Clinicopathological Correlations in Anti-GAD65 and Anti-Glycine Neurologic Autoimmunity: Linking Excitatory Phenotypes to Inhibitory Neuron Dysfunction
Mary Benson1, Samuel Guzman2, Aaron Carlson4, Samuel Aragon5, Candace Bretsch3, Jeremiah Phares3, Campbell Pontin3, Ann-Charlotte Granholm-Bentley3, Angus Tolan6, Ken Jones3, Amanda Piquet1
1Neurology, 2Pathology, University of Colorado, 3University of Colorado, 4University of Colorado, School of Medicine, Department of Neurology, 5University of Colorado Anschutz Medical Campus, 6Children's Hospital Colorado
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.
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