Neuronal accumulation of hyperphosphorylated tau protein predicts stable memory impairment in people living with HIV

Abstract

Objectives:As lifespans increase in people with HIV (PWH), there is concern that age-related neurodegenerative disorders may contribute to cognitive decline. We asked whether brain accumulation of Alzheimer's disease (AD)-associated proteins amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) predicted cognitive performance in middle-aged PWH.Methods:In a prospectively followed, cognitively-characterized autopsy sample of 135 PWH, we used immunohistochemistry to assess Aβ plaques and neuronal p-tau in medial temporal and lateral frontal lobes. These pathologies were tested for associations with cognitive performance in seven domains: motor, speed of information processing, working memory, memory encoding, memory retrieval, verbal fluency, and abstraction/executive function. Univariate and multivariate analyses accounting for HIV-associated variables, reading level, and comorbidities were conducted. Longitudinal trajectories of memory functions were evaluated in 60 individuals with a median follow-up of 6.0 years.Results:In this population with mean age 51.4 ± 0.9 years, 58% displayed neuronal p-tau and 29% Aβ plaques. Neuronal p-tau, but not Aβ, predicted worse memory encoding and retrieval, but not other cognitive functions. With an ordinal hierarchy of neuronal p-tau locations (entorhinal, hippocampal, neocortical), decreased memory performance correlated with neocortical distribution. Memory function trajectories could not be distinguished between individuals with and without neuronal p-tau, and over 80% of the sample showed no change over time.Conclusion:In this middle-aged sample, neuronal p-tau accumulation contributes to memory deficits, but is not associated with accelerated decline in function over time. In the absence of AD-like deterioration, other etiologies for neuronal p-tau in cognitively impaired PWH must be considered.

CSF Extracellular Vesicle Aβ42 and Tau/Aβ42 Ratio Are Associated with Cognitive Impairment in Older People with HIV

“…The association of total Tau levels with HIV or HAND remains controversial. Some studies reported an increased deposition of aggregated Tau in brain [ 61 ] or increased Tau in CSF [ 62 , 63 , 64 ], whereas others found no significant difference [ 19 , 27 , 65 ]. Further studies are needed to determine the specificity and diagnostic significance of Aβ and Tau biomarkers in PWH.…”

“…However, it is a nonspecific marker that reflects axonal injury in many neurological disorders. β amyloid (1–42) (Aβ42) aggregates and hyperphosphorylated Tau-containing neurofibrillary tangles are hallmarks of AD that are detected in the brains of some older PWH [ 17 , 18 , 19 , 20 ]. An increased CSF Tau/Aβ42 ratio is a biomarker associated with risk of aMCI and AD; increased CSF Tau reflects its release from degenerating neurons while decreased CSF Aβ42 reflects higher amyloid deposition in the brain [ 21 , 22 , 23 , 24 ].…”

Neuropathogenic role of astrocyte‐derived extracellular vesicles in HIV‐associated neurocognitive disorders

“…The prevalence of HIV‐associated neurocognitive disorders (HAND) in PLWH ranges from 19% to 52% in developed countries (Atashili et al., 2013 ; Lawler et al., 2010 ), and 14% to 64% in developing countries (Debalkie Animut et al., 2019 ; Lawler et al., 2010 ). Accumulating evidence suggests that common pathways and factors are modulated in the brains of HIV + and Alzheimer's disease (AD) patients, thus pointing out similarities and convergence of these two pathologies (Achim et al., 2009 ; Chai et al., 2017 ; Esiri et al., 1998 ; Garces et al., 2023 ; Gelman & Schuenke, 2004 ; Gonzalez et al., 2023 ; Green et al., 2005 ; Izycka‐Swieszewska et al., 2000 ; Kim et al., 2013 ; Meehan et al., 2023 ; Nebuloni et al., 2001 ; Raja et al., 1997 ; Stern et al., 2018 ; Xu & Ikezu, 2009 ). As regards the development of Alzheimer's‐like pathology in older HIV + survivors, it remains unclear whether the disease develops independently or as a comorbidity of HIV‐1.…”

“…In contrast, there are conflicting reports demonstrating no correlation between the levels of cerebrospinal fluid (CSF) Amyloid beta (Aβ 42) and the deposition of fibrillary brain amyloids assessed by magnetic resonance imaging (MRI) using Pittsburgh Compound B, in HIV‐infected‐individuals with HAND (Ances et al., 2012 , 2010 ; Clifford et al., 2009 ). Despite this discrepancy in the field, several studies have reported deposition of diffused amyloid depositions in the brains of HAND patients in the post‐cART era and the development of Alzheimer's‐like pathology (Achim et al., 2009 ; Chai et al., 2017 ; Esiri et al., 1998 ; Fields et al., 2020 ; Garces et al., 2023 ; Gelman & Schuenke, 2004 ; Gonzalez et al., 2023 ; Howdle et al., 2020 ; Izycka‐Swieszewska et al., 2000 ; Kim et al., 2013 ; Meehan et al., 2023 ; Nebuloni et al., 2001 ; Raja et al., 1997 ; Stern et al., 2018 ; Xu & Ikezu, 2009 ). There are reports demonstrating that HIV‐1 infected people on anti‐retrovirals, specifically, protease inhibitors, had higher amounts of neurotoxic amyloids and phospho Tau (pTau) levels in the CSF (Fields et al., 2020 ).…”