Conceptual framework for the definition of preclinical and prodromal frontotemporal dementia

Abstract

The presymptomatic stages of frontotemporal dementia (FTD) are still poorly defined and encompass a long accrual of progressive biological (preclinical) and then clinical (prodromal) changes, antedating the onset of dementia. The heterogeneity of clinical presentations and the different neuropathological phenotypes have prevented a prior clear description of either preclinical or prodromal FTD. Recent advances in This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

How can we define the presymptomatic C9orf72 disease in 2022? An overview on the current definitions of preclinical and prodromal phases

“…Overall, research results coming from the abovementioned initiatives contributed to generate a conceptual framework useful to define and further classify the presymptomatic phases of FTD and ALS, which could be thus employed in the context of C9orf72 expansions, responsible of both these diseases. Key recommendations have been recently defined in the works by Benussi et al (2021) [38] and Benatar et al (2021) [39], and are summarized below (Figure 1).…”

“…However, the limited information obtainable from pathological biomarkers in vivo does not allow to determine how early these degenerative changes occur. Therefore, it is currently unclear whether a "no disease" stage, characterized by the absence of any pathological lesions exists, and the boundary between this latter and the subsequent preclinical phase is particularly hard to identify [38]. During the preclinical stage, clinical symptoms are completely absent, and no ongoing denervation changes should be found on EMG [39].…”

“…The prodromal disease stage is defined by the appearance the first subtle cognitive, behavioral and motor signs, and lasts up to the onset of full-blown disease. Prodromal FTD is characterized by gradual changes affecting social cognition, executive functions or language, as well as recent behavioral modifications including reduced initiative, diminished empathy, change in dietary habits, repetitive or ritualized actions or behaviors [38]. These changes from the individual's baseline status should be of such intensity as to preserve independence in daily living, albeit a mild impact on close relationships or highly demanding professional tasks cannot be excluded [38].…”

Stratifying the Presymptomatic Phase of Genetic Frontotemporal Dementia by SerumNfLandpNfH: A Longitudinal Multicentre Study

“…9,10 However, these presymptomatic stageswhich encompass the accumulation of progressive molecular and cellular changes in the nervous system before the onset of dementiaremain poorly defined. 11 To pave the way for future interventional trials, stratification of the presymptomatic stages based on objective and easily accessible biomarkers is hence urgently needed. This applies particularly to the conversion stage, which immediately precedes the onset of clinically manifest disease and is the likely most treatment-relevant stage in the presymptomatic period.…”

Common Fatal Neurodegenerative Diseases Revisited: Beyond Age, Comorbidities, and Devastating Terminal Neuropathology There Is Hope With Prevention

“…We definitely have current biomarkers limitations in the diagnosis of AD and other major neurodegenerative diseases ( 50 , 51 ) and their overlap cannot be ignored because the prevalence of AD with α-synuclein and TDP-43 will most certainly complicate efforts to identify therapies to treat lethal diseases as clearly stated by Karanth et al ( 28 ).…”