Preventing Neurocognitive Decline in Adults Aging with HIV: Implications for Practice and Research

Abstract

Mild to moderate forms of neurocognitive impairment persist among people living with HIV (PLWH), despite being virally suppressed on antiretroviral therapy. PLWH are disproportionally impacted by physiological and psychosocial comorbidities compared to those without HIV. As adults live longer with HIV, the neurocognitive burden of physiological and psychosocial stressors can impair everyday functioning and may contribute to the development of neurodegenerative diseases such as Alzheimer’s disease. This article outlines neurocognitive consequences of everyday stressors in PLWH. While some lifestyle factors can exacerbate inflammatory processes and promote negative neurocognitive health, novel interventions including the use of cannabinoids may be neuroprotective for aging PLWH who are at risk for elevated levels of inflammation from comorbidities. Studies of integrated neurocognitive rehabilitation strategies targeting lifestyle factors are promising for improving neurocognitive health, and may over time, reduce the risk of Alzheimer’s disease in PLWH.

Keywords

Aging Alzheimer’s disease HIV neurocognitive impairment neuroinflammation

HIV AND NEUROCOGNITIVE AGING

More than half of people living with HIV (PLWH) in the United States are 50 years of age or older, largely due to effective HIV viral suppression from adhering to antiretroviral therapy (ART); such viral suppression has allowed them to live longer and healthier lives [1]. The number of older PLWH is growing significantly compared to the early epidemic when some PLWH were expected to live only a few years after diagnosis. While ART has decreased the prevalence of AIDS-defining conditions, many chronic diseases that occur in the general aging population (e.g., cardiovascular disease, diabetes, cancer) occur earlier or more acutely in the lifespan for some PLWH, often referred to as the accentuation or the acceleration of aging [2]. Some studies suggests that HIV and aging synergistically interact and lead to the development of age-related conditions at higher rates and at an earlier age in PLWH compared to age-matched controls without HIV [3, 4]. One systematic review reports no evidence of accentuated aging in PLWH found in the literature, but evidence of premature or accelerated neurocognitive aging were reported in a few longitudinal studies with larger samples of older PLWH [4]. Patterns of abnormal neurocognitive aging in PLWH remain unclear, given there are several limitations to this systematic review including underpowered studies, lack of age-matched controls, few studies with large samples of older PLWH, and inconsistent neurocognitive measures in PLWH [4]. Numerous factors including chronic HIV-associated inflammation and age-related immune and inflammatory responses may explain why some PLWH have a greater risk for neurocognitive impairment, including dementia, as they age [5, 6].

Neurocognitive impairment among PLWH is well documented with nearly 50% of PLWH experiencing mild to moderate forms of neurocognitive impairment also known as HIV-Associated Neurocognitive Disorder (HAND) [7]. In a systematic review of eighteen studies (sample sizes ranging from 206 to 1,555 PLWH), HAND prevalence was estimated at 44.9% based on the Frascati criteria [7]. According to the Frascati criteria, diagnostic criteria for HAND is based on psychological and functional testing of multiple neurocognitive domains (verbal/language; attention/working memory; abstraction/executive; memory; speed of information processing; sensory-perceptual, motor skill) and classified into three categories: asymptomatic neurocognitive impairment, mild neurocognitive impairment, and severe neurocognitive impairment or HIV-associated dementia [8]. Asymptomatic neurocognitive impairment is defined as having neurocognitive impairment in at least two domains (scores at least 1 standard deviation below the mean for age-education norms) with no impairment in everyday functioning. Mild neurocognitive impairment is defined as having neurocognitive impairment in at least two domains (scores at least 1 standard deviation below the mean for age-education norms) with mild impairment in everyday functioning. HIV-associated dementia is defined as having neurocognitive impairment in multiple domains (scores at least 2 standard deviations below the mean for age-education norms) with severe impairment in everyday functioning [7 –9].

The prevalence of HAND persists among PLWH who are treated with ART, and this is concerning for those aging with HIV who may also be susceptible to neurodegenerative diseases such as Alzheimer’s disease (AD). Some studies report an impact of the apolipoprotein E (APOE) ɛ4 allele, a genetic risk factor for AD, on neurocognitive outcomes in PLWH. In a study of 76 adults with HIV (age 60 and older), APOE ɛ4 carriers had poorer executive function, reduced brain white matter integrity, and brain atrophy compared to non-carriers [10]. Similarly, in a study of 259 older (>50 years) and younger PLWH, Panos et al. found that 94% of the older APOE ɛ4 carriers were diagnosed with HAND and had worse executive function and processing speed performance compared to their age-matched non-carriers [11]. These findings opposed those of cross-sectional and longitudinal studies of PLWH (<65 years of age) in which there were no associations found between APOE ɛ4 genotype and neurocognitive outcomes such as HAND [12, 13]. However, the impact of APOE ɛ4 on brain health and neurocognition in older PLWH should be further explored, especially since APOE ɛ4 genotype has been linked to other age-related comorbidities (e.g., cardiovascular disease) that negatively impact neurocognition [10].

