Prodromal frontotemporal dementia: clinical features and predictors of progression

Abstract

Background: The prodromal phase of frontotemporal dementia (FTD) is still not well characterized, and conversion rates to dementia and predictors of progression at 1-year follow-up are currently unknown.

Methods: In this retrospective study, disease severity was assessed using the global CDR plus NACC FTLD. Prodromal FTD was defined to reflect mild cognitive or behavioural impairment with relatively preserved functional independence (global CDR plus NACC = 0.5) as well as mild, moderate and severe dementia (classified as global CDR plus NACC = 1, 2, 3, respectively). Disease progression at 1-year follow-up and serum NfL measurements were acquired in a subgroup of patients.

Results: Of 563 participants, 138 were classified as prodromal FTD, 130 as mild, 175 as moderate and 120 as severe FTD. In the prodromal and mild phases, we observed an early increase in serum NfL levels followed by behavioural disturbances and deficits in executive functions. Negative symptoms, such as apathy, inflexibility and loss of insight, predominated in the prodromal phase. Serum NfL levels were significantly increased in the prodromal phase compared with healthy controls (average difference 14.5, 95% CI 2.9 to 26.1 pg/mL), but lower than in patients with mild FTD (average difference -15.5, 95% CI -28.4 to -2.7 pg/mL). At 1-year follow-up, 51.2% of patients in the prodromal phase had converted to dementia. Serum NfL measurements at baseline were the strongest predictors of disease progression at 1-year follow-up (OR 1.07, 95% CI 1.03 to 1.11, p < 0.001).

Conclusions: Prodromal FTD is a mutable stage with high rate of progression to fully symptomatic disease at 1-year follow-up. High serum NfL levels may support prodromal FTD diagnosis and represent a helpful marker to assess disease progression.

Keywords: Conversion; Frontotemporal dementia; Mild; Prodromal; Progression; Serum neurofilament light.

Fig. 1

Evolution of severity scores according to the global CDR plus NACC FTLD. Symptom severity in FTLD patients grouped according to the global CDR plus NACC FTLD. NfL = neurofilament light chain; CDR plus NACC FTLD = clinical dementia rating plus National Alzheimer’s Coordinating Center behaviour and language domains FTLD; MMSE = mini mental state examination; FBI = frontal behavioural inventory; BADL = basic activities of daily living; IADL = instrumental activities of daily living; TMT-B = trial making test part B

Fig. 2

Radar plot of FBI subscores according to the global CDR plus NACC FTLD. Positive symptoms (FBI part A) are reported on the right (light yellow), negative symptoms (FBI part B) are reported on the left (light green). CDR plus NACC FTLD = clinical dementia rating plus National Alzheimer’s Coordinating Center behaviour and language domains; FBI = frontal behavioural inventory

Fig. 3

Serum NfL levels according to the global CDR plus NACC FTLD. Serum NfL levels (pg/mL) according to A global CDR plus NACC FTLD and B global CDR plus NACC FTLD divided in progressors and non-progressors. CDR plus NACC FTLD = clinical dementia rating plus National Alzheimer’s Coordinating Center behaviour and language domains; NfL = neurofilament light; HC = healthy controls. Box plots represent median and interquartile range, while whiskers represent 5–95% percentiles. *Significant difference between groups (for panel A, only differences with CDR plus NACC FTLD = 0.5 are shown) after Bonferroni-corrected post hoc tests

Fig. 4

Sankey diagram showing the evolution of patients according to the global CDR plus NACC FTLD. The changes of patients over time at different time points are represented in different global CDR plus NACC FTLD groups. The height of the boxes and the thickness of the stripes are proportional to the number of patients belonging to each group and moving from each group, respectively