Trends in mortality in people with HIV from 1999 to 2020: a multi-cohort collaboration.

BACKGROUND: Mortality among people with HIV declined with the introduction of combination antiretroviral therapy. We investigated trends over time in all-cause and cause-specific mortality in people with HIV from 1999-2020. METHODS: Data were collected from the D:A:D cohort from 1999 through January 2015 and RESPOND from October 2017 through 2020. Age-standardized all-cause and cause-specific mortality rates, classified using Coding Causes of Death in HIV (CoDe), were calculated. Poisson regression models were used to assess mortality trends over time. RESULTS: Among 55716 participants followed for a median of 6 years (IQR 3-11), 5263 participants died (crude mortality rate [MR] 13.7/1000 PYFU; 95%CI 13.4-14.1). Changing patterns of mortality were observed with AIDS as the most common cause of death between 1999- 2009 (n = 952, MR 4.2/1000 PYFU; 95%CI 4.0-4.5) and non-AIDS defining malignancy (NADM) from 2010 -2020 (n = 444, MR 2.8/1000 PYFU; 95%CI 2.5-3.1). In multivariable analysis, all-cause mortality declined over time (adjusted mortality rate ratio [aMRR] 0.97 per year; 95%CI 0.96, 0.98), mostly from 1999 through 2010 (aMRR 0.96 per year; 95%CI 0.95-0.97), and with no decline shown from 2011 through 2020 (aMRR 1·00 per year; 95%CI 0·96-1·05). Mortality due all known causes except NADM also declined over the entire follow-up period. CONCLUSION: Mortality among people with HIV in the D:A:D and/or RESPOND cohorts decreased between 1999 and 2009 and was stable over the period from 2010 through 2020. The decline in mortality rates was not fully explained by improvements in immunologic-virologic status or other risk factors.

Incidence and risk factors for suicide, death due to substance use, and violent/accidental death in people with HIV.

OBJECTIVE: Deaths due to suicide, substance use and violence/accident may reflect similar risk factors and overlap in their classification. This study aimed to investigate incidence and risk factors of mortality among people with HIV (PWH) due to these three related causes. DESIGN: Prospectively collected data from PWH at least 18 years old and under active follow-up in the EuroSIDA study from 2007 to 2019 were analysed. METHODS: Cause-specific Cox regression analysis was used to assess risk factors. RESULTS: A total of 17 881 participants were included, comprising 149 327 person-years of follow-up (PYFU). Forty participants died by suicide {incidence rate [IR] [95% confidence interval (CI)]: 0.3/1000 PYFU (0.2, 0.4)} 93 from substance use [IR (95% CI): 0.6/1000 PYFU (0.5, 0.8)], and 57 by violence/accident [IR (95% CI): 0.4/1000 PYFU (0.3, 0.5)]. An AIDS diagnosis within the last 12 months was associated with nine-fold increased risk of suicide vs. no history of AIDS [adjusted hazard ratio (aHR): 9.06; 95% CI: 2.07, 39.7]. Male gender was associated with double the risk of violent/accidental death (aHR: 2.28; 95% CI: 1.09, 4.78). PWH in Eastern Europe and those who acquired HIV by injection drug use (IDU) demonstrated a greater risk of death due to substance use or violence/accident. CONCLUSIONS: The association between a recent diagnosis of AIDS and suicide highlights a critical period for intervention. HIV infection acquired through IDU demonstrated an expected relationship with death due to substance use and violent/accidental deaths. Increased risk of death due to substance use and violence/accident in Eastern Europe demands investigation into specific differences that may drive that association.

Feasibility of an at-home, web-based, interactive exercise program for older adults.

