In the last 10 years, the science of frontotemporal dementias has exploded, thanks to big openings in the molecular pathologies behind these disorders. Rapidly growing interest among academia and industry was on display at the 10th International Conference on Frontotemporal Dementias, held August 31 to September 2 in Munich. Organizers had to cap attendance at a record 760 participants, who included more junior researchers than previous conferences. Days packed with talks, panel discussions, and poster sessions left attendees little time to enjoy the city’s picturesque streets and legendary outdoor beer gardens; even so, lively hallway and café discussions signaled enthusiasm throughout the conference. While the presentations spanned the range of basic to clinical science, there was a dominant theme: a collective push toward trials. Efforts appeared most intense on two fronts: to delineate the underlying mechanisms of each of this group of diseases in search of the best therapeutic targets for it, and to identify useful biomarkers to enable trials.

“In the last two years, the field has achieved important steps toward deciphering frontotemporal lobar degeneration and laying the groundwork for trials,” conference president Janine Diehl-Schmid of the Technical University, Munich, told the audience.

Frontotemporal lobar degeneration is an umbrella term that covers a wide range of related clinical syndromes, some with signature behavioral symptoms, others language, yet others mostly motor. On the motor end, disorders include amyotrophic lateral sclerosis, progressive supranuclear palsy, and corticobasal degeneration; on the other, behavioral variant frontotemporal dementia and language disorders such as semantic dementia and progressive non-fluent aphasia. The syndromes have atrophy of the front of the brain in common, hence the name, but different molecular pathologies underlie each condition, with the two most common being aggregation of tau and TDP-43 (see Apr 2016 conference news). Genetically, a host of rare mutations can cause FTD. With such heterogeneity, and given the rarity of the diseases, trials have been difficult to run. Only a handful have been completed to date. 

Enrollment in the longitudinal GENFI study has climbed steadily since 2012. [Courtesy of Jonathan Rohrer.]

Speakers at ICFTD presented data from three recent trials, with uniformly negative findings (see Part 2 of this series). Undeterred, industry scientists said they were encouraged by the progress in mounting trials in this population. Many other therapeutics are in the pipeline, and speakers updated the audience on several that are preparing to enter human testing. Meanwhile, biomarkers and new clinical measures dominated the meeting, with around two dozen talks and 200 posters devoted to the topic (see Part 3 of this series). The most excitement swirled around the potential of neurofilament light (NfL) as a fluid marker of disease progression, but a plethora of imaging data was also on display. Speakers tied specific behavioral and cognitive symptoms to disruptions of particular brain networks. 

On the clinical side, measures of social cognition were a hot topic (see Part 4 of this series). Many speakers believe they will provide more sensitive outcome markers than the cognitive tests currently in use for FTD. On the basic science front, many talks and posters delved into FTD’s genetics and molecular pathology (see Part 5 and Part 6). Scientists urgently need better animal models, and a new TREM2 model, as well as new data on an inducible TDP-43 model, were well-received (see Part 6). Check back in coming days for in-depth stories on all these topics.

Strength in Numbers: Cohort Studies Clarify Disease Progression
FTD researchers are advancing quickly in part because they can follow a path laid down by their Alzheimer’s colleagues. In AD, longitudinal studies such as the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL), Alzheimer's Disease Neuroimaging Initiative (ADNI), the Alzheimer’s Prevention Initiative (API), and the Dominantly Inherited Alzheimer Network (DIAN) have transformed scientists’ understanding of the disease. FTD scientists have launched their own cohort studies, most focusing on familial forms of the disorders, where the molecular pathology is known. By tracking mutation carriers who do not yet have symptoms, researchers can record their preclinical biomarker changes. The idea is to know the natural history of the disease as a basis for trials, as well as build a pool of people interested in enrolling. The FTD cohorts include the Genetic Frontotemporal Dementia Initiative (GENFI) in Europe, as well as the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (ARTFL) in the United States (see Jul 2012 conference newsNov 2014 conference news). GENFI1 has concluded, but GENFI2 is enrolling and gathering baseline data, as are LEFFTDS and ARTFL. At ICFTD, researchers presented interim updates as well as preliminary biomarker data from GENFI1 (see Part 3 of this series). 

GENFI, led by Jonathan Rohrer of University College London, is the longest-standing of the cohorts. Researchers previously reported baseline and one-year follow-up findings from GENFI1, which comprised 365 people symptomatic or at risk for genetic forms of FTD (see Nov 2014 conference news). Additional findings from this study were sprinkled throughout the conference. GENFI2, now in its second year, expanded from 13 centers to 27, and currently has 550 people enrolled. Many of them continued onward from GENFI1. Recruitment has been so successful that researchers expect to exceed their original target of 600 participants, perhaps reaching 800, Rohrer told Alzforum. All participants come from families that harbor mutations in either tau, progranulin, or C9ORF72. Participants will return for two follow-ups visits at one-year intervals. About 200 have completed their first follow-up. GENFI2 will institute its first data freeze at the end of 2016, Rohrer said.

