Cognitive impairment, medial temporal lobe changes, and fluid biomarkers of Alzheimer’s disease and neurodegeneration following herpes simplex virus type 1 encephalitis

Abstract Background Herpesvirus encephalitis is a severe brain infection, in adults most often caused by herpes simplex virus type 1 (HSV-1). It predominantly affects the medial temporal lobes (MTL), which are critical for memory functions. Links have been discussed between herpes virus infections and Alzheimer’s disease (AD). We therefore investigated cognitive function, structural brain changes, and fluid biomarkers related to AD and other neurodegenerative processes in individuals with previous herpes simplex virus type 1 encephalitis (HSE). Methods Eleven patients with prior HSE were retrospectively identified using a clinical CSF laboratory database. Control groups included 44 cognitively unimpaired (CU) individuals, 44 mild cognitive impairment (MCI), and 22 AD dementia patients from the Swedish BioFINDER-2 study. Groups were stratified by amyloid-β (Aβ) status using CSF Aβ42/Aβ40. All participants underwent neuropsychological testing. Structural brain changes were assessed using 7T or 3T MRI including visual evaluation of lesions and automated segmentation of MTL subregions. Plasma biomarkers (tau phosphorylated at position 217 (p-tau217), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL)) were measured using immunoassays. Results The mean follow-up time since infection was 6.5 years. The encephalitis group (mean age 49 years, 55% females) was age-matched to the CU Aβ- group but younger than other groups. MRI findings in the encephalitis group ranged from marked unilateral MTL atrophy to no visible changes. Compared with CU individuals, encephalitis patients showed significantly impaired episodic memory (delayed recall) and lower global cognition, comparable to MCI but less severe than AD dementia. Within the encephalitis group, episodic memory impairment was associated with visually assessed MTL atrophy ( p = 0.0185). In hemispheres without gross atrophy, MTL subregional volumes resembled CU and MCI but were larger than in AD dementia. Plasma p-tau217 and GFAP levels were elevated in the full HSE-group compared with Aβ-negative CU and MCI, but lower than in AD dementia. P-tau181 and NfL levels were similar to CU. P-tau217 was not significantly different between Aβ-negative HSE and Aβ-negative CU. Associations between GFAP and cognitive performance were no longer significant after exclusion of the two patients with Fazekas grade 3 white matter lesions. Conclusions Previous HSE was associated with substantial heterogeneity in long-term cognitive performance, with poorer delayed recall associated with longer time since infection. Cognitive findings were also related to focal MTL atrophy, supporting a contribution of structural injury to long-term cognitive outcomes. Only a minority of the patients had signs of AD pathology by CSF biomarkers. Larger longitudinal studies are needed to determine the trajectories and mechanisms of cognitive change following HSE.