Association between a lower T-CD4+/CD8+ lymphocyte ratio and cognitive impairment in older persons with HIV

doi:10.21203/rs.3.rs-4682928/v1

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Research Article

Association between a lower T-CD4+/CD8+ lymphocyte ratio and cognitive impairment in older persons with HIV

https://doi.org/10.21203/rs.3.rs-4682928/v1

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Purpose

to determine the association between a lower LT-CD4+/CD8 + ratio and cognitive impairment among people ≥ 50 years with HIV.

Methods

cross-sectional study, including 207 adults aged > 50 years with HIV, receiving care at a tertiary-care hospital in Mexico City. Participants underwent a standardized geriatric and neuropsychological assessment to establish the presence of HIV-associated neurocognitive disorder using validated criteria. Multivariate logistic regression models were performed to determine the association between T-CD4+/CD8 + lymphocyte ratio tercile values (0.57–0.91, and < 0.56; being > 0.91 the reference category) and cognitive impairment.

Results

Participants’ median age was 56 (IQR 53–62) years and 173 (83.6%) were men. The prevalence of any kind of cognitive impairment according to the Antinori criteria was 66.2% (n = 137); the highest proportion being asymptomatic neurocognitive impairment (n = 114, 83.2%). Adjusted logistic regression analyses showed that the lowest LT-CD4+/CD8 + ratio tercile values (< 0.56) were independently associated with the presence of cognitive impairment (OR 3.16; 95% CI: 1.22–8.16, p = 0.017).

Conclusion

lower LT-CD4+/CD8 + ratios are independently associated with cognitive impairment older persons with HIV, which represents another factor that could be addressed to modulate this outcome.

CD4+/CD8 + ratio

HIV

Cognitive impairment

Older adults

Aim To determine the association between a lower (<1) T-CD+4/CD8+ lymphocyte ratio and cognitive impairment in persons ≥ 50 years with HIV.

Findings A T-CD+4/CD8+ lymphocyte ratio of < 0.56 is associated with the presence of cognitive impairment.

Message Using easy-to-obtain markers can help us detect a population at risk of cognitive decline.

Global access to combination antiretroviral therapy (cART) has led to an increase in the population of older persons with HIV (OPWH). [1, 2] Given a negative synergism between the aging process and HIV, people with HIV may experience an earlier development of a range of adverse health-related conditions, both traditional comorbidities and geriatric syndromes such as sarcopenia, frailty, or cognitive impairment. [2–4] This phenomenon highlights some of the complexity and the challenges faced by people with HIV as they age. This earlier presentation of classical comorbidity (e.g., metabolic diseases) as well as geriatric syndromes occurs even in individuals within treatment goals according to classically used markers (T-CD4 + lymphocytes count, viral load). [5–8] Among these conditions, cognitive impairment is a highly prevalent problem among OPWH [9, 10] and plays a key role in health and autonomy preservation of this group. [11]

One of the proposed theories for the early development of geriatric syndromes, including cognitive impairment, focuses an underlying state of chronic low-grade inflammation and relative immune dysfunction, within an individual context of risk factors. [12–16] Identifying and quantifying this inflammatory state remains a challenge in daily clinical practice. However, there are easily accessible markers that are regaining interest, as they have been found to correlate with both chronic inflammatory as well as immune senescence indicators. [17] One such marker is the T-CD + 4/CD8 + lymphocyte ratio (LT-CD4/CD8). [17] Recent studies have shown that the inversion of the LT-CD4/CD8 ratio has been associated with an increased risk of age-related conditions, as well as non-AIDS-related morbidity and mortality. [18–20] Amongst these outcomes, ratios < 1 have been associated with cognitive impairment. [21–23] However, there are no studies that have examined this association specifically in older adults, as the available research has been carried out in relatively younger populations. [21–23] Considering the LT-CD4/CD8 ratio’s role in reflecting part of the physiological determinants of specific age-related conditions, as well as being an easily measurable parameter in busy clinics, the objective of this study is to determine the association between a lower (< 1) LT-CD4/CD8 ratio and cognitive impairment in persons ≥ 50 years with HIV.

