Chronic immune activation and gut barrier dysfunction is associated with neuroinflammation in ART-suppressed SIV+ rhesus macaques.

HIV-associated neurocognitive disorders (HAND) affect ~40% of virally suppressed people with HIV (PWH), however, the precise viral dependent and independent changes to the brain are unclear. Here we characterized the CNS reservoir and immune environment of SIV-infected (SIV+) rhesus macaques during acute (n = 4), chronic (n = 12) or ART-suppressed SIV infection (n = 11). Multiplex immunofluorescence for markers of SIV infection (vRNA/vDNA) and immune activation was performed on frontal cortex and matched colon tissue. SIV+ animals contained detectable viral DNA+ cells that were not reduced in the frontal cortex or the gut by ART, supporting the presence of a stable viral reservoir in these compartments. SIV+ animals had impaired blood brain barrier (BBB) integrity and heightened levels of astrocytes or myeloid cells expressing antiviral, anti-inflammatory or oxidative stress markers which were not abrogated by ART. Neuroinflammation and BBB dysfunction correlated with measures of viremia and immune activation in the gut. Furthermore, SIV-uninfected animals with experimentally induced gut damage and colitis showed a similar immune activation profile in the frontal cortex to those of SIV-infected animals, supporting the role of chronic gut damage as an independent source of neuroinflammation. Together, these findings implicate gut-associated immune activation/damage as a significant contributor to neuroinflammation in ART-suppressed HIV/SIV infection which may drive HAND pathogenesis.

Elevation of cell-associated HIV-1 transcripts in CSF CD4+ T cells, despite effective antiretroviral therapy, is linked to brain injury.

Antiretroviral therapy (ART) can attain prolonged undetectable HIV-1 in plasma and cerebrospinal fluid (CSF), but brain injury remains prevalent in people living with HIV-1 infection (PLHIV). We investigated cell-associated (CA)-HIV-1 RNA transcripts in cells in CSF and blood, using the highly sensitive Double-R assay, together with proton Magnetic Resonance Spectroscopy (1H MRS) of major brain metabolites, in sixteen PLHIV. 14/16 CSF cell samples had quantifiable CA-HIV-1 RNA, at levels significantly higher than in their PBMCs (median 9,266 vs 185 copies /106 CD4+ T-cells; p<0.0001). In individual PLHIV, higher levels of HIV-1 transcripts in CSF cells were associated with greater brain injury in the frontal white matter (Std ß=-0.73; p=0.007) and posterior cingulate (Std ß=-0.61; p=0.03). 18-colour flow cytometry revealed that the CSF cells were 91% memory T-cells, equally CD4+ and CD8+ T-cells, but fewer B cells (0.4 %), and monocytes (3.1%). CXCR3+CD49d+integrin ß7-, CCR5+CD4+ T-cells were highly enriched in CSF, compared with PBMC (p <0.001). However, CA-HIV-1 RNA could not be detected in 10/16 preparations of highly purified monocytes from PBMC, and was extremely low in the other six. Our data show that elevated HIV-1 transcripts in CSF cells were associated with brain injury, despite suppressive ART. The cellular source is most likely memory CD4+ T cells from blood, rather than trafficking monocytes. Future research should focus on inhibitors of this transcription to reduce local production of potentially neurotoxic and inflammatory viral products.

Regional Analysis of Intact and Defective HIV Proviruses in the Brain of Viremic and Virally Suppressed People with HIV.

Here, we provide the first regional analysis of intact and defective HIV reservoirs within the brain. Brain tissue from both viremic and virally suppressed people with HIV (PWH) harbored HIV pol DNA in all regions tested, with lower levels present in basal ganglia and cerebellum relative to frontal white matter. Intact proviruses were primarily found in the frontal white matter but also detected in other brain regions of PWH, demonstrating frontal white matter as a major brain reservoir of intact, potentially replication competent HIV DNA that persists despite antiretroviral therapy. ANN NEUROL 2023;94:798-802.

The roles of the kynurenine pathway in COVID-19 neuropathogenesis.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the highly contagious respiratory disease Corona Virus Disease 2019 (COVID-19) that may lead to various neurological and psychological disorders that can be acute, lasting days to weeks or months and possibly longer. The latter is known as long-COVID or more recently post-acute sequelae of COVID (PASC). During acute COVID-19 infection, a strong inflammatory response, known as the cytokine storm, occurs in some patients. The levels of interferon-γ (IFN-γ), interferon-ß (IFN-ß), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) are particularly increased. These cytokines are known to activate the enzyme indoleamine 2,3-dioxygenase 1 (IDO-1), catalysing the first step of tryptophan (Trp) catabolism through the kynurenine pathway (KP) leading to the production of several neurotoxic and immunosuppressive metabolites. There is already data showing elevation in KP metabolites both acutely and in PASC, especially regarding cognitive impairment. Thus, it is likely that KP involvement is significant in SARS-CoV-2 pathogenesis especially neurologically.

