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

Abstract

Introduction: It 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.

Methods: The 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.

Results: We 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.

Discussion: These data and samples, which are available to interested investigators worldwide, will facilitate planning for upcoming disease-modifying therapeutic trials in f-FTLD.

Keywords: C9orf72; Frontotemporal dementia; GRN; Genetics; MAPT; TDP-43; Tau.

Figure 1.. Schema and research approach of familial FTLD.

The alterations in the molecular biology (red curve) of tau, progranulin and the granulins, C9RAN proteins, etc., undoubtedly occur early in life during the presymptomatic phase. As neuronal and/or glial dysfunction evolves, changes in neuronal networks occur which can be demonstrated on neuroimaging measures (orange curve), with functional MR changes likely preceding structural MR changes. Other measures including neuropsychological measures (light blue curve) and clinical (including behavioral and motor measures, as shown in the dark blue curve) likely show the evolution of clinically silent (represented by an FTLD-CDR rating of 0) to very minimally evident cognitive, behavioral or motor changes over the several year transitional period from presymptomatic to prodromal to minimally symptomatic phases of f-FTLD (represented by an FTLD-CDR rating of 0.5). MR-based and other imaging measures likely change over this transitional period also. Additional changes occur with the onset of overt features (represented by an FTLD-CDR rating ≥1) and continue onward through the mild, moderate, severe and terminal phases of the symptomatic period. For each set of measures, there is likely a slow change phase, followed by an acceleration phase, then a deceleration phase, and then a terminal slow change phase. Those individuals who do not carry a mutation (shown as the green line) are expected to show no consistent change across these measures. This hypothesized cascade of dynamic changes is analogous to what has been proposed in the evolution of Alzheimer’s disease. See text for abbreviations.

Figure 2.. Protocol Schema.

Three hundred subjects (100 among kindreds with a mutation in MAPT, 100 among kindreds with a mutation in PGRN, and 100 among kindreds with the C9orf72 mutation) are enrolled and followed at one of the eight sites. Within each gene, approximately 1/3 are symptomatic (reflected by darker shades of orange, yellow or green) whereas 2/3 are asymptomatic (reflected by lighter shades of the colors). The lighter shade areas are divided by a dashed line, which reflects one half of the asymptomatic are non-mutation carrier/family controls while the other half are mutation carriers. Each subject can participate in four research arms – clinical, biofluid-blood, biofluid-CSF and MRI; the CSF arm is optional. Each subject can also participate in a 5^th arm (not shown) in which clinical genetic counseling and testing can be performed. The clinical data is entered into an electronic data capture system (RAVE), and the majority of this data is uploaded to the NACC. Biofluid samples are submitted to NCRAD for processing and storage. See text for abbreviations.

Figure 3.. Study Procedures and Timeline.

See text in Section 4 for details and abbreviations.

Figure 4.. Diagnostic Assessment Scheme.

*measures from the NACC UDS version 3 and FTLD Module; additional references: [, –63]. See text in Section 4.4 for details and abbreviations.