19 Mar 2021

For people with FTD and their caregivers, the disease takes a deep personal toll, straining the social and emotional connections at the core of their relationships. Mirroring the diversity of human personality and behavior, the symptoms of FTD, which is actually a group of syndromes, are remarkably varied, spanning social, emotional, executive, behavioral, language, and even motor dysfunction. How can researchers measure these symptoms objectively, let alone encapsulate them within standardized tests? The challenge is real, but a necessary one to tackle, as the field moves into an era of clinical treatment and even prevention trials. Such measures will need to be sensitive enough to find out whether an investigational drug worked in a clinical trial, yet inclusive enough to encompass FTD’s clinical manifestations.

Because FTD is rare and complicated, large international consortia, particularly Europe’s GENFI and North America’s ALLFTD, have been key to devising and validating such tests (see Part 1 of this series). Composite measures that detect an ever-widening swath of deficits are beginning to be put to use in clinical trials, while new measures of social and emotional cognition—from a “faux pas detector” to eye tracking—are opening windows to specific neuronal circuits that malfunction in the disease (see Part 5 of this series). These clinical tests will be used in conjunction with fluid and imaging biomarkers to track the course of the disease (see Part 2 and Part 3). 

In a flush of recent papers, and at the International Conference for FTD, held virtually March 3–5, researchers described their attempts to wrestle the breadth of FTD symptoms into standardized tests, as well as their explorations of the neurophysiology of those symptoms.

One low-hanging fruit in the search for clinical tests in FTD has been to pick off tools already in place for Alzheimer’s. In that disease, the clinical dementia rating scale sum of boxes (CDR-SB) assesses impairment by tallying deficits in six cognitive and functional domains. To tailor it to FTLD, researchers long ago added two domains for language and behavior (Knopman et al., 2008). The amended version got the pithy name “CDR plus National Alzheimer’s Coordinating Center (NACC) Behavior and Language Domains”, aka CDR plus NACC FTLD. This composite measure weighs all eight domains equally, whereas the memory-centric CDR-SB weighs memory deficits more heavily.

How does the CDR plus NACC FTLD do? Scores tracked reliably with diagnoses among 970 people with sporadic and familial forms of FTD who participated in the ARTFL/ LEFFTDS cohorts, now thankfully renamed ALLFTD (Miyagawa et al., 2020). Compared to the CDR-SB, which did not show deficits among people with mild behavioral or language disturbances, the CDR plus NACC FTLD reliably picked up deficits—i.e., scored above zero— among people who had been separately diagnosed with mild FTD symptoms, such as sluggishness or a slight delay in finding words. The CDR-NACC-FTLD is the primary outcome measure in Alector’s Phase 3 trial of its anti-sortilin antibody AL001. 

Even as this FTLD-ified CDR makes its debut in clinical trials, ALLFTD investigators want more comprehensive, inclusive tests. One candidate is the MIR, or multidomain impairment rating, developed by Bradley Boeve at the Mayo Clinic in Rochester, Minnesota, and ALLFTD colleagues (Dec 2018 conference news). This composite tacks visuospatial, parkinsonian, and motor function domains onto the CDR plus NACC-FTLD. Casting such a wide net offers the best chance to catch and track the range of symptoms afflicting people with FTLD, Howard Rosen of University of California, San Francisco, told Alzforum.

A test like this could be especially useful in “basket trials,” which enroll participants with a common genetic mutation and/or core neuropathology even if they show different symptoms. For example, the MIR could quantify disease progression in a trial with C9ORF72 carriers who have bvFTD, ALS, or a combination of the two syndromes. In a tauopathy trial, the MIR could track symptoms of progressive supranuclear palsy, corticobasal degeneration, as well as bvFTD. Similarly, trials aimed at TDP-43 pathology might include participants with a range of clinical phenotypes that the MIR could chart.

Existing tests of executive dysfunction are also contenders for outcome measures. One, the NIH-EXAMINER, includes measures of working memory, cognitive control, word fluency, and multitasking. UCSF researchers reported that the test picks up deficits among mutation carriers who, according to their score of zero on the CDR plus NACC FTLD, are considered still presymptomatic (Staffaroni et al., 2020). However, researchers estimated that to detect a 40 percent slowing in decline on this composite, a clinical trial would need to enroll more than 2,000 participants per treatment arm. In FTD, that is unrealistic. At ICFTD, Adam Staffaroni called this number “sobering,” but said his study used no biomarkers to pick participants on the verge of symptoms, which would presumably lower the numbers of participants needed to see an effect.

Staffaroni has built a Bayesian disease-progression model with data from ALLFTD and GENFI participants. It estimates an individual’s “disease age” by taking into account his or her plasma NfL, volumetric MRI, neuropsychological measures, and even CDR-NACC-FTLD score. Using such a model could help offer a patient a prognosis, and also help select the right participants for clinical trials, Staffaroni said. He is currently developing an interactive online platform that will aid in trial planning.