INTRODUCTION: Increased physical exercise is linked to enhanced brain health and reduced dementia risk. Exercise intervention studies usually are conducted at facilities in groups under trainer supervision. To improve scalability, accessibility, and engagement, programs may need to be structured such that individuals can execute and adjust routines in their own homes. METHODS: One hundred eighty-three healthy older adults from two sites (the United States and Sweden) were screened. One hundred fifty-six subjects (mean age 73.2), randomly assigned to one of four interventions (PACE-Yourself physical exercise program, mindfulness meditation, or Cogmed® adaptive or nonadaptive computerized working memory training) began the study. All interventions were structurally similar: occurring in subjects' homes using interactive, web-based software, over five weeks, ∼175 minutes/week. In the PACE-Yourself program, video segments presented aerobic exercises at different pace and intensity (P&I). The program paused frequently, allowing subjects to indicate whether P&I was "too easy," "too hard," or "somewhat hard." P&I of the subsequent exercise set was adjusted, allowing subjects to exercise at a perceived exertion level of "somewhat hard." Program completion was defined as finishing ≥60% of sessions. RESULTS: A high percentage of participants in all groups completed the program, although the number (86%) was slightly lower in the PACE-Yourself group than the other three. Excluding dropouts, the PACE-Yourself group had a lower adherence rate of 93%, compared with the other three (∼98%). Over the five weeks, PACE-Yourself participants increased exercising at the highest intensity level, consistent with augmented aerobic activity over time. The number of exercise sessions completed predicted the postintervention versus preintervention increase in self-reported level of physical activity. DISCUSSION: This study supports the feasibility of a home-based, subject-controlled, exercise program in which P&I is regulated via real-time participant feedback, which may promote self-efficacy. Further study is needed to determine if similar results are found over longer periods and in more diverse populations.

Differential Effects of Physical Exercise, Cognitive Training, and Mindfulness Practice on Serum BDNF Levels in Healthy Older Adults: A Randomized Controlled Intervention Study.

Previous studies have indicated that an active lifestyle is associated with better brain health and a longer life, compared to a more sedentary lifestyle. These studies, both on human and animal subjects, have typically focused on a single activity, usually physical exercise, but other activities have received an increasing interest. One proposed mechanism is that physical exercise increases levels of brain-derived neurotrophic factor (BDNF) in the brain. For the first time, the long-term effects on serum BDNF levels were compared in persons who engaged in either physical exercise training, cognitive training, or mindfulness practice during 5 weeks, and compared with an active control group. Two cohorts of healthy older individuals, one from the Boston area in the US and one from the Växjö area in Sweden, participated. A total of 146 participants were randomly assigned to one of the four groups. All interventions were structurally similar, using interactive, computer-based software that directed participants to carry out specified activities for 35 minutes/day, 5 days per week for 5 weeks. Blood samples were obtained at baseline and soon after the completion of the 5-week long intervention program, and serum BDNF levels were measured using a commercially available ELISA. Only the group that underwent cognitive training increased their serum BDNF levels after 5 weeks of training (F1,74 = 4.22, p = 0.044, partial η2 = 0.054), corresponding to an average 10% increase. These results strongly suggest that cognitive training can exert beneficial effects on brain health in an older adult population.

Markers of Novelty Processing in Older Adults Are Stable and Reliable.

Exploratory behavior and responsiveness to novelty play an important role in maintaining cognitive function in older adults. Inferences about age- or disease-related differences in neural and behavioral responses to novelty are most often based on results from single experimental testing sessions. There has been very limited research on whether such findings represent stable characteristics of populations studied, which is essential if investigators are to determine the result of interventions aimed at promoting exploratory behaviors or draw appropriate conclusions about differences in the processing of novelty across diverse clinical groups. The goal of the current study was to investigate the short-term test-retest reliability of event-related potential (ERP) and behavioral responses to novel stimuli in cognitively normal older adults. ERPs and viewing durations were recorded in 70 healthy older adults participating in a subject-controlled visual novelty oddball task during two sessions occurring 7 weeks apart. Mean midline P3 amplitude and latency, mean midline amplitude during successive 50 ms intervals, temporospatial factors derived from principal component analysis (PCA), and viewing duration in response to novel stimuli were measured during each session. Analysis of variance (ANOVA) revealed no reliable differences in the value of any measurements between Time 1 and 2. Intraclass correlation coefficients (ICCs) between Time 1 and 2 were excellent for mean P3 amplitude (ICC = 0.86), the two temporospatial factors consistent with the P3 components (ICC of 0.88 and 0.76) and viewing duration of novel stimuli (ICC = 0.81). Reliability was only fair for P3 peak latency (ICC = 0.56). Successive 50 ms mean amplitude measures from 100 to 1,000 ms yielded fair to excellent reliabilities, and all but one of the 12 temporospatial factors identified demonstrated ICCs in the good to excellent range. We conclude that older adults demonstrate substantial stability in ERP and behavioral responses to novel visual stimuli over a 7-week period. These results suggest that older adults may have a characteristic way of processing novelty that appears resistant to transient changes in their environment or internal states, which can be indexed during a single testing session. The establishment of reliable measures of novelty processing will allow investigators to determine whether proposed interventions have an impact on this important aspect of behavior.

