigue in
certain diseases where fatigue is prominent, such as cancer, multiple
sclerosis, amyotrophic lateral sclerosis, and end-stage renal disease.

Future questions:

-   If older adults rely more on oxidative metabolism, does reduced
    delivery of oxygen to muscle (in peripheral vascular disease, for
    example) impair muscle function more in this population?

-   What is the relationship between muscle function and the symptom of
    fatigue? Can older pre-frail adults serve as a model to examine the
    sequence of events leading to fatigue?

-   What is the role of the central nervous system in altered muscle
    function and symptomatic fatigue?

**Dehydration and electrolyte disturbances**

Mild hyponatremia (\<135 mmol/L) is the most common electrolyte
abnormality in any patient group, whether hospitalized or chronically
diseased ambulatory. Incidence increases markedly with age, and is
associated with higher mortality. Body fluid homeostasis is
significantly affected by three age-associated changes: body
composition, kidney function, and brain function. Sarcopenia leads to a
5-10% decrease in total body water and a 15-20% decrease in plasma
volume. As a result, older adults exhibit greater fluxes of electrolyte
concentrations and osmolality, and are likely to develop greater
hyperosmolality with the same level of dehydration. Decreased glomerular
filtration rate with aging leads to a decreased ability to conserve
water and sodium. Finally, older adults have decreased thirst perception
and increased vasopressin secretion. All of these mechanisms can
contribute to symptoms of fatigue. Altered blood volume, decreased heat
tolerance, and elevated core temperature may be important consequences
of body fluid derangements.

**Inflammatory mediators**

An evolving definition of inflammation in geriatrics is a low grade
activation of the innate immune system that leads to chronic production
of inflammatory mediators. Chronic inflammation influences adverse
outcomes through symptoms such as fatigue, pathological changes in
multiple tissues, worsening of chronic diseases, and activation of new
diseases. It is associated with frailty, disability, and early
mortality.

Commonly studied inflammatory mediators include IL-6, C-reactive
protein, TNF-alpha, and NF-kappa-B. Inflammatory mediators increase with
age, probably as a result of increased chronic diseases, altered body
composition, increased free radicals, and decreased anabolic hormones.
Multiple studies link increased cytokine levels with frailty,
disability, mortality, disease states, and decline in muscle function.
Inflammatory mediators affect skeletal muscle function through
inhibition of myogenic differentiation and skeletal muscle regeneration
(TNF-α), and possibly effects on muscle stimulation capacity.

IL-6 and CRP are significantly associated with vital exhaustion in older
women after recent myocardial infarction \[41\]. IL-6, CRP, and IL-1
receptor antagonist are associated with fatigue in cancer patients
\[42\]. Multiple clinical and rodent models show a relationship between
pro-inflammatory cytokines and sickness behavior, of which fatigue is
one component.

Potential mechanisms of inflammatory mediators leading to fatigue
include indirect mechanisms via disease states and multiple system
changes triggered by chronic inflammation, and direct mechanisms via
action on the central nervous system, specifically the HPA axis. IL-6
appears to be the main endocrine communicator between the periphery and
brain. IL-6 acts on brain vasculature to produce prostaglandin E2,
leading to altered HPA axis activity and behavioral responses such as
anorexia and hypoactivity.

There may be clinical utility in blocking inflammatory mediators to
treat fatigue. Aspirin and ibuprofen are already in widespread use for
sickness symptoms, such as with upper respiratory infections or
influenza. It is unclear, however, whether there is a specific effect on
fatigue.

Future questions:

-   Are there "best markers" for fatigue? Can we develop aggregate
    inflammatory and HPA axis markers that are most predictive of
    symptoms and adverse outcomes?

-   Can we more appropriately and directly target specific components of
    inflammatory pathways?

-   Can we identify genotypes/phenotypes "at risk" for fatigue and
    target individuals for intervention?

