In contrast, both groups showed comparable performance on a DD task that that involved making choices about hypothetical rewards provided in the more distant future. These findings point to key alterations in how people with schizophrenia value different types of rewards.Due to the advent of anti-retroviral therapy in the mid-1990s, HIV is now considered a chronic medical condition rather than a devastating terminal illness. Currently, over 50% of PWH in the United States are over the age of 50, with aging trends projected to continue . As such, researching aging with HIV is critical to better understand the impact of HIV on the aging process and how it may differ from the general population. Aging with HIV is associated with an increased risk of HIV-associated neurocognitive disorders , the current research term to describe neurocognitive impairments associated with HIV disease, with some evidence of accelerated brain aging . Given the potentially compounding effects of HIV and aging on the brain, the rapidly growing population of aging PWH may be at increased risk for Alzheimer’s disease and its precursor, amnestic mild cognitive impairment . As such, there is an urgent public health need to identify clinical tools to accurately identify older PWH on the AD trajectory and understand biological mechanisms that may put PWH at higher risk of aMCI/AD. To clarify, in the HIV literature, “older” PWH usually refers to PWH aged 50 and over; however, in the aging literature, “older” usually refers to people aged 65 and older, and “middle-age” refers to people aged 45 to 64. To rectify this discrepancy in terminology, the aging literature terminology will be used when discussing both the HIV literature and the aging literature.HAND remains prevalent in the ART era . While the pathogenesis of HAND is not entirely clear, HAND is thought to be the result of the neurotoxic cascade initiated by HIV .
The majority of neurocognitive deficits associated with HAND are in the mild range and do not significantly impact everyday functioning ,cannabis grow system and executive functioning, learning, and memory deficits are most common . Importantly, longitudinal studies have shown that HAND is usually non-progressive . AD is a neurodegenerative disease associated with progressive cognitive and functional impairment . AD is the most common cause of dementia, and it affects 10% of persons without HIV over the age of 65 and 17% between the ages of 75-84 . AD is characterized by the accumulation amyloid plaques and tau tangles in the brain, that start in the medial temporal lobe and result in initial atrophy of the medial temporal lobe and later more widespread atrophy . These brain changes start years to decades before clinical symptoms appear . On neuropsychological testing, AD typically presents initially with impairment in memory, which progresses to global impairment and loss of independent functioning . Mild cognitive impairment is defined as the transitional stage between cognitively normal and major neurocognitive impairment in which persons have observable cognitive deficits but these deficits are not yet significantly impacting everyday functioning. MCI can be further divided into amnestic and non-amnestic MCI sub-types, with aMCI being more associated with AD . While participants are often dichotomized as “MCI” or “cognitively unimpaired,” cognitive decline associated with AD is insidious; therefore, even milder deficits in memory in participants classified as cognitively unimpaired are associated with underlying AD pathology such as amyloid accumulation or medial temporal lobe atrophy . Due to the overlap in cognitive presentation , middle-aged and older PWH are at risk of erroneously being classified as HAND, due to HIV diagnosis, when they may instead be on an AD trajectory. Given that aMCI is associated with progressive cognitive and functional impairment, as opposed to HAND, which is more stable, it is imperative that the etiology of the cognitive impairment is correctly identified .
While there is currently no cure for AD, a misdiagnosis of HAND when a person with HIV has aMCI limits the opportunity for early intervention when interventions may be most beneficial . For example, early identification of AD allows more time for life planning and the acquisition of compensation strategies, which may prolong independent functioning, and, by extension, sustain quality of life . Furthermore, accurate diagnosis is important to allay concerns in PWH without indication of an AD trajectory. It is hypothesized that PWH may be at increased risk of AD due to the compounding effects of HIV and aging on the brain , chronic inflammation despite viral suppression, increased prevalence of vascular and metabolic risk factors , and potentially common pathophysiological pathways . While little work has been done in this space, several recent case reports on AD in PWH have highlighted the risk of delayed diagnosis, detailed complications determining the etiology of cognitive impairment, and underscored the clinical need for tools to differentiate HAND and aMCI . Additionally, there is some evidence from the HIV and aging literature to suggest that memory may be particularly affected in older PWH; however, most of these studies do not consider other etiologies that may be contributing to the observed findings. For example, Goodkin et al. found that there was a greater than expected effect of aging on episodic memory in PWH aged 50 and over, and Seider et al. found that verbal memory declines more rapidly with age in PWH as compared to HIV-negative comparison participants. Moreover,in a recent study using latent class analysis to examine a group of PWH aged 50 and over, we found that three classes emerged: a multi-domain impaired group, a learning and memory impaired group, and a cognitively unimpaired group . Due to the medial temporal lobe involvement in aMCI, the cognitive profile is described as “amnestic”, with encoding, storage, and rapid forgetting deficits observed as poor learning, recall, and recognition on memory tests .
