EEG-motor correlation as early Alzheimer’s disease index in herpes simplex virus-1-infected mice

Abstract Alzheimer's disease is a neurodegenerative disorder characterized by cognitive decline and memory impairment. Early treatment requires reliable tests to identify the initial manifestations for developing treatments that modify disease progression. Neuroinflammation has been implicated as a key driver of the onset and progression of Alzheimer's disease. Herpes simplex virus type-1 (HSV-1), a neurotropic virus that establishes latency within the central nervous system, has been associated with increased proinflammatory cytokines, cognitive impairment and Alzheimer's disease-like pathology in human and rodent brains. This study employed a murine model showing an Alzheimer's disease-related phenotype, induced by HSV-1 infection and recurrent reactivation through thermal stress, to investigate previously unexplored motor function impairments and their correlation with EEG changes predictive of Alzheimer's disease-like pathology. Mice were subjected to two (2×TS) or seven thermal stress (7×TS) HSV-1 reactivations to reproduce mild and severe cognitive impairments, respectively, and were tested for recognition memory using Novel Object Recognition test and for spatial memory using the Y-maze test. Motor performance was assessed using grip strength and grid walking tests. Local field potential recordings, immunohistochemical, morphological and molecular analyses were performed to characterize the effects of HSV-1 on neural circuits. 2×TS HSV-1 mice showed a reduced preference index in Novel Object Recognition compared to mice receiving mock infection (i.e., vehicle inoculum), whereas 7×TS HSV-1 mice displayed severe cognitive decline across the different memory domains. Motor function was preserved after the 2nd thermal stress but was impaired after the 7th thermal stress, with reduced forelimb force and increased foot faults starting from the 4th reactivation. Following the 7th reactivation, HSV-1 mice showed astrogliosis and phosphorylated Tau accumulation. In vivo, electrophysiological recordings revealed increased functional connectivity across frequency bands in 2×TS HSV-1 mice compared to controls, with negative correlations between total coherence and grip strength. Increased spine density in the frontal cortex of 2×TS HSV-1 mice supports early neuronal network alterations. From a translational perspective, we preliminarily evaluated comparable motor indices in healthy human participants, in patients with mild cognitive impairment, and in patients with Alzheimer's disease. As expected, both grip strength and dynamic balance were lower in patients with Alzheimer's disease compared to healthy and mild cognitive impairment subjects. Notably, grip strength was significantly reduced in mild cognitive impairment subjects, who displayed early motor impairment. Our findings highlight the potential of EEG-based biomarkers for early Alzheimer's disease detection and suggest motor indices as novel prognostic markers.