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Vascular cognitive impairment and HIV-associated neurocognitive disorder: a new paradigm
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11 January 2019
J of Neurovirology
Lucette A. Cysique1,2,3 & Bruce J. Brew2,3,4,5
"it is urgent to link NeuroHIV and VCI research efforts.....Long-term and large studies need to be carried out internationally to assess the risk of dementia in the HIV population at large, measuring CVD, VCI, and mild HAND optimally, while taking into account the survivor bias. The exclusion of the highest risk groups for both VCI and mild HAND should be systematically avoided, as it will lead to erroneous epidemiological figures and disease burden with consequences for research funding and healthcare policies."
"Risk factors for vascular cognitive impairment in people ageing with HIV infection: Racial minorities in Western countries are at higher risk of CVD and VCI and once diagnosed at greater risk of morbid progression. CVD and depression has demonstrated a bi-directional relation between major depression and CVD, while depression is a risk factor for VCI. The HIV population psychiatric burden is 3-5 times higher than the general population. The experience of stigma, stress, and traumatic events are higher in the HIV population and worsen with ageing due to social isolation. Some ART agents which were/are prescribed in mid-life are associated with metabolic abnormalities (Friis-Moller et al. 2010); this could represent an added risk for mild VCI, mild HAND, and neurodegeneration in old age. Viral replication directly or indirectly causes vascular disease, CVD burden in PLWH relates to increased hypertension (van Zoest et al. 2017), heart failure (Hsue and Waters 2017), (Lacson et al. 2017), and ischaemic heart disease, Chronic HIV is a vascular risk factor, Persistence of vascular complications in optimally treated PLWH support the growing body of evidence that chronic inflammation despite cART and potentially through Tat and Nef (Atluri et al. 2015) is directly and causally associated with a higher age prevalence of CVD and the accelerated development of atherosclerosis, Predicted 10-year CVD disease risk remains relatively low at present in the majority of PLWH; it will increase in relation to the progressive ageing, Ageing is a risk factor for both CVD and VCI, Emerging evidence that mild VCI (i.e. CSVD) is more prevalent in ageing PLWH, Biological age is premature and accelerated in PLWH when defined as telomere shortening, immune ageing, and frailty indexes, Longitudinal studies clearly show that HAND persists in virally suppressed PLWH with low (Gott et al. 2017) and high comorbidities (Rubin et al. 2017) and that age is a risk factor. There is increased recognition that stroke is becoming a complex health problem in long-term-treated PLWH with some studies showing premature occurrence compared to the general population, especially in low-middle-income countries (Barnes et al. 2017). One to five percent of PLWH experience clinical stroke. Ischaemic lesions are seen in 4-34% of brain autopsies, but recent data show that stroke of undetermined aetiology is also common (Chow et al. 2017). However, the HIV research field should also be aware that cerebrovascular disease in HIV does not necessarily equate to stroke
.....by definition, ageing PLWH reaching their 60s are entering the dementia risk range by virtue of their chronological age, which is prematurely older at least in some PLWH. Another important concept not adequately captured by the general HIV and ageing research is that the dementia risk pattern is exponential over the age of 60 years (Milanini and Valcour 2017). Currently, not enough studies have been conducted in large samples of PLWH aged 60+ to make any valid predictions....."VCI refers to the entire spectrum of vascular brain pathologies that contribute to any degree of cognitive impairment, ranging from subjective cognitive decline to dementia". .....The neurological profile of major VCI closely resembles the more severe forms of HAND, namely HAD, where abnormal motor signs are more prominent, although these signs can emerge in ageing PLWH.....Various systemic conditions have been associated with the risk of dementia, but all research points to one overwhelming factor: CVD, particularly in mid-life. CVD are a recognised risk factor for vascular dementia (VaD), mixed dementia, and Alzheimer's disease (AD)......the dementia field has established that clinically relevant and subclinical CVD is a fundamental causal factor for dementia at the molecular, cellular, and system level.....HIV-related CVD and HAND share common pathogenic pathways, which include immunosuppression and unsuppressed viral load in untreated or poorly adherent PLWH (Barnes et al. 2017; Gutierrez et al. 2017; Lacson et al. 2017). In treated HIV infection, mild VCI and mild HAND share common pathogenic pathways through persistent subclinical and clinically relevant CVD (HIV as a vascular risk factor; Barnes et al. 2017; Gutierrez et al. 2017; Lacson et al. 2017), chronic immune activation, and immune senescence, some of which probably relates to viral reservoir activity (Gelman 2015; Holloway and Boccara 2017; Hsue et al. 2012; Smail and Brew 2018).....The overlapping risk factor burden between CVD, VCI, and established risk factors for HIV disease progression and HAND despite cART is striking. In addition to an overlapping burden, most risk factors in PLWH have a higher prevalence and severity of burden than in the general population......Even from the most conservative perspective, this cumulative profile of risk factors represents one of the worst profiles for dementia in old age in modern clinical neurosciences/neurology.
