Understanding how PrEP is made successful: Implementation science needs an evidence-making approach

After a decade of oral HIV pre-exposure prophylaxis (PrEP), the next generation of PrEP is being anticipated, including long-acting pills, injections, and implants. The unevenness of international PrEP implementation is increasingly recognised, with successful rollout in some settings and failure in others. There is a need to better understand conditions of PrEP implementation, and its localised (and sometimes unanticipated) effects. Implementation science explores how contexts and health systems shape the successful translation of health interventions. In this essay, we consider how PrEP is evolving and argue for an ‘evidence-making’ approach in relation to evidence and intervention translations. This approach emphasises how both interventions and their implementation contexts are co-constituted and evolve together. Unsettling the assumed universality of an intervention’s effects and potential in relation to its implementation contexts helps to harness the localised possibilities for what PrEP might become. As the next generation of PrEP offers renewed promise, we must explore how PrEP is put to use and made to work in relation to its evolving situations. We urge implementation science to consider implementation processes as ‘evidence-making events’ in which evidence, intervention and context evolve together

Dosing practices made mundane: Enacting HIV pre-exposure prophylaxis adherence in domestic routines

Maintaining routines of medication dosing requires effort amidst the variabilities of everyday life. This article offers a sociomaterial analysis of how the oral HIV prevention regimen, pre-exposure prophylaxis (PrEP), is put to use and made to work, including in situations which disrupt or complicate dosing regimes. Other than a daily pill, PrEP can be taken less frequently based on anticipated sexual activity and HIV risk, including ‘on-demand’ and ‘periodic’ dosing. Drawing on 40 interviews with PrEP users in Australia in 2022, we explore PrEP and its dosing as features of assemblages in which bodies, routines, desires, material objects and the home environment interact. Dosing emerges as a practice of coordination involving dosette boxes, blister packs, alarms, partners, pets, planning sex, routines and domestic space, and as an effect of experimentations with timing to suit life circumstances and manage side effects. Dosing is materialised in the mundane; a practice that is made to work, as well as domesticated, in its situations. Although there are no ‘simple’ solutions to adherence, our analysis offers practical insights into how routine, planning and experimentation come together to capacitate PrEP to work in people’s lives, in sometimes unexpected ways, including through adaptations of PrEP dosing

Diffusion Tensor Imaging Predictors of Episodic Memory Decline in Healthy Elders at Genetic Risk for Alzheimer’s Disease

Objectives: White matter (WM) integrity within the mesial temporal lobe (MTL) is important for episodic memory (EM) functioning. The current study investigated the ability of diffusion tensor imaging (DTI) in MTL WM tracts to predict 3-year changes in EM performance in healthy elders at disproportionately higher genetic risk for Alzheimer’s disease (AD). Methods: Fifty-one cognitively intact elders (52% with family history (FH) of dementia and 33% possessing an Apolipoprotein E ε4 allelle) were administered the Rey Auditory Verbal Learning Test (RAVLT) at study entry and at 3-year follow-up. DTI scanning, conducted at study entry, examined fractional anisotropy and mean, radial and axial diffusion within three MTL WM tracts: uncinate fasciculus (UNC), cingulate-hippocampal (CHG), and fornix-stria terminalis (FxS). Correlations were performed between residualized change scores computed from RAVLT trials 1–5, immediate recall, and delayed recall scores and baseline DTI measures; MTL gray matter (GM) and WM volumes; demographics; and AD genetic and metabolic risk factors. Results: Higher MTL mean and axial diffusivity at baseline significantly predicted 3-year changes in EM, whereas baseline MTL GM and WM volumes, FH, and metabolic risk factors did not. Both ε4 status and DTI correlated with change in immediate recall. Conclusions: Longitudinal EM changes in cognitively intact, healthy elders can be predicted by disruption of the MTL WM microstructure. These results are derived from a sample with a disproportionately higher genetic risk for AD, suggesting that the observed WM disruption in MTL pathways may be related to early neuropathological changes associated with the preclinical stage of AD. (JINS, 2016, 22, 1005–1015

Interactive Effects of Physical Activity and APOE-ε4 On White Matter Tract Diffusivity in Healthy Elders