Is Computerized Working Memory Training Effective in Healthy Older Adults? Evidence from a Multi-Site, Randomized Controlled Trial.

BACKGROUND: Developing effective interventions to attenuate age-related cognitive decline and prevent or delay the onset of dementia are major public health goals. Computerized cognitive training (CCT) has been marketed increasingly to older adults, but its efficacy remains unclear. Working memory (WM), a key determinant of higher order cognitive abilities, is susceptible to age-related decline and a relevant target for CCT in elders. OBJECTIVE: To evaluate the efficacy of CCT focused on WM compared to an active control condition in healthy older adults. METHODS: Eighty-two cognitively normal adults from two sites (USA and Sweden) were randomly assigned to Cogmed Adaptive or Non-Adaptive (active control) CCT groups. Training was performed in participants' homes, five days per week over five weeks. Changes in the performance of the Cogmed trained tasks, and in five neuropsychological tests (Trail Making Test Part A and Part B, Digit Symbol, Controlled Oral Word Association Test and Semantic Fluency) were used as outcome measures. RESULTS: The groups were comparable at baseline. The Adaptive group showed robust gains in the trained tasks, and there was a time-by-group interaction for the Digit Symbol test, with significant improvement only after Adaptive training. In addition, the magnitude of the intervention effect was similar at both sites. CONCLUSION: Home-based CCT Adaptive WM training appears more effective than Non-Adaptive training in older adults from different cultural backgrounds. We present evidence of improvement in trained tasks and on a demanding untrained task dependent upon WM and processing speed. The benefits over the active control group suggest that the Adaptive CCT gains were linked to providing a continuously challenging level of WM difficulty.

Task-Irrelevant Novel Sounds have Antithetical Effects on Visual Target Processing in Young and Old Adults.

In young adults, primary visual task processing can be either enhanced or disrupted by novel auditory stimuli preceding target events, depending on task demands. Little is known about this phenomenon in older individuals, who, in general, are more susceptible to distraction. In the current study, age-related differences in the electrophysiological effects of task-irrelevant auditory stimuli on visual target processing were examined. Under both low and high primary task loads, the categorization/updating process in response to visual targets preceded by auditory novels, as indexed by the target P3 component, was enhanced in young, but diminished in old adults. In both age groups, the alerting/orienting response to novel auditory stimuli, as measured by the P3a, was smaller under high task load, whereas redirecting attention to the visual task after a novel auditory event, as indexed by the reorienting negativity (RON), tended to be augmented under high task load. Old subjects generated a smaller P3a and RON. We conclude that task irrelevant novel auditory stimuli have the opposite effect on the processing of visual targets in young and old adults. This finding may help explain age-related increases in the disruption of primary task activity by irrelevant, but salient auditory events.

Increased Early Processing of Task-Irrelevant Auditory Stimuli in Older Adults.

The inhibitory deficit hypothesis of cognitive aging posits that older adults' inability to adequately suppress processing of irrelevant information is a major source of cognitive decline. Prior research has demonstrated that in response to task-irrelevant auditory stimuli there is an age-associated increase in the amplitude of the N1 wave, an ERP marker of early perceptual processing. Here, we tested predictions derived from the inhibitory deficit hypothesis that the age-related increase in N1 would be 1) observed under an auditory-ignore, but not auditory-attend condition, 2) attenuated in individuals with high executive capacity (EC), and 3) augmented by increasing cognitive load of the primary visual task. ERPs were measured in 114 well-matched young, middle-aged, young-old, and old-old adults, designated as having high or average EC based on neuropsychological testing. Under the auditory-ignore (visual-attend) task, participants ignored auditory stimuli and responded to rare target letters under low and high load. Under the auditory-attend task, participants ignored visual stimuli and responded to rare target tones. Results confirmed an age-associated increase in N1 amplitude to auditory stimuli under the auditory-ignore but not auditory-attend task. Contrary to predictions, EC did not modulate the N1 response. The load effect was the opposite of expectation: the N1 to task-irrelevant auditory events was smaller under high load. Finally, older adults did not simply fail to suppress the N1 to auditory stimuli in the task-irrelevant modality; they generated a larger response than to identical stimuli in the task-relevant modality. In summary, several of the study's findings do not fit the inhibitory-deficit hypothesis of cognitive aging, which may need to be refined or supplemented by alternative accounts.