As shown in Fig. 1, numerous physiological and psychosocial stressors can exacerbate neurocognitive conditions in older PLWH and negatively impact quality of life. While ART reduces some HIV-associated neuroinflammation, PLWH remain at a higher risk for being burdened with inflammatory-inducing physiological comorbidities such as cardiovascular disease and cancer compared to those without HIV [2]. Other physiological stressors that can be detrimental to neurocognition include poor sleep [14], physical inactivity [15], and poor nutrition [16]; fortunately, these are modifiable. Equally important, psychosocial stressors such as mental health challenges, lack of social support, and substance use commonly occur among PLWH and are associated with poor neurocognitive health [17, 18]. Unfortunately, many older PLWH may experience combined physiological and psychological stressors that can lead to geriatric syndromes such as frailty, neurocognitive impairments, and functional decline, all of which increase poor quality of life [19]. Given physiological stressors can exacerbate psychosocial stressors and vice versa [20], integrated therapies to manage comorbidities can be beneficial to promote successful neurocognitive aging among PLWH [13]. As shown in Table 1, some interventions that target these stressors may improve neurocognitive function and/or even prevent AD in people aging with HIV.

Fig. 1

Conceptual Overview of Psychological/Psychosocial Stressors on CNS/Brain Health with Corresponding Prevention, Intervention, and Health Promotion Strategies. This model shows examples of physiological and psychosocial stressors and their potential negative effects on the central nervous system, which can result in poor cognition in people living with HIV. Prevention, intervention, and health promotion strategies to prevent or lessen these neurocognitive effects are presented. CNS, central nervous system; ART, antiretroviral therapy; HPA, hypothalamic-pituitary-adrenal.

Table 1

Physiological and Psychological Stressors Associated with Neurocognitive Impairment and Possible Stressor-specific Neurocognitive Interventions

Stressors associated with neurocognitive impairment	Mechanisms leading to neurocognitive impairments	Possible stressor-specific neurocognitive interventions
Physiological Stressors
ART Neurotoxicity	•Long term use of ART with higher BBB penetrance	•Monitor treatment toxicity and change ART as needed
	•Decreased glutamate uptake	•Administered only ART with low neurotoxicity profile
	•Altered brain metabolism and atrophy
	•Low amyloid-beta and tau
Physiological Comorbidities	•Increased oxidative stress	•Promote healthy lifestyle behaviors to prevent and treat physiological comorbidities (e.g., physical activity)
	•Increased risk of cerebrovascular damage	•Monitor and treat physiological comorbidities (e.g., medications)
	•Chronic systemic inflammation
Sleep Disturbances	•Exacerbate chronic pain conditions that facilitate CNS inflammation	•Promote good sleep hygiene practices
	•Disrupt mood and/or exacerbate depression	•Monitor and treat associated pain and mood disorders
Chronic Pain	•Neuropathic pain can affect areas of the brain (e.g., dorsolateral prefrontal cortex)	•Manage chronic pain (pharmacological and nonpharmacological therapies)
	•Brain atrophy, higher proinflammatory cytokine levels, and microglial activation	•Monitor for altered pain perception•Monitor and treat associated comorbidities
	•Contribute to psychosocial stressors (e.g., poor sleep)	•Monitor and treat associated comorbidities
Sedentary Lifestyle	•Increased cardiovascular risk	•Promote daily physical exercise
	•Decreased oxygen consumption to the brain	•Monitor and treat mood disorders (e.g., psychotherapy and/or medications)
	•Contribute to psychosocial stressors (e.g., mood disorders)
Nutrition	•Poor nutrition can decrease brain metabolism	•Encourage dietary intake of unprocessed meats and vegetables
	•Intake of sugar and processed foods can contribute to increased metabolic risk	•Encourage dietary intake of food and drinks that are low in carbohydrates and sugar
Psychosocial stressors
Stigma	•Increased levels of inflammatory gene expression	•Manage and treat depression
	•Lower ART adherence due to depression	•Monitor ART adherence
Substance Use/Abuse	•Increased frailty risk	•Screen and refer for treatment of substance use disorder
	•Decreased neural activity on MRI in areas of the brain	•Manage and treat chronic pain conditions
	•Increased CNS inflammation depending on frequency of usage

ART, antiretroviral therapy; BBB, blood-brain barrier; CNS, central nervous system. Caveat: These points are a reflective sample of the broader literature and are not exhaustive.

As PLWH age, they may become susceptible to impairments in everyday function secondary to physiological and psychosocial stressors [20]. Interactions between HIV and age-related neurodegeneration increase the risk for impairment in medication management for older PLWH [21]. Cooley et al. examined 146 older adults with HIV and found that they performed significantly worse on a medication management measure compared to older adults without HIV [21]. In addition, older PLWH reported a higher pill burden, and executive function was a significant predictor of medication management [21]. Similarly, Kamal et al. found a 50% decline in medication adherence among PLWH with HAND compared to those with normal neurocognitive function or a non-HIV-related neurocognitive impairment [22]. Executive function impairments may explain an individual’s difficulty adhering to medications, which is problematic for older PLWH who are often burdened with multiple medications to treat comorbidities.

Impairments in driving ability can occur among PLWH, especially for those experiencing neurocognitive impairments [23]. Poorer speed of processing performance was found to be related to poorer driving performance among adults with HIV aged 40 and older [23, 24]. Several studies suggest HIV and age-related effects on neurocognitive and motor functions may impair driving ability [23, 24], and in a recent study of truck drivers with HIV, Gouse et al. found that drivers with neurocognitive impairment were most likely to crash compared to those without neurocognitive impairment [25]. Advances in technology have led to the use of the Internet to complete instrumental activities of daily living tasks such as shopping, scheduling medical appointments, managing banking accounts, and communicating with friends and family [26]. Among a sample of 134 people with and without HIV, individuals with HAND were most likely to fail the online shopping tasks and had errors in Internet navigation (e.g., log-in errors) compared to PLWH without HAND or those without HIV [26]. Internet navigation skills were correlated with executive function, one domain compromised in adults with HAND [26].