**Psychoneuroimmunologic mechanisms**

Adverse events, chronic stress, and depression are interpreted or
perceived by the central nervous system, leading to changes in both
central (e.g., cognition, behavior, and affect) as well as peripheral
functions (e.g., physiologic and immunologic responses). Communication
between these central and peripheral components is bidirectional.
Traditionally, it was thought that the hypothalamic-pituitary-adrenal
axis was the main mediator of this communication. Currently, CNS output
is known to affect immune function through over 20 different mediators.
A hypothetical model of fatigue in aging proposes that psychosocial
factors (e.g., stress and depression) plus individual differences (e.g.,
personality and neuroticism) can lead to fatigue directly or indirectly
through inflammation. Both fatigue and inflammation interact with, and
potentially modify, disease.

"Sickness behavior" is a syndrome of anhedonia, anorexia, fatigue, sleep
changes, fever, and exaggerated responses to pain. Sickness behavior can
be elicited experimentally through administration of bacterial
lipopolysaccharide (LPS), which also causes a large-magnitude release of
IL-1, TNF-α, and IL-6. Aged mice have an increased IL-6 response and
prolonged sickness behavior after LPS injection compared to younger
adult mice \[43\], and pre-administration with IGF-1 abolishes this
sickness behavior response \[44\]. As such, cumulative environmental and
immunological burdens may lead to increased inflammatory mediators and
decreased IGF-1, which may lead to increased diseases of aging, fatigue,
and mortality.

In five clinical studies (Moynihan et al., submitted), fatigue was
measured using three questions from the CES-D (inertia, psychomotor
retardation, tiredness). In all five populations, depressive symptoms
(as measured by the CES-D-R minus the three fatigue items) were
correlated with reported fatigue, as has been shown by others
\[36;45-49\]. As well, trait Neuroticism and poor sleep quality were
also significantly associated with fatigue; however, after controlling
for depression, these relationships were no longer significant. Given
the strong link between Neuroticism and depression \[50\], this
observation may suggest a mediating relationship in which dispositional
Neuroticism functions as a "distal" risk factor for fatigue, its effects
being mediated more proximally by depression. Poor sleep quality, high
levels of perceived stress, loneliness, and poorer social and emotional
functioning are also common correlates of depression, and their apparent
association with fatigue appears to be mediated by depressive symptoms
also. This suggests that while multiple factors may mark increased
fatigue, depression may function as a "final common pathway" through
which dispositional stress-reactivity, situational stress, social
isolation, and poor sleep operate to induce fatigue. Unexpectedly, the
oldest age groups reported the lowest fatigue according to questions
from the CES-D. There was no significant correlation between fatigue and
plasma IL-6 or IGF-1.

**Psychosocial influences**

Fatigue may be best characterized as the absence of energy and the
mind-body response to that absence. In order to obtain a comprehensive
picture of fatigue, it is essential to explore the interaction of
biological (e.g., illness), psychological (e.g., affect), and social
factors (positive and negative interactions). Between-persons analyses
identify "who" has more fatigue, while within-person analyses over time
show "when" people have more fatigue; analyses that combine both
approaches show who has the greatest fatigue when experiencing pain,
stress, or other events.

In a study of women with osteoarthritis, rheumatoid arthritis, or
fibromyalgia, subjects kept daily diaries that included fatigue ratings
throughout the day. Fibromyalgia patients reported the greatest levels
and fluctuations of fatigue throughout the day \[22\]. Physical
functioning was predicted by fatigue and pain combined, but not by pain
alone. In addition, fatigue was predicted by the presence of negative
affect as well as the absence of positive affect, with the effect size
of the latter double that of the former. (Increasing evidence supports
the view that positive affect and negative affect are independent
constructs rather than two ends of a continuum.)

Compared to non-depressed patients, increased daily fatigue in depressed
patients is associated with greater increases in daily pain, greater
decline in daily enjoyment of interpersonal events, and greater daily
negative affect. Stressful or positive interpersonal events predict
daily fatigue, even after accounting for pain, depression, and sleep.
Fatigue in rheumatoid arthritis patients with greater social engagement
is unaffected by negative interpersonal events. In fibromyalgia or
rheumatoid arthritis, positive interpersonal events led to less fatigue
on that day, but paradoxically higher fatigue on the following day.

Interpersonal stress can be imposed acutely in a laboratory setting.
Discussing a recent negative interpersonal stressor is associated with
increases in heart rate and systolic blood pressure. Greater perceived
stressfulness is associated with increased fatigue, while ability to
preserve positive affect (emotional well-being) was associated with less
fatigue.

