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Accelerated Brain Aging: WHICH IS IT - No evidence for accelerated ageing-related brain pathology in treated HIV: longitudinal neuroimaging results from the Comorbidity in Relation to AIDS (COBRA) project - OR - Progressive Brain Atrophy Despite Persistent Viral Suppression in HIV Over Age 60
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from Jules: Here are 3 studies, the 2 just below finding accelerated brain atrophy & premature aging of the brain. while the recently published just this week study from Cobra group in Europe finds differently, this study was reported at CROI with some controversy about this finding that brain function is worse in HIV vs HIV-neg but not accelerated anymore than in the control group they used over a 2 year period of time. What are the differences in these study findings due t? are they due merely to differences in patient characteristics? The 1st study below WAS in HIV+ over 60, which to me makes a big difference, separating out older group. The Cobra study is over only a 2 year period and looked at younger group, <65 mostly I think.. There are other factors besides HIV I suppose that can affect brain atrophy and aging, so is that the resin for these differences between study findings. In the end my opinion is that once people in general reach 65 the immune system decline slope worsens & other studies in HIV found this slope is worse in HIV vs HIV-neg regarding I recall CVD & bone, which makes sense to me.
..........and then there were these studies at CROI 2017, finding differently that brain aging evolved over years in HIV+ or it did not in the imaging study from Wash U. This study looked at HIV+ with average age 47 [13.5] so its not a group entirely over 60-65 so it cant look at if HIV+ over 65 progress more quickly, if the slope of decline increases, and it does not look at differences in decline in those over 65 with low CD4 nadir, although the study says lower nadir CD4 correlated at trend level with smaller putamen, globus pallid is, and thalamus volumes (p<0.1) and authors suggest early ART might provide cognitive benefits: CROI: LONGITUDINAL ASSESSMENT OF REGIONALLY SPECIFIC BRAIN VOLUMES IN TREATED HIV+ PATIENTS - (02/24/17).
Then there is this study finding 57% of patients had neurocognitive decline evolved with 14% of HIV+ declining vs 4.5% of HIV-negatives, they looked at NP battery assessing 7 categories of cognitive domains, in Australia: CROI:Cognitive Trajectories in Suppressed HIV Infection Indicate Evolving Disease Activity - (02/24/17). And then there was at CROI this study from Cobra that was just published ahead which I distributed this morning, attached again here. And there are these 2 recently published studies in mid 2017 finding aging in HIV+ did cause evolving or increased or worsening or accelerated brian/nuerocognitive decline - however you choose to name it. In my opinion there are for sure some HIV+ who experience accelerated or evolving neurocognitive decline; and in older HIV+ over 65 the slope of decline will increase for some as immunity or immunosenesence worsens at this older age in HIV+ vs HIV-neg. What about HCV, for those with HCV & HIV neurocognitive decline could evolve more quickly despite SVR; for those with diabetes, lipid abnormalities, CVD neurocognitive decline might evolve more quickly.
Progressive Brain Atrophy Despite Persistent Viral Suppression in HIV Over Age 60 - (07/19/17)
"Despite persistent control of plasma viremia, these older HIV-infected participants demonstrate more rapid progressive brain atrophy when compared to healthy aging. Either HIV or other factors that differ between older HIV-infected participants and healthy controls could be responsible for these differences."
"In longitudinal ROI models adjusted for age and sex, we uncovered progressive atrophy in the HIV-infected group exceeding rates seen among healthy controls (Table 2, bottom panel) with faster annualized rates of progressive atrophy in the cerebellum (0.42% vs 0.02%, p=0.016), caudate (0.74% vs 0.03%, p=0.012), frontal lobe (0.48% vs 0.01%, p=0.034), total cortical gray matter (0.65% vs 0.16%, p=0.027), brainstem (0.31% vs 0.01%, p=0.026), and pallidum (0.73% vs 0.39%, p=0.046) (Figure 1).
We did not identify differences in longitudinal volume rates of change between those with compared to without HAND; however, the HAND group differed from controls with faster rates of progressive atrophy in the cerebellum (0.50% vs 0.02%, p=0.006), caudate (1.07% vs 0.03%, p=0.015), temporal lobes (0.83% vs 0.18%, p=0.049), total cortical gray matter (0.87% vs 0.16%, p=0.039), brainstem (0.52% vs 0.01%, p=0.005), pallidum (0.81% vs 0.39%, p=0.047), and thalamus (0.82% vs 0.44%, p=0.018) but not in total cerebral white matter (0.50% vs 0.55%, p=0.821). Analyses comparing controls to those without HAND did not identify any significant differences in atrophy rates."
HIV prematurely ages the brain - new study & Commentary - (07/19/17)
"In an Article in The Lancet HIV,1 Karl Goodkin and colleagues answer the controversial question of whether chronic HIV infection leads to premature ageing in the combination antiretroviral therapy (ART) era: it does.