There are many dimensions of quality of life impacted by neurocognitive impairments [27, 28]. Alford et al. conducted a scoping review and found lower scores on measures of global quality of life: physical health quality of life (i.e., pain and low energy), psychological quality of life (i.e., depression and anxiety symptoms), social quality of life (i.e., ability to develop and maintain friendships), environmental quality of life (i.e., ability to work), and level of independence (i.e., instrumental activities of daily living) among PLWH with HAND [28]. It is well documented that PLWH report significantly worse quality of life outcomes (e.g., depression, physical disabilities, etc.) compared to those without HIV [29, 30]. While longer life expectancies are seen, the additive effects of HAND can worsen quality of life outcomes for PLWH as they age with comorbidities [28].

The purpose of this narrative review is to highlight psychological and psychosocial stressors that can impact neurocognitive aging among PLWH. Given that PLWH are more susceptible to psychological and psychosocial stressors than those without HIV [18], HIV-related health disparities are discussed throughout the article. A greater number of PLWH taking ART are living well into their fifties, sixties, and beyond, and despite being virally suppressed, are experiencing comorbidities and symptoms (e.g., fatigue and depression), that can be detrimental to quality of life. In addition to the ’90-90-90’ targets for HIV testing and treatment set by the World Health Organization, Lazarus et al. proposed a ‘fourth 90’ to ensure that 90% of people who are virally suppressed have good health-related quality of life [31]. The ‘fourth 90’ focuses on chronic care and management of comorbidities and non-HIV related diseases (e.g., cardiovascular disease) in PLWH virally suppressed on ART [31]. This review represents the importance of addressing the ‘fourth 90’ and includes the most relevant literature related to lifestyle risk factors that are associated with increased risk for HAND and AD. Most importantly, this review acknowledges potential clinical challenges with managing and treating comorbidities and neurocognitive disorders (e.g., HAND and AD) in people aging with HIV. Given the development of HAND and AD have some shared risk factors, it is important to include evidence of interventions that target lifestyle risk factors and their neurocognitive benefits which may be neuroprotective in those aging with HIV. We conclude this narrative review with implications for clinical practice and research related to integrated and novel therapies to promote successful neurocognitive aging among PLWH.

ADDRESSING PHYSIOLOGICAL STRESSORS

ART neurotoxicity

With the development of ART, there has been increased life expectancy for PLWH resulting in an upward trend in mild to moderate forms of neurocognitive impairment [32]. HIV can invade the central nervous system early in the disease process, thus leading to neuroinflammation, decreased neurocognitive reserve, and neurocognitive impairments [17]. Researchers have examined the ability of certain ARTs to penetrate the blood brain barrier with studies demonstrating higher penetrance scores correlating with lower viral load [17]. There are mixed study findings regarding whether better or worse neurocognitive functioning correlated with increased drug penetrance [33]. Unfortunately, Lanman et al. found that highly penetrating ART regimens also have higher potential to cause neurotoxicity with long-term use [32]. Further studies are needed to examine ART regimens that can optimize viral suppression in the central nervous system and minimize neurotoxicity in the aging HIV population.

As adults live longer with HIV, one potential challenge for clinic providers will be distinguishing whether neurocognitive decline is a result HAND and/or AD. Neurocognitive symptoms in people with HAND on ART are typically mild and fluctuate, compared to a progressive neurocognitive decline seen with AD [34]. There are only two documented cases in the literature of AD in people with HIV, and each case involved distinguishing features on neuropsychological testing, cerebrospinal fluid (CSF) biomarkers, and neuroimaging which suggested a concern for a mixed HAND/AD diagnosis [35, 36]. In one case, a 63-year-old woman with HIV stable on ART had worsening memory deficits over the years, had decreased glutamate uptake in various parts of the brain (e.g., bilateral parietal lobes) seen on the positron emission tomography (PET) scan, and no improvement in neurocognitive symptoms with treatment of a possible CSF escape [35]. Similarly, a 71-year-old man with HIV exhibited deficits in several neurocognitive domains with progressive declines in working memory, had altered brain metabolism and atrophy seen on neuroimaging, low amyloid-beta and tau CSF biomarkers, and amyloid deposition consistent with AD seen on neuroimaging [36]. Both of these cases suggest neuroimaging, CSF biomarkers, and neurocognitive performance may be important assessment tools to help distinguish HAND from early-stage AD [35, 36]. Specifically, HAND has been described to include neurocognitive deficits in multiple domains with intact recognition memory, compared to patients with AD who have difficulty with recognition, recall, and episodic memory (e.g., remembering recent events/conversations). Neuropsychiatric symptoms such as depression, sleeping problems, and agitation may be more severe with advanced AD compared to HAND, but these symptoms have been reported in older PLWH without neurocognitive impairment [34]. Table 2 outlines some potential key differences between HAND and AD including diagnostic tests, neuropsychological performance, neuroimaging, CSF biomarkers, and disease management.