New Detection of Locally Acquired Japanese Encephalitis Virus Using Clinical Metagenomics, New South Wales, Australia.

In the context of an emerging Japanese encephalitis outbreak within Australia, we describe a novel locally acquired case in New South Wales. A man in his 70s had rapidly progressive, fatal meningoencephalitis, diagnosed as caused by Japanese encephalitis virus by RNA-based metagenomic next-generation sequencing performed on postmortem brain tissue.

Low incidence of advanced neurological burden but high incidence of age-related conditions that are dementia risk factors in aging people living with HIV: a data-linkage 10-year follow-up study.

Although increasing research is focusing on age-related comorbidities (ARC) among people living with HIV (PLHIV), no studies have concomitantly assessed non-HIV age-related neurological disorders (e.g., Alzheimer's dementia). A total of 254 PLHIV and 69 HIV-negative controls completed baseline medical history and cognitive testing. ARC data were collected from medical records over the subsequent 9-10 years and included all types of strokes, all types of dementia, mild cognitive impairment, Parkinson's disease, motor neuron disease (grouped into a non-HIV age-related neurological category), cardiovascular disease, chronic kidney disease, chronic liver disease, chronic lung disease, non-AIDS cancers, osteoporosis, and diabetes. Kaplan-Meier curves assessed differences in the incident rates (per 1000 person year) of groups of ARC as defined above and combined ARC (i.e., development of any of the ARC) among younger (baseline age < 50) and older (baseline age ≥ 50) PLHIV and younger and older controls. Cox-proportional hazard models assessed the individual and interaction effects of HIV status and chronological age, in addition to a range of demographic and clinical variables including historical and baseline HIV brain involvement on the risk of developing combined ARC. Older PLHIV had a higher incidence of cardiovascular disease, osteoporosis, and combined ARC compared to other groups (p < 0.05). Incident rate of non-HIV age-related neurological disorders was 2.3 [0.93, 4.79] per 1000 person year. While this incident rate was higher in older PLHIV (5.37 [1.97, 11.92]) than older HIV-negative participants (3.58 [0.18-17.67]), this was not significant. In multivariate analyses, HIV status and chronological age, but not their interaction, and smoking were associated with higher risk of combined ARC (p < 0.05). In analyses focusing on PLHIV, older age and taking abacavir/efavirenz/atazanavir/darunavir containing antiretroviral treatments at the time of diagnosis were associated with greater ARC (p < 0.05). Non-HIV age-related neurological disorders are uncommon in older PLHIV, where the majority were < 70 years of age at the end of follow-up. However, the greater burden of ARC among older PLHIV, most of which are established dementia risk factors, warrants the establishment of commensurate prevention strategies and greater attention to neurocognitive screening.

Intact HIV Proviruses Persist in the Brain Despite Viral Suppression with ART.

OBJECTIVE: Human immunodeficiency virus (HIV) persistence in blood and tissue reservoirs, including the brain, is a major barrier to HIV cure and possible cause of comorbid disease. However, the size and replication competent nature of the central nervous system (CNS) reservoir is unclear. Here, we used the intact proviral DNA assay (IPDA) to provide the first quantitative assessment of the intact and defective HIV reservoir in the brain of people with HIV (PWH). METHODS: Total, intact, and defective HIV proviruses were measured in autopsy frontal lobe tissue from viremic (n = 18) or virologically suppressed (n = 12) PWH. Total or intact/defective proviruses were measured by detection of HIV pol or the IPDA, respectively, through use of droplet digital polymerase chain reaction (ddPCR). HIV-seronegative individuals were included as controls (n = 6). RESULTS: Total HIV DNA was present at similar levels in brain tissues from untreated viremic and antiretroviral (ART)-suppressed individuals (median = 22.3 vs 26.2 HIV pol copies/106 cells), reflecting a stable CNS reservoir of HIV that persists despite therapy. Furthermore, 8 of 10 viremic and 6 of 9 virally suppressed PWH also harbored intact proviruses in the CNS (4.63 vs 12.7 intact copies/106 cells). Viral reservoirs in CNS and matched lymphoid tissue were similar in the composition of intact and/or defective proviruses, albeit at lower levels in the brain. Importantly, CNS resident CD68+ myeloid cells in virally suppressed individuals harbored HIV DNA, directly showing the presence of a CNS resident HIV reservoir. INTERPRETATION: Our results demonstrate the first evidence for an intact, potentially replication competent HIV reservoir in the CNS of virally suppressed PWH. ANN NEUROL 2022;92:532-544.