Resilience is the natural capacity to recover from stress. In patients
with osteoarthritis or fibromyalgia, experimental stress followed by an
induced positive mood improved joviality in both patients groups;
however, stress followed by neutral mood improved joviality in
osteoarthritis, but not in fibromyalgia. Therefore, patients with
osteoarthritis may have greater resilience.

Future questions:

-   Is it more useful for studies to focus on the presence of fatigue or
    the absence of energy?

-   Can exploration of central dopaminergic pathways help to explain the
    neurobiology of resilience?

-   Can interventions be developed that increase positive affect without
    costly energy; for example, meditation or relaxation?

**ASSESSMENT OF FATIGUE**

**Self-report measures**

Given the subjective nature of fatigue, self-report may provide insights
into the nature of an individual's fatigue that are difficult to
ascertain through objective measures. Self-report instruments can
measure multiple dimensions (temporal characteristics, severity, impact)
and/or manifestations (physical, cognitive, emotional, behavioral).
Although there are several validated tools for measurement of fatigue,
there is no gold-standard.

Measurement of fatigue has many parallels with pain, and it may be
useful to refer to the pain literature to examine the manner in which
similar issues have been addressed regarding multidimensionality and
measurement. The ideal self-report instrument should have the smallest
possible number of items to complete (acceptable to patients), validity
and reliability demonstrated within the target population, a scaling
method that is easy for patients to use, easily understood items,
straightforward scoring and interpretation, easy translation for
cross-cultural validity, and clinical utility.

Examples of unidimensional scales include the Avlund Tiredness Scales,
Brief Fatigue Inventory, Fatigue Severity Scale, Functional Assessment
of Chronic Illness Therapy -- Fatigue (FACIT-F), Global Vigour and
Affect Scale, and Schedule of Fatigue and Anergia (SOFA).
Multidimensional scales include Fatigue Assessment Instrument, Fatigue
Impact Scale, Fatigue Symptom Inventory, Multidimensional Assessment of
Fatigue and the Global Fatigue Index, Multidimensional Fatigue
Inventory, Multidimensional Fatigue Symptom Inventory, Piper Fatigue
Scale / Revised Piper Fatigue Scale, and visual analogue scales.

Each type of measure has its own strengths and weaknesses.
Unidimensional measures are easy to administer and interpret, but they
suffer from questionable reliability, especially for single-item
measures, and lack of information about symptom duration, interference,
quality, or variability. Multidimensional scales provide more in-depth
assessment and potential for greater clinical utility, but they suffer
from questionable evidence for their proposed dimensional structures,
and many questions within scales yield redundant information. Syndromal
measures, such as cancer-related fatigue syndrome, can reliably estimate
prevalence of clinically significant symptomatology and have the
potential to distinguish cancer-related fatigue from other forms of
fatigue, but the diagnostic criteria used are of questionable validity
and their utility in clinical decision-making is unclear.

When assessing self-reported fatigue in older individuals, it is
important to consider who comprises the comparison group. Subjects may
report different levels of current fatigue depending on whether they are
comparing themselves to others of their own age, to themselves at a
particular time in the past, or to themselves at their optimal level in
the past.

While self-report of fatigue symptoms can be a powerful tool, it can
sometimes also be problematic. There are multiple synonyms for fatigue,
but they are not necessarily interchangeable. In a community sample,
self-reported "fatigue" was twice as common as "exhaustion", 10 times
more common than "feeling generally run down", and up to 10 times more
common than "weakness" \[51\]. Prevalence differs depending on how the
question is asked: \~40% report "general fatigue" but only \~8% report
"tired all the time" \[52\]. Furthermore, self-report scales include
questions that may have face-validity for fatigue, but not necessarily
validity. Muscle weakness may sound related to fatigue, but the 2 terms
are not always related. In multiple sclerosis, there is increased motor
fatigue and muscle weakness, but no significant correlation between
motor fatigue and muscle weakness \[53\]. Scales must be reliable in
order to be valid; convergent validity is meaningless if there is a
correlation among multiple scales that are not reliable. Furthermore,
definitions can be arbitrary, in CFS, fatigue is present for ≥ 6months,
while in multiple sclerosis, fatigue of chronic type is ≥ 6 weeks.

