Preliminary Evidence that Memantine Enhances Prepulse Effects on Startle Magnitude and Latency in Patients with Alzheimer’s Disease

Article type: Research Article

Authors: Swerdlow, Neal R.^{a; b} | Joshi, Yash B.^{a; b} | Sprock, Joyce^{a; b} | Talledo, Jo^a | Molina, Juan L.^{a; b} | Delano-Wood, Lisa^a | Iwanaga, Dylan^a | Kotz, Juliana E.^c | Huege, Steven^a | Léger, Gabriel C.^d | Light, Gregory A.^{a; b}

Affiliations: [a] Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, CA, USA | [b] VISN-22 Mental Illness, Research, Education and Clinical Center (MIRECC), VA San Diego Healthcare System, San Diego, CA, USA | [c] Department of Health Policy and Management, Fielding School of Public Health, University of California, Los Angeles, CA, USA | [d] Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, USA

Correspondence: [*] Correspondence to: Neal R. Swerdlow, MD, PhD, Distinguished Professor, Department of Psychiatry 0804, UCSD School of Medicine, 9500 Gilman Dr., La Jolla, CA 92093-0804, USA. E-mail: nswerdlow@ucsd.edu.

Abstract: Background:The uncompetitive NMDA antagonist, memantine (MEM), enhances prepulse inhibition of startle (PPI) across species. MEM is used to treat Alzheimer’s disease (AD); conceivably, its acute impact on PPI might be used to predict a patient’s sensitivity to MEM’s therapeutic effects. Objective:To begin to test this possibility, we studied MEM effects on PPI and related measures in AD patients. Methods:18 carefully screened individuals with AD (mean age = 72.8 y; M:F=9 : 9) completed double-blind order-balanced testing with MEM (placebo versus 20 mg), assessing acoustic startle magnitude, habituation, PPI, and latency. Results:Fifteen out of 18 participants exhibited reliable startle responses. MEM did not significantly impact startle magnitude or habituation. Compared to placebo responses, PPI was significantly increased after MEM (p < 0.04; d = 0.40); this comparison reached a large effect size for the 60 ms interval (d = 0.62), where maximal MEM effects on PPI were previously detected. Prepulses reduced peak startle latency (“latency facilitation”) and this effect was amplified after MEM (p = 0.03; d = 0.41; for 60 ms intervals, d = 0.69). No effects of MEM were detected on cognition, nor were MEM effects on startle associated with cognitive or clinical measures. Conclusion:MEM enhances prepulse effects on startle magnitude and latency in AD; these changes in PPI and latency facilitation with MEM suggest that these measures can be used to detect an AD patient’s neural sensitivity to acute MEM challenge. Studies in progress will determine whether such a “biomarker” measured at the outset on treatment can predict sensitivity to MEM’s therapeutic effects.

Keywords: Alzheimer’s disease, memantine, neurocognition, prepulse inhibition

DOI: 10.3233/JAD-220769

Journal: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 355-362, 2023