......The multi-morbid features inherent to old age and accentuated in PLWH are challenging. Guaraldi and Pallela have proposed a new discipline to address this challenge: HIV geriatrics (Guaraldi and Palella Jr. 2017). Taking this beyond the clinical management in which it was first proposed, this framework could also help guide our research questions and study design. Indeed, "multidisciplinary and multidimensional process, designed to evaluate an older person's functional ability, physical health, cognition, overall mental health, and socio-environmental circumstances" could become a standard way of assessing dementia risk in ageing PLWH.....a multidisciplinary approach for age-related neurological complication risk should aim to propose a unifying mechanism that is relevant to the entire HIV population (men, women, and children globally), involve the role of HIV (even controlled or restricted) along with the role of HIV-specific and non-specific immune activation and immune senescence, account for the high CVD burden in the HIV population, and further reflect the most common regional distribution of brain abnormalities in chronic-treated HIV (striato-frontal/temporal white matter injury, fronto-parietal grey matter and the hippocampus)......At present, the main treatment for VCI is prevention by treating vascular diseases and other risk factors for VCI, such as hypertension and diabetes mellitus. However, van der Flier et al. (2018) propose a more comprehensive management regime in addition to prevention that resembles the HIV geriatric principle developed by Guaraldi and Palella Jr. (2017). van der Flier et al. also provide an excellent review of the ongoing research on pharmaceutical and non-pharmaceutical treatments (van der Flier et al. 2018). Figure 1 summarizes the steps for prevention, management and treatment of VCI. Similar efforts should continue in NeuroHIV with a special focus on boosting the early detection of neurocognitive impairment and brain injury rather than the opposite (Gates and Cysique 2016) and refining assessment of interventions (Cody and Vance 2016) in order to improve quality of life and concerns about potential cognitive deterioration (Cummins et al. 2018; Terpstra et al. 2018).
In this context, it is important to remember that the majority of the first generation of ageing PLWH are survivors of the pre-cART era as they typically have long HIV duration. This impact is far from being accurately identified in ageing HIV studies, and it is even more relevant in NeuroHIV research......in HIV neurocognitive ageing where there is undeniable evidence that HIV-related neurological complications strongly predict subsequent mortality.....In all, survivor bias has many ramifications for the accuracy of dementia detection as it influences representation of dementia genetic/epigenetic/disease risks, the degree of biological resilience, and is further confounded by attrition, some of which is due to old age and more severe or rapidly progressive dementia (Weuve et al. 2015). Without taking this into account, the conclusion, based on studies that have included people in their 40-60s (Milanini and Valcour 2017), that there are no major dementia signals needs to be viewed cautiously. Indeed, there are studies showing some signals, even in those with low comorbidities, of premature genetic and epigenetic ageing (Lagathu et al. 2017), and premature brain ageing....."
In this review, we propose that vascular cognitive impairment (VCI), with relevance for the global HIV population, is fundamentally and clinically linked to the persistence of mild forms of HIV-associated neurocognitive disorders (HAND) in ageing people living with HIV infection (PLWH). After placing our review within the context of the general literature on HIV and ageing, we review non-VCI risks for dementia in ageing PLWH. We then present the recently updated VCI nomenclature and show that the neuropsychological and neuroimaging phenotypes of VCI and HAND are largely overlapping, suggesting that further research is needed to accurately distinguish them. We further link VCI and HAND at the mechanistic level by advancing the innovative proposal that the neuro-vascular unit (NVU) may represent the primary target of HIV-related brain injury in treated HIV infection. To this, we add the fundamental impact of mild and major VCI on the NVU. Importantly, we show that the potential contribution of vascular damage to overall brain damage in ageing PLWH is probably much higher than currently estimated because of methodological limitations, and because this research is only emerging. Finally, because all VCI risk factors are more prevalent, premature, and sometimes accelerated in the HIV population at large, we conclude that the probable total burden of VCI in the global HIV population is higher than in the general population and would need to be compared to chronic conditions such as type I diabetes and multiple sclerosis to account for the disease chronicity and lifelong treatment effects. Therefore, this review is also a call to action. Indeed, it is fully established that this amount of VCI burden is a major risk factor for dementia at aged 60+.

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