The NIH Patient-Reported Outcomes Measurement Information System
(PROMIS) is a consortium of 7 universities operating under a cooperative
agreement through the NIH Roadmap. It was designed to develop, validate,
and standardize item banks to measure patient-reported outcomes relevant
across common medical conditions in 5 domains: pain, fatigue, social
functioning, physical functioning, and emotional functioning. PROMIS
uses item response theory and computer adaptive testing to assess
outcomes efficiently and reliably. Item banks will be developed for
public access so that researchers can construct their own individual
instruments.

Future questions:

-   In existing datasets that include fatigue-related items not
    originally intended to measure fatigue, how can these items be used
    validly and appropriately?

-   Can the multiple questions and dimensions of the various fatigue
    scales be consolidated or distilled into one or a few representative
    scales?

**Measures of energy utilization**

One approach to measuring energy utilization is to determine the rate of
oxygen consumption with activity. Submaximal oxygen consumption exercise
tests may be easier and safer for older adults, may better predict
functional ability, and can predict health outcomes, especially in
congestive heart failure. Measurement of oxygen uptake before, during,
and after submaximal treadmill walking yields two parameters: oxygen
deficit (delay to reach steady state oxygen uptake at beginning of
walk), and oxygen debt (delay to return to baseline oxygen uptake during
recovery period). Elderly with lower peak VO~2~ have greater oxygen
deficit and oxygen debt with submaximal walking \[54\].

Another approach to understanding energy utilization is to measure
metabolic rate. Resting metabolic rate (RMR) is the minimal amount of
energy intake needed to maintain energy balance and stable weight,
measured at rest, but awake. It is determined largely by skeletal muscle
mass, plus smaller contributions from highly metabolically active organs
(heart, kidney, brain, liver). High metabolic rate is characteristic of
short-lived animals. In humans, metabolic rate is increased with
illness, and higher metabolic rate may be associated with shorter
lifespan and greater mortality. Factors associated with higher RMR
include younger age, male gender, non-African American ethnicity, higher
calorie intake, greater physical activity, and greater physiological
stress (eg. trauma, chronic illness). Earlier studies showed an age
effect on RMR, but newer studies show minimal age effects.

Extra-muscle lean body mass is more metabolically active than non-active
muscle mass, but because muscle mass is such a large proportion of total
body mass, RMR is largely explained by changes in muscle mass;
therefore, caution is needed in interpreting data when RMR is normalized
to muscle mass alone. In order to estimate RMR more precisely, methods
are needed to measure non-skeletal muscle organs that are highly
metabolically active. Furthermore, more precise measures of muscle mass
are needed, as the assumptions inherent with dual-energy X-ray
absorptiometry (DXA) or 24-hour urine creatinine could be inaccurate.
Some investigators currently use MRI to evaluate organ mass.

Future questions:

-   How does aerobic function relate to mobility performance and
    symptoms of exertion and fatigue?

-   What is the relationship between rating of perceived exertion (Borg
    scale) and self-reported fatigue during activity? There is a high
    correlation between heart rate and Borg scale rating. Does the same
    relationship hold for heart rate and self-reported fatigue?

-   How can performance-based measures of fatigue be distinguished from
    measures of the consequences of fatigue?

**Functional correlates**

The relationship between functional ability and self-reported fatigue
was studied in the InChianti dataset, a population-based study of older
adults in Tuscany, Italy \[55\]. This analysis involved 1,055
non-cognitively impaired adults, age 65+ years. Fatigue was assessed
according to two fatigue-related items of the CES-D. Prevalence of
fatigue increased with age among men, but not women. Adjusted for age,
the fatigued group among men was older, had greater self-reported
inactivity, and reported more diseases than the non-fatigued group;
these differences were absent among women. Among both men and women, the
fatigued group had greater disability, weaker handgrip strength, poorer
functional performance as measured by the Short Physical Performance
Battery (SPPB), lower walking speed (400 m), more depressive symptoms,
poorer sleep, and poorer self-rated health than the non-fatigued group.
After further adjusting for health behaviors, diseases, inflammatory
markers, and thyroid function, fatigue remained associated with SPPB,
lower walking speed, inability to walk 400 meter, and disability in
instrumental activities of daily living.

