Prion disease is a rare, invariably fatal neurodegenerative disease characterized by rapid neuronal degeneration; Mutations to PRNP gene cause genetic prion disease (GPD). In animal models, microglial activation, astrocytosis, and release of neurofilament precede the onset of frank symptoms (Sorce & Nuvolone 2020, Minikel 2020). In humans at risk for GPD, prodromal pathology appears to occur in only a brief window prior to symptom onset (Vallabh et al. 2020, Thompson et al. 2021), but some data suggest that known PRNP mutation carriers may exhibit cognitive abnormalities prior to meeting clinical diagnostic criteria (Mole et al., 2021). We aim to examine pre-symptomatic differences in cognitive processing speed (CPS) and executive function (EF) in PRNP mutation carriers and controls.

Our sample includes two groups from an ongoing observational study on GPD (Vallabh et al., 2020): known PRNP mutation carriers (N = 32, Age M = 45.77, SD = 14.75) and control group of non-carriers with a family history of GPD and healthy controls with no known history (N = 11, Age M = 42.01, SD = 12.43). All participants completed a full cognitive battery at baseline and on an annual basis. We compared first visit cognitive testing measuring CPS and EF using: National Institute of Health (NIH) Toolbox [Pattern Comparison (NIH-PC), Flanker, Dimensional Card Sorting Task (NIH-DCCS)], Trail Making Test (TMT) A and B, and Delis-Kaplan Executive Function System (D-KEFS) Color-Word Interference Test (CWIT).

Independent t-tests and Mann-Whitney U tests compared cognitive test performance between groups. Across all cognitive test measures assessed, none exhibited significant differences between groups after Bonferroni correction for N=10 tests (corrected P > 0.05). Mean scores for mutation carriers were non-significantly lower than controls on TMT-B (Z-score Mdn = .29, SD = 1.33 vs. Z-score Mdn = .96, SD = .97), NIH-PC (Age-corrected Standard Score [ACSS] M = 100.13, SD = 20.76 vs. ACSS score M = 114.82, SD = 14.61) and NIH-Flanker (ACSS score M = 83.58, SD = 9.72 vs. ACSS score M = 90.64, SD = 10.94), and NIH-DCCS (ACSS M = 101.29, SD = 16.37 vs. ACSS score M = 112.00, SD = 16.28) but not for TMT-A or all four conditions of CWIT.

We did not detect any significant cognitive deficits in known PRNP mutation carriers. This is consistent with the lack of prodromal pathological biomarker changes or cognitive changes as reported in Vallabh et al 2020, and with the finding of Mole et al. 2021 that most tests reveal impairment only at a stage where carriers report subjective symptoms. Our results suggest an opportunity for primary prevention to preserve full cognitive health in at-risk individuals. However, small sample size and limited test sensitivity may leave us underpowered to detect subtle deficits. Future research is warranted to further investigate the neuropsychological profile of pre-symptomatic GPD.