Participants

Cross-sectional study including 207 adults aged > 50 years with HIV, all receiving cART and care at a tertiary-care hospital in Mexico City. Participants were identified through the HIV clinic database and appointment records between 2012–2019. They were invited either in person or via telephone to participate in the study. Patients who agreed to participate underwent a standardized comprehensive geriatric assessment by trained staff using validated tools. This is an ancillary study of a clinical cohort interested in functional impairment in people with HIV. Therefore, exclusion criteria were conditions that negatively influence functional status including prevalent and severe non HIV-associated dementia (Functional Assessment Staging = 5–7 for Alzheimer's dementia, Clinical Dementia Rating = 3 for non-Alzheimer's dementia); severe heart failure (New York Heart Association functional class III-IV); severe chronic obstructive pulmonary disease (Global Initiative for Chronic Obstructive Lung Disease); stage rheumatoid arthritis III-IV (American College of Rheumatology classification); stage IV-V Parkinson’s disease (Hoehn and Yahr scale); and individuals with a history of stroke with motor sequelae and myocardial ischemia within the previous 3 months. All participants gave their written informed consent, and the study was approved by the institutional ethics committee.

Covariates

Sociodemographic variables such as age, sex, and educational level were included. Previous diagnoses of hypertension, diabetes, dyslipidemia, cancer, stroke, ischemic heart disease, chronic obstructive pulmonary disease or osteoarthritis were obtained from the clinical record. The presence of each of these conditions was summed up in a comorbidity score between 0 and 8. Functional status was assessed using the Barthel index and Lawton scale for basic (ADL) and instrumental (IADL) activities of daily living, respectively. [24, 25] Depressive symptoms were assessed using the Geriatric Depression Scale (GDS-SF) with a score > 5 indicating the presence of depressive symptoms. [26] The Mini-Mental State Examination (MMSE) was used a screening test to assess global cognitive performance. Scores range from 0 to 30, with higher score indicates better cognitive status. [27] Other variables considered were the history of opportunistic infections (yes/no), time since HIV diagnosis in years (up to the time of assessment), and the nadir T-CD4 + lymphocyte count (lowest historically recorded value).

Cognitive assessment

Trained psychologist administered a cognitive assessment comprising the following test and scales:

- The neuropsychological “Neuropsi” battery [28] was used to assess a wide spectrum of cognitive domains including:
orientation to time (day, month, and year), and space (city and specific place), personal semantics (how old are you? or, when were you born);
attention: backwards digits (up to six digits), visual detection (in a sheet that includes 16 figures, each one repeated 16 times, the participants are requested to cross-out those figures equal to the one presented as the model; the 16 matching figures are equally distributed at the right and at the left visual fields and the test is stopped after 1 minute), and 20 − 3 (five consecutive times);
visual memory: copy of a semi-complex figure, like the Rey-Osterrieth Complex figure, but simpler. Later, recall of the semi-complex figure was requested;
verbal memory: 6 common nouns corresponding to 3 different semantic categories – animals, fruits, and body parts – are presented 3 times; after each presentation, the participant is asked to remember as many words as possible; the score is the average number of words remembered in the 3 trials; intrusions, perseverations, recency and primacy effects are noted. Later, recall of verbal information was also requested;
language skills: naming (eight-line drawing figures are presented to be named – animals, musical instruments, body parts, and objects), repetition (the participant is asked to repeat one monosyllabic word, one three syllabic word, one phrase with three words, and one seven-word sentence), comprehension (on a sheet of paper, two circles – small and large – and two squares – small and large – are drawn. Six consecutive commands, similar to those used in the Token Test are given to the participant. The easiest one is “point the small square” and the hardest one is “in addition to the circles, point to the small square”), semantic verbal fluency (animals), phonological verbal fluency (words beginning with the letter F);
writing-reading: the participant is asked to read a short story and then 3 questions about the story are provided; to write under dictation a 6-word sentence, and to write by copying a different 6-word sentence;
conceptual function: similarities (3 pairs of words are presented, and the participant has to provide the main similarity – e.g., orange-pear), calculation abilities (three simple arithmetical problems are presented), sequences (the subject is asked to continue a sequence of figures drawn on a paper);
motor function: hanging the position of the hand (to repeat three positions with both hands. The model is presented by the examiner up three times) alternating the movements of the hands (to alternate the position of the hands – right hand close, left hand open, and to switch), opposite reactions (if the examiner shows the finger, the subject has to show the fist; if the examiner shows the fist, the subject has to show the finger).

In total, 26 different scores are obtained. Maximum total score is 130. The Neuropsi includes items which are relevant for Spanish-speaking communities and can be applied to illiterate persons and individuals with a low educational level.