**Physiologic mechanisms of fatigue perception**

In older patients with congestive heart failure, self-reported fatigue
is highly correlated with patients' perceived symptom burden (lower limb
swelling) \[56\], but the correlation may not be as great with the
clinician's assessment of symptom burden. The traditional model of
symptom generation in heart failure is that failure of muscle perfusion
leads to fatigue and breathlessness. However, the sensing mechanisms
that alert to diminished muscle perfusion and/or increased exertion are
unclear.

Previous studies have used breathlessness as a surrogate for fatigue.
Brachial arterial occlusion following exercise caused increased
ventilation compared to non-occluded controls, providing the first
evidence for the existence of a mechanism for sensing work performed by
muscle, dubbed "ergoreceptor." In heart failure patients, there was much
higher ventilation during exercise, and ventilation remained high with
arterial occlusion, suggesting hypersensitive ergoreceptors in heart
failure. Exercise training decreased ventilation post-occlusion closer
to controls, suggesting that exercise can desensitizes ergoreceptors,
which may also be an intervention for improving fatigue and quality of
life in heart failure \[57\]; however, these were not consistent
findings.

Ergoreceptor hyper-responsiveness correlates with reduced muscle mass,
poor exercise tolerance, NYHA functional class, lower ejection fraction,
and cachexia \[58\]. In cycle-based exercise, subjects stopped more
often because of fatigue, while with treadmill exercise, subjects
stopped more often stop because of breathlessness. It is unclear whether
weight bearing leads to greater ergoreflex activation or simply causes
more muscles to be metabolically active?

Ergo receptors may be metaboreceptors (group IV afferents, unmyelinated,
vanilloid-1 receptors, capsaicin augmented) and/or mechanoreceptors
(group III afferents, thinly myelinated, P2X receptors (purinergic),
ATP-augmented). In addition, they may be activated by substance P and
tachykinin. Triggers of ergoreceptors might include inactivity,
renin-angiotensin-aldosterone system activation, sympathetic nervous
system activation, inadequate nutrient blood flow, cytokines, and other
factors.

Future questions:

-   Can a typology of fatigue include level of ergoreceptor activity?
    Fatigue in heart failure may involve ergoreceptor overactivity,
    while in multiple sclerosis, there may be ergoreceptor
    underactivity.

-   Given that older adults have impaired thermoregulatory responses,
    could faster increases in core temperature amplify the ergoreceptor
    response?

**Assessing cognitive fatigue**

Cognitive aging can be characterized in terms of the building blocks of
cognition: speed of cognitive processes, capacity (working memory),
durability of memory traces, and accrued effects of experience (world
knowledge). Speed, capacity and durability of memory decrease steadily
with age, but world knowledge increases steadily \[59\]. Older adults
have more trouble ignoring or inhibiting irrelevant information and are
more likely to remember events through reliance on feelings of
familiarity rather than explicit information. There are age-related
declines in brain volume in multiple brain regions.

Unlike cognitive function, brain neural activity [increases]{.underline}
with age. In cognitive tasks, older subjects recruit more brain regions
than younger subjects for the same task. Furthermore, cognitive decline
with aging is magnified in the setting of increased physical fatigue;
therefore, physical fatigue may limit cognitive resources.

Objective measurement of cognitive fatigue can be performed in several
ways depending on the question: over an extended time (eg. across a
workday), [during]{.underline} sustained mental effort,
[after]{.underline} challenging mental exertion, or after challenging
[physical]{.underline} exertion. So far, the best evidence for
demonstrating fatigue under these conditions is with during sustained
mental effort.

Neuroimaging of fatigue has revealed no evidence of structural changes
(eg. brain volume, lesion load, atrophy), but functional changes include
hypoactivation of cortical and subcortical regions including basal
ganglia and frontal lobes in multiple sclerosis subjects during a simple
motor task, and activation of more brain regions during simple and
complex cognitive tasks. In the latter, subjective fatigue after task
completion was correlated with performance on more complex tasks.
Multiple other studies have also shown increased brain activation in
fatigued subjects for the same task. Fatigue does not necessarily result
in decreased performance, but it may require more effort.

