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Self-Reported Decline in Everyday Function, Cognitive Symptoms, and Cognitive Function in People With HIV
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JAIDS Nov 2017 - Rosanna Laverick, MRes,* Lewis Haddow, PhD, MBChB,* Marina Daskalopoulou, MSc,* Fiona Lampe, PhD,* Richard Gilson, MD, MBBS,* Andrew Speakman, PhD,* Andrea Antinori, MD, Tina Bruun, MD, Anna Vassilenko, MD,ยง Simon Collins, and Alison Rodger, PhD, MBChB,* for the Cognitive Impairment in People with HIV in the European Region (CIPHER) Study Group
"In this study of HIV+ outpatients at 5 clinics in Europe, 80% reported cognitive symptoms in the past 4 weeks, and just over 20% reported decline in their ADLs and attributed this to cognitive impairment."
Abstract
Background:
We determined factors associated with self-reported decline in activities of daily living (ADLs) and symptoms of cognitive impairment in HIV positive adults in 5 European clinics.
Methods:
HIV+ adults underwent computerized and pen-and-paper neuropsychological tests and questionnaires of cognitive symptoms and ADLs. We considered cognitive function in 5 domains, psychosocial factors, and clinical parameters as potentially associated with symptoms. Separate regression analyses were used to determine factors associated with a decline in ADL (defined as self-reported decline affecting ≥2 ADLs and attributed to cognitive difficulties) and self-reported frequency of symptoms of cognitive impairment. We also estimated the diagnostic accuracy of both questionnaires as tests for cognitive impairment.
Results:
Four hundred forty-eight patients completed the assessments [mean age 45.8 years, 84% male, 87% white, median CD4 count 550 cells/mm3, median time since HIV diagnosis 9.9 years, 81% virologically suppressed (HIV-1 plasma RNA <50 copies/mL)]. Ninety-six (21.4%) reported decline in ADLs and attributed this to cognitive difficulties. Self-reported decline in ADLs and increased symptoms of cognitive impairment were both associated with worse performance on some cognitive tests. There were also strong associations with financial difficulties, depressive and anxiety symptoms, unemployment, and longer time since HIV diagnosis. Both questionnaires performed poorly as diagnostic tests for cognitive impairment.
Conclusions:
Patients' own assessments of everyday function and symptoms were associated with objectively measured cognitive function. However, there were strong associations with other psychosocial issues including mood and anxiety disorders and socioeconomic hardship. This should be considered when assessing HIV-associated cognitive impairment in clinical care or research studies.
INTRODUCTION
Several studies have reported high prevalence of cognitive impairment in HIV+ patients, with the highest estimates exceeding 50%.1,2 However, a large proportion of individuals scoring below specified thresholds on cognitive testing and meeting the criteria for HIV-associated neurocognitive disorder (HAND) have no interference with everyday functioning and are categorized as having asymptomatic neurocognitive impairment (ANI) by the Frascati criteria.3 Others have used participant self-report methods such as the modified Lawton & Brody Instrumental Activities of Daily Living Scale (IADLS) to discriminate mild neurocognitive disorder (MND) from ANI.2,4-6 Deterioration, if defined as a change from ANI to MND, is based solely on the assessment of difficulties with activities of daily living (ADL), therefore discerning this change is highly important. Functional decline and cognitive symptoms may also be the main driver of patients coming to clinicians' attention in clinical settings.
Some studies have suggested limited validity of patient self-report with commonly used questionnaires when used to predict objectively measured cognitive function.7-10 But even if symptoms are only weakly correlated with cognitive impairment, they are in some sense highly important to the patient. There are likely to be psychological and other factors underlying reported symptoms and understanding these factors may steer the clinician away from investigations such as brain imaging and lumbar puncture and toward the patients' more pertinent needs. In this analysis, we aimed to measure the strength of association between self-reported decline in ADL, self-reported symptoms of cognitive impairment, and objectively measured cognitive function. We then sought to determine which other factors were associated with these symptoms of cognitive difficulties.
DISCUSSION
In this study of HIV+ outpatients at 5 clinics in Europe, 80% reported cognitive symptoms in the past 4 weeks, and just over 20% reported decline in their ADLs and attributed this to cognitive impairment. There were associations between poorer cognitive function (especially reaction time, speed, and attention) and both self-reported decline in ADLs and increasing frequency of cognitive symptoms. However, symptoms of depression and anxiety, longer time since HIV diagnosis, unemployment, and difficulty affording basic needs were also strongly associated with cognition-related symptoms and functional decline. In addition, lower educational attainment and comorbid medical conditions were associated with cognitive symptoms. All of our observed associations may have multiple explanations, and causality could be in either direction (particularly in the relationships between employment and financial means and the outcomes of interest). The accuracy of both questionnaires, modeled as diagnostic tests for cognitive impairment, was relatively poor and below a level likely to be acceptable for individual patient use.