Testing was performed in a single session. Normative data for grading the test comes from validations performed in Mexican population and is adjusted according to age and educational attainment. [28]

The Antinori criteria for HIV-associated neurocognitive disorder (HAND)

The four items from the Antinori criteria for HIV-associated neurocognitive disorder (HAND) were established. [29] These criteria classify the presence or absence of HAND according to four scenarios based on the clinical and neuropsychological assessment (i.e., the Neuropsi test): 1) cognitively non-impaired, 2) HIV-associated asymptomatic neurocognitive impairment (ANI), 3) HIV-associated mild neurocognitive disorder (MND), and 4) HIV-associated dementia (HAD). The classification was established as recommended, according to the following: 1) performance on cognitive tests; 2) interference of cognitive function on everyday functioning; 3) cognitive impairment is not explained by delirium; and 4) cognitive impairment is not explained by other comorbidities. ANI was defined by 1) the presence of cognitive impairment demonstrated as a performance of ≥1 standard deviation (SD) below the mean of age-education adjusted normative scores in at least two cognitive domains, 2) the impairment does not interfere with everyday functioning, 3) the impairment does not occur solely as part of delirium or dementia, and 4) the diagnosis is only possible if the cognitive impairment cannot be explained by other comorbidities. MND was determined when 1) performance in at least 2 domains was 1 SD or more below the mean of age-education adjusted normative scores, 2) the cognitive impairment produces at least mild interference in daily functioning: self-report or observation by a knowledgeable informant that the individual has undergone decline in at least ≥ 2 instrumental activities of daily living, 3) the cognitive impairment does not meet criteria for delirium or dementia, and 4) it is not fully explained by comorbid conditions. HAD was defined by 1) acquired moderate-to-severe cognitive impairment, documented by a score at least 2 SD below demographically corrected normative means in at least two different cognitive areas, 2) marked difficulty in activities of daily living (ADLs) due to the cognitive impairment, 3) the impairment does not meet criteria for delirium, and 4) the impairment is not adequately explained by comorbid conditions.

For the study’s objective, the outcome was treated as a binomial variable (presence or absence of cognitive impairment) according to the Antinori criteria in any of its categories, including ANI.

T-CD4+/CD8 + lymphocyte ratio

Measurements of T-CD4 + and CD8 + lymphocytes were performed using flow cytometry (BD FACSCalibur®). Measurements closest to the evaluation date (no more than one month before or after) were considered. The LT-CD4+/CD8 + ratio at the time of assessment was collected as a continuous variable by dividing the absolute LT-CD4 + count by the total LT-CD8 + count. The LT-CD4+/CD8 + ratio was stratified into terciles, with the following cut-off points: < 0.56; 0.57–0.91; and > 0.91. Terciles were used given that the available literature shows associations with adverse outcomes for different ratio values, with the lowest ratios (< 0.5 in most studies) being consistently associated with such outcomes. [17, 30]

Statistical analyses

Variables were described using means and standard deviations (SD), medians and interquartile ranges (IQR), or frequencies and proportions, according to their nature. Comparative analyses (with or without cognitive impairment) were performed using Chi², Mann-Whitney U test, or Student’s t tests.

To determine the association between the different categories of the T-CD4+/CD8 + lymphocyte ratios (0.57–0.91, and < 0.56; being > 0.91 the reference category) and the presence of cognitive impairment, logistic regression models adjusted for relevant confounding factors (age, sex, time since HIV diagnosis, history of opportunistic infections, comorbidity score, and depressive symptoms) were performed. A P value of < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS software for Windows (version 25.0; SPSS, Inc., Chicago, IL) and R Studio 4.2.1.

Participants’ median age was 56 (IQR 53–62) years and 173 (83.6%) were men. The median schooling was 12.5 (IQR 9–16) years. In terms of comorbidities, dyslipidemia was recorded in 115 (55.6%) of the participants, followed by hypertension in 64 (30.9%) participants. Depressive symptoms were documented in 25 (12.1%) participants and the median for the MMSE was 28.5 (IQR 27–29). The median time since HIV diagnosis was 12 (IQR 6–16) years, with a median LT-CD4 + nadir of 129.5 (IQR 43.2-229.7) cells. The median for LT-CD4/CD8 ratio was of 0.73 (IQR 0.5–1.01).

The prevalence of any kind of cognitive impairment according to the Antinori criteria was 66.2% (n = 137), with the highest proportion being ANI (n = 114, 83.2%). Table 1 shows the socio-demographic and health related characteristics according to the presence or absence of cognitive impairment. Compared to those without cognitive impairment, participants with cognitive impairment had lower educational level (16 ys vs. 12 ys, p = 0.02), and lower median LT-CD4+/CD8 + ratios (0.88 vs. 0.69, p = 0.03). Figure 1 shows the boxplot and distribution density for the LT-CD4+/CD8 + ratio values according to cognitive impairment groups. No differences were found between cognitive impairment groups for age, sex, comorbidities, functional status (ADLs), depressive symptoms, time since HIV diagnosis, history of opportunistic infections, or the LT-CD4 + nadir.

