Longitudinal changes in qualitative aspects of semantic fluency in presymptomatic and prodromal genetic frontotemporal dementia

BackgroundThe semantic fluency test is one of the most widely used neuropsychological tests in dementia diagnosis. Research utilizing the qualitative, psycholinguistic information embedded in its output is currently underexplored in presymptomatic and prodromal genetic FTD.MethodsPresymptomatic MAPT (n = 20) and GRN (n = 43) mutation carriers, and controls (n = 55) underwent up to 6 years of neuropsychological assessment, including the semantic fluency test. Ten mutation carriers became symptomatic (phenoconverters). Total score and five qualitative fluency measures (lexical frequency, age of acquisition, number of clusters, cluster size, number of switches) were calculated. We used multilevel linear regression modeling to investigate longitudinal decline. We assessed the co-correlation of the qualitative measures at each time point with principal component analysis. We explored associations with cognitive decline and grey matter atrophy using partial correlations, and investigated classification abilities using binary logistic regression.ResultsThe interrater reliability of the qualitative measures was good (ICC = 0.75-0.90). There was strong co-correlation between lexical frequency and age of acquisition, and between clustering and switching. At least 4 years pre-phenoconversion, GRN phenoconverters had fewer but larger clusters (p < 0.001), and fewer switches (p = 0.004), correlating with lower executive function (r = 0.87-0.98). Fewer switches was predictive of phenoconversion, correctly classifying 90.3%. Starting at least 4 years pre-phenoconversion, MAPT phenoconverters demonstrated an increase in lexical frequency (p = 0.009) and a decline in age of acquisition (p = 0.034), correlating with lower semantic processing (r = 0.90). Smaller cluster size was predictive of phenoconversion, correctly classifying 89.3%. Increase in lexical frequency and decline in age of acquisition were associated with grey matter volume loss of predominantly temporal areas, while decline in the number of clusters, cluster size, and switches correlated with grey matter volume loss of predominantly frontal areas.ConclusionsQualitative aspects of semantic fluency could give insight into the underlying mechanisms as to why the traditional total score declines in the different FTD mutations. However, the qualitative measures currently demonstrate more fluctuation than the total score, the measure that seems to most reliably deteriorate with time. Replication in a larger sample of FTD phenoconverters is warranted to identify if qualitative measures could be sensitive cognitive biomarkers to identify and track mutation carriers converting to the symptomatic stage of FTD.

Automated summary

Research suggests that qualitative measures of semantic fluency can provide valuable insights into the progression of different genetic mutations associated with Frontotemporal Dementia (FTD). Specifically, GRN mutation carriers show a decrease in clustering and an increase in cluster size, which is associated with decline in executive function. On the other hand, MAPT mutation carriers display an increase in lexical frequency and a decline in age of acquisition, which is associated with decline in semantic processing. These qualitative measures have the potential to serve as sensitive cognitive biomarkers for the diagnosis and monitoring of FTD.