Treatable traits for long COVID.

Long COVID, or post-acute COVID-19 sequelae, is experienced by an estimated one in eight adults following acute COVID-19. Long COVID is a new and complex chronic health condition that typically includes multiple symptoms that cross organ systems and fluctuate over time; a one-size-fits-all approach is, therefore, not likely to be appropriate nor relevant for long COVID treatment. 'Treatable Traits' is a personalized medicine approach, purpose-built to address the complexity and heterogeneity of complex chronic conditions. This comprehensive review aimed to understand how a treatable traits approach could be applied to long COVID, by first identifying the most prevalent long COVID treatable traits and then the available evidence for strategies to target these traits. An umbrella review of 22 systematic reviews identified 34 symptoms and complications common with long COVID, grouped into eight long COVID treatable trait clusters: neurological, chest, psychological, pain, fatigue, sleep impairment, functional impairment and other. A systematic review of randomized control trials identified 18 studies that explored different intervention approaches for long COVID prevention (k = 4) or management (k = 14). While a single study reported metformin as effective for long COVID prevention, the findings need to be replicated and consensus is required around how to define long COVID as a clinical trial endpoint. For long COVID management, current evidence supports exercise training or respiratory muscle training for long COVID treatable traits in the chest and functional limitation clusters. While there are studies exploring interventions targeting other long COVID treatable traits, further high-quality RCTs are needed, particularly targeting treatable traits in the clusters of fatigue, psychological, pain and sleep impairment.

Reversible large-scale network disruption correlates with neurocognitive improvement in HIV-associated minor neurocognitive disorder with combined anti-retroviral therapy intensification: a prospective longitudinal resting-state functional magnetic resonance imaging study.

OBJECTIVE: HIV-associated neurocognitive disorder (HAND) affects multiple cognitive domains and currently, the neuropsychological testing is the gold standard to identify these deficits. The aim of this longitudinal 12-month pilot study is to determine the effect of intensified combination antiretroviral therapy (cART) on rs-fMRI in virally suppressed (both in CSF and blood) patients with active HAND (those who have progressive neurocognitive impairment) and correlated with neurocognitive function tests. METHODS: In this pilot study, we have evaluated sixteen patients with active HAND with viral suppression in both blood and CSF to study the effect of cART on functional connectivity. Participants underwent rs-fMRI at the baseline (time point-1 (TP-1) and 12-month visits (time point-2 (TP-2)). Connectivity in the five major networks was measured at TP-1 and TP-2 using the seed-based approach. All the participants underwent a five-domain neuropsychological battery at TP-1 and TP-2. Neurocognitive scores (NC) as well as blood and CSF markers were correlated with functional connectivity (FC). RESULTS: There was a significant increase in the FC between the two time points within the executive, salience, default mode, dorsal attention, and visual networks at voxel level threshold of p < 0.001 and cluster level threshold of p < 0.05 and corrected for false detection rate (FDR). The neurocognitive scores were positively correlated with all the networks at similar cluster and voxel level thresholds. CONCLUSIONS: These results indicate that rs-fMRI can be potentially used as one of the biomarkers for treatment efficacy in HAND.

Cerebrospinal Fluid Viral Load Across the Spectrum of Untreated Human Immunodeficiency Virus Type 1 (HIV-1) Infection: A Cross-Sectional Multicenter Study.