Fibromyalgia is a chronic pain syndrome associated with fatigue.
Patients with fibromyalgia performed the same as age-matched controls in
speed of processing information; however, they performed like older
controls on tasks of working memory, long term memory, and verbal
fluency. In addition, patients with fibromyalgia have poorer access to
vocabulary than older controls or age-matched controls. Fibromyalgia
patients recruit more brain regions than age-matched controls on a
complex cognitive task involving visuospatial processing, language, and
working memory \[60\]

Future questions:

-   What are the sources of age-related cognitive fatigue?

-   Is the age-related increase in brain activity compensatory for a
    declining brain? Is it another symptom of inefficient and declining
    neural function?

-   Do older people require increased mental effort to overcome
    age-related fatigue?

-   Do older adults get more tired after the same amount of mental
    effort than younger adults?

-   Can fatigue arise when individuals cannot inhibit default cognitive
    patterns?

**INTERVENTIONS**

**Exercise**

Multiple studies have found that slowly graded exercise therapy improves
fatigue in chronic fatigue syndrome with no significant adverse effects
\[61\]. Potential mechanisms causing unexplained fatigue include
psychological causes (fear of exertion, abnormal perception of symptoms)
and functional causes (muscular deconditioning, abnormal reaction to
exercise). As such, physical exercise may treat both causes. Randomized
controlled studies with long-term follow-up are needed to determine
whether patients who respond to exercise maintain health.
Standardization of outcomes and definitions of fatigue across studies is
essential.

Future questions:

-   Can measurement of non-exercise activity help to describe more
    comprehensively the effect of interventions for fatigue?

-   Can examination of social and psychological effects of exercise or
    other interventions help to paint a more complete picture of the
    effect of the intervention?

-   Can extending widely used tests to expose decrements in performance
    with effort or time bridge the divide between self-report and
    objective measures? For example, in a 400-meter walk test, would it
    be informative to compare walking speed at the end of the walk with
    the beginning, while assessing concomitantly self-reported fatigue
    at both times?

**Pharmacotherapy**

Evidence for pharmacologic therapy for fatigue is of poor quality. It is
difficult to make a recommendation because 1) fatigue is poorly defined,
leading to heterogeneity in subject selection; 2) therapies are
empirically selected, leading to poor linkage between pathophysiology,
mechanisms, and therapy; 3) studies often have small sample sizes,
heterogeneous outcome measures and scales, and high placebo response
rates; and 4) little attention is given to functional impact; i.e.,
physical activity or fatigue-activity relationships. Furthermore,
pharmacologic interventions for fatigue have not typically followed the
usual steps in the drug discovery process of target identification,
preclinical proof of concept, biomarker development, preclinical
toxicology, and finally, clinical trials.

Potential pathophysiologic contributors to fatigue include
cardiovascular, ventilatory, musculoskeletal, and central mechanisms.
Pharmacologic agents that have been evaluated for fatigue include
centrally acting drugs (methylphenidate, caffeine, SSRIs, cholinesterase
inhibitors, modafinil), promyogenic agents (testosterone, growth
hormone), agents that improve aerobic capacity/endurance
(erythropoietin, growth hormone), immune modulators / anti-inflammatory
agents (anti-TNFα, hydrocortisone, aspirin, interferon-α,
immunoglobulin), and others (DHEA, ACE inhibitors). Of approximately 50
randomized, non-randomized, and open-label trials, there is no
consistent evidence for successful treatment effect of any drug. Of
note, fluoxetine improves mood in chronic fatigue syndrome, but not
fatigue.

The best evidence for pharmacologic effect on fatigue is with
erythropoietin in cancer fatigue, but more recently appreciated
complications of treatment (thromboembolic events, red cell aplasia,
etc.) and target hemoglobin concentrations need to be considered.

Testosterone increases lean body mass in older adults, increases grip
strength, and increases self-reported physical function. There are
inconsistent effects on observed physical function. Preliminary data
suggests testosterone increases mitochondrial area. In open-label trials
in hypogonadal men, testosterone improved mood and increased energy or
pep. One potential explanation for testosterone's effects on fatigue is
increased hemoglobin concentration.

