| |
Alzheimers Blood Markers - Plasma Aβ42/Aβ40
Ratios in Older People Living With Human Immunodeficiency Virus
|
| |
| |
Download the PDF here
Clinical Infectious Diseases 05 January 2023 Sarah A. Cooley,1, Brittany Nelson, 1 Anna Boerwinkle,1 Kevin E. Yarasheski,2 Kris M. Kirmess, 2 Matthew R. Meyer, 2 Suzanne E. Schindler, 1,3 John C. Morris, 1,3,4 Anne Fagan, 3 Beau M. Ances, 1,a and Jane A. O’Halloran 5,a
A total of 66 PWH (age >40 years), avg age 55-66, with high current CD4 but low nadir CD4, duration of HIV 20 years+, (HIV RNA <50 copies/mL) and 195 PWoH provided blood samples, underwent magnetic resonance imaging, and completed a neuropsychological battery or clinical dementia rating scale - 23 of the 66 HIV were mildly cognitively impaired see Table 1 below. Of the 195 PWoHIV 57 had alzheimers & 138 were cognitvely normal.
For PWH, all cognitive domain z scores and the global cognition z score were significantly lower in the PWH_CI than in the PWH_CN group (P <.01). The attention, psychomotor speed, and delayed recall domains demonstrated the largest differences in scores between the PWH_CN and PWH_CI groups (average group difference in z scores, 1.2, 1.0, and 1.0, respectively).
Overall, analyses demonstrated a significant group difference in log Aβ42/Aβ40 ratios (P < .001) (Figure 1). Pairwise comparisons revealed a significantly lower Aβ42/Aβ40 ratio for the PWoH_AD group (mean ratio [SD], -1.03 [0.03]) compared with the 3 other groups ( -0.97 [0.03], -0.98 [0.05], and -0.99 [0.06] for PWoH_CN, PWoH_CN, and PWH_CI, respectively; P < .01). There were no other significant differences between these groups, including between PWH who did and those who did not have cognitive impairment (P > .05). Results did not change when comparing the oldest PWH with the youngest PWoH_AD participants
Among PWH, there were no significant relationships between the plasma Aβ42/Aβ40 ratio or APS and the nadir CD4 T-cell count, current CD4 and CD8 T-cell counts, CD4/CD8 ratio, or duration of known HIV infection (P > .05).
Results indicated that the plasma Aβ42/Aβ40 ratio and APS were sensitive in discriminating the PWoH_AD group from PWoH_CN and the 2 PWH groups. Within PWH, the plasma Aβ42/Aβ40 ratio and APS did not significantly differ between cognitively normal and cognitively impaired PWH. In addition, neither the Aβ42/Aβ40 ratio nor the APS was associated with any of the examined HIV disease characteristics (eg, CD4 and CD8 T-cell counts) in this sample. Finally, we observed the expected relationship between lower plasma Aβ42/Aβ40 ratio and smaller hippocampal volumes within the symptomatic AD group, but this relationship was not significant for the cognitively normal PWoH or the 2 PWH groups. These results suggest that, within this sample, HIV-related cognitive changes were likely not attributable to brain amyloid accumulation and lower hippocampal volume, and the plasma Aβ42/Aβ40 ratio and APS may be useful in distinguishing AD-related cognitive changes from HIV-related cognitive changes.
Our results are consistent with those of previous studies of Aβ in HIV that demonstrated no significant differences in amyloid between PWH and cognitively unimpaired PWoH, using either CSF biomarkers or PET imaging [11-13, 17, 19]. Taken together, these results suggest that while there may be some evidence of accelerated brain aging in PWH [2-5], it is unlikely that these changes can be attributed to an accelerated AD phenotype, as we observed no significant reduction in Aβ42/Aβ40 ratio or increase in APS in PWH compared with age-matched PWoH_CN. Instead, changes to brain integrity in older PWH may be more attributable to other factors, such as legacy effects of early untreated HIV infection, comorbid conditions (eg, cardiovascular disease and diabetes), environmental factors, and ongoing neuroinflammation [33-37].
Virologically well-controlled PWH with or without cognitive impairment did not exhibit reduced plasma Aβ42/Aβ40 ratios or increased APSs compared with cognitively unimpaired PWoH. Only PWoH with symptomatic AD demonstrated significantly lower plasma Aβ42/Aβ40 ratios and higher APSs, which were also correlated with smaller hippocampus volumes. Clinical markers of HIV disease were not associated with the plasma Aβ42/Aβ40 ratio or APS. Overall, these results demonstrate that the plasma Aβ42/Aβ40 ratio, a marker that can be quickly and easily obtained during a clinical visit, may help differentiate the effects of HIV from AD within PWH, but larger studies with older PWH are needed. The ability to distinguish causes will help inform the best treatments to help relieve or potentially slow cognitive decline.
Abstract
Background
As people with human immunodeficiency virus (HIV) (PWH) age, it remains unclear whether they are at higher risk for age-related neurodegenerative disorders-for example, Alzheimer disease (AD)-and, if so, how to differentiate HIV-associated neurocognitive impairment from AD. We examined a clinically available blood biomarker test for AD (plasma amyloid-β [Aβ] 42/Aβ40 ratio) in PWH who were cognitively normal (PWH_CN) or cognitively impaired (PWH_CI) and people without HIV (PWoH) who were cognitively normal (PWoH_CN) or had symptomatic AD (PWoH_Ad).
Methods
A total of 66 PWH (age >40 years) (HIV RNA <50 copies/mL) and 195 PWoH provided blood samples, underwent magnetic resonance imaging, and completed a neuropsychological battery or clinical dementia rating scale. Participants were categorized by impairment (PWH_CN, n = 43; PWH_CI, n = 23; PWoH_CN, n = 138; PWoH_Ad, n = 57). Plasma Aβ42 and Aβ40 concentrations were obtained using a liquid chromatography-tandem mass spectrometry method to calculate the PrecivityAD amyloid probability score (APS). The APS incorporates age and apolipoprotein E proteotype into a risk score for brain amyloidosis. Plasma Aβ42/Aβ40 ratios and APSs were compared between groups and assessed for relationships with hippocampal volumes or cognition and HIV clinical characteristics (PWH only).
Results
The plasma Aβ42/Aβ40 ratio was significantly lower, and the APS higher, in PWoH_AD than in other groups. A lower Aβ42/Aβ40 ratio and higher APS was associated with smaller hippocampal volumes for PWoH_AD. The Aβ42/Aβ40 ratio and APS were not associated with cognition or HIV clinical measures for PWH.
Conclusions
The plasma Aβ42/Aβ40 ratio can serve as a screening tool for AD and may help differentiate effects of HIV from AD within PWH, but larger studies with older PWH are needed.
|
|
| |
| |
|
|
|
