Abstract Details

Title Novel Intrathecal Parvalbumin Autoantibodies in Down Syndrome

Topic Autoimmune Neurology

Presentation(s) N2 - Neuroscience in the Clinic: Neurological Care of Individuals with Down Syndrome Across the Lifespan (4:45 PM-4:57 PM)

Poster/Presentation
Number 003

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.

Authors/Disclosures
Hannah Mager PRESENTER	Ms. Mager has received research support from National Institute of Mental Health. Ms. Mager has received personal compensation in the range of $50,000-$99,999 for serving as a Graduate student with National Institute of Mental Health.
GenaLynne Mooneyham, MD	Dr. Mooneyham has received research support from National Institutes of Health.
PRITI R. PANDIT, PhD	Dr. PANDIT has nothing to disclose.
Pavel Khil, PhD	Dr. Khil has received personal compensation for serving as an employee of Axle Informatics.
Daniela Ospina Cardona, Neurobiologist	Mrs. Ospina Cardona has nothing to disclose.
Christopher M. Bartley, MD, PhD (National Institute of Mental Health)	Dr. Bartley has stock in NowRx, Inc.. The institution of Dr. Bartley has received research support from Deeda Blair Research Initiative for Disorders of the Brain (FNIH). The institution of Dr. Bartley has received research support from Howard Hughes Medical Institute. Dr. Bartley has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Commonwealth Club.
Jonathan Santoro, MD (Department of Neurology, Children's Hospital Los Angeles)	Dr. Santoro has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for UCB. Dr. Santoro has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Cycle Pharma. Dr. Santoro has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Dianthus. Dr. Santoro has received personal compensation in the range of $500-$4,999 for serving as a Consultant for National Down Syndrome Society.

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