These results imply that patients who report symptoms of cognitive impairment, or declining everyday function, should be assessed for depression, anxiety, concomitant medical conditions, and financial difficulties. Failure to recognize these important elements of patients' lived experiences risks diagnostic delay, failure to address important needs, unnecessary investigations, and further anxiety. This is similar to the conclusions of a large cohort study of HIV-negative older adults in Amsterdam: "when an older person complains about his or her memory and does not show actual cognitive impairment or cognitive decline, one should be aware that these complaints might reflect psycho-affective or health problems. Adequate intervention in these psycho-affective or health problems may improve quality of life."33
The relationships between cognitive impairment, low mood, and functional decline are complex and multidirectional. Secondary analyses suggested that the effects of mood and cognition on everyday function were relatively independent, although we cannot exclude other explanations. In our recently published report of the same study population, we showed that severe depressive symptoms were associated with cognitive impairment, particularly on timed tests.11 A controlled intervention to improve patients' depression or anxiety symptoms might tease out the effect of low of mood on subjective and objective cognitive outcomes.
Limitations to CIPHER study methodology and Cogstate in general have been discussed in earlier reports,11,25 but some deserve further mention here. Notably, selection biases may have arisen as a result of our opportunistic sampling strategy, with patients choosing to participate in the study on the basis of their own concerns and self-perceived cognitive symptoms. Also, the largely computerized neuropsychological methods did not provide as comprehensive an assessment as traditional assessment conducted by a neuropsychologist.
Importantly, the lack of HIV-negative controls prevents us from determining whether our findings are specific to PLWH. However, there is a body of literature from the general population concluding that psychological and psychiatric factors are as important as cognitive function to subjective memory complaints. In their conceptual framework for research into subjective cognitive decline in preclinical Alzheimer disease, Jessen et al34 note that mood- and anxiety-related symptoms may be both a confounder of the relationship between subjective cognitive decline and subsequent dementia and an early symptom of dementia. An analogous situation might be at work in HIV-related cognitive impairment.
Despite initially positive results with a three-question symptom tool1 and the MOS-HIV cognitive questions,35 several studies have reported poor test accuracy of ADL and cognitive symptom scales in HIV+ patients.7-10 In 290 PLWH over 50 years in Great Britain and Ireland and 97 seronegative controls, other patient-reported outcome measures, including depression, falls, sexual function, and general health, correlated poorly with cognitive impairment.8 Thames et al36 divided 107 HIV-positive patients into 4 groups, on the basis of whether they were impaired or unimpaired, and whether they were accurate or inaccurate in their self-assessment of this. Notably, only 38% were accurate, 33% were impaired but did not report a decline, and 25% reported a decline but did not have cognitive impairment. In similar studies, it was reported that only 3337 and 37%38 of patients gave answers to symptom questions that concurred with their objective cognitive test scores. In an analysis of CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort patients (n = 277) in the United States, impaired everyday function was associated with depression, unemployment, findings on neuromedical examination, and physician-assigned Karnofsky score. Although patients were able to rate their own overall level of ability, they were poor at correctly attributing their difficulties to cognitive versus physical problems.7
Patients' symptoms are important because they guide clinical decisions, but clearly there are reasons other than neurological disease why patients and study participants may report symptoms. First, PLWH may have psychiatric problems, excessive substance use, or some other reversible cause for their symptoms. Second, depression or anxiety may cause them to perceive a functional decline that is not present. Third, they may be hypervigilant for symptoms or worried about normal everyday experiences, although not having any psychiatric disorder. Fourth, there may be desirability bias: they say what they think the clinician or researcher wants to hear. Fifth, there may be secondary gain as a result of misreporting their symptoms. And sixth, the measuring instruments may lack construct validity and fail to measure what they purport to measure.
Differentiation of asymptomatic from symptomatic HAND relies solely on estimating daily function at ADL, and most published research in this area relies predominantly on participants' self-report. There are limited data on more accurate and reliable measures of everyday performance, such as third-party observation or performance-based measures.12,13 This has crucial implications for the interpretation of longitudinal studies in which the risk of change from ANI to MND is measured, such as the United States CHARTER cohort,39 the Canadian OHTN Cohort,6 and the French Aquitaine cohort.40 For example, in the Ottawa cohort, depression was a major risk factor for change from ANI to MND.6 Because self-reported functional impairment is associated with depression, change from ANI to MND does not always indicate decline in neurocognitive abilities. In addition, change from ANI to MND in longitudinal studies should not be viewed as progressive, unidirectional deterioration (as is implied using Kaplan-Meier plot analyses). The CHARTER cohort used a more robust method of both self-reported and performance-based assessments to discriminate ANI from MND.39 These issues should be taken into consideration in the design and analysis of future HAND cohort studies.
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