Table 2

Key Differences between HIV-Associated Neurocognitive Disorder (HAND) and Alzheimer’s Disease (AD)

Characteristic	HAND	AD
Diagnostic Tests	•Neuropsychological testing with or without impairment in everyday activities	•Clinical history, exclusion of other causes of neurocognitive impairment, and biomarkers
Neuropsychological Performance	•Fluctuating and variable	•Progressive decline
	•Concentration and attention deficits	•Learning and consolidation deficit
	•Impaired executive function	•Visuospatial deficit
	•Poor learning efficiency and retrieval	•Semantic memory
	•Recognition likely less impaired	•Global neurocognitive deficit
	•Psychomotor slowing even in milder forms	•Recognition impairment
		•Gait changes in advanced stages of AD
Neuroimaging	•Frontal lobe abnormalities (basal ganglia, thalamus, cerebellum, and cortical motor strip), atrophy, and reduced cortical thickness	•Early cortical atrophy in the hippocampus
	•Widespread white matter abnormalities that correlate with neurocognitive impairment	•White matter changes occur predominantly in the posterior rather than frontal brain regions
	•Decreased white matter in the parietal region, splenium, globus pallidus, thalamus, putamen	•Hypometabolism of the parietal cortex and increased binding of amyloid plaques in the frontal, temporal, and parietal lobes bilaterally which correlate with APOEɛ4 status
	•Hypermetabolism of bilateral basal ganglia
CSF Biomarkers	•Mixed reports of low/normal levels of amyloid-beta with elevated or reduced t-tau and p-tau	•Decreased amyloid-beta levels and increased total tau (t-tau) and p tau
Disease Management	•Optimal viral suppression with antiretroviral therapy and adjunct anti-inflammatory medications	•Cholinesterase inhibitors (e.g., donepezil)
	•Central nervous system drug delivery	•Immunotherapies to reduce amyloid plaques
	•Management of comorbidities	•Management of comorbidities
	•Nonpharmacological and pharmacological therapies to treat associated symptoms	•Nonpharmacological therapies and pharmacological to treat associated symptoms

AD, Alzheimer’s disease; CSF, cerebrospinal fluid; HAND, HIV-associated neurocognitive disorder.

Physical comorbidities

ART regimens including the use of protease inhibitors have been associated with the development of metabolic syndrome with insulin resistance, dyslipidemia, and hypertension [37]. HIV and physical comorbidities lead to oxidative stress and chronic inflammation which can negatively impact neurocognitive function [38]. Oxidative stress can occur from HIV infection alone due to the release of proinflammatory cytokines and excess production of reactive oxidative species, thus causing cell and mitochondrial damage and neurotoxicity [38]. High levels of oxidative damage are associated with age-related chronic conditions (e.g., cardiovascular disease) and have been observed in PLWH taking ART who are virally suppressed [39, 40], thus suggesting that prolonged use of ART and age-related comorbidities may contribute to neurocognitive impairments and an increased AD risk in PLWH. Given Non-Hispanic African Americans have higher rates of cardiovascular disease and HIV compared to Non-Hispanic Whites [41], the risk of vascular-associated neurocognitive disorders may be greater in this population [42]. Several studies indicate impairments in neurocognitive performance for individuals with HIV and cardiovascular disease [42 –44]. McIntosh et al. conducted a recent systematic review and found that vascular related factors (i.e., diabetes type II, hyperlipidemia, current smoking, and previous cardiovascular disease) correlated with neurocognitive impairments particularly in domains of attention/speed of processing, executive function, and fine motor skills [44]. In a large sample of 900 men with HIV and 1,149 men without HIV, Yang et al. observed that men with diabetes experienced poorer neurocognitive functioning than those without diabetes [45]. Some studies suggest that management of comorbidities may improve neurocognitive function [46, 47]. Management of comorbidities may be important for neurocognitive aging in older PLWH, especially given their increased susceptibility to developing chronic diseases and weakened immune function.

Increasing evidence suggests that cardiovascular disease, diabetes mellitus, chronic kidney and liver disease, osteoporosis, and cancer occur more frequently and/or at earlier ages in PLWH [46]. Approximately 25% of PLWH in the United States are coinfected with Hepatitis C (HCV), and coinfection is linked to liver inflammation and cancer and increased risk of other inflammatory conditions [48]. Studies indicate that, compared to individuals infected with HIV or HCV, those with HIV/HCV coinfection have significantly higher levels of macrophage expression of proinflammatory cytokines which can contribute to neurodegeneration and possibly HAND [49]. However, Clifford et al. found no significant association between neurocognitive performance and HIV/HCV coinfection in the absence of HIV-associated liver damage [50]. It may be possible that treatment of HCV may reduce inflammation and improve neurocognitive function, especially in older adults with comorbidities and HIV/HCV coinfection.

Furthermore, chronic obstructive pulmonary disorder (COPD) is an emerging comorbidity with a prevalence of approximately 10% in PLWH [51]. Mechanistically, COPD can increase systemic inflammation, oxidative, and physiological stress [52]. Up to 50% of individuals with COPD have metabolic syndrome, a cluster of conditions including diabetes and prediabetes, abdominal obesity, high cholesterol, and high blood pressure [52]. Age-related comorbidities such as cardiovascular disease and metabolic factors (e.g., diabetes) are risk factors for cerebrovascular damage, especially when uncontrolled, thus contributing to neurocognitive impairment and even HAND [53]. Similarly, chronic systemic inflammation can contribute to cerebrovascular damage and neurocognitive impairment in people with COPD, which may be more profound in those with HIV [52]. As COPD’s importance is recognized as PLWH age, further studies will be needed to examine neuroprotective mechanisms for PLWH with comorbid COPD.