Table 1

Sociodemographic and clinical characteristics according to the presence of cognitive impairment.
Variable	All (n = 207)	No cognitive impairment (n = 70)	Cognitive impairment (n = 137)	P value
Age, median (IQR)	56 (53–62)	55 (53-63.2)	56 (53–61)	0.87
Sex (men), n (%)	173 (83.6)	63 (90)	110 (80.3)	0.075
Schooling in years, median (IQR)	12.5 (9–16)	16 (9–16)	12 (9–16)	0.02
Comorbidity, median (IQR)^a	1 (0–2)	1 (0–2)	2 (1–2)	0.26
Dyslipidemia, n (%)	115 (55.6)	40 (57.1)	75 (54.7)	0.74
Hypertension, n (%)	64 (30.9)	19 (27.1)	45 (32.8)	0.40
Barthel index (ADL), median (IQR)	100 (95–100)	100 (100–100)	100 (95–100)	0.48
Lawton (IADL), median (IQR)	8 (7–8)	8 (7–8)	8 (7–8)	0.88
MMSE, mean (SD)	27.8 (2.5)	28.5 (1.3)	27.5 (2.9)	< 0.01
Depressive symptoms, n (%)	25 (12.1)	7 (10)	18 (13.1)	0.51
Time of HIV diagnosis, median (IQR)	12 (6–16)	10.73 (6.03–16.36)	12.75 (5.95–16.94)	0.84
Nadir CD4+, median (IQR)	129.5 (43.2-229.7)	130 (67–234)	129 (36–230)	0.36
History of opportunistic infections, n (%)	56 (27.1)	15 (21.4)	41 (29.9)	0.60
CD4+/CD8 + lymphocyte ratio, median (IQR)	0.73 (0.5–1.01)	0.88 (0.54–1.14)	0.69 (0.49–0.92)	0.03
IQR interquartile range, ADL activities of daily living, IADL instrumental activities of daily living, MMSE mini mental state examination
^aHypertension, diabetes, dyslipidemia, cancer, stroke, ischemic heart disease, chronic obstructive pulmonary disease, or osteoarthritis were obtained from medical records.

The proportions of participants in each tercile of the LT-CD4+/CD8 + ratio were as follows: < 0.56 (n = 68, 32.9%); 0.57–0.91 (n = 71, 34.3%); and > 0.91 (n = 68, 32.9%).

Table 2 shows the logistic regression models of cognitive impairment. The unadjusted model showed that a LT-CD4+/CD8 + ratio of 0.57–0.91 (OR 2.13; 95% CI: 1.05–4.31, p = 0.034) and of < 0.56 (OR 2.16; 95% CI: 1.05–4.40, p = 0.034) are associated with the presence of cognitive impairment. However, after the adjustment for confounding variables such as age, educational level, time since HIV diagnosis, CD4 + nadir, history of opportunistic infections, comorbidity score, and depressive symptoms, only an LT-CD4+/CD8 + ratio of < 0.56 remained statistically significant (OR 3.16; 95% CI: 1.22–8.16, p = 0.017); ratio of 0.57–0.91 (OR 1.74; 95% CI: 0.76–3.98, p = 0.18).

Table 2

Logistic regression for the T-CD4+/CD8 + lymphocyte ratio and cognitive impairment
Variable	OR (IC 95%)	P value
Unadjusted
CD4+/CD8 + lymphocyte ratio • > 1	Ref	-
CD4+/CD8 + lymphocyte ratio • 0.57–0.91	2.13 (1.05–4.31)	0.03
CD4+/CD8 + lymphocyte ratio • < 0.56	2.16 (1.05–4.40)	0.03
Adjusted
CD4+/CD8 + lymphocyte ratio • > 1	Ref	-
CD4+/CD8 + lymphocyte ratio • 0.57–0.91	1.74 (0.76–3.98)	0.18
CD4+/CD8 + lymphocyte ratio • < 0.56	3.16 (1.22–8.16)	0.01
Age	0.98 (0.93–1.03)	0.48
Schooling, years	0.95 (0.89–1.02)	0.23
Time since HIV diagnosis, years	0.99 (0.95–1.04)	0.95
CD4 + lymphocyte nadir	1.00 (0.99-1.00)	0.97
History of opportunistic infection	1.02 (0.44–2.40)	0.95
Comorbidity score^a	1.09 (0.84–1.40)	0.48
Geriatric Depression Scale (GDS)	0.99 (0.86–1.13)	0.88
^aHypertension, diabetes, dyslipidemia, cancer, stroke, ischemic heart disease, chronic obstructive pulmonary disease, or osteoarthritis were obtained from medical records.

