Epidemiological studies have shown that persons taking anti-inflammatory drugs for diseases such as rheumatoid arthritis had a reduced risk of developing AD . Moreover, small, randomized control trials examining anti-inflammatory drugs such as TNF-a inhibitors , though preliminary, have yielded encouraging results . If larger studies show that anti-inflammatory drugs can lower the risk of AD, PWH may particularly benefit. Brain changes associated with future cognitive decline are evident in midlife, several years before cognitive impairment in aMCI and AD . Additionally, longitudinal research studies have shown that more subtle differences in episodic memory in midlife is associated with a decline in memory years later . Additionally, Jak et al. found that midlife memory performance is associated with hippo campal atrophy. As a result, there has been a shift in the aging field to characterize and identify middle-aged adults in the preclinical phase of AD rather than primarily focusing on elderly cohorts in which symptoms and pathology are already present . Furthermore, there is a growing literature suggesting that midlife risk factors are associated with future cognitive decline, suggesting that midlife may be a critical time point when some interventions may be efficacious in augmenting cognitive trajectories . In the HIV literature, most aging research has focused on PWH in midlife. The majority of older PWH are currently between the ages of 50 to 65, with a much smaller percentage over the age of 65. However,cannabis vertical farming aging trends in the HIV population are predicted to continue . Additionally, age-associated physical comorbidities appear 5-10 years earlier in PWH , and, there is evidence of premature brain aging .
Due to the neurotoxic effects of HIV and ART, as well as medical comorbidities and possible accelerated brain aging, PWH also may have less brain reserve to compensate for accumulating neurodegenerative pathology. Therefore, cognitive deficits indicative of aMCI could appear earlier in PWH compared to HIV-negative peers. Taken together, examining PWH in mid-life is advantageous as it could identify those with early signs of aMCI when interventions may be particularly efficacious. After excluding participants that did not meet inclusion/exclusion criteria as detailed below, the study included 92 PWH between the ages of 45 to 68 years old. All participants underwent at least one structural MRI scan between 2008 and 2010, comprehensive neuropsychological, neuromedical, and neuropsychiatric evaluation, as well as a blood draw. Most participants completed at least one follow-up neuropsychological, neuromedical, and neuropsychiatric study visit occurring in 6-month intervals. Participants were drawn from five participating sites: Johns Hopkins University, Mt. Sinai School of Medicine, University of California San Diego, University of Texas Medical Branch, and University of Washington. All CHARTER study procedures were approved by local Institutional Review Boards, and all participants provided written informed consent. UC San Diego IRB approval was sought for the current study, and it was determined by the IRB that this study was exempt. The CHARTER study aimed to recruit PWH to reflect the geographic and sociodemographic diversity of PWH around university-affiliated treatment centers in the U.S.; thus, CHARTER inclusion criteria were minimal and did not exclude participants with comorbid conditions that may impact cognitive function. To determine the extent to which non-HIV related comorbidities have contributed to neurocognitive impairment, developmental and medical histories of each participant were determined by Dr. R. K. Heaton and re-reviewed by an independent CHARTER clinician investigator.
Participants with severe “confounding” comorbidities, as defined by Frascati criteria , were excluded from this project. Severe “confounding” comorbid conditions include comorbidities that could sufficiently explain neurocognitive deficits and thus preclude a HAND diagnosis. During clinician review, time course of comorbidities in relation to HIV and cognitive decline as well as the severity of comorbidities were considered when making comorbidity classification determination. Comorbid conditions that were reviewed and considered include history of neurodevelopmental disorders , cerebrovascular events , systemic medical comorbidities , non-HIV neurological conditions , and substance-related comorbidities . This comorbidity classification system has been shown to have excellent inter-rater reliability . The decision to exclude confounding comorbidities was further supported by a recent CHARTER paper showing that those with severe “confounding” comorbidities had worse brain integrity, but those with moderate comorbidities had fairly equivalent brain abnormalities as those with mild comorbidities . Additionally, CHARTER recruited a wide range of ages. To study the effect of aging with HIV, the age range for the current study was restricted to participants that were aged 45 or older at the time of the MRI scan. Additionally, one participant was excluded from the study given that their T1 structural MRI scan did not yield usable data .At each study visit, participants completed a standardized battery of neurocognitive tests. Prior to neuropsychological testing, participants were administered and passed the Hiscock Digit Memory Test, which is a free-standing performance validity test . The test battery assessed seven cognitive domains commonly affected by HIV: verbal fluency, executive functioning, processing speed, learning, delayed recall, attention/working memory, and motor skills . See Table 2 for a list of neuropsychological tests that were examined in the current study.
