Hannah Mager1, GenaLynne Mooneyham1, Priti Pandit1, Pavel Khil1, Daniela Cardona-Ospina1, Christopher Bartley2, Jonathan Santoro3
1National Institutes of Mental Health, 2National Institute of Mental Health, 3Department of Neurology, Children's Hospital Los Angeles
Objective:
To compare AD biomarkers and autoantibody profiles between Down Syndrome Regression Disorder (DSRD) and Down Syndrome without regression (DSWR).
Background:
Down Syndrome (DS) is the most common genetic cause of intellectual disability. Between ages 10-30, DS individuals are at risk of an acute or subacute neurocognitive decline with neuropsychiatric features, DSRD. After 40, the risk of Alzheimer’s Disease in DS dramatically increases. However, the high response rate to immunomodulatory therapies suggests that DSRD is a neuroinflammatory disorder, possibly autoimmune.
Design/Methods:
Cerebrospinal fluid (CSF) Aβ₄₀, Aβ₄₂, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were quantified in DSRD (n=40) and DSWR (n=28) cohorts via Quanterix Simoa. The Benjamini-Hochberg-corrected Wilcoxon signed rank test was used to compare biomarker levels between DSRD and DSWR. DSRD CSF was screened by full-length protein array. Candidate autoantibodies were validated by nanoluciferase immunoprecipitation (nLIPS). The specificity of validated autoantibodies was evaluated by comparing their frequency in DS (DSRD + DSWR) to control (healthy, n=28; pediatric neurosurgical, n=5; and autism spectrum n=23 CSF) using Fisher’s exact test.
Results:
Aβ₄₀ (p<0.0001), Aβ₄₂ (p<0.0001), and GFAP (p=0.0026) were significantly increased in DSWR relative to DSRD. However, the Aβ42/Aβ40 ratio, a more accurate indicator of AD status, was no different between age-matched DSWR and DSWR. By protein array, 8/40 DSRD cases exhibited elevated parvalbumin immunoreactivity. By nLIPS, 15/27 DSWR and 9/40 DSRD CSF harbored anti-parvalbumin autoantibodies, compared to 3/55 controls.
Conclusions:
Intrathecal anti-parvalbumin autoantibodies are significantly more prevalent in all DS vs controls (p=1x105), and DSWR vs. DSRD (p=0.0109). Prior studies report that parvalbumin-positive interneurons (PV+) are less abundant in DS brains, and that parvalbumin protein levels are lower in the CSF and brains of DS subjects vs controls and AD subjects. Therefore, our data suggest that anti-parvalbumin antibodies may reflect a DS-specific PV+ neuropathological process that differs between DSRD and DSWR.
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