VCAM-1 and ICAM-1 are released in response to inflammation and facilitate the adhesion and migration of immune and viral factors into and across the vascular endothelium . While VCAM-1 is exclusively expressed on endothelial cells, ICAM-1 is also expressed on leukocytes, astrocytes, and microglial cells . uPAR is a glycoprotein expressed on endothelial cells, in addition to immune and neuronal cells, that facilitates increased vascular permeability, immune cell trafficking, and mitogenic activity, leading to endothelial dysfunction. Blood levels of soluble uPAR are increased in untreated PWH , reduced upon ART initiation , and almost normalized with sustained ART . The associations between the vascular biomarker composite and neurocognitive T-scores were stronger than those of individual biomarkers alone suggesting that each may contribute uniquely to impairment. However, of the three vascular biomarkers, VCAM-1 was the only individual vascular biomarker to emerge as a significant predictor of all three neurocognitive domains when controlling for vascular risk factors and other relevant covariates. It was also the only vascular biomarker that was significantly elevated in our sample of virally suppressed PWH relative to PWoH. This is consistent with studies that have found persistent elevation in VCAM-1 but not ICAM-1 levels following ART and viral suppression .
Given its sensitivity to viral replication and potential for persistent elevations following prolonged ART,indoor weed growing accessories VCAM-1 may be a useful prognostic marker for CVD risk and related neurocognitive sequelae in both treated and untreated PWH. Collectively these findings support the presence of persistent lowgrade inflammation in PWH but highlight endothelial dysfunction as a key mechanism underlying NCI in treated PWH. In our study, inflammation was elevated in PWH relative to PWoH though only weakly associated, and regardless of HIV status, with worse performance in the motor skills domain. Other studies conducted in PWH have also failed to find associations between persistent inflammation and NCI in the context of treated and well-controlled HIV . Persistent immune activation and inflammation in PWH, while present, may not be a primary or direct contributor to NCI in the context of treated and well-controlled HIV disease. One exception may be the selective impact of persistent inflammation on motor deficits, a domain that historically has been most impacted among PWH with chronic disease and/or a history of immunosuppression . This inflammation-motor link replicates another study in virally suppressed PWH that was conducted in a different sample by investigators from our group . Specifically, they found that inflammation, as indexed by a composite burden score that included levels of IL-6, CCL2/MCP-1, sCD14, TNF-a and d-dimer, was associated with poorer performance within the motor skills domain but not other domains. Our weaker results with regard to inflammation may be due differences in individual biomarkers or our approach to constructing composites . Regardless, persistent inflammation may continue to impact NCI in other domains indirectly via its adverse effects on the vascular system and non-HIV-associated complications. This study is among the first to directly compare systemic vascular and inflammatory biomarkers in relation to empirically-derived profiles of neurocognition in a well-characterized cohort of virally-suppressed PWH. However, we acknowledge several limitations.
The crosssectional nature of our data limits our ability to identify temporal patterns regarding the development of inflammation, endothelial dysfunction, and neurocognitive deficits in the context of chronic HIV disease and treatment. Thus, a future analysis that leverages longitudinal data can help address whether subsequent reductions in vascular biomarkers track with improvements in neurocognition among PWH. The current study also did not have access to data for medications that treat cardiovascular conditions, including statin use. Although vascular biomarkers can still show elevations with statin use , prior work has shown that PWH with untreated cardiovascular risk performed worse than those with treated cardiovascular risk on multiple neurocognitive domains, including processing speed, learning/memory, and executive functioning . It is compelling to hypothesize that the elevated vascular biomarker levels in the Dysexecutive/Slow group reflect particular vulnerabilities in fronto-striatal and fronto-parietal networks, possibly in white matter tracts sensitive to neurovascular dysfunction and HIV disease, yet our data do not include direct measurements of structural or functional integrity of specific brain regions . Although similar numbers of clusters/classes and patterns of NC domain impairment have been observed across clinical and non-clinical samples and statistical methods , it is possible that cluster analyses in larger independent HIV samples may reveal other clinically relevant neurocognitive profiles. Last, the PWoH comparison group cannot be interpreted as absolute ‘controls’ given their medical and neuropsychiatric backgrounds – however, these background factors more closely resemble the PWH group, which strengthens our observations of HIV-specific relationships between vascular biomarkers and neurocognition.
