Abstract Details

Title Clinicopathological Correlations in Anti-GAD65 and Anti-Glycine Neurologic Autoimmunity: Linking Excitatory Phenotypes to Inhibitory Neuron Dysfunction

Topic Autoimmune Neurology

Presentation(s) P2 - Poster Session 2 (8:00 AM-9:00 AM)

Poster/Presentation
Number 8-016

Objective This study investigates four pathological evaluations of stiff person syndrome spectrum disorder (SPSD) and GAD65-associated epilepsy. While serostatus varied, all patients exhibited similar excitatory clinical phenotypes and histological evidence of disrupted inhibitory neuron function, suggesting a shared pathogenic mechanism beyond antibody status.

Background GAD65 is a key enzyme that converts glutamate to GABA, crucial for inhibitory signaling in the brain. GABAergic neurons, constituting 20% of cortical neurons, inhibit excitatory pathways and are classified into subtypes with varying GAD65 expression. In the motor cortex, parvalbumin (PV) and somatostatin (SST) inhibitory neurons predominate. The proposed underlying pathophysiology of SPSD relates to disruptions in these GABAergic pathways.

Design/Methods Consent for autopsy was obtained through the Rocky Mountain MS Center Tissue Bank, including two control patients and four study patients. Histopathologic controls included patients with low-positive serum GAD65 titers who did not meet clinical criteria for SPSD. Brain tissues were stained for inflammatory markers, GAD65/67, Glycine receptor (GlyR)-alpha-3 subunit, and parvalbumin, and analyzed by a board-certified neuropathologist. All antibody testing premortem was completed at Mayo Clinic Laboratories.

Results Four patients were included in the analysis: one GAD65-positive SPSD case (50.7 nmol/L serum, 6.76 nmol/L CSF), two progressive encephalomyelitis with rigidity and myoclonus (PERM) cases (one seronegative, one GlyR CSF positive), and one GAD65-associated epilepsy case (237 nmol/L serum, 23 nmol/L CSF). Despite serologic variations, all four exhibited excitatory clinical phenotypes and histopathologic evidence of disrupted inhibitory neuron function, particularly in layers 4 and 5 of the motor cortex.

Conclusions

Anti-GAD65 and anti-GlyR neurologic autoimmunity share a common excitatory pathophysiology in an initial review of neuropathological specimens. The observed disrupted inhibitory neuron networks in the motor cortex may provide a novel histological fingerprint for SPSD. Evaluating interneuron classes on histological and molecular levels will aid in developing biomarkers and therapeutic targets.

Authors/Disclosures
Samuel Aragon, BS (University of Colorado Anschutz Medical Campus) PRESENTER	Mr. Aragon has nothing to disclose.
Mary N. Gallanis, MD	Dr. Gallanis has nothing to disclose.
Samuel Guzman	Samuel Guzman has nothing to disclose.
Aaron M. Carlson, MD (University of Colorado, School of Medicine, Department of Neurology)	Dr. Carlson has received research support from Horizon Therapeutics (Amgen).
Candace Bretsch	Mrs. Bretsch has nothing to disclose.
Jeremiah Phares, BS	Mr. Phares has nothing to disclose.
Campbell A. Pontin	Miss Pontin has nothing to disclose.
Ann-Charlotte E. Granholm-Bentley, PhD	The institution of Dr. Granholm-Bentley has received research support from NIH. Dr. Granholm-Bentley has a non-compensated relationship as a Board member Colorado Chapter with Alzheimer Association that is relevant to AAN interests or activities.
Angus Toland, MD	Dr. Toland has received intellectual property interests from a discovery or technology relating to health care.
Ken Jones, PhD	Dr. Jones has stock in Bioinformatic Solutions, LLC. An immediate family member of Dr. Jones has stock in Bioinformatic Solutions. The institution of Dr. Jones has received research support from NIH.
Amanda L. Piquet, MD, FAAN (University of Colorado)	The institution of Dr. Piquet has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genentech/Roche. The institution of Dr. Piquet has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion. The institution of Dr. Piquet has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Kyverna . The institution of Dr. Piquet has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech/Roche. The institution of Dr. Piquet has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Kyverna. The institution of Dr. Piquet has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Piquet has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Sands Anderson PC. Dr. Piquet has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Joe Jones Law Firm. Dr. Piquet has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Cortez & Associates. Dr. Piquet has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Falk Waas. The institution of Dr. Piquet has received research support from Rocky Mountain MS Center. The institution of Dr. Piquet has received research support from Roche/Genentech. The institution of Dr. Piquet has received research support from NYU. The institution of Dr. Piquet has received research support from Anokion. The institution of Dr. Piquet has received research support from UCB . The institution of Dr. Piquet has received research support from Foundation for Sarcoidosis. The institution of Dr. Piquet has received research support from Kyverna . Dr. Piquet has received publishing royalties from a publication relating to health care. Dr. Piquet has received publishing royalties from a publication relating to health care. Dr. Piquet has received personal compensation in the range of $10,000-$49,999 for serving as a Litigative Consultant with US-Dept HHS/DICP. Dr. Piquet has a non-compensated relationship as a Medical Advisory Board Member with Autoimmune Encephalitis Alliance (AEA) that is relevant to AAN interests or activities. Dr. Piquet has a non-compensated relationship as a Medical Advisory Board Member with Stiff Person Syndrome Research Foundation (SPSRF) that is relevant to AAN interests or activities.

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