Brain amyloid in virally suppressed HIV-associated neurocognitive disorder

Abstract

ObjectiveTo determine whether virally suppressed HIV neuropathogenesis, a chronic neuroinflammatory state, promotes abnormal brain amyloid deposition.MethodsA total of 10 men with virally suppressed HIV-associated neurocognitive disorder (HAND), aged 46–68 years, underwent 11C-labeled Pittsburgh compound B PET. Data from the Australian Imaging, Biomarkers and Lifestyle (AIBL), including 39 cognitively normal individuals (aged 60–74 years), 7 individuals with mild cognitive impairment (MCI) (aged 64–71 years), and 11 individuals with Alzheimer disease (AD) (aged 55–74 years), were used as reference. Apart from more women, the AIBL cohort was demographically comparable with the HIV sample. Also, the AIBL PET data did not differ by sex. Cerebellum standardized uptake value ratio amyloid values within 22 regions of interest were estimated. In the HIV sample, apolipoprotein E (APOE) was available in 80%, CSF biomarkers in 60%, and 8–10 years of long-term health outcomes in 100%.ResultsHAND and the AIBL group with no cognitive deficits had similar amyloid deposition, which was lower than that in both the MCI and AD groups. At the individual level, one HAND case showed high amyloid deposition consistent with AD. This case also had a CSF-AD–like profile and an E4/E4 for APOE. Clinically, this case declined over 18 years with mild HAND symptoms first, followed by progressive memory decline 8–9 years after the study PET, then progression to severe dementia within 2–3 years, and lived a further 6 years. Another HAND case showed increased amyloid deposition restricted to the hippocampi. Two other HAND cases showed abnormally decreased amyloid in subcortical areas.ConclusionsRelative to cognitively normal older controls, brain amyloid burden does not differ in virally suppressed HAND at the group level. However, individual analyses show that abnormally high and low amyloid burden occur.

Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

“…While Alzheimer’s disease is characterized by neuritic, extracellular amyloid plaques, studies of HAND tissue show diffuse and intracellular expression of amyloid-β that may be a precursor to neuritic plaques [ 46 , 50 , 51 ]. However, more recent PET imaging studies measured amyloid deposition in the brains of living HAND patients and did not show amyloid-β accumulation [ 52 – 55 ], and a recent neuroimaging study reported no change in amyloid levels in virally suppressed patients [ 56 ]. The conflicting results from these studies may be due to different factors.…”

Zinc and Copper Ions Differentially Regulate Prion-Like Phase Separation Dynamics of Pan-Virus Nucleocapsid Biomolecular Condensates

“…High Cu 2+ that outcompetes Zn 2+ for correct folding, activity, or multimerization of essential cellular proteins as BMCs may rather nucleate their aggregation as insoluble pathological plaques of neurodegenerative diseases (Figure 2A). Indeed, virus infections have been shown to exacerbate neurodegenerative disease phenotypes [68][69][70][71][72], and just as Zn 2+ supplementation has been successfully used as treatment against many viruses [160], Zn 2+ supplementation is also described as a paradigm-shifting practice for neurodegenerative disease associated with Zn 2+ and/or Cu 2+ homeostasis abnormalities [316]. Elevated Cu/Zn ratios central to so many diseases, combined with the essential role of Zn 2+ for BMC formation regulating many cellular processes, suggests that prolonged altered Cu/Zn ratios may represent an underappreciated and underlying feature of diseases (Figure 2).…”

“…Our findings are supported by reports that modulation in Cu/Zn ratios and altered expression of proteins maintaining cellular and physiological ion homeostasis are hallmarks of both virus infections and neurological diseases. We and others have contributed to the greater body of literature promoting the theory that towards their own replicative benefit, underlying virus infections induce neurocognitive disorders and may exacerbate neurological diseases [ 68 , 69 , 70 , 71 , 72 ]. We extend this concept, demonstrating that viruses alter metal ion homeostasis and Cu/Zn ratios, creating cell-clogging, insoluble pathological prion-like aggregates of proteins otherwise undergoing LLPS supporting normal cellular functions.…”

Investigating vascular diseases in people living with HIV by nuclear imaging

“…42,43 However, recent PET studies do not show major differences in amyloid deposition stratified by HIV serostatus or HAND severity. 44,45 Others propose that cognitive impairment in PLWH in the ART era might be related to cerebrovascular diseases. 46 Asymptomatic intracranial atherosclerosis has been increasingly recognized as a risk factor of cognitive impairment in the general population.…”