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Fatigue is associated with worse cognitive
and everyday functioning in older persons with HIV
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Download the PDF PCSK9 - Fatigue is associated with worse cognitive and
everyday functioning in older persons with HIV
AIDS May 1 2022
Laura M. Campbella,b, Ni Sun-Suslowb, Anne Heatonb, Robert K. Heatonb, Ronald J. Ellisb, David J. Mooreb and Raeanne C. Mooreb
Abstract
Objective:
The aim of this study was to determine whether there are relationships between fatigue, cognition, and everyday functioning in older persons with and without HIV and to examine if associations remain after accounting for depression, anxiety, and sleep quality.
Methods:
Sixty-nine persons with HIV (PWH) and 36 persons without HIV, aged 50-74 years, were recruited from ongoing studies at UC San Diego's HIV Neurobehavioral Research Program and from the community. Participants completed neuropsychological testing, a performance-based measure of everyday functioning, and self-report questionnaires of fatigue, depression, anxiety, sleep quality, and everyday functioning. Multivariable linear regressions and logistic regressions stratified by HIV serostatus were used to examine relationships between fatigue, cognition, and everyday functioning. Psychiatric symptoms and sleep quality were examined as covariates.
PWH in this study were between the ages of50 and 74 years from the San Diego area with high rates of ART use and viral suppression, and participants were primarily male; thus, these findings may not generalize to other groups of PWH.
Results:
In this cross-sectional study, PWH had significantly greater fatigue than the HIV-negative group (g = 0.83; P < 0.01). When stratifying by HIV serostatus, greater fatigue was significantly associated with worse global cognition (β = -0.56;P < 0.01) in PWH even when controlling for covariates;however, fatigue was not significantly associated with global cognition in persons without HIV. In PWH and when accounting for covariates, fatigue was also associated with greater risk of self-reported everyday functioning impairment [odds ratio (OR) = 1.66 for 10-point increase in fatigue, P = 0.04] but not performance-based everyday functioning (P = 0.95).
Conclusion:
Fatigue is associated with cognition, particularly measures with a speeded component, and self-reported everyday functioning in older PWH. Findings suggest that fatigue is important to assess and consider in the context of aging with HIV.
Results:
In this cross-sectional study, PWH had significantly greater fatigue than the HIV-negative group (g = 0.83; P < 0.01). When stratifying by HIV serostatus, greater fatigue was significantly associated with worse global cognition (β = -0.56;P < 0.01) in PWH even when controlling for covariates;however, fatigue was not significantly associated with global cognition in persons without HIV. In PWH and when accounting for covariates, fatigue was also associated with greater risk of self-reported everyday functioning impairment [odds ratio (OR) = 1.66 for 10-point increase in fatigue, P = 0.04] but not performance-based everyday functioning (P = 0.95).
Conclusion:
Fatigue is associated with cognition, particularly measures with a speeded component, and self-reported everyday functioning in older PWH. Findings suggest that fatigue is important to assess and consider in the context of aging with HIV.
In conclusion, we found that greater fatigue was negatively associated with cognition in older PWH, even when covarying for depression, anxiety, sleep quality. This relationship was primarily driven by neurocognitive tests with a speeded component. Moreover, fatigue was also associated with greater risk of IADL dependence. More research is needed to better understand the biological underpinnings of fatigue in PWH as this may lead to better treatment or prevention of fatigue, which may in turn promote cognitive and everyday functioning in older PWH.
In our sample of older PWH, fatigue was associated with subjective everyday function via a modified Lawton-Brody IADL Questionnaire.
There are a number of different biological mechanisms that have been explored in attempts to understand fatigue in PWH. Neuroanatomically, fatigue in PWH is thought to be modulated by the thalamostriatocortical circuitry involving the basal ganglia, which is particularly affected in HIV [45], but the relationship between fatigue and these brain regions has been more extensively studied in other diseases and disorders, such as multiple sclerosis and chronic fatigue syndrome [46,47]. This hypothesis is particularly relevant for these findings given that these brain regions are associated with processing speed. The literature on brain correlates of fatigue in PWH is limited, but one study did find that there were lower levels of a cellular energy marker (i.e. creatine) in the basal ganglia in PWH with fatigue [25]. Furthermore, among PWH, fatigue has been found to associate with increased inflammation and number of polymorphisms in genes involved in inflammatory expression [48,49]. It is well established that these brain regions and neuroinflammation are implicated in the pathogenesis of HAND [50]; therefore, fatigue and cognition may be associated with one another because of some common underlying mechanisms. Lastly, mitochondrial dysfunction in the brain is also thought to contribute to fatigue. Although this relationship has not been extensively studied in PWH, mitochondrial dysfunction is observed in PWH and has been associated with HAND [51,52]. The underlying cause of fatigue in PWH is complex and likely multifactorial; a better understanding of these underlying mechanisms may lead to improved treatment or prevention of fatigue in PWH.
Our findings have a number of clinical implications. In terms of medications, a randomized, double-blind study found that PWH with fatigue that were treated with modafinil significantly improved performance on neurocognitive tests (i.e. WAIS-III Digit Symbol and Grooved Pegboard) as compared with those in the placebo group [53].
Additionally, preliminary research also suggests that medication may be a helpful adjunct to psychotherapy. For example, a pilot study found that PWH with clinically significant fatigue who received combined behavioral activation and armodafinil were more successful in attaining work-related goals than PWH than those who received armodafinil alone (63 vs. 28%) [54]. Overall, this suggests that pharmacological treatment of fatigue, potentially combined with psychotherapy, may be helpful for both cognition and everyday functioning. With regard to neuropsychological testing, the present study suggests that in PWH with significant fatigue, speed of information processing should be assessed but it is important to incorporate nonspeeded tests of other cognitive domains in order to accurately tease apart processing speed versus other cognitive abilities. Fatigue is sometimes viewed as a symptom of depression, and our study demonstrates that fatigue in older PWH may relate to objective cognitive deficits, and interventions to improve fatigue may be beneficial for both cognition and daily functioning. For example, cognitive training programs focused on improving processing speed in PWH have been shown to improve lab-based IADL functioning [55,56]. However, these studies did not specifically examine fatigue; therefore, future studies should examine if cognitive training programs can improve processing speed, and by extension everyday functioning, in PWH with fatigue.
We should note that fatigue is a complex construct and has overlapping characteristics with a number of other constructs, such as ‘brain fog’ and chronic fatigue syndrome (CFS). As stated above, the MFIS was used to define fatigue as a feeling of physical tiredness and lack of energy. The scale measured how an individual rated the effect their fatigue has on their physical, cognitive, and psychosocial functioning. In many ways, questions on the MFIS aimed at capturing cognitive outcomes of fatigue (i.e. ‘I have been unable to think clearly’ and ‘I have been less alert’) overlap with ‘brain fog’, a term used to describe one's thinking as sluggish, fuzzy, or not sharp. The important distinction is that fatigue may be independent of cognitive changes, whereas brain fog is a subjective experience (not a medical term) that describes a state that may be caused by a variety of conditions (e.g. pregnancy, medication use jetlag). Brain fog’ is a common outcome of fatigue but the two constructs can be independent of each other. In terms of CFS, the MFIS can be used to measure the severity of fatigue in this chronic condition that is defined as having extreme fatigue that lasts at least 6 months and cannot be explained by an underlying condition [57]. However, unlike CFS, fatigue has no duration constraints and can be because of conditions, such as HIV.
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