23 Mar 2021

Compared to Alzheimer’s disease, frontotemporal lobar degeneration is far rarer and more diverse in terms of its clinical manifestations and their underlying genetic and neuropathological causes. This makes the illness maddeningly difficult to understand at every level, let alone target with disease-modifying therapies. On the former front, scientists have made real progress charting FTLD’s complexity through cohort studies. Europe’s GENFI and North America’s ALLFTD have dutifully tracked the variable trajectories of the disease and hunted for fluid, neuroimaging, and cognitive markers of its progression (Parts 1, 2, 3, 4, and 5 of this series). Now, the field is poised to put that observational rubber to the road. The FTD Prevention Initiative is the über-consortium that unites multicenter cohort studies across the globe. The FPI aims to harmonize FTD data from around the world, work with industry to design and execute international clinical trials, and create an international registry of participants keen to join. As its name implies, another goal is to enroll presymptomatic mutation carriers in trials, i.e., eventually prevent FTD.

In an FPI paper, and at the International Conference for FTD, held virtually March 3–5, researchers reported the fruits of their initial efforts to pull together data from the cohorts under the FPI umbrella. In particular, the meeting featured a session dedicated to a new Latin American project that is poised to expand knowledge about all aspects of FTD, and will join FPI.

Launched in 2019, FPI is led jointly by Jonathan Rohrer of University College London, who heads GENFI, and Adam Boxer of the University of California, San Francisco, who co-leads ALLFTD (Rohrer and Boxer, 2021). Other observational studies within FPI are Australia’s Dominantly Inherited Non-Alzheimer Dementias study (DINAD), New Zealand’s FTD Genetic Study (FTDGeNZ) and, importantly, South America’s Research Dementia Latin America (ReDLaT) study. Patient-advocacy groups and FTD research foundations have also signed on, including the Association for Frontotemporal Degeneration, the Bluefield Project to Cure FTD, and the FTD Disorders Registry. 

The Struggle for Power
FPI addresses a tall hurdle standing in the way of effective clinical trials for FTD, AFTD’s Susan Dickinson told Alzforum. It’s how to achieve power in a rare, heterogeneous disease. Only collaborative, international clinical trials will be able to recruit enough participants to detect a statistically significant effect. “The more we can do to pool data and work together, the easier it will be to make these trials a reality,” Dickinson said, adding, “The small number of available patients will be a defining feature of how we approach these trials, no question.”

FPI’s first order of business is to harmonize data from longitudinal cohort studies across countries. So far, FPI has one paper out that weaves in data from GENFI, ALLFTD, and DINAD. Published just as the COVID-19 pandemic started its march across the globe, the study addressed basic parameters of familial FTD, comparing age at disease onset and at death among people who carried a pathogenic mutation in C9ORF72, GRN, or MAPT (Moore et al., 2020). 

The largest study of familial FTD to date, it reports data from 3,403 people from 1,492 families. Behavioral variant FTD was the most common clinical syndrome, but people with primary progressive aphasias, amyotrophic lateral sclerosis, corticobasal degeneration, and progressive supranuclear palsy were also included. Of the participants, 1,433 had a C9ORF72 hexanucleotide expansion, 1,179 had a GRN mutation, and 791 had a MAPT mutation. The frequency of mutations was somewhat different in different parts of the world. For example, GRN mutations were most prevalent in Italy and Spain, while MAPT mutations were predominant in the Netherlands and on the west coast of the United States (see below).

Global Tally. The number of FPI participants who carry a mutation in C9ORF72, GRN, or MAPT is shown for each region included. Countries shaded in dark blue participated in the study; individual centers in red. [Courtesy of Moore et al., Lancet Neurology, 2020.]

How did timing and severity of the disease differ between mutation carriers? MAPT mutation carriers showed symptoms first, at an average age of 49, followed by C9ORF72 carriers at 58, and GRN carriers at 61. MAPT carriers lived for an average of 9.3 years after diagnosis, while C9ORF72 and GRN carriers lived for an average of 6.4 and 7.1 years, respectively. Within each mutation group, age at onset varied markedly, ranging from the 20s to the 90s in the GRN and C9ORF72 groups, and from age 17 to the 80s in the MAPT group.

When FTD Starts. Age at symptom onset and death, charted for more than 3,400 carriers of autosomal-dominant mutations in GRN, MAPT, and C9ORF72. For each causative gene, the age span is enormous. [Courtesy of Moore et al., Lancet Neurology, 2020.]

Across the cohort, men and women were of similar age at symptom onset. However, symptoms cropped up later in women than men in the GRN and C9ORF72 groups.

Within families burdened by FTD across generations, the scientists found, alarmingly perhaps, that symptoms emerged a few years earlier with each successive generation across all mutation groups. The strength of the association between an individual’s age at onset with that of their parent’s varied among the groups, with MAPT mutations having a strong tie, whereas in C9ORF72 or GRN carriers, the age at which their affected parent had gotten sick poorly predicted when the next generation would.

With the basic parameters of FTD now laid down across mutations, FPI’s next data merger will compare measurements of plasma NfL, the most advanced FTD biomarker to date, across the initiative’s cohorts. An upcoming paper shows remarkable agreement among the cohorts in the relationship between plasma NfL and symptom onset, Boxer said, but its authors declined to say more about it while the manuscript is being reviewed.