Our results showed an independent association between a lower LT-CD4+/CD8 + ratio and the presence of cognitive impairment. This finding is relevant and original, given that most of the previous research on this topic has mainly focused on younger adults with HIV, without specific attention to older people. Comparing the findings with the available literature, starting with the severity of cognitive impairment, what was observed is in line with the available literature focused on HAND. [31] ANI was by far the most common category of impairment, followed by MND [32], which could also explain the observed mean MMSE values for the population, as well as their functional status (ADL assessment). Regarding the association between a lower LT-CD4+/CD8 + ratio and cognitive impairment, it is also consistent with studies of younger populations. For instance, a study of 200 patients > 18 years [mean age 52 (SD 10.1) years] showed that a LT-CD4+/CD8 + ratio < 1 was independently associated with the presence of symptomatic cognitive impairment. [23] On the other hand, T. Le, et al, reported in a longitudinal study that negative changes over time in the LT-CD4+/CD8 + ratio were associated with worse performance in specific cognitive domains, such as processing speed. [22] Similarly, a cohort of 86 people aged > 18 years reported a longitudinal correlation between the decrease in the LT-CD4/CD8 ratio and the degree of cognitive impairment. [21] Our results can be seen as complementary to those published in this area, as none of the previous studies focused on older persons.

From a physiological perspective, this association can be explained by the relationship that has been observed between an inverted LT-CD4+/CD8 + ratio (i.e., a proxy of immune dysfunction) and the presence of inflammation, including in the central nervous system. [17] By having a robust correlation with markers of underlying inflammation (and its drivers), even in individuals on treatment goals, the ratio could capture a part of the risk factors leading to cognitive impairment or to neurodegenerative processes. [33, 34] Consistent with this, the significant association with cognitive impairment in our study was observed in persons with the worst LT-CD4+/CD8 + ratios, and probably with an unfavorable underlying immune/inflammatory profile. Nevertheless, it is important to keep in mind that multiple other conditions (including genetic, environmental, psycho-social, and age-related) will also play a role in the development of this outcome. Although these other conditions play an active role in the development of cognitive impairment, having a readily available marker that is associated with some of its determinants (in this case underlying inflammation or immune dysfunction) may help us to identify vulnerable populations in busy clinics and thus address as many of the potentially modifiable factors as possible, by involving geriatric medicine in the care of this population. [35, 36] In this sense, it could also help to further assess people even if they are at treatment goals, without necessarily adding supplementary studies.

This study has several limitations, the main one being its cross-sectional design, which precludes establishing a causal relationship, highlighting the need for subsequent longitudinal research in this population to establish the role of the ratio as a predictor of cognitive impairment. Although the sample size is relatively small, it is important to note that it is comparable to other previously published studies in this field. Likewise, being a single-center study, the results may not be representative of our general population. Another point to consider is that most HAND cases were ANI. Although this is an asymptomatic state that is usually only identified in clinical studies by neuropsychological assessment, there is evidence that it may also be a factor that increases the risk of progression to symptomatic forms of HAND, and therefore, a target for intervention by comprehensive brain health strategies. [37, 38]

However, several strengths should be highlighted, such as its specific focus and design on OAWH. In addition, a robust and standardized assessment of cognitive impairment was used. Our results represent an original contribution to the field and provide a useful message for the clinic, indicating that simple to collect markers can help us detect vulnerable groups and thus encourage the involvement of specialists in aging in order to address potentially modifiable risk factors for cognitive impairment. In the absence of highly efficient and specific treatments for cognitive impairment in general, targeting factors that have a negative impact on brain aging trajectories remains one of the best strategies we can offer in the care of OPWH.

Competing interests

The authors have no (financial or non-financial) conflict of interest to disclose.

Author Contributions

CARM and VHR designed, drafted the manuscript, and directly accessed and verified the underlying data reported in the manuscript.

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Editorial decision: Major revisions
31 Jul, 2024
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15 Jul, 2024
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Association between a lower T-CD4+/CD8+ lymphocyte ratio and cognitive impairment in older persons with HIV

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Abstract

Purpose

Methods

Results

Conclusion

Figures

Key summary points

INTRODUCTION

METHODS

Participants

Covariates

Cognitive assessment

The Antinori criteria for HIV-associated neurocognitive disorder (HAND)

T-CD4+/CD8 + lymphocyte ratio

Statistical analyses

RESULTS

DISCUSSION

Declarations

Competing interests

Author Contributions

References

Status:

Version 1