Sleep disturbances

A meta-analysis of 27 studies estimates 58% of the HIV population experiences poor sleep [54]. Reports of insomnia or difficulty falling asleep, staying asleep, and/or frequent awakening is as high as 70% in PLWH compared with 10-15% in the U.S. general adult population [55, 56]. Several studies suggest that sleep disturbances are linked to neurocognitive function in PLWH. In a study of 1,124 people with and without HIV, PLWH who reported poor sleep behaviors such as frequent daytime sleepiness had significantly poorer neurocognitive performance compared to those without HIV [57]. Similarly, in a study of 66 PLWH and 50 without HIV, PLWH who self-reported poorer sleep quality had poorer scores in neurocognitive domains of learning and memory compared to those with better sleep quality [14]. These studies suggest that good sleep plays a critical role in the neurocognitive function of PLWH. Evidence mounts that sleep disturbances often occur with other comorbidities (e.g., chronic pain and depression) [58, 59], all of which can facilitate persistent CNS inflammation and contribute to neurocognitive impairment in PLWH [60]. Therefore, as PLWH age and become more susceptible to age-related sleep changes, sleep disturbances should be considered a risk factor in the progression of neurocognitive impairments such asHAND [60].

Chronic pain

Chronic pain is a common comorbidity with reports of higher incidence in PLWH compared to those without HIV. Chronic pain has been associated with other neurocognitive risk factors including depression and poor sleep [58]. The relationship between chronic pain and neurocognitive impairment is complex. However, there is evidence that neuropathic pain (e.g., pain and numbness in the legs) affects areas of the brain (e.g., dorsolateral prefrontal cortex) and is associated with worsening neurocognitive impairment in PLWH [61, 62]. In a study of 148 PLWH, significantly greater neuropathic symptoms and chronic pain were reported among participants with cognitive impairment compared to those without cognitive impairment [61]. In addition, those with chronic pain demonstrated neurocognitive deficits in domains of verbal learning and emotional recognition [61]. Findings from this study indicate that neurocognitive impairment in PLWH may alter pain perception and the presence of chronic pain may contribute to neurocognitive deficits, thus suggesting a bidirectional relationship between these comorbidities. Brain atrophy has been associated with chronic pain in older non-HIV adults [63], which suggest that PLWH with chronic pain may also be at a greater risk for neurocognitive decline. Inflammation is one potential mechanism that may link chronic pain to poorer neurocognitive outcomes in PLWH, given higher proinflammatory cytokine levels and microglial activation have been found in PLWH with chronic pain compared to those without chronic pain [64]. Chronic pain can also contribute to psychosocial stressors such as poor sleep, substance use, and depression, which can contribute to neurocognitive impairment and HAND [58 –60]. Future pain studies to examine mechanisms linking chronic pain and neurocognitive impairment in PLWH can yield a better understanding of the role of chronic pain in biological brain aging. Pain management in PLWH may be a viable strategy to slow biological brain aging and neurocognitive decline which may reduce risk of HAND and AD in people aging with HIV.

Sedentary lifestyle

Physical activity is known to exert anti-inflammatory properties, promote cerebral angiogenesis, improve cerebral and peripheral vascular reactivity, increase upregulation of neurotrophins, increase neurogenesis, and decrease hippocampus apoptosis [65]. In several populations including PLWH, engagement in physical activity has been shown to result in better neurocognitive function. Dufour et al. conducted a longitudinal study of 291 adults with and without HIV and found better neurocognitive function at baseline and over time for participants with consistent physical activity compared to those who reported inconsistent or no physical activity [66]. Furthermore, two studies found level of physical activity in PLWH correlated with domain specific neurocognitive improvements. In the longitudinal Multicenter AIDS Cohort Study of men with and without HIV, high engagement in physical activity was associated with lower odds of impairment in the domains of learning, memory, and motor function, and these effects were more pronounced among men living with HIV in comparison to those without HIV [67]. Similarly, Fazeli et al. examined physical activity using a 7-10-day activity monitor in 75 PLWH (aged 40+) and found that light physical activity was associated with better executive function, working memory/attention, and speed of processing [15]. These findings suggest that various levels of physical activity may yield domain-specific neurocognitive improvements in PLWH, some of which may also be impaired in those with HAND and AD.

While the mechanisms in which physical activity impact neurocognitive function are unclear, some studies suggest physical exercise reduces proinflammatory cytokines and increases brain blood flow, thus improving vascular health [68, 69]. In addition to anti-inflammatory effects, evidence suggests physical activity improves neurocognitive function by increasing maximal oxygen consumption to areas of the brain, reuptake of proteins for neuron survival and growth, and decreased hippocampus cell death [70, 71]. Engagement in physical activity has been linked to structural changes such as increased brain volume and elevated biomarker levels of brain-derived neurotrophic factor (BDNF), a protein found in the brain that contributes to neuronal growth, survival, and development of new neurons [72, 73]. Decreased BDNF has been linked to AD risk [74], therefore physical activity alone and/or in conjunction with other interventions may be neuroprotective against HAND and AD via numerous biological pathways including stimulation of BDNF. There is evidence that high intensity interval training, which involves short periods of exercise performed at high intensity (80-95% of the individual’s maximum heart rate), improves cardiometabolic health (blood pressure and insulin and glucose regulation) which may in turn improve neurocognitive function [75]. Other benefits of physical activity include better mood which has been shown to improve neurocognitive function [76]. Future studies should examine the types and frequency of physical activity that are likely to produce long-term neurocognitive benefits in PLWH, specifically in older adults with HIV with an increased risk of HAND and AD.