Latin American Cohort Joins the Fight
To date, most FPI participants are of European descent. This is about to change, as the Multi Partner Consortium to Expand Research in Latin America (ReDLaT) joins the effort. This cohort includes people with FTD, but also AD and healthy controls, in Argentina, Brazil, Chile, Colombia, Mexico, and Peru. Funded by the National Institutes of Health, the Alzheimer’s Association, and others, the consortium is jointly led by Agustín Ibañez at Universidad de San Andrés, Buenos Aires, and Bruce Miller at the University of California, San Francisco.

ReDLaT aims to enroll 4,500 participants. In accordance with the prevalence of different dementias, the majority of participants will be healthy controls or people with AD, followed by people with FTD. The study will track them with clinical, neuroimaging, and fluid biomarker measurements, applying protocols already in use within the ALLFTD cohort. The COVID-19 pandemic slowed down this project, as it did clinical research everywhere, but ReDLaT still managed to get 11, soon to be 12, study sites up and running, Ibañez said at ICFTD.

ReDLaT aims to establish the genetic basis of AD and FTD in diverse Latin American cohorts. Jennifer Yokoyama of UCSF heads ReDLaT’s genetics effort. She explained that the diversity of genetic backgrounds in South American populations—which include indigenous peoples, people of African descent, Europeans and, of course, mixtures of all these—is sure to increase the number of genetic variants linked to FTD. At ICFTD, Yokoyama offered a sneak peek of preliminary genetic data collected in ReDLaT so far, reporting unexpected pathogenic variants, such as in LRRK2 and Notch3, in people with AD. As genomic studies expand in the cohort, the scientists can test how polygenic risk scores (PRS), which so far have only been validated in non-Hispanic white populations, perform in Hispanic people, as well.

Aside from FPI, ReDLaT also has its own goals in advancing the understanding of dementia syndromes in Latin America. One aim is to assess how socioeconomic status, low access to formal education and healthcare, and exposure to political and gender violence—all factors with strong sway on the overall health of populations in Latin America—might influence manifestations of FTD there. At ICFTD, ReDLaT researchers Andrea Slachevsky of the University of Chile and Stefanie Piña Escudero of the Global Brain Health Institute reported on how measures of these so-called social determinants of health are being incorporated into clinical assessments of people in the ReDLaT cohort. Separately, they hope to educate physicians and the public about FTD, which is still a relatively unknown disease in South America, Ibañez said.—Jessica Shugart

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References

News Citations

1. Merged Consortia Forge Path to Trials in Frontotemporal Dementia 13 Mar 2021
2. FTD Fluid Markers for Degeneration: Check. For Pathology: Not Yet. 16 Mar 2021
3. Imaging Exposes Hugely Heterogeneous Brain Changes Among FTDs 19 Mar 2021
4. Moving Target: Can Standardized Tests Track Symptoms of FTD? 19 Mar 2021
5. From Specialized to Standardized: Social-Emotional Tests for FTD 19 Mar 2021

Paper Citations

1. Moore KM, Nicholas J, Grossman M, McMillan CT, Irwin DJ, Massimo L, Van Deerlin VM, Warren JD, Fox NC, Rossor MN, Mead S, Bocchetta M, Boeve BF, Knopman DS, Graff-Radford NR, Forsberg LK, Rademakers R, Wszolek ZK, van Swieten JC, Jiskoot LC, Meeter LH, Dopper EG, Papma JM, Snowden JS, Saxon J, Jones M, Pickering-Brown S, Le Ber I, Camuzat A, Brice A, Caroppo P, Ghidoni R, Pievani M, Benussi L, Binetti G, Dickerson BC, Lucente D, Krivensky S, Graff C, Öijerstedt L, Fallström M, Thonberg H, Ghoshal N, Morris JC, Borroni B, Benussi A, Padovani A, Galimberti D, Scarpini E, Fumagalli GG, Mackenzie IR, Hsiung GR, Sengdy P, Boxer AL, Rosen H, Taylor JB, Synofzik M, Wilke C, Sulzer P, Hodges JR, Halliday G, Kwok J, Sanchez-Valle R, Lladó A, Borrego-Ecija S, Santana I, Almeida MR, Tábuas-Pereira M, Moreno F, Barandiaran M, Indakoetxea B, Levin J, Danek A, Rowe JB, Cope TE, Otto M, Anderl-Straub S, de Mendonça A, Maruta C, Masellis M, Black SE, Couratier P, Lautrette G, Huey ED, Sorbi S, Nacmias B, Laforce R Jr, Tremblay ML, Vandenberghe R, Damme PV, Rogalski EJ, Weintraub S, Gerhard A, Onyike CU, Ducharme S, Papageorgiou SG, Ng AS, Brodtmann A, Finger E, Guerreiro R, Bras J, Rohrer JD, FTD Prevention Initiative. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study. Lancet Neurol. 2020 Feb;19(2):145-156. Epub 2019 Dec 3 PubMed.

External Citations

1. Association for Frontotemporal Degeneration
2. Bluefield Project to Cure FTD
3. FTD Disorders Registry

Further Reading

No Available Further Reading