Changes in Neural Activity Underlying Working Memory after Computerized Cognitive Training in Older Adults.

Computerized cognitive training (CCT) may counter the impact of aging on cognition, but both the efficacy and neurocognitive mechanisms underlying CCT remain controversial. In this study, 35 older individuals were randomly assigned to Cogmed adaptive working memory (WM) CCT or an active control CCT, featuring five weeks of five ∼40 min sessions per week. Before and after the 5-week intervention, event-related potentials were measured while subjects completed a visual n-back task with three levels of demand (0-back, 1-back, 2-back). The anterior P3a served as an index of directing attention and the posterior P3b as an index of categorization/WM updating. We hypothesized that adaptive CCT would be associated with decreased P3 amplitude at low WM demand and increased P3 amplitude at high WM demand. The adaptive CCT group exhibited a training-related increase in the amplitude of the anterior P3a and posterior P3b in response to target stimuli across n-back tasks, while subjects in the active control CCT group demonstrated a post-training decrease in the anterior P3a. Performance did not differ between groups or sessions. Larger overall P3 amplitudes were strongly associated with better task performance. Increased post-CCT P3 amplitude correlated with improved task performance; this relationship was especially robust at high task load. Our findings suggest that adaptive WM training was associated with increased orienting of attention, as indexed by the P3a, and the enhancement of categorization/WM updating processes, as indexed by the P3b. Increased P3 amplitude was linked to improved performance; however. there was no direct association between adaptive training and improved performance.

Increasing Working Memory Load Reduces Processing of Cross-Modal Task-Irrelevant Stimuli Even after Controlling for Task Difficulty and Executive Capacity.

The classic account of the load theory (LT) of attention suggests that increasing cognitive load leads to greater processing of task-irrelevant stimuli due to competition for limited executive resource that reduces the ability to actively maintain current processing priorities. Studies testing this hypothesis have yielded widely divergent outcomes. The inconsistent results may, in part, be related to variability in executive capacity (EC) and task difficulty across subjects in different studies. Here, we used a cross-modal paradigm to investigate whether augmented working memory (WM) load leads to increased early distracter processing, and controlled for the potential confounders of EC and task difficulty. Twenty-three young subjects were engaged in a primary visual WM task, under high and low load conditions, while instructed to ignore irrelevant auditory stimuli. Demands of the high load condition were individually titrated to make task difficulty comparable across subjects with differing EC. Event-related potentials (ERPs) were used to measure neural activity in response to stimuli presented in both the task relevant modality (visual) and task-irrelevant modality (auditory). Behavioral results indicate that the load manipulation and titration procedure of the primary visual task were successful. ERPs demonstrated that in response to visual target stimuli, there was a load-related increase in the posterior slow wave, an index of sustained attention and effort. Importantly, under high load, there was a decrease of the auditory N1 in response to distracters, a marker of early auditory processing. These results suggest that increased WM load is associated with enhanced attentional engagement and protection from distraction in a cross-modal setting, even after controlling for task difficulty and EC. Our findings challenge the classic LT and offer support for alternative models.

One of the most well-established age-related changes in neural activity disappears after controlling for visual acuity.

Numerous studies using a variety of imaging techniques have reported age-related differences in neural activity while subjects carry out cognitive tasks. Surprisingly little attention has been paid to the potential impact of age-associated changes in sensory acuity on these findings. Studies in the visual modality frequently report that their subjects had "normal or corrected- to-normal vision." However, in most cases, there is no indication that visual acuity was actually measured, and it is likely that the investigators relied largely on self-reported visual status of subjects, which is often inaccurate. We investigated whether differences in visual acuity influence one of the most commonly observed findings in the event-related potentials literature on cognitive aging, a reduction in posterior P3b amplitude, which is an index of cognitive decision-making/updating. Well-matched young (n=26) and old adults (n=29) participated in a visual oddball task. Measured visual acuity with corrective lenses was worse in old than young adults. Results demonstrated that the robust age-related decline in P3b amplitude to visual targets disappeared after controlling for visual acuity, but was unaffected by accounting for auditory acuity. Path analysis confirmed that the relationship between age and diminished P3b to visual targets was mediated by visual acuity, suggesting that conveyance of suboptimal sensory data due to peripheral, rather than central, deficits may undermine subsequent neural processing. We conclude that until the relationship between age-associated differences in visual acuity and neural activity during experimental tasks is clearly established, investigators should exercise caution attributing results to differences in cognitive processing.