Tests of memory in the CHARTER study included the Hopkins Verbal Learning Test – Revised and the Brief Visuospatial Memory Test-Revised . The HVLT-R and the BVMT-R include three learning trials, a long delay free recall trial in which participants are asked to recall the stimuli previously presented, and a recognition trial in which participants are presented both target stimuli and non-target stimuli and asked if stimuli were presented in the learning trials. The delayed recall raw score is the total number of words correctly recalled during the long-delay free-recall trial. A recognition discrimination raw score was calculated by subtracting false positives from the total number of true positives. Note, this score is reflective of recognition discriminability, but this will be referred to simply as “recognition” throughout the text. Both the HVLT-R and BVMT-R have six alternate forms to attempt to correct for practice effects. Raw recognition scores were converted to Z-scores that account for demographic variables using normative data from the HNRP . Given that practice effect correction was not available for recognition and participants had a varying number of previous administrations, number of prior neuropsychological evaluations was included as a covariate in statistical analyses examining recognition. Raw delayed recall scores were converted to T-scores that account for demographic variables and practice effects using normative data from the HNRP. HVLT-R and BVMT-R delayed recall T-scores were averaged to create a delayed recall composite. Test-retest reliability estimates of the and HVLT-R recognition ranges from r = 0.27 – 0.40 and delayed recall ranges from r = 0.36 – 0.39. HVLT-R recognition and delayed recall show adequate convergent validity with other tests of verbal memory . The BVMT-R recognition and delayed recall trial have been shown to have adequate convergent validity with other tests of visual memory . Recognition and delayed recall were initially examined continuously rather than dichotomously splitting participants into impaired versus unimpaired groups. Examining recognition and delayed recall continuously is advantageous because it increases variability and more subtle differences observed in mid-life may not be captured by diagnostic cut-points. However, when examining linear regression analyses from aim 1,cannabis drying racks the recognition analyses did not meet all assumptions for linear regression . Therefore, recognition was dichotomized into an impaired recognition group and an unimpaired recognition group for all analyses. Processing speed and psychomotor T-scores were used to examine processing speed and psychomotor performance . Raw scores from individual tests were converted to T-scores that adjust for the effect of age, sex, education, race/ethnicity, and practice effects using center-specific normative data. The T-scores from all tests in the domain are then averaged to obtain a domain T-score . The Wide Range Achievement Test-III , which has been shown to be a measure of premorbid verbal IQ in PWH , was reported to characterize the sample. Five inflammation biomarkers were examined in this study. All inflammatory biomarkers have been found to be elevated in the context of HIV and aMCI . Plasma for biomarker assays was collected via routine venipuncture and EDTA vacuum tubes from all participants.
All plasma biomarkers were measured using commercially available, multiplex, bead-based immunoassays according to manufacturer protocols; CRP was plated on a separate immunoassay given that it required a different dilution than other plasma biomarkers. Biomarker precision was ensured by assaying specimens in duplicate and repeating measurements with coefficients of variation greater than 20% or outliers that were more than 4standard deviations from the mean. Additionally, 10% of all assays were repeated to ensure batch consistency. The concentrations of these biomarkers typically have skewed distributions; therefore, the data were log-transformed prior to statistical analysis. Demographic and clinical characteristics are displayed in Table 3. Data presented in Table 3 represents participants’ first visit for this analysis, which is when the MRI and blood draw for biomarker analysis were completed. On average, participants were in their early-50s [range = 45 – 68], approximately half were African American/Black, were predominantly male, and had some college education. With regard to neurocognitive functioning, approximately one-third were classified as neurocognitively impaired via Frascati criteria . The average T-score for global cognition, recall, and processing speed was around 50, and the average Z-score for recognition was Z=-0.1; however, the average psychomotor skills T-score was lower than average at a T-score of 44. Approximately 20% of the sample was classified as impaired on delayed recall, and 13.2% were impaired on recognition. Recognition and delayed recall were correlated at r=0.358 . Of the 18 participants that were impaired on delayed recall, 7 were impaired on recognition whereas 11 were not impaired on recognition. Meaning that of the 12 that were impaired on recognition, 7 participants were impaired on delayed recall whereas 5 participants were not impaired on delayed recall. The majority of participants had HCV, a history of major depressive disorder, and a lifetime history of a substance use disorder , cocaine , cannabis , opioid , and methamphetamine. Ten participants met criteria for current major depressive disorder and four met criteria for a current substance use disorder . Approximately one quarter of participants had at least one APOE ε4 allele. This study closely examined episodic memory and the biological correlates of episodic memory. This is one of the first studies to examine the relationship between episodic memory, particularly recognition, and brain integrity both cross sectionally and longitudinally in middle-aged PWH without significant confounding comorbid conditions. This study had the potential to help validate recognition as a clinical marker that could aid in distinguishing aMCI and an AD trajectory from HAND, which could have led to diagnostic improvements in disentangling HAND and aMCI. While this study did not support that recognition is associated with more AD-related markers , it did demonstrate that episodic memory in middle-aged PWH is possibly related to frontally mediated etiologies, such as HIV, and that there was little decline in episodic memory in this group. Moreover, this is one of the first to examine the role of peripheral inflammation and its association with brain integrity and episodic memory in middle-aged and older PWH, although there were few associations with peripheral inflammation. While many of the findings of this study were not in line with the hypotheses, these findings are still clinically important and help to address gaps in our understanding of the biological associations of episodic memory in middle aged PWH. Broadly, the first aim of this study was to examine how recognition and delayed recall were associated with the medial temporal lobe, which is more implicated in preclinical AD, and the basal ganglia and prefrontal cortex, which are more associated with HAND. Aim 1a examined the relationship between recognition and these three regions of interest. It was hypothesized that recognition memory would be more strongly related to medial temporal lobe structures given that recognition memory deficits are more associated with AD. Because recognition scores were skewed, as is common given that most people attain a near-perfect score with low variability in scores, this variable was dichotomized as examining it continuously violated multi-variable linear regression assumptions. In this sample of 92 participants, only 12 of participants were impaired on recognition. As discussed later, this sample of PWH may not be generalizable and thus the group that was impaired on recognition is both small and may also not be generalizable to other groups; additionally, recognition impairment at baseline may not be reliable given the instability of the recognition impairment across visits.