BACKGROUND: The aim of this large multicenter study was to determine variations in cerebrospinal fluid (CSF) HIV-RNA in different phases of untreated human immunodeficiency virus type 1 (HIV-1) infection and its associations with plasma HIV-RNA and other biomarkers. METHODS: Treatment naive adults with available CSF HIV-RNA quantification were included and divided into groups representing significant disease phases. Plasma HIV-RNA, CSF white blood cell count (WBC), neopterin, and albumin ratio were included when available. RESULTS: In total, 1018 patients were included. CSF HIV-RNA was in median (interquartile range [IQR]) 1.03 log10 (0.37-1.86) copies/mL lower than in plasma, and correlated with plasma HIV-RNA (r = 0.44, P < .01), neopterin concentration in CSF (r = 0.49, P < .01) and in serum (r = 0.29, P < .01), CSF WBC (r = 0.34, P < .01) and albumin ratio (r = 0.25, P < .01). CSF HIV-RNA paralleled plasma HIV-RNA in all groups except neuroasymptomatic patients with advanced immunodeficiency (CD4 < 200) and patients with HIV-associated dementia (HAD) or opportunistic central nervous system (CNS) infections. Patients with HAD had the highest CSF HIV-RNA (in median [IQR] 4.73 (3.84-5.35) log10 copies/mL). CSF > plasma discordance was found in 126 of 972 individuals (13%) and varied between groups, from 1% in primary HIV, 11% in neuroasymptomatic groups, up to 30% of patients with HAD. CONCLUSIONS: Our study confirms previous smaller observations of variations in CSF HIV-RNA in different stages of HIV disease. Overall, CSF HIV-RNA was approximately 1 log10 copies/mL lower in CSF than in plasma, but CSF discordance was found in a substantial minority of subjects, most commonly in patients with HAD, indicating increasing CNS compartmentalization paralleling disease progression.

Atypical presentations and course of JC virus infection.

There is increasing evidence that the spectrum of human polyomavirus 2 (JCV) CNS disease includes novel syndromes other than progressive multifocal leukoencephalopathy (PML), the appreciation of which is increasingly important in the context of MS therapies and immunodeficiency states. Our objective is to describe unusual presentations of JCV infection to heighten clinician awareness. We describe three case reports of various PML presentations. Firstly a 56-year-old HIV positive male with decades of viral suppression and normal immune function presented with 1 month of non-specific headache that spontaneously resolved despite an MRI showing a new area of PML and CSF being JC DNA + . He had had two similar episodes in 2013 and 2014 with MRI scans consistent with PML, CSF, JCV, and PCR positivity once and brain biopsy-positive twice. Another 61-year-old male presented with subacute binocular vision loss and was found to have newly diagnosed HIV and JCV DNA detected in CSF. MRI brain only demonstrated symmetrical chiasmo-hypothalamic enhancement. There has been some improvement with combination antiretroviral therapy and corticosteroids for immune reconstitution inflammatory syndrome (IRIS). Thirdly, a 65-year-old male presented with subacute progressive confusion and behavioural disturbance, one year post-bilateral lung transplantation. MRI brain demonstrated no evidence of PML but CSF on three occasions demonstrated a progressively increasing JCV DNA load. Despite reduction in his immunosuppression, the patient developed profound encephalopathy without localising features leading to death two months later. These cases emphasise the atypical presentations of JCV: chronic relapsing, unusual symmetrical visual pathway disease, and non-localising encephalopathy without MRI evidence of PML.

Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review.

Despite evidence of premature, accentuated and accelerated aging for some age-related conditions such as cardiovascular diseases in people living with HIV (PLHIV), the evidence for these abnormal patterns of aging on neurocognition remains unclear. Further, no systematic review has been dedicated to this issue. Using PRISMA guidelines, we searched standard databases (PubMed, EMBASE, CINAHL and PsycINFO). Articles were included if they analyzed and reported the effect of age on neurocognition among PLHIV as one of their major findings, if they were conducted in the combination anti-retroviral therapy era (after 1996) and published in a peer-reviewed journal in English. Quality appraisal was conducted using the Joanna Briggs Institute (JBI) appraisal tools. To systematically target the abnormal patterns of neurocognitive aging, we define premature cognitive aging as significant interaction effect of HIV status and age on cross-sectional neurocognitive test performance covering both the normal and abnormal performance range; accentuated cognitive aging as significant interaction effect of HIV status and age on cross-sectional neurocognitive impairment (NCI) rate, thus covering the abnormal performance range only; accelerated cognitive aging as significant interaction effect of HIV status and age on longitudinal neurocognitive test performance or incidence of NCI. Because these definitions require an age-comparable HIV-negative (HIV-) control group, when no controls were included, we determined the range of the age effect on neurocognitive test performance or NCI among PLHIV. A total of 37 studies originating from the US (26), UK (2), Italy (2), Poland (2), China (2), Japan (1), Australia (1), and Brazil (1) were included. Six studies were longitudinal and 14 included HIV- controls. The quality appraisal showed that 12/37 studies neither used an age-matched HIV- controls nor used demographically corrected cognitive scores. A meta-analysis was not possible because study methods and choice of neurocognitive measurement methods and outcomes were heterogeneous imposing a narrative synthesis. In studies with an HIV- control sample, premature neurocognitive aging was found in 45% of the cross-sectional analyses (9/20), while accelerated neurocognitive aging was found in 75% of the longitudinal analyses (3/4). There was no evidence for accentuated aging, but this was tested only in two studies. In studies without an HIV- control sample, the age effect was always present but wide (NCI OR = 1.18-4.8). While large sample size (> 500) was associated with abnormal patterns of cognitive aging, most of the studies were under powered. Other study characteristics such as longitudinal study design and higher proportion of older participants were also associated with the findings of abnormal cognitive aging. There is some support for premature and accelerated cognitive aging among PLHIV in the existing literature especially among large and longitudinal studies and those with higher proportion of older samples. Future HIV and cognitive aging studies need to harmonize neuropsychological measurement methods and outcomes and use a large sample from collaborative multi-sites to generate more robust evidences.

