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Staffaroni AM, Quintana M, Wendelberger B, Heuer HW, Russell LL, Cobigo Y, Wolf A, Goh SM, Petrucelli L, Gendron TF, Heller C, Clark AL, Taylor JC, Wise A, Ong E, Forsberg L, Brushaber D, Rojas JC, VandeVrede L, Ljubenkov P, Kramer J, Casaletto KB, Appleby B, Bordelon Y, Botha H, Dickerson BC, Domoto-Reilly K, Fields JA, Foroud T, Gavrilova R, Geschwind D, Ghoshal N, Goldman J, Graff-Radford J, Graff-Radford N, Grossman M, Hall MG, Hsiung GY, Huey ED, Irwin D, Jones DT, Kantarci K, Kaufer D, Knopman D, Kremers W, Lago AL, Lapid MI, Litvan I, Lucente D, Mackenzie IR, Mendez MF, Mester C, Miller BL, Onyike CU, Rademakers R, Ramanan VK, Ramos EM, Rao M, Rascovsky K, Rankin KP, Roberson ED, Savica R, Tartaglia MC, Weintraub S, Wong B, Cash DM, Bouzigues A, Swift IJ, Peakman G, Bocchetta M, Todd EG, Convery RS, Rowe JB, Borroni B, Galimberti D, Tiraboschi P, Masellis M, Finger E, van Swieten JC, Seelaar H, Jiskoot LC, Sorbi S, Butler CR, Graff C, Gerhard A, Langheinrich T, Laforce R, Sanchez-Valle R, de Mendonça A, Moreno F, Synofzik M, Vandenberghe R, Ducharme S, Le Ber I, Levin J, Danek A, Otto M, Pasquier F, Santana I, Kornak J, Boeve BF, Rosen HJ, Rohrer JD, Boxer AL, Frontotemporal Dementia Prevention Initiative (FPI) Investigators. Temporal order of clinical and biomarker changes in familial frontotemporal dementia. Nat Med. 2022 Oct;28(10):2194-2206. Epub 2022 Sep 22 PubMed.
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AbbVie
This is a fantastic study in the sense that for the first time we now have data on reasonably large groups of patients with genetically defined forms of FTD and we can directly track changes on biomarkers and clinical end points over time. Long overdue!
The data suggest that GRN carriers have a more aggressive course, followed by MAPT and then C9ORF carriers in both clinical and biomarker readouts. While the differences seem to be lost when looking at a global measure (CDR+NACC), the differential rates of progression for more sensitive items could easily enable more adaptive designs.
Assuming that one runs a trial in which all three forms of FTD are enrolled, then knowing about these differential rates would enable more efficient interim analyses and more efficient utilization of subjects with very rare disorders, e.g., tailoring the numbers of subjects to enroll and their duration of treatment, etc.
View all comments by Michael GoldI think this is a beautiful example of how coordinated, highly collaborative research efforts are necessary to move the needle. The tempo and type of biomarker change varies by actual etiology—e.g., distinct genetic forms have distinct early presentations and trajectories in terms of biomarkers. This fits with the framing of neurodegenerative disorders, such as AD, FTD, PD, etc., more generally as syndromes, rather than discrete diseases. This is similar to cancer, where the underlying biological drivers, such as specific mutations, manifest distinct clinical challenges and treatments.
View all comments by Daniel GeschwindVU University Medical Center
This study provides relevant and reliable information about the trajectory of changes of known biomarkers for familial FTD, namely atrophy and NfL levels, before and after latent disease age. It informs trial design in terms of numbers to include per FTD mutations in C9ORF72, GRN, and MAPT. Compared to GRN and MAPT mutation carriers, about twice as many C9ORF72 and MAPT mutation carriers would have to be included in two-year trials if the endpoint is a clinical one, namely CDR+ NACC-FTD-SB. The numbers are even more divergent if MRI would be chosen as primary endpoint.
Other outcomes are remarkable: the consistency of the results between the centers, located in North America and Europe; the heterogeneity in results and the consequent lack of thresholds for inclusion, which show that it is hard to use MRI and NfL for inclusion at the individual levels. That the NfL increases largely coincided with the earliest clinic symptoms, and often in parallel with increases in atrophy in medial, temporal, or frontal lobes, corroborates the order of changes in, for example, AD, and is a consequence of NfL being an axonal damage marker, lying downstream of specific neuronal disruptions. The thalamic atrophy observed in a very early stage in C9ORF72 mutation carriers implies that the earliest biological alterations can be measured quite well. It is useful for trial design to understand the prognostic value of these regional atrophy changes.
Large, multicenter collaborations, similar to this one by Stafforoni et al., are needed, and they will enable the precise mapping of f-FTD mutation-specific changes. Our efforts should be directed toward the identification of low-invasive biomarkers for the earliest changes, and toward inclusion thresholds to further support trial inclusion.
View all comments by Charlotte TeunissenMake a Comment
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