"Older age was significantly associated with lower performance in all five neuropsychological domains tested (working memory, episodic memory, motor function, executive function, and information processing speed; p<0⋅0001 for all comparisons)...... results should spur the development of geriatric medicine into an integrated multidisciplinary model of care for ageing patients with HIV.....large studies are needed to address whether ageing people with HIV are at increased risk of age-associated neurodegenerative disorders, such as vascular cognitive impairment6, 7 and perhaps Alzheimer's disease"
"A greater than expected effect of ageing on episodic memory and motor function with advanced stages of HIV infection suggests that these two domains are most susceptible to the progression of neurocognitive impairment caused by ageing in individuals with HIV. This deficit pattern suggests differential damage to the hippocampus and basal ganglia (specifically nigrostriatal pathways). Older individuals with HIV infection should be targeted for regular screening for HIV-associate neurocognitive disorder, particularly with tests referable to the episodic memory and motor domains."
HIV Infection and Aging Independently Affect Brain Function as Measured by Functional Magnetic Resonance Imaging - BRIEF REPORT - (01/25/09) Functional brain demands in HIV-positive subjects were equivalent to those of HIV-negative subjects who were 15-20 years older.....HIV infection was equivalent to a 21-year increase in brain age, compared with HIV-negative control subjects
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No evidence for accelerated ageing-related brain pathology in treated HIV: longitudinal neuroimaging results from the Comorbidity in Relation to AIDS (COBRA) project
Clinical Infectious Diseases 04 January 2018 - James H Cole1,2, Matthan WA Caan3, Jonathan Underwood4, Davide De Francesco5, Rosan A
van Zoest6, Ferdinand WNM Wit6,7, Henk JMM Mutsaerts3,8, Rob Leech1, Gert J Geurtsen9, Peter
Portegies10,11, Charles BLM Majoie3, Maarten F Schim van der Loeff12,13, Caroline A Sabin5, Peter
Reiss6,7, Alan Winston4 and David J Sharp1 on behalf of the COBRA collaboration.
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Discussion
In PLWH with suppressed viraemia on cART, we found no evidence for accelerated changes in brain structure, function or brain-predicted age and no evidence for cognitive decline over two years. Cross-sectional abnormalities in brain structure, brain-predicted age, and cognitive function were apparent in our group of PLWH compared to controls. Importantly, these differences between the two groups remained stable over time. Overall, we observed longitudinal changes in neuroimaging measures, likely related to ageing. Importantly, studies of other neurological or neurodegenerative conditions (e.g., Alzheimer's disease, traumatic brain injury) commonly report changes above and beyond expected ageing-related declines in shorter timescales [36, 37]. Hence, our results indicate that in PLWH on suppressive cART, any progressive changes to the brain that occur are no greater than those seen in appropriately-matched HIV-negative controls. Our comprehensive multi-modality neuroimaging study clarifies previous reports that suggested progressive brain injury was occurring in PLWH, perhaps due to key methodological differences. For example, Gongvatana and colleagues reported two-year progressive changes in neural metabolites in PLWH, but this MRS study did not include an HIV-negative control group [25]. We also observed reductions in NAA over time, but these were similar in PLWH and HIV-negative controls and so are likely a consequence of ageing or secondary factors other than HIV-infection. Pfefferbaum and
colleagues [26] reported greater reductions in regional brain volumes in PLWH. Their control group had more years of education, fewer depressive symptoms, higher socioeconomic status, higher IQ and lower rates of smoking. These factors may have introduced bias as they are known to interact with age-related volume loss [30, 32]. Most recently, Clifford and colleagues reported more rapid rates of brain volume loss in PLWH aged ≥60 years compared to healthy controls. The controls here had lower rates of current and past smoking, and showed very little change in brain volumes over time (e.g., 0.16% annualised grey matter volume reduction, compared to 0.65% in PLWH). Studies in the general population report around 0.4%/year [38]. By contrast, the HIV-negative controls in the current study lost a mean 0.89% of grey matter volume per year. Potentially, Clifford and colleagues' controls had particularly good brain health for their age, which may not be attributable solely to the absence of HIV. This highlights the importance of using appropriate controls, not only for HIV research, but for any studies considering brain health during ageing. Limiting the impact of lifestyle and demographic factors is essential to disentangle the effects of ageing, disease and common comorbidities, particularly for such longitudinal studies.
The composition of the HIV-positive group can also strongly influence neuroimaging results. We restricted analysis to PLWH on cART with suppressed viraemia and no history of CNS infections. This is broadly representative of PLWH in Europe and North America and allows us to address the natural history of chronic HIV infection when HIV viraemia is adequately suppressed. This has not been possible in all previous longitudinal studies. For example, whilst Cardenas and colleagues [24] reported results in comparison with a control group, only 53% of PLWH were virally-suppressed at both time points and people with a history of CNS opportunistic infections were included. Untreated HIV or a history of CNS infections likely leads to progressive neural deterioration. In our study of virologically-suppressed PLWH this progression was not observed.