Effect of antiretroviral treatment on blood-brain barrier integrity in HIV-1 infection.

BACKGROUND: Blood-brain barrier (BBB) injury is prevalent in patients with HIV-associated dementia (HAD) and is a frequent feature of HIV encephalitis. Signs of BBB damage are also sometimes found in neuroasymptomatic HIV-infected individuals without antiretroviral therapy (ART). The aim of this study was to investigate the integrity of the BBB before and after initiation of ART in both neuroasymptomatic HIV infection and in patients with HAD. METHODS: We determined BBB integrity by measuring cerebrospinal fluid (CSF)/plasma albumin ratios in archived CSF samples prior to and after initiation of ART in longitudinally-followed neuroasymptomatic HIV-1-infected individuals and patients with HAD. We also analyzed HIV RNA in blood and CSF, IgG Index, CSF WBC counts, and CSF concentrations of ß2-micoglobulin, neopterin, and neurofilament light chain protein (NfL). RESULTS: We included 159 HIV-infected participants; 82 neuroasymptomatic individuals and 77 with HAD. All neuroasymptomatic individuals (82/82), and 10/77 individuals with HAD, were longitudinally followed with a median (interquartile range, IQR) follow-up of 758 (230-1752) days for the neuroasymptomatic individuals, and a median (IQR) follow-up of 241 (50-994) days for the individuals with HAD. Twelve percent (10/82) of the neuroasymptomatic individuals and 80% (8/10) of the longitudinally-followed individuals with HAD had elevated albumin ratios at baseline. At the last follow-up, 9% (7/82) of the neuroasymptomatic individuals and 20% (2/10) of the individuals with HAD had elevated albumin ratios. ART significantly decreased albumin ratios in both neuroasymptomatic individuals and in patients with HAD. CONCLUSION: These findings indicate that ART improves and possibly normalizes BBB integrity in both neuroasymptomatic HIV-infected individuals and in patients with HAD.

MR spectroscopy in HIV associated neurocognitive disorder in the era of cART: a review.

Neuroimaging has been a critical tool for understanding the neuropathological underpinnings observed in HIV. The pathophysiology of HAND is chiefly driven by neuroinflammation. Despite adhering to cART, low levels of viraemia probably persist in the brain in some patients leading to chronic immune activation with resultant neuroinflammation and consequent neuronal injury. MR spectroscopy has been widely used as a biomarker for the presence and severity of HAND in several studies. By studying the MRS signatures, it is possible to characterise the presence of neuroinflammation and neural injury. Furthermore, metabolite concentrations measured by MRS could be used as a quantitative indicator of HIV cerebral involvement, thereby affording the opportunity to assess the efficacy of cART in HAND. However, currently there are three significant limitations in the MRS HIV research literature: the relative paucity of prospective studies, the small number of regions of interrogation due to current methodology (single voxel MRS), and the evolving understanding of the impact of co-morbidities (e.g. ageing, mood disorders, alcoholism etc.) on MRS measurements. This review critically addresses the current literature of MRS studies in people living with HIV (PWH) with HAND to determine its value, especially in the context of the current cART era. In addition, we discuss technical considerations related to the disease and the future direction in HAND using MRS.

Kynurenine pathway modulation reverses the experimental autoimmune encephalomyelitis mouse disease progression.