Older adult apolipoprotein-E epsilon 4 (APOE-ε4) allele carriers vary considerably in the expression of clinical symptoms of Alzheimer\u27s disease (AD), suggesting that lifestyle or other factors may offer protection from AD-related neurodegeneration. We recently reported that physically active APOE-ε4 allele carriers exhibit a stable cognitive trajectory and protection from hippocampal atrophy over 18 months compared to sedentary ε4 allele carriers. The aim of this study was to examine the interactions between genetic risk for AD and physical activity (PA) on white matter (WM) tract integrity, using diffusion tensor imaging (DTI) MRI, in this cohort of healthy older adults (ages of 65 to 89). Four groups were compared based on the presence or absence of an APOE-ε4 allele (High Risk; Low Risk) and self-reported frequency and intensity of leisure time physical activity (PA) (High PA; Low PA). As predicted, greater levels of PA were associated with greater fractional anisotropy (FA) and lower radial diffusivity in healthy older adults who did not possess the APOE-ε4 allele. However, the effects of PA were reversed in older adults who were at increased genetic risk for AD, resulting in significant interactions between PA and genetic risk in several WM tracts. In the High Risk-Low PA participants, who had exhibited episodic memory decline over the previous 18-months, radial diffusivity was lower and fractional anisotropy was higher, compared to the High Risk-High PA participants. In WM tracts that subserve learning and memory processes, radial diffusivity (DR) was negatively correlated with episodic memory performance in physically inactive APOE-ε4 carriers, whereas DR was positively correlated with episodic memory performance in physically active APOE-ε4 carriers and the two Low Risk groups. The common model of demyelination-induced increase in radial diffusivity cannot directly explain these results. Rather, we hypothesize that PA may protect APOE-ε4 allele carriers from selective neurodegeneration of individual fiber populations at locations of crossing fibers within projection and association WM fiber tracts

Interactive Effects of Physical Activity and APOE-ε4 on BOLD Semantic Memory Activation in Healthy Elders

Evidence suggests that physical activity (PA) is associated with the maintenance of cognitive function across the lifespan. In contrast, the apolipoproteinE-ε4 (APOE-ε4) allele, a genetic risk factor for Alzheimer\u27s disease (AD), is associated with impaired cognitive function. The objective of this study was to examine the interactive effects of PA and APOE-ε4 on brain activation during memory processing in older (ages 65–85) cognitively intact adults. A cross-sectional design was used with four groups (n = 17 each): (1) Low Risk/Low PA; (2) Low Risk/High PA; (3) High Risk/Low PA; and (4) High Risk/High PA. PA level was based on self-reported frequency and intensity. AD risk was based on presence or absence of an APOE-ε4 allele. Brain activation was measured using event-related functional magnetic resonance imaging (fMRI) while participants performed a famous name discrimination task. Brain activation subserving semantic memory processing occurred in 15 functional regions of interest. High PA and High Risk were associated with significantly greater semantic memory activation (famous\u3eunfamiliar) in 6 and 3 of the 15 regions, respectively. Significant interactions of PA and Risk were evident in 9 of 15 brain regions, with the High PA/High Risk group demonstrating greater semantic memory activation than the remaining three groups. These findings suggest that PA selectively increases memory-related brain activation in cognitively intact but genetically at-risk elders. Longitudinal studies are required to determine whether increased semantic memory processing in physically active at-risk individuals is protective against future cognitive decline

FreeSurfer vs. Manual Tracing: Distinguishing Stable from Cognitively Declining Elders Using Prospectively Measured Hippocampal Volume

Objective: Alzheimer’s disease (AD) pathology is thought to begin years before symptom onset. Hippocampal volume is sensitive to age-related cognitive decline and conversion from MCI to AD. Measurement of hippocampal volumes has used either automated methods such as FreeSurfer (FS) or manual tracing (MT). We compared the ability of FS and MT in detecting baseline volume differences in cognitively intact older individuals who subsequently showed significant cognitive decline. Participants and Methods: Seventy-five cognitively intact elders underwent baseline and 18-month follow-up structural MRI scan and neuropsychological testing. Participants were classified as Declining (n=27) or Stable (n=48) based on the baseline to 18-month changes on a listlearning task and a measure of general cognitive functioning. A 2 (left, right) x 2 (anterior, posterior) x 2 (Declining, Stable) repeated measures ANOVA was conducted for both the MT and FS hippocampal volumes derived at baseline. Results: MT identified significantly smaller left and right hippocampal volumes and smaller anterior than posterior hippocampal volumes in Declining compared to Stable subjects. In contrast, no group differences in hippocampal volumes were observed using FS. Notably, MT included more subiculum and entorhinal cortex, while FS included more of the amygdala and the CA region of the hippocampus. Conclusions: MT was superior to FS for detecting prospective volumetric differences associated with cognitive decline in cognitively intact older participants. MT afforded more unique coverage of the anterior hippocampus than FS. The differences in regional coverage of the mesial temporal lobe between MT and FS may account for the different findings in discriminating Stable and Declining groups