Nutrition

While there is evidence that dietary intake plays a role in the prevention of AD and associated dementias [77 –79], there is little research on dietary intake within the context of HIV and neurocognitive impairment. A growing body of evidence suggests that brain hypometabolism is a contributor to HAND [80, 81]. Brain imaging studies indicate ketones provide a better energy source for hypometabolic neurons in comparison to glucose [80]. In a study of 729 women with HIV and 346 women without HIV, Rubin et al. conducted neuropsychological testing of 7 domains and used T-scores to categorize participants into one of three global and domain-specific profiles: neuropsychological healthy, fluctuating, or stably impaired. Rubin et al. found dietary intake of certain foods (e.g., processed meats, sugary beverages, and whole milk) was associated with domain specific neurocognitive impairment whereas a higher intake of vegetables was associated with less neurocognitive impairment in women with HIV [82]. Findings suggest that dietary intake of vegetables may be neuroprotective against neurocognitive decline and AD risk in PLWH because of its anti-inflammatory properties and role in reducing cardiovascular risk [82]. On the other hand, the intake of processed meats and sugary beverages can contribute to the development of hypertension and diabetes, both of which can contribute to cardiovascular disease and neurocognitive decline in PLWH [82]. Similarly, evidence has emerged showing that a ketogenic diet, a diet characterized by low carbohydrate and high fat, can improve neurocognitive functioning in adults suffering neurocognitive impairment, including PLWH [81]. For example, Morrison et al. randomized 14 PLWH experiencing mild to moderate neurocognitive impairment to either a ketogenic diet or a diet of patient choice for 12 weeks followed by a 6-week washout period. Compared to the group who completed the patient choice diet, the ketogenic group demonstrated improved executive function and speed of processing at week 12 suggesting potential effectiveness in treating HAND [81]. Although consistent with other studies examining the ketogenic diet in neurocognitively-impaired aging populations, these findings must be interpreted with caution given several limitations including the small sample size and the control group was able to select their diet [78, 79]. Additional studies are warranted to determine whether ketogenic diets can increase the brain’s energy supply, which may promote positive downstream effects on neurocognitive function in older PLWH.

ADDRESSING PSYCHOSOCIAL STRESSORS

Stigma

Psychosocial stressors such as intersectional stigmas based upon HIV status, age, race, and/or sex are nonmodifiable and commonly experienced by people aging with HIV [83, 84]. Stigma and discrimination have been linked to increased levels of inflammatory gene expression which may contribute to poor neurocognitive performance [83]. There is growing concern regarding direct and indirect cognitive consequences of stigma and ageism for people aging with HIV. Thompson et al. found that internalized HIV-related stigma or acceptance of societal negative perceptions about people with HIV was associated with overall poor neurocognitive function in women with HIV [84]. Furthermore, Turan et al. found that higher internalized HIV-related stigma predicted lower ART adherence, and mediation analyses revealed higher internal HIV-related stigma predicted lower ART adherence through depression symptoms [85]. Given depression and ART adherence alone have been associated with poor neurocognitive function in PLWH [16, 86], these findings suggest that treatment of depression in PLWH may improve ART adherence which may also yield improvements in neurocognitive function.

Substance use

Substance use represents another common comorbidity in PLWH and has been associated with poor physical and neurocognitive outcomes [46]. Paolillo et al. found that PLWH who use methamphetamine had significantly higher frailty index scores, which were associated with worse neurocognitive and everyday functioning. Even alcohol binge drinking has been found to worsen learning, delayed recall, and motor skills in PLWH, with these effects appearing more pronounced in older adults [87]. Similarly, magnetic resonance imaging (MRI) revealed decreased neural activity in the parietal and frontal brain regions for PLWH who consumed greater levels of alcohol, thus suggesting negative effects of HIV and alcohol on attention and working memory networks [88]. Regarding cannabis use, there are inconsistent findings related to its potential impact on neurocognitive function in PLWH, with some studies reporting neurocognitive decline in PLWH with lifetime use of cannabis [89]. Heaton et al. found that a lifetime history of cannabis use disorder was associated with neurocognitive decline in PLWH, thus suggesting that substance use disorder that occurred between baseline and 12-month follow-up may have contributed to CNS injury [90]. Additional studies suggest adverse neurocognitive effects of cannabis use on memory, speed of processing, and executive functioning [91, 92], which may be detrimental for older adults who are already neurocognitively impaired such as those with HAND and/or AD. Opposing these findings, other studies found associations between cannabis use and lower risk of neurocognitive impairment and lower central nervous system inflammation in PLWH, due to its anti-inflammatory properties in alleviating HIV-associated symptoms [93, 94]. These anti-inflammatory effects may be true when cannabis is used in moderation. Additional studies show that heavy cannabis use in PLWH taking ART was associated with lower frequency of activated T-cells compared to PLWH who were nonusers, thus suggesting immunological and reduced systematic anti-inflammatory benefits of cannabis use [95, 96]. Cannabinoid receptors (CB2), located in the periphery and expressed in immune cells, have been suggested as a target therapy for PLWH given their role in reducing monocyte circulation, which is linked to neuroinflammation and neurocognitive decline [95, 97]. Specifically, there is evidence of activation of CB2 receptors in cannabis users that reduces permeability of the blood-brain barrier and inhibits mitochondrial damage from proinflammatory cytokines, which may be a potential neuroprotective mechanism for HAND [95, 97]. A growing body of work suggests using cannabis as a therapeutic approach may decrease microbial translocation caused by HIV and comorbidities, which in turn will decrease gut-brain inflammation and improve neurocognition [93, 95]. Additional studies are needed to determine whether cannabinoid use may be neuroprotective against HAND and AD for people aging with HIV who are at risk for neurocognitive decline due to elevated levels of inflammation from HIV and age-relatedcomorbidities.

