The longitudinal evaluation of familial frontotemporal dementia subjects protocol: Framework and methodology

Abstract

IntroductionIt is important to establish the natural history of familial frontotemporal lobar degeneration (f‐FTLD) and provide clinical and biomarker data for planning these studies, particularly in the asymptomatic phase.MethodsThe Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects protocol was designed to enroll and follow at least 300 subjects for more than at least three annual visits who are members of kindreds with a mutation in one of the three most common f‐FTLD genes—microtubule‐associated protein tau, progranulin, or chromosome 9 open reading frame 72.ResultsWe present the theoretical considerations of f‐FTLD and the aims/objectives of this protocol. We also describe the design and methodology for evaluating and rating subjects, in which detailed clinical and neuropsychological assessments are performed, biofluid samples are collected, and magnetic resonance imaging scans are performed using a standard protocol.DiscussionThese data and samples, which are available to interested investigators worldwide, will facilitate planning for upcoming disease‐modifying therapeutic trials in f‐FTLD.

Rates of Brain Atrophy Across Disease Stages in Familial Frontotemporal Dementia Associated With MAPT, GRN, and C9orf72 Pathogenic Variants

“…In this longitudinal case-control study, we included 160 members of families affected by f-FTLD, most of whom were enrolled in the Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) or Longitudinal Evaluation of Familial Frontotemporal Dementia (LEFFTDS) studies, which were conducted through a consortium of 18 academic medical centers across the United States and Canada between May 2015 and September 2018. For LEFFTDS, 19 at least 1 family member must have a pathogenic variant in the MAPT , GRN , or C9orf72 genes. For ARTFL, 21 families with any f-FTLD pathogenic variant or without a known pathogenic variant can enroll, but only carriers of MAPT , GRN , or C9orf72 pathogenic variants were included in this analysis.…”

“…The emergence of large, comprehensive studies 3 , 19 , 20 of f-FTLD that include presymptomatic and symptomatic pathogenic variant carriers allows direct study of the natural history of disease using longitudinal observations. The present analysis, based on data from 2 of these large natural history studies, 19 , 21 addresses limitations in previous work by incorporating longitudinal data across the disease course in participants carrying the 3 most common f-FTLD–associated pathogenic variants.…”

“…The emergence of large, comprehensive studies 3 , 19 , 20 of f-FTLD that include presymptomatic and symptomatic pathogenic variant carriers allows direct study of the natural history of disease using longitudinal observations. The present analysis, based on data from 2 of these large natural history studies, 19 , 21 addresses limitations in previous work by incorporating longitudinal data across the disease course in participants carrying the 3 most common f-FTLD–associated pathogenic variants. Based on theoretical models 11 and previous observational studies of Alzheimer disease 22 , 23 and FTLD, 13 , 24 our hypothesis was that pathogenic variants in all 3 genes would produce a nonlinear pattern of neurodegeneration, with acceleration of volume loss as patients develop symptoms.…”

Quality of life and caregiver burden in familial frontotemporal lobar degeneration: Analyses of symptomatic and asymptomatic individuals within the LEFFTDS cohort

“…This study was completed as part of a larger longitudinal study, the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS), which included eight study sites 24 . This study has been approved by the Institutional Review Board of each participating site.…”

“…The detailed protocol, inclusion/exclusion criteria, and methods for recruitment are described elsewhere 24 . Individuals were eligible for inclusion if they were members of families with a known mutation in one of the three major FTLD‐related genes (microtubule associated protein tau [ MAPT ], progranulin [ GRN ], or chromosome 9 open reading frame 72 [C 9orf72 ]), age 18 or older, and willing to participate and complete required visits and testing (magnetic resonance imaging [MRI] and neuropsychological testing).…”