Frontal Release Signs and Future Decline in Research Participants With Intact Cognition

Frontal release signs (FRS) are primitive reflexes that regress with brain maturation and reappear in the setting of brain injury or neurodegeneration. Despite their association with dementia, the prognostic utility of this finding in the setting of early cognitive decline and preclinical disease is poorly understood.

To evaluate the association of FRS with future cognitive decline in research participants.

This cohort study examined the presence of FRS (from 2005-2024) among research cohort participants with intact cognition or mild impairment at study baseline. The study used single-center data collection of longitudinal research cohort data through the Uniform Data Set at the University of Kentucky Alzheimer Disease Research Center (UK ADRC). Participants aged 70 years or older at first assessment were identified at baseline enrollment as having intact cognition or mild impairment based on consensus report and had at least 2 total annual assessments that included standard protocols involving assessment of FRS on neurological exam from the UK ADRC.

Participants were noted to be FRS positive or FRS negative.

The main outcome of interest was incident dementia based on annual consensus diagnosis. Cause-specific hazard models were used to estimate the risk of transition to dementia when at least 2 FRS were present (FRS positive) at baseline vs when 0 or 1 FRS were present (FRS negative), and linear mixed models were used to investigate the association of baseline FRS positivity with cognitive performance over time.

A total of 873 participants (mean [SD] age, 76.9 [5.6] years; 527 female [60.4%]) were included, with a mean (SD) of 16.1 (2.8) years of education. The prevalence of FRS positivity at baseline was 59 of 672 participants (8.8%) with intact cognition and 48 of 201 participants (23.9%) with mild impairment. FRS positivity was associated with an increased risk of dementia for participants who were cognitively intact; in this group, 15 of 59 participants who were FRS positive (25.4%) progressed to dementia compared with 89 of 613 participants (14.5%) who were FRS negative (hazard ratio, 1.78; 95% CI, 1.02-3.09).

This study's findings suggest that FRS may be a quick, noninvasive, and low-cost adjunct to neurological examination with prognostic utility in the earliest stages of cognitive decline.