Prediction of Longitudinal White Matter Change in Healthy Elderly Individuals

Diffusion Tensor Imaging (DTI) studies have shown that significant alteration in white matter (WM) integrity differentiates healthy older adults from persons with Mild Cognitive Impairment (MCI) and Alzheimer\u27s disease (AD). Most studies, however, have been cross-sectional and have not related longitudinal DTI changes to cognitive change. Here we report changes in WM integrity and cognition in healthy older adults over an 18-month interval. Sixty-seven cognitively intact elders underwent neuropsychological testing and DTI at baseline to follow-up on the Rey Auditory Verbal Learning Test (recall sum across trials 1-5, delayed recall) and Mattis Dementia Rating Scale-2. Declining participants (N=21) showed a minimum of 1 SD reduction on at least one cognitive measure, while Stable participants (N=46) showed comparable scores at each time point. WM regions-of-interest were derived from Freesurfer. Hierarchical linear regression was used to predict fractional anisotropy (FA) change in regions frequently identified in DTI studies of MCI and AD including transentorhinal cortex, temporal lobe, and posterior cingulate. Groups did not differ at baseline in age, cognition, FA, or WM volume. After controlling for age and baseline FA, cognitive status (Declining, Stable) predicted the baseline to 18-month reduction in FA in the right hippocampal gyrus (p=.004) and left fusi-form gyrus (p=.01) with a trend in the left middle temporal gyrus (p=.06). Future research should examine WM changes in other brain regions and determine whether DTI diffusivity measures are related to cognitive decline

Does Physical Activity Influence Semantic Memory Activation in Amnestic Mild Cognitive Impairment?

The effect of physical activity (PA) on functional brain activation for semantic memory in amnestic mild cognitive impairment (aMCI) was examined using event-related functional magnetic resonance imaging during fame discrimination. Significantly greater semantic memory activation occurred in the left caudate of High- versus Low-PA patients, (P=0.03), suggesting PA may enhance memory-related caudate activation in aMCI

Longitudinal Associations between Physical Activity, Cognitive Status, and Brain Function in Older Adults at Genetic Risk for Alzheimer’s Disease

The apolipoproteinE epsilon4 (APOE-?4) allele is associated with cognitive decline in old age and is a risk factor for Alzheimer\u27s disease (AD). Physical activity (P A) is associated with a reduced risk of incident cognitive impairment, particularly among APOE-?4 carriers. We recently reported greater semantic memory related brain activation in cognitively intact physically active (High P A) APOE-?4 carriers compared to physically inactive (Low PA) ?4 carriers and non-carriers (Smith et al., 2011). Here, we compared longitudinal changes in semantic memory-related brain activation in High PA and Low PA APOE-?4 carriers. Thirty-two older ?4 carriers completed neuropsychological testing and a fMRI semantic memory task (famous name discrimination) at baseline and after 18 months. All participants were cognitively intact at baseline and were classified as High PA (n = 16) or Low PA (n = 16) based on self-report. After 18 months, 5 of 16 High P A and 13 of 16 Low P A were classified as cognitively declining by at least 1 SD decrease in neurocognitive performance (Group difference, p = .011, Fisher\u27s exact test). A fROI analysis of the fMRI data and repeated measures ANOV As revealed significant Group by Time interactions for intensity of semantic memory-related activation. Significantly greater activation at baseline in the High PA group was attenuated over time (no change in Low P A) and resulted in no group differences at the 18-month follow-up. These findings suggest that greater P A at baseline is associated with greater cognitive stability over 18-months in APOE-?4 carriers and reduced neural activation during fame discrimination