CLINICAL IMPLICATIONS

Integrated interventions

Integrated interventions that target physiological and psychosocial stressors may protect neurocognitive functioning in older PLWH. Some interventions can be individually tailored to address factors that negatively impact neurocognitive function such as poor sleep hygiene, physical inactivity, mental/intellectual inactivity, depression, and many others. Vance et al. proposed a neurocognitive prescription in which lifestyle factors can be manipulated individually or collectively to improve neurocognitive functioning in older adults [98]. For example, in an older patient with HIV with neurocognitive impairment, the clinician and patient can develop a neurocognitive prescription to improve reported symptoms of physical inactivity and depression which may in turn positively impact neurocognitive function. There are ongoing studies examining the role of neurocognitive prescriptions in preventing neurocognitive impairment in middle-aged adults [99]. Similarly, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was the first large, randomized control trial to demonstrate neurocognitive improvement in older adults (age 60-77) participating in a multi-component intervention with improvements sustaining two years post-intervention [100]. Multi-component interventions have also been investigated in Germany with the AgeWell.de Study to prevent or delay neurocognitive decline in older adults at risk for dementia [101]. In this study, older patients (age 60–77) participate in a multi-component intervention (e.g., nutritional counseling, education regarding vascular comorbidities, and management of depressive symptoms) to address factors that increase AD risk which may also lead to improvements in secondary outcomes such as depression and quality of life [101]. Similar interventions can be used to target lifestyle factors and comorbidities in older adults with HIV, and improvements in lifestyle factors over time may also lead to downstream effects in reducing AD risk in this population.

Neurocognitive training

Neurocognitive rehabilitation therapies have been studied in older adults with and without HIV with documented neurocognitive benefits. Vance et al. adapted a neurocognitive training protocol from the largest randomized control trial of neurocognitive training in older adults, the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) Study, to improve global and domain specific neurocognitive functioning in PLWH. PLWH (40 years and older) performed better on a measure of visual speed of processing after completing 10 hours of computerized speed of processing training over 5-6 weeks compared to the no contact control group [23]. Similar improvements in speed of processing performance and self-rated neurocognitive health were evident among PLWH engaging in speed of processing training in a home setting [102]. Benefits of neurocognitive training for PLWH with HAND have been shown in one case study of three older PLWH with HAND randomized to receive either 10 hours of speed of processing training, 20 hours of speed of processing training, or 10 hours of sham computer training [103]. The participant who received 20 hours of speed of processing training no longer met the criteria for HAND, thus suggesting neurocognitive training may be a promising rehabilitative approach for those with HAND [103]. Neurocognitive training can be combined with other neurocognitive interventions such as transcranial direct current stimulation to produce greater neurocognitive gains [104].

Spaced retrieval method

Compensatory strategies such as spaced retrieval method and mnemonics may be used to help PLWH with neurocognitive impairments compensate when neurocognitive function cannot be restored. Spaced retrieval method is a type of mnemonic used to improve memory recall of newly learned information [17]. Woods et al. randomized 41 PLWH to one of two groups to learn four statements about a disease: a control group that was asked to recall the information after 20 minutes, or a spaced-retrieval condition group that received prompting/self-generated boosters to help them recall any of the four statements that they missed during the 20-minute delayed recall [69]. Compared to participants in the control group, those in the spaced-retrieval condition group were four times more likely to recall at least one statement at the 20-minute delay, thus suggesting the spaced retrieval method as a strategy for improving learning and memory among PLWH at risk for AD [69]. Moreover, Woods et al. found that older PLWH who received combined compensatory supports (e.g., internal and external cues and monitoring) demonstrated better time-based prospective memory (e.g., remembering to carry out a task at a future time) compared to HIV controls [105]. The use of visual and auditory external memory aids may help PLWH with neurocognitive impairment remember important tasks such as attending clinic visits and taking HIV medications.

RESEARCH IMPLICATIONS

Future research on neurocognitive aging in PLWH is needed regarding ongoing and proposed multi-component interventions as well as emerging novel therapies. Additional research on integrated clinical interventions, including those outlined above, is needed to understand the cumulative impact of multi-component interventions. The overlapping of HIV and age-related neurodegenerative disorders is a critical clinical issue as increasing numbers of PLWH approach age 65, the age where AD begins to escalate. Routine neurocognitive screening can provide information regarding progression of symptoms and domain specific neurocognitive changes which may indicate features of HAND, AD, and/or a mixed diagnosis. Assessment of lifestyle risk factors can help clinicians identify physical and psychological stressors that can be targeted with individualized multicomponent interventions, many of which may preserve neurocognitive function with aging. Although studies have demonstrated differences in neuroimaging findings between PLWH with HAND and those with AD, these findings should be interpreted carefully given most of these studies involved PLWH who were not virally suppressed and much younger than the aging HIV population. Future population-based longitudinal studies should compare neurocognitive changes on examination, neuroimaging, and CSF biomarkers in older, virally suppressed PLWH with and without HAND with age-matched adults without HIV with AD.