Investigating age-related changes in anterior and posterior neural activity throughout the information processing stream.

Event-related potential (ERP) and other functional imaging studies often demonstrate age-related increases in anterior neural activity and decreases in posterior activity while subjects carry out task demands. It remains unclear whether this "anterior shift" is limited to late cognitive operations like those indexed by the P3 component, or is evident during other stages of information processing. The temporal resolution of ERPs provided an opportunity to address this issue. Temporospatial principal component analysis (PCA) was used to identify underlying components that may be obscured by overlapping ERP waveforms. ERPs were measured during a visual oddball task in 26 young, 26 middle-aged, and 29 old subjects who were well-matched for IQ, executive function, education, and task performance. PCA identified six anterior factors peaking between ∼140 ms and 810 ms, and four posterior factors peaking between ∼300 ms and 810 ms. There was an age-related increase in the amplitude of anterior factors between ∼200 and 500 ms, and an age-associated decrease in amplitude of posterior factors after ∼500 ms. The increase in anterior processing began as early as middle-age, was sustained throughout old age, and appeared to be linear in nature. These results suggest that age-associated increases in anterior activity occur after early sensory processing has taken place, and are most prominent during a period in which attention is being marshaled to evaluate a stimulus. In contrast, age-related decreases in posterior activity manifest during operations involved in stimulus categorization, post-decision monitoring, and preparation for an upcoming event.

In vivo evidence for neuroplasticity in older adults.

Neuroplasticity can be conceptualized as an intrinsic property of the brain that enables modification of function and structure in response to environmental demands. Neuroplastic strengthening of synapses is believed to serve as a critical mechanism underlying learning, memory, and other cognitive functions. Ex vivo work investigating neuroplasticity has been done on hippocampal slices using high frequency stimulation. However, in vivo neuroplasticity in humans has been difficult to demonstrate. Recently, a long-term potentiation-like phenomenon, a form of neuroplastic change, was identified in young adults by differences in visual evoked potentials (VEPs) that were measured before and after tetanic visual stimulation (TVS). The current study investigated whether neuroplastic changes in the visual pathway can persist in older adults. Seventeen healthy subjects, 65 years and older, were recruited from the community. Subjects had a mean age of 77.4 years, mean education of 17 years, mean MMSE of 29.1, and demonstrated normal performance on neuropsychological tests. 1Hz checkerboard stimulation, presented randomly to the right or left visual hemi-field, was followed by 2min of 9Hz stimulation (TVS) to one hemi-field. After 2min of rest, 1Hz stimulation was repeated. Temporospatial principal component analysis was used to identify the N1b component of the VEPs, at lateral occipital locations, in response to 1Hz stimulation pre- and post-TVS. Results showed that the amplitude of factors representing the early and late N1b component was substantially larger after tetanic stimulation. These findings indicate that high frequency visual stimulation can enhance the N1b in cognitively high functioning old adults, suggesting that neuroplastic changes in visual pathways can continue into late life. Future studies are needed to determine the extent to which this marker of neuroplasticity is sustained over a longer period of time, and is influenced by age, cognitive status, and neurodegenerative disease.

Age-related differences in early novelty processing: using PCA to parse the overlapping anterior P2 and N2 components.

Previous work demonstrated age-associated increases in the anterior P2 and age-related decreases in the anterior N2 in response to novel stimuli. Principal component analysis (PCA) was used to determine if the inverse relationship between these components was due to their temporal and spatial overlap. PCA revealed an early anterior P2, sensitive to task relevance, and a late anterior P2, responsive to novelty, both exhibiting age-related amplitude increases. A PCA factor representing the anterior N2, sensitive to novelty, exhibited age-related amplitude decreases. The late P2 and N2 to novels inversely correlated. Larger late P2 amplitude to novels was associated with better behavioral performance. Age-related differences in the anterior P2 and N2 to novel stimuli likely represent age-associated changes in independent cognitive operations. Enhanced anterior P2 activity (indexing augmentation in motivational salience) may be a compensatory mechanism for diminished anterior N2 activity (indexing reduced ability of older adults to process ambiguous representations).