The identification of plasma biomarkers that sensitively track with particular neurocognitive deficits and medical profiles will inform efforts to improve neuroHIV clinical care through scalable assessments and tailored interventions. In the present study, our findings support the growing recognition for a vascular subtype of HIV-associated NCI that exhibits a profile of deficits in executive functions and speed-dependent tasks, similar to the classic presentation of vascular cognitive impairment. Our data also highlight endothelial dysfunction as a potential direct mechanism driving this deficit profile, which underscores the importance of neurovascular pathology in the context of viral suppression. Taken together, this vascular NCI subgroup of PWH may benefit the most from interventions that target the neurovascular unit directly and indirectly , which will improve early detection and treatment of NCI, as well as preventing further decline, particularly as the HIV population grows older. Recent years have seen an advent in population-based studies that examine the prevalence, etiology, and developmental trajectories of diverse sub-clinical psychopathological symptoms that pose a risk for the later development of severe mental illnesses. It is increasingly recognized that most categorically defined psychiatric disorders occur on a spectrum or continuum that is not necessarily normally distributed , show high heterogeneity and symptom overlap, and share genetic and environmental risk factors . Therefore, population-based studies of psychopathology in youth assess a broad spectrum of symptoms as well as genetic risk, cognitive and general functioning, socioeconomic, and environmental factors to yield a more complete understanding of symptom etiology and development. Pediatric population-based studies with longitudinal study designs may be helpful for defining normative growth charts of diverse disease dimensions that in turn may aid in developing individual risk predictions . Here, we review different aspects of population-based studies with regard to the psychosis spectrum; we discuss neurodevelopmental underpinnings of psychosis spectrum symptoms, brain morphometric and functional alterations in individuals experiencing psychotic symptoms in the general population, and the role of genetic liability for psychosis. Given the overwhelming evidence offered by this body of recent work that even sub-clinical psychotic symptoms pose a risk for severe mental illnesses,rolling benches we highlight promising strategies that facilitate access to mental health services for adolescents, a group highly vulnerable to mental health problems. Even though further research is needed, in particular to understand risk and resilience factors for longitudinal symptom progression, policy making should take available data into account to further reduce mental health stigma and to invest in prevention and early intervention programs.Despite the longstanding conceptualization of a continuum of psychotic symptoms , this is not reflected in current diagnostic manuals . Recent findings in both help-seeking individuals experiencing PS, and studies on PS in the general population have further emphasized this notion . Presumably, the psychosis continuum is characterized by qualitatively similar PS that vary in levels of conviction and duration, ranging from sub-clinical schizotypal symptoms to severe psychosis spectrum disorders such as schizophrenia. PS, as typically studied in population-based cohorts, include positive symptoms such as hallucinations and delusions. Sometimes negative symptoms such as flat affect are also considered when establishing sub-clinical psychosis categories for detailed discussion on psychometric issues.
The concept of a psychosis continuum has further facilitated the adoption of a clinical staging model . Symptoms typically observed in the general population refer to stage 1a, nonspecific general psychopathologies such as depressive and anxiety symptoms alongside subthreshold PS, and stage 1b with more specific PS, i.e., commonly termed clinical- or ultra-high risk state . Stage 0 in this model is defined by a genetic risk through a positive family history of severe mental illness and other states are characterized by above-threshold PS , persistence of symptoms , and severe, non-remitted psychotic disorders . Importantly, individuals do not necessarily change stages with time but may remain in their initially assigned stage. Similarly, studies on clinical high-risk cohorts specifically examining conversion to full-blown psychosis, i.e., changes of clinical stages, find low transition rates of approximately 20-35% over 2 years . Furthermore, the clinical staging model is primarily based on retrospective studies and requires further prospective validation. The fact that the majority of individuals with a first episode of psychosis have not sought help before their ‘psychotic break’ highlights the necessity to broaden the target symptoms and audience of early intervention strategies for psychosis spectrum disorders. Populationbased studies have become an important strategy to validate the concept of a psychosis continuum, and may be helpful to tailor future primary prevention strategies to the general population by examining longitudinal trajectories of PS development across childhood and adolescence to detect early predictors . Studies on PS in the general population can further be viewed as an alternative to the CHR approach, an enrichment sampling focused on help-seeking individuals fulfilling certain diagnostic criteria . Given that clinical ascertainment is required, CHR cohorts may not reflect the broader population experiencing PS, which may at least partially explain higher pluripotentiality of PS observed in population-based studies relative to CHR samples . Similar to overt psychotic disorders, PS in the general population ) are often accompanied by cognitive impairments , reduced quality of life , higher rates of substance use, functional disability, suicidality , and alterations in brain structure and function , rendering PS an important public health issue. In accordance with a clinical staging model, PS pose an elevated risk for the later development of overt mental illness; not only severe psychosis spectrum disorders but also depression, anxiety disorder, and bipolar disorder , amplifying the significance as a public health concern. However, recent epidemiological and genetic findings highlight the complex relationship between PS and severe mental illnesses : overt psychotic disorders may exhibit diverse psychopathological precursors and similarly, PS in childhood and adolescence do not always foreshadow persistent psychosis and/or schizophrenia later in life. For example, in the Philadelphia Neurodevelopmental Cohort a positive predictive value of 0.51 was reported for initial screening of PS , but in a small Irish youth sample childhood PS had a positive predictive value of >0.59 for adolescent externalizing and internalizing problems . Population-based longitudinal studies on subclinical/ subthreshold PS in children and adolescents offer promise for identifying disease biomarkers that predict progression to overt mental illness . Ultimately, these efforts aim at improving early identification of at-risk youth in order to improve long-term functional outcomes. Risk factors for subthreshold PS and overt psychotic disorders, include genetic risk, both family history and high impact copy number variations such as 22q11.2 deletion syndrome , exposure to drugs as well as childhood adversities/trauma, obstetric complications, and socioeconomic difficulties, including ethnic minority and immigrant status . Importantly, all forms of prevention, i.e., universal, selective, and indicated , can be tailored to these risk factors . For example, universal prevention targets the general population and could involve destigmatization and anti-bullying campaigns to improve mental well-being overall. Selective preventions for people with increased risk for developing psychiatric disorders could be implemented in clinics by providing services for families of patients with severe mental illnesses, and indicated prevention is aimed at improving outcome in CHR individuals . Overall, general population studies allow for larger and unbiased samples, without typical confounders in clinical populations such as medication and illness duration. Such studies can therefore inform and shape policy making for preventive measures of severe mental illnesses. Table 1 provides an overview of population-based studies cited in this review. A pressing question, requiring longitudinal study, is whether sub-clinical PS in youth in the general population are in fact associated with the onset of overt psychosis later in life. One such study is the Dunedin Multidisciplinary Health and Development study, a birth cohort study out of New Zealand that followed the initial cohort over 38 years.