Pharmacologic interventions for fatigue require well-designed,
adequately powered randomized controlled trials with rigorous and
uniform entry criteria and outcomes. Initial trials should be conducted
in discrete, well-defined patient populations. Selection of therapeutic
agents should be guided by disease pathophysiology and mechanism of drug
action, and efficacy should be judged by both self-reported measures of
fatigue perception and impact, and objective measures of physical
activity, physical function, and fatigue-activity relationships.

**Cognitive Behavioral Therapy**

Fatigue is probably a CNS phenomenon and may be a final common pathway
acting as a fundamental "alarm" that forces an individual to stop
activity and understand what is wrong. Fatigue is rarely "explained" by
identifiable disease. Only a fraction of the symptoms presented in
primary care settings (fatigue, chest pain, dizziness, headache, edema,
back pain, dyspnea, insomnia, abdominal pain, and numbness) are found to
have a cause in identifiable disease pathology \[62\]. Even in chronic
medical conditions, symptoms are poorly related to severity of the
pathology

The traditional medical model focuses on pathology giving rise to
symptoms. Consequently, because of their disease focus, physicians find
it more difficult to help patients who have symptoms that are not easily
explained by an organic cause \[63\]. An alternative approach to
understand symptoms such as fatigue is to start with the symptom and
attempt to identify biological, psychological, behavioral, social
cultural, and interpersonal factors that contribute it. The contributing
factors can be categorized into predisposing, precipitating, or
perpetuating factors. Cognitive behavioral therapy (CBT) attempts to
address perpetuating psychological factors, such as worrying about
fatigue or seeing fatigue as uncontrollable or a barrier to activity.

There are different kinds of CBT (adaptive vs. rehabilitative), but all
forms help patients identify and change unhelpful symptom-perpetuating
thoughts and behaviors. Older adults tend to be more compliant with CBT,
possibly due to greater conscientiousness and/or fewer distractions.

Multiple studies have demonstrated efficacy of CBT on fatigue in chronic
fatigue syndrome and cancer-related fatigue. Of note, beneficial effects
may continue and even increase after treatment stops. There is modest
evidence for effect from brief CBT or psycho-educational interventions,
though the strongest effect if from more intensive CBT.

Exercise has been thought to improve fatigue through improvements in
physical fitness; however, recent studies suggest that exercise itself
may help patients to focus less on their fatigue \[64\]. As such, it may
be misleading to categorize treatments as either exercise or CBT, as
both may work in the same way.

Future questions:

-   Does CBT work for all types of fatigue?

-   What is the active ingredient of CBT? Or does CBT need several
    ingredients?

-   Does CBT do more than simply make patients more adherent to
    increased activity?

-   Is exercise really a psychological intervention?

-   Can very brief and simple interventions work?

-   Can we prevent fatigue?

**Complementary and Alternative Medicine Approaches**

Complementary and alternative medicine modalities are classified into
mind-body medicine, biologically-based therapies, manipulative and
body-based systems, and energy therapies. Yoga is a form of mind-body
medicine. In a randomized controlled trial of yoga or walking in
patients with multiple sclerosis, both yoga and walking improved
energy/vitality (SF-36) compared to wait-list controls, but there was no
effect on depression. Furthermore, fatigue measures were not markedly
associated with baseline functional impairment \[65\].

In a randomized controlled trial of yoga or walking in healthy 65-85
year olds who did not need to be sedentary for inclusion, yoga, but not
exercise, improved energy/vitality (SF-36), but there was no effect on
general fatigue (Multidimensional Fatigue Inventory) \[66\].

Although perception of fatigue is important, objective measures are
needed because many subjects lack insight into their deficits. For
example, in multiple sclerosis patients, self-reported cognitive
difficulty was correlated with depression, but not with measured
cognitive ability \[67\]. Examples of objective measures include EEG and
motor strength with repetition; for example, serial handgrips.

Future questions:

-   What is the underlying mechanism mediating benefit of mind-body
    interventions for fatigue?

-   Can certain medications that cause fatigue as a side-effect be used
    as a clinical model to test fatigue interventions? Anti-epileptic
    drugs may be one such example.

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