BACKGROUND: Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system characterized by demyelination, neuroinflammation, and neurodegeneration. Activation of the kynurenine pathway (KP) results from acute and chronic neuroinflammation leading to both immune suppression and neurotoxicity. However, the exact effects of KP metabolites and changes in neurodegenerative diseases over time are not fully understood. Studies, including those in MS models, have reported that short-term KP activation is beneficial through immune tolerance. However, the effects of long-term KP activation are poorly understood. We hypothesized that such chronic activation is responsible for the neurodegeneration in MS, and further, modulating the KP in EAE-induced mice could significantly decrease the EAE disease severity. METHODS: We biochemically altered the KP at different stages of the disease in experimental allergic encephalomyelitis (EAE) mouse model of MS and at two different enzymatic levels of the KP (IDO-1 (indoleamine 2,3 dioxygenase)) and KMO (kynurenine monooxygenase). CNS tissue and blood samples were analyzed longitudinally using GCMS, HPLC, IHC, and RT-PCR. RESULTS: We showed that the KP was steadily upregulated correlating with disease severity and associated with a shift towards increasing concentrations of the KP metabolite quinolinic acid, a neuro- and gliotoxin. KP modulation by inhibition of IDO-1 with 1-methyl tryptophan (1-MT) was dependent on the timing of treatment at various stages of EAE. IDO-1 inhibition at EAE score 2 led to significantly higher numbers of FoxP3 cells (p < 0.001) in the spleen than earlier IDO-1 inhibition (prophylactic 1-MT treatment group (p < 0.001)), 1-MT treatment after EAE induction (EAE score 0; p < 0.001), and 1-MT treatment at EAE score of 1 (p < 0.05). Significant improvement of disease severity was observed in EAE mice treated with 1-MT at EAE score 2 compared to the untreated group (p < 0.05). KP modulation by KMO inhibition with Ro 61-8048 led to significantly greater numbers of Foxp3 cells (p < 0.05) in Ro 61-8048 treated mice and even more significant amelioration of EAE disease compared to the 1-MT treatment groups. CONCLUSIONS: These results provide a new mechanistic link between neuroinflammation and neurodegeneration and point to KP modulation at the KMO level to preserve immune tolerance and limit neurodegeneration in EAE. They provide the foundation for new clinical trials for MS.

Black blood imaging of intracranial vessel walls.

Traditional vascular imaging focuses on non-invasive cross-sectional imaging to assess luminal morphology; however, the vessel wall itself may be specifically involved in many diseases. Newer pulse sequences, and particularly black blood MRI of intracranial vessels, have brought a paradigm shift in understanding the pathophysiology of many vasculopathies. Black blood MRI of intracranial vessel walls can help in a range of pathologies with differing pathophysiology, including intracranial atherosclerosis, aneurysms, vasculitis and vasculopathy, moyamoya disease, dissection and vertebrobasilar hypoplasia. This review highlights how vessel wall imaging can contribute to the clinical diagnosis and management of patients with intracranial vascular pathology.

Vascular cognitive impairment and HIV-associated neurocognitive disorder: a new paradigm.

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+.

Effectiveness of the progestin-only pill for migraine treatment in women: A systematic review and meta-analysis.

Background Migraine is highly prevalent in women (18%). Peak morbidity affects their most productive years, coinciding with peak fertility. Hormonal contraception is often tailored for migraine prevention. Estrogen-containing contraceptives may be contraindicated in women experiencing migraine with aura due to the risk of vascular events. While improvements in migraine with a progestin-only pill (POP), which inhibits ovulation are documented, the strength and quality of evidence has not been formally evaluated. Objectives To determine the effectiveness of progestin-only contraceptives for migraine treatment by systematic review and meta-analysis. Data sources and selection MEDLINE, EMBASE and Cochrane Libraries were searched (1980 to September 2016) for studies on progestin-only treatments for migraine. Studies in English on >4 non-menopausal women aged 18-50 with migraine diagnosed by formal criteria were included. Data extraction and analysis Data were quality-assessed using the GRADE system. A random effects model was used for pooled analyses. Results Pooled analyses of four studies demonstrated that desogestrel 75 mcg/day, POP significantly but modestly reduced the number of migraine attacks and migraine days. Reduced intensity and duration, reduced analgesic and triptan use were observed, along with improved headache-related quality of life. GRADE analysis indicated evidence was low to very low for each outcome measure. Adverse effects resulted in treatment cessation for <10% of participants. Two studies compared desogestrel POP to a combined oral contraceptive, demonstrating similar migraine outcomes for both treatments. Conclusions The desogestrel POP shows promise in improving migraine in women. Current evidence is observational and based on small samples of women using only one oral progestin-only formulation. Further randomized trials on additional progestin-only contraceptives are required to confirm their role in migraine management.