To run effective, sufficiently powered trials, the FTD community will need to deploy a combination of outcomes, and pool resources. One model is cooperative studies such as the DIAN-TU platform trial, which tests multiple drugs at once against a shared placebo group (Mar 2021 news). 

Even a decade into GENFI, however, honing clinical outcome measures, particularly for people in the presymptomatic and earliest symptomatic stages of FTD, remains a critical challenge, said its leader, Jonathan Rohrer of University College London. “We’ve learned a lot about how MRI and fluid biomarkers change, but we still don’t have the perfect clinical outcome measure,” he conceded.—Jessica Shugart

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

1. Merged Consortia Forge Path to Trials in Frontotemporal Dementia 13 Mar 2021
2. From Specialized to Standardized: Social-Emotional Tests for FTD 19 Mar 2021
3. FTD Fluid Markers for Degeneration: Check. For Pathology: Not Yet. 16 Mar 2021
4. Imaging Exposes Hugely Heterogeneous Brain Changes Among FTDs 19 Mar 2021
5. Tracking Onset and Progression of Frontotemporal Dementia 5 Dec 2018
6. Aiming at the Tangle’s Heart? DIAN-TU Trial to Torpedo Tau’s Core 18 Mar 2021

Therapeutics Citations

1. Latozinemab

Paper Citations

1. Knopman DS, Kramer JH, Boeve BF, Caselli RJ, Graff-Radford NR, Mendez MF, Miller BL, Mercaldo N. Development of methodology for conducting clinical trials in frontotemporal lobar degeneration. Brain. 2008 Nov;131(Pt 11):2957-68. PubMed.
2. Miyagawa T, Brushaber D, Syrjanen J, Kremers W, Fields J, Forsberg LK, Heuer HW, Knopman D, Kornak J, Boxer A, Rosen HJ, Boeve BF, Appleby B, Bordelon Y, Bove J, Brannelly P, Caso C, Coppola G, Dever R, Dheel C, Dickerson B, Dickinson S, Dominguez S, Domoto-Reilly K, Faber K, Ferrell J, Fishman A, Fong J, Foroud T, Gavrilova R, Gearhart D, Ghazanfari B, Ghoshal N, Goldman JS, Graff-Radford J, Graff-Radford N, Grant I, Grossman M, Haley D, Hsiung R, Huey E, Irwin D, Jones D, Jones L, Kantarci K, Karydas A, Kaufer D, Kerwin D, Kraft R, Kramer J, Kukull W, Litvan I, Lucente D, Lungu C, Mackenzie I, Maldonado M, Manoochehri M, McGinnis S, McKinley E, Mendez MF, Miller B, Multani N, Onyike C, Padmanabhan J, Pantelyat A, Pearlman R, Petrucelli L, Potter M, Rademakers R, Ramos EM, Rankin K, Rascovsky K, Roberson ED, Rogalski E, Sengdy P, Shaw L, Tartaglia MC, Tatton N, Taylor J, Toga A, Trojanowski JQ, Wang P, Weintraub S, Wong B, Wszolek Z. Utility of the global CDR® plus NACC FTLD rating and development of scoring rules: Data from the ARTFL/LEFFTDS Consortium. Alzheimers Dement. 2020 Jan;16(1):106-117. PubMed.
3. Staffaroni AM, Bajorek L, Casaletto KB, Cobigo Y, Goh SM, Wolf A, Heuer HW, Elahi FM, Ljubenkov PA, Dever R, Kornak J, Appleby B, Bove J, Bordelon Y, Brannelly P, Brushaber D, Caso C, Coppola G, Dheel C, Dickerson BC, Dickinson S, Dominguez S, Domoto-Reilly K, Faber K, Ferrall J, Fields JA, Fishman A, Fong J, Foroud T, Forsberg LK, Gavrilova R, Gearhart D, Ghazanfari B, Ghoshal N, Goldman J, Graff-Radford J, Graff-Radford N, Grant I, Grossman M, Haley D, Hsiung GY, Huey ED, Irwin DJ, Jones DT, Jones L, Kantarci K, Karydas A, Kaufer DI, Kerwin DR, Knopman DS, Kraft R, Kremers WK, Kukull WA, Litvan I, Lucente D, Lungu C, Mackenzie IR, Maldonado M, Manoochehri M, McGinnis SM, McKinley E, Mendez MF, Miller BL, Multani N, Onyike C, Padmanabhan J, Pantelyat A, Pearlman R, Petrucelli L, Potter M, Rademakers R, Ramos EM, Rankin KP, Rascovsky K, Roberson ED, Rogalski E, Sengdy P, Shaw LM, Syrjanen J, Tartaglia MC, Tatton N, Taylor J, Toga A, Trojanowski JQ, Weintraub S, Wang P, Wong B, Wszolek Z, Boxer AL, Boeve BF, Kramer JH, Rosen HJ, ARTFL/LEFFTDS consortium. Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH-EXAMINER as a potential clinical trial endpoint. Alzheimers Dement. 2020 Jan;16(1):11-21. PubMed.

Further Reading

No Available Further Reading