Conversely, HIV particularly impacts fronto-striatal systems , and the frontostriatal involvement associated with HAND accounts for a “sub-cortical” cognitive presentation. Thus, memory deficits in HAND are characterized by relatively normal memory storage and retention but impaired encoding and retrieval resulting in poor learning and delayed recall, but intact recognition . This “subcortical” presentation in HAND has been observed even as PWH age . Therefore, recognition may be more indicative of aMCI than HAND and a useful tool for differential diagnosis . However, because recognition has historically been spared in HAND and only recently have PWH been reaching the ages at which they may develop aMCI/AD, there is little research examining recognition deficits in the context of HIV. Of note, deficits in other domains are unlikely to aid in differential diagnosis without further research. For example, while aMCI is characterized by memory deficits, other deficits, such as executive dysfunction, are also quite common in aMCI and AD . Therefore, the presence of executive functioning deficits, which are common in HAND, could be indicative of HAND, aMCI, or a mixed HAND and aMCI profile. Moreover, biomarkers may aid in differential diagnosis in the future; however, elevated amyloid beta is observed in HIV , so more research is needed in order for biomarkers to be beneficial in differential diagnosis of HAND and aMCI. Our research group at the HIV Neurobehavioral Research Program has begun to examine neuropsychological methods to identify aMCI among PWH using adapted Jak/Bondi MCI criteria. Jak/Bondi MCI criteria is an empirically based MCI criteria that has been shown to have greater associations with AD biomarkers and identify more participants who progress to dementia than traditional MCI diagnostic approaches . Our group utilized the basis of the Jak/Bondi criteria and adapted it to capitalize on the neuropsychological differences between HAND and aMCI . Thus,marijuana grow system aMCI was defined as impairment on at least two memory tests with the adaptation that at least one impaired test be a test of recognition. In a sample of 80 PWH from the National NeuroAIDS Tissue Consortium with neuropathologically characterized Aβ42 and neuropsychological testing within a year of death, 40 participants met the adapted criteria for aMCI. Twenty-nine of the participants with aMCI were also classified with HAND. The aMCI group was 3.5 times more likely to have the presence of Aβ42 plaques. Conversely, when the same sample was split into HAND and no HAND groups, the presence of Aβ42 plaques was not significantly associated with the HAND group. In sum, these findings provide preliminary data to further support that aMCI may go undetected in a large proportion of PWH with HAND, and these PWH may be misclassified or have a mixed HAND and aMCI profile. Secondly, these preliminary analyses also suggest that recognition deficits in older PWH are sensitive to AD pathology .Magnetic resonance imaging has shed light on brain changes associated with aMCI and AD and is increasingly used in clinical assessment of suspected AD . Medial temporal lobe atrophy is a core feature of aMCI/AD and has been shown to correlate with disease progression and predict progression from cognitively normal to aMCI . However, AD is also associated with more widespread cortical and sub-cortical atrophy and white matter abnormalities, particularly as the disease progresses . While neuroimaging has been used extensively to study aging and AD, mostof these neuroimaging studies exclude PWH . Consequently, it is unclear if aging/AD research is generalizable to older PWH. HIV has historically been associated with early changes to fronto-striatal circuits , although recent neuroimaging studies also report cortical atrophy . Similarly, HAND has been associated with fronto-striatal circuits, and, in more recent years, has also been associated with more cortical structures . Neuroimaging studies have examined neuroanatomical correlates of delayed recall as well as the effect of age on the brain within the context of HIV .
Studies comparing PWH with HAND and HIV-negative participants with MCI or AD have shown that hippo campal volumes were able to discern HAND and MCI/AD . Additionally, within the context of HIV, decline in memory has been associated with hippo campal atrophy . However, there are notable limitations to the current literature. For example, most studies have been couched in the context of HAND, are not aimed at examining aMCI within the context of HIV, nor do they consider other etiologies . Additionally, several neuroimaging studies examining the effect of aging in PWH have samples with mean ages in the late 30s or early 40s, which is likely before the initiation of AD pathology . Moreover, memory recognition, which could improve differentiation of HAND and aMCI, was not examined in these studies. Both HIV and aMCI are associated with chronic, low-grade inflammation . As such, inflammation may be one biological mechanism that puts PWH at greater risk of aMCI. Peripheral inflammatory markers can cross the blood-brain barrier, and there is mounting evidence to support the hypothesis that chronic inflammation exacerbates both Ab42 and p-tau pathology and plays a role in the pathogenesis of AD . There is ample evidence linking increased inflammation to brain atrophy, cognition, and cognitive decline in late life , with emerging evidence that this link is present even in midlife . Chronic inflammation is also present in PWH despite viral suppression , and is hypothesized to contribute to and exacerbate HAND . Due to this overlap, inflammation may be one factor that also puts PWH at greater risk of aMCI/AD. While the literature has highlighted the need to investigate this association, little research currently exists . Determining how inflammation impacts brain integrity and cognition in middle-aged PWH could have great implications for our overall understanding of the role of inflammation in AD and for the development of early intervention strategies to lower the risk of AD within PWH. I have begun to examine the relationship between inflammation and change in memory. These preliminary analyses included 57 PWH aged 50 and older with peripheral inflammatory markers and neuropsychological testing at baseline and at 1-year follow-up. Overall, I found that baseline concentrations of inflammatory biomarkers were not associated with baseline memory performance. However, using multi-variable linear regressions, IL-6 and TNF-a were associated with decline in delayed recall, and greater baseline concentrations of CCL2 were associated with decline in recognition . These inflammatory markers were not significantly associated with change in any other cognitive domain. Overall, these findings support the hypothesis that inflammatory markers may be related to cognitive changes associated with abnormal memory decline . As AD drug trials targeting amyloid continue to fail, there is increased focus on repositioning current drugs, such as anti-inflammatory drugs, to reduce the risk of AD .