It is currently estimated that more than half of people infected with HIV in the United States are over the age of 50 years (CDC 2022). The prevalence of older persons living with HIV (PLWH) is likely to continue to rise in coming years, as younger adults with HIV who can access and adhere to modern antiretroviral therapies are living longer and older adults represent approximately 10% of new HIV diagnoses (CDC 2022). In general, older PLWH are at greater risk of immune senescence, medical comorbidities (e.g., vascular disease), and polypharmacy (e.g., Langebeek et al. 2017; Rodriguez-Penney et al. 2013). Older PLWH are therefore more susceptible to frailty (Guaraldi et al. 2011; Bloch 2018), poorer daily functioning (Oursler et al. 2011), lower quality of life (Basavaraj et al. 2010), and mortality (CDC 2022). Yet there is considerable heterogeneity in the clinical course of HIV disease among older adults. A meaningful subset of older PLWH experience successful aging in one or more domains, such as biological health, cognitive efficiency, mental health, social competence, productivity, personal control, and life satisfaction (Vance et al. 2019). As such, it is important to understand the facilitators and barriers for different aspects of successful aging for older PLWH.
The current study focuses specifically on successful cognitive aging (SCA) among older PLWH. The central nervous system (CNS) is vulnerable to the combined effects of HIV and aging. There is evidence of both accelerated and accentuated brain aging in the setting of HIV disease (Peterson et al. 2021; Sheppard et al. 2017). Neuroimaging studies show evidence of the combined effects of HIV and aging on white matter integrity (Kuhn et al. 2018) and cortical and subcortical volume loss (e.g., Guha et al. 2016). Older PLWH are at greater risk for neurocognitive deficits (Deng et al. 2021), particularly in the domains of declarative memory (Woods et al. 2010), executive functions (e.g., Iudicello et al. 2012; Müller-Oehring et al. 2022), and motor abilities (e.g., DeVaughn et al. 2015; Tierney et al. 2019). Moreover, the frequency (e.g., Valcour et al. 2004) and incidence (e.g., Sheppard et al. 2015a) of prodromal (e.g., mild cognitive impairment; Sheppard et al. 2015b; 2019) and syndromic neurocognitive disorders tends to be higher in older PLWH.
Despite the additive effects of age and HIV on the CNS, there are still considerable differences in cognitive outcomes among older PLWH. Indeed, not all older PLWH will develop cognitive deficits, and many will age quite "successfully” in this regard (Malaspina et al. 2011; Saloner et al. 2019). Malaspina and colleagues (2011) were the first to describe SCA among PLWH, reporting that approximately one-third of PLWH were without cognitive symptoms in daily life and showed normatively intact performance on a cognitive battery. Subsequent literature suggests that the frequency of SCA is lower in PLWH as compared to seronegative older adults, with an estimated prevalence of between 19% (Moore et al., 2014) and 32% (Malaspina et al., 2011). Not surprisingly, SCA is associated with better everyday functioning, including medication adherence and healthcare self-efficacy (e.g., Malaspina et al. 2011). Other correlates of SCA include better emotional well-being (Moore et al. 2014), resilience (Mayo et al. 2022; Rubtsova et al. 2019), and optimism (Rubtsova et al. 2019).
Depression and vascular disease may play an important role in SCA in PLWH. Depression is one of the most prevalent neuropsychiatric disorders among PLWH (Chichetto et al. 2021; Dew et al. 1997; Rabkin 2008) and has been associated with greater disease progression and mortality (So-Armah et al. 2020). Similarly, vascular disease is a leading cause of morbidity and mortality in HIV (Miller et al. 2014), and by the year 2030, it is estimated that almost 80% of older individuals with HIV will have vascular disease (Smit et al. 2015). PLWH with depression show greater incidence of carotid plaques (Levy et al. 2020; Parruti et al. 2013), hypertension (Castilho et al. 2020), and stroke (Sico et al. 2021). Furthermore, biomarkers of vascular disease (e.g., glucose, hemoglobin A1C) have been associated with depression in PLWH. Both depression (Bryant et al. 2015; Shimizu et al. 2011) and vascular disease (Cysique and Brew 2019; McCutchan et al. 2012) have been linked to neurocognitive impairment in PLWH, but little is known about their combined influence on the structure and function of the CNS, including SCA.
The co-occurrence of vascular disease and depression in older adults led Alexopoulos and colleagues (1997) to propose the vascular depression hypothesis (VasDep), which suggests that vascular disease may “predispose, precipitate, or perpetuate” geriatric depression. The VasDep hypothesis specifically proposes that some aspects of depression result from disrupted mood-related brain networks (i.e., frontal-subcortical circuits) by way of white matter lesions (Krishnan et al. 1997). It is also plausible that depression may increase risk of vascular disease and/or exacerbate pre-existing vascular disease-related conditions that then further amplify depressive symptoms (Kirton et al. 2014; Dotson et al. 2013). Of clinical relevance, individuals with VasDep have greater risk of functional disability and cognitive impairment (e.g., executive dysfunction and slowed processing speed) relative to individuals with non-vascular depression (Aizenstein et al. 2016). It is estimated that 3.4% of adults met criteria for VasDep (González et al. 2012), with the frequency being higher among middle-aged and older persons with a lifetime history of major depressive disorder (MDD) and vascular disease comorbidity. Additionally, persons who met criteria for VasDep demonstrated increased disease burden relative to non-depression and major depression alone populations.
VasDep may be common and impactful among PLWH. In a cross-sectional study, Beltran-Najera and colleagues (2023) reported on the frequency and everyday functioning implications of VasDep in 536 PLWH and 272 seronegative individuals. VasDep was operationalized as the presence of two or more vascular conditions and depression, as determined by a normative elevation on the Depression/Dejection subscale of the Profile of Mood States (POMS; McNair et al. 1981) or a diagnosis of MDD per the Composite International Diagnostic Interview (CIDI; World Health Organization 1998). Findings indicated that PLWH had a three-fold increased rate of VasDep (15.7%) relative to seronegative individuals (4.8%). Among PLWH, VasDep was associated with worse historical HIV disease markers (e.g., lower nadir CD4 counts) and older age; furthermore, PLWH with VasDep were over 5 times more likely to be dependent in everyday functioning as compared to PLWH with either vascular disease or depression alone.
As such, it is plausible that VasDep may play a role in SCA among older PLWH. Further support for the contributions of both vascular disease and depression in SCA is evident in studies in healthy adults and PLWH. For example, lifestyle factors that are known to increase risk of vascular disease (e.g., poor diet, lack of exercise, and smoking) are associated with a reduced likelihood of SCA in seronegative samples (Aguero-Torres et al. 2001; Tomaszewski Farias et al. 2009). The scant literature on vascular disease, depression, and SCA among PLWH is mixed thus far. Some studies show a positive association between SCA and vascular disease (Moore et al. 2018; Wallace et al. 2017) and depression (e.g., Malaspina et al. 2011; Moore et al. 2018), whereas others report null findings (e.g., Moore et al. 2014). However, no studies have examined these two clinical variables in combination through the lens of VasDep in relationship to SCA. In the present study, we aimed to investigate the effects of VasDep on SCA in older adults with HIV. Considering the above-reviewed literature and findings from our prior study (Beltran-Najera et al. 2023), we hypothesized that older PLWH with VasDep would demonstrate lower rates of SCA as compared to older PLWH without VasDep.