We observed baseline differences in brain structure between PLWH and controls in several neuroimaging modalities. These included evidence of lower grey matter volume, higher WHM load and extensive areas of white matter abnormalities, in line with previous reports [9, 13, 14]. Crosssectional differences were not observed in measures of resting-state functional connectivity (fMRI), neural metabolite concentrations (MRS) or cerebral perfusion (ASL), contrary to previous reports during the cART era [11, 12, 15]. The discrepancy between our findings and these studies could be explained by differing samples or scanner-related and MRI-protocol differences. Additionally, these modalities may measure more dynamic aspects of HIV-associated brain injury that may improve with successful treatment compared with volumetric measures (e.g., grey-matter volume loss), which may be irreversible. An important contributing factor could be the noise levels in fMRI, MRS and ASL, relative to diffusion-MRI, T2-FLAIR and particularly T1-weighted MRI. As our study pooled data from three scanners, scanner-related variability is also an issue. That structural MRI measures were sensitive to group differences in this multi-centre study is important when considering future study
design, particularly regarding longitudinal assessment and clinical trials.
PLWH had poorer cognitive performance at baseline, as previously observed [14, 20]. Longitudinally, performance was generally stable, though improvements were seen in memory, potentially reflecting practice effects. Interestingly, performance in measures of attention decreased in HIV-negative controls, but not in PLWH. The noticeably high baseline attention scores of HIV-negative participants suggests that this reduction could be a regression towards the 'true' group mean. Overall, the cognitive performance of both groups was high, compared to the normative average T-score of 50. This may reflect a 'research participant' effect; that nearly half had tertiary-level education illustrates the difficulties faced in recruiting truly representative study samples. To better understand trajectories of cognitive ageing in PLWH, future studies would benefit from larger numbers, more frequent assessments and run-in periods to mitigate practice effects.
Differences in longitudinal rates of changes in brain structure or brain function between the two groups were absent. This suggests that the cross-sectional neuroimaging and cognitive deficits observed are the result of historical pathological processes, such as the direct pathogenic effect of HIV on the CNS or the initial immune response to infection, rather than an ongoing pathological process. Further work to clarify the pathogenic processes leading to these abnormalities is warranted. Nevertheless, the presence of the cross-sectional differences in PLWH is important, as it could mean that PLWH reach a symptomatic threshold for age-related cognitive decline earlier that HIV-negative people, despite appearing to be on the same trajectory.
Some strengths and weakness of our study should be noted. Strengths include the large sample size for a longitudinal neuroimaging study, which gave sufficient statistical power to detect even small changes in brain structure over two years. The two-year follow-up period limits extrapolation to longer-term changes, however the consistently parallel nature of the group 'slopes' of change suggests that brain changes in PLWH with suppressed viraemia are not diverging from those seen in HIV-negative people. Our control group was similar to the PLWH group, ethnicity notwithstanding, potentially reducing confounding factors that may independently affect brain ageing. Another strength is the use of six neuroimaging modalities, sensitive to many different neurobiological phenomena, allowing a comprehensive assessment of the brain. Weaknesses include the potential for recruitment bias whereby PLWH may be higher functioning that the majority of the HIV population, reflected by a willingness to enter a longitudinal study. Also, we specifically recruited non-depressed PLWH to be able to interpret the cognitive findings. However, depression is commonly reported in PLWH [39] and brain ageing may differ in subjects with depressive illnesses. The use of three different scanners, including a system upgrade during the baseline phase, may have influenced some neuroimaging measures. However, we explicitly controlled for this in our statistical analysis, and crucially, proportions of PLWH and HIV-negative controls scanned at each site were similar. The proportion of PLWH and HIV-negative controls affected by the upgrade (i.e., different
scanners at baseline and follow-up) was similar to the overall group proportions in the study, thus are representative and did not introduce bias. To investigate scanner effects further, we analysed data from London only (Supplementary Table S2). There were only minor differences in cross-sectional results and the longitudinal results were the same as the overall results, providing further reassurance that the combination of scanners did not influence our findings. Another potential limitation is survivor bias, whereby only unrepresentatively healthy individuals completed longitudinal assessment. However, we found no systematic differences between participants who dropped out and participants who completed both assessments (Supplementary Table S3) and given the high retention rate (94.4%), any residual survivor bias is likely to be minimal.
In conclusion, our study finds no evidence of accelerated ageing-related changes in brain structure, function, and brain-predicted age in well-treated PLWH. This provides reassurance that, with virological suppression, PLWH in middle-age are not at increased risk of progressive cognitive decline and abnormal deterioration to brain health over two years.
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