Some evidence suggests that interventions focused on physiological and psychological stressors, such as neurocognitive training programs, or exercise interventions, can improve neurocognitive function in PLWH. Albeit a gap in the literature exists concerning multi-component interventions, such as our hypothetical combined physical inactivity and depression intervention or the ongoing FINGER and AgeWell.de Study interventions [100, 101]. For example, future research can examine whether singular and/or multicomponent interventions reverse HAND or protect further neurocognitive impairment in people aging with HIV. It is important to consider how all components of these interventions impact neurocognitive function for PLWH. Research evaluating the impact of multi-component clinical interventions has the potential to promote successful neurocognitive aging in PLWH.

Novel therapies

Several emerging novel therapies suggest improved neurocognition for PLWH with HAND. Continued research on these therapies can potentially build the evidence base for successful interventions and further inform ongoing multi-component interventions. First, Nicholson et al. proposed the use of transcutaneous vagus nerve stimulation (tVNS) as a novel therapy for treating depression and other comorbidities PLWH experience [106]. tVNS provides restoration to central nervous system functions that are disrupted through stress and inflammatory responses. Evidence shows that tVNS may be effective for treating neurocognitive disorders in PLWH given its role in reducing depression and associated symptoms (e.g., poor appetite and sleep), regulating inflammatory responses to stress, and promoting the release of BDNF which is a protein that strengthens brain health and improves learning and memory [106]. While vagus nerve stimulation is established as a successful therapeutic tool for depression, epilepsy, and pain conditions, it is being considered in research trials for other populations [107, 108]; however, the direct and indirect neurocognitive benefits of using tVNS in PLWH remains largely unstudied.

Second, as referred to earlier, another novel therapy outlined by Wilson et al. involves decreasing microbial translocation through cannaboids [93]. Cannabis is established as an effective therapy for symptoms PLWH and people with cancer frequently experience [109 –112]. Indeed, the literature suggests cannabis is effective for pain and nausea management related to HIV [112]; however, additional research is needed to build the evidence-base regarding the cannabis and gut-brain axis relationship [93].

Finally, evidence suggest that resilience or “the process of adapting well in the face of adversity, trauma, tragedy, threats or even significant sources of stress” is associated with better mental health outcomes in PLWH [113, 114]. Studies suggest that resiliency training can strengthen psychological resources (e.g., social support and adaptive coping skills) which may protect against neurocognitive effects of stress and depression in PLWH [115, 116]. Fazeli et al.’s work demonstrates that higher resilience is associated with better neurocognitive function and overall functioning and that older PLWH find resilience interventions acceptable [116]. Evidence mounts that a higher resilience may be neuroprotective against allostatic load (cumulative stress) or adverse effects of day-to-day stressors (e.g., stigma) commonly experienced by older adults with HIV. Stress activates the hypothalamic-pituitary axis which is responsible for the release of stress hormones (e.g., cortisol) and inflammatory cytokines which can lead to cardiovascular disease and diabetes, both of which are linked to neurocognitive decline [116, 117]. Future resilience interventions should examine predictors of AD risks related to resiliency to age and HIV-specific stressors (e.g., treatment challenges, disclosure concerns, ageism, and stigma) as well as refining and testing the efficiency of resiliency training programs.

CONCLUSION

By 2030, it is estimated that 70% of PLWH will be aged 50 and older [5]. The risk of AD in people aging with HIV is concerning given nearly half of PLWH have HAND, estimates that are likely to increase with longer life expectancies. Physiological and psychological stressors across the lifespan can negatively impact brain health in PLWH as they age, thus reducing neurocognitive reserve over the lifespan. Interventions targeting lifestyle factors (e.g., physical activity and depressive symptoms) can directly and indirectly improve domain specific neurocognitive performance, which can be beneficial for neurocognitive health in those aging with HIV. Many of these lifestyle factors may exacerbate HIV and age-related comorbidities (e.g., cardiovascular disease), which are associated with APOE ɛ4 genotype, neurocognitive decline, and increased AD risks. Fortunately, ongoing studies of novel therapies such as cannabis are promising given its role in stress response and anti-inflammatory properties, which may be neuroprotective in people aging with HIV who are APOE ɛ4 carriers.

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgements to report.

FUNDING

Dr. Miller is supported by a Robert Wood Johnson Foundation Health Equity Scholars for Action program grant (80065). Dr. Fazeli is supported by an NIH/National Institute of Mental Health grant (1R01MH131177), an NIH/National Institute on Aging grant (R21AG076377), and an Alzheimer’s Association and National Academy of Neuropsychology (ALZ-NAN-22-926241). Dr. Goodin is supported by an NIH/National Heart Lung and Blood Institute grant (R01HL147603). Dr. Cody is supported by a research supplement to promote diversity in health-related research under this award. Dr. Vance is supported by an NIH/National Institute of Mental Health grant (1R01MH106366-01A1) and an NIH/National Institute on Aging grant (R21AG077957).

CONFLICT OF INTEREST

The authors have no conflict of interest to report.

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