Like GENFI, LEFFTDS enrolls only people at autosomal-dominant genetic risk for FTD. In Munich, Brad Boeve of the Mayo Clinic in Rochester, Minnesota, gave an update. LEFFTDS now consists of 209 mostly Caucasian volunteers with a mean age of 50. The cohort comprises about equal parts of each of the three main FTLD genes. About one-third of each group already have disease symptoms. As in GENFI, participants will return for two annual follow-up visits each at the eight participating North American centers.

ARTFL, active at 15 North American centers and led by Adam Boxer of the University of California, San Francisco, casts a broader net. As of August 1, it had enrolled 192 people with sporadic FTLD, plus 240 with a family history, of whom 188 carry a known FTLD gene. Participants have a mean age of 58; 90 percent are Caucasian. ARTFL and LEFFTDS collect biospecimens including DNA, RNA, plasma, serum, monocytes and lymphocytes, as well as CSF from some volunteers. Volunteers with sporadic disease participate in project 1, which seeks to characterize idiopathic FTLD. Researchers are currently investigating blood cytokine profiles of this group. Those with a family history take part in project 2, which tracks clinical and biomarker change over one year.

The three cohorts have joined forces, along with the Australian Dominantly Inherited Non-Alzheimer Dementias (DINAD) study, to form the FTD Prevention Initiative (FPI). DINAD, led by John Hodges and Glenda Halliday at Neuroscience Research Australia, Sydney, has just gotten started and plans to recruit participants with genetic forms of FTD. The FPI umbrella group will establish minimum shared datasets to facilitate the pooling of findings. LEFFTDS and ARTFL already share their database and use the same assessments. Meanwhile, researchers are putting finishing touches on the FTD Disorders Registry in hopes of speeding up recruitment for studies and trials. The registry is expected to go live in October, Boxer said.

Calculating the Cost of FTD
Families are desperately awaiting trials because there are currently no treatments for FTD. Symptoms typically strike in middle age, and can tear families apart. While many anecdotal reports recount the burden of the disease, few studies have tried to quantify its societal and economic cost. James Galvin of Florida Atlantic University, Boca Raton, filled this gap with a Web-based survey administered through the website of the Association for Frontotemporal Degeneration. The survey’s 250 questions take about two hours to complete, which respondents could do over several sessions. To measure the personal toll of the disease, Galvin used the Health Utilities Index 3 (HUI3) and Quality-Adjusted Life Years (QALYs). The HUI3 rates a person’s function on eight attributes pertaining to vision, hearing, speech, ambulation, dexterity, emotion, cognition, and pain. A rating of 1 indicates perfect function, 0 represents death, and a rating below 0 signifies a state perceived to be even worse than death—for example, someone who is bedbound in extreme pain. QALYs are scored similarly, with 1 representing one year of perfect health, 0 death, and negative numbers signifying a state considered worse than death. Scores are multiplied by the number of years spent in that state.

At ICFTD, Galvin reported that 956 people began the survey and 674 completed it. Most were caregivers for someone with behavioral variant FTD. Caregivers reported a very high personal burden, regardless of the stage of their loved one’s disease. More than one-third had quit their jobs to care for their family member, and two-thirds reported declines in their own health. Adult children caring for a parent with the disease reported a worse quality of life than did spouses, with the highest burden falling on daughters caring for mothers. For the person with FTD, on the other hand, quality of life depended on the stage of their disease. At mild stages, caregivers reported an average HUI3 of 0.55 and QALY of 1.2 for their loved one. By moderate disease stages, the HUI3 dropped to 0.24 and the QALY to 0.8. For patients at severe stages, both scores fell into the negative, at -0.09 and -0.64, respectively. The numbers did not depend on what subtype of FTD a patient had; all were scored as equally devastating.

Financial costs were also extremely high. One-third of caregivers reported using paid care several times per week. FTD patients need frequent hospitalizations, more than AD patients do, Galvin said. They can become violent, and often break laws and flout social norms. Reflecting this, caregivers reported spending money on childcare and on moving children to safer locations, as well as legal fees. Caregivers who still worked missed many work days. Overall, they reported a decline in household income after an FTD diagnosis. The survey estimated the yearly cost from an FTD diagnosis to be $135,000 per patient. This is about three times higher than the cost of AD, which has been estimated at $56,000 per year. These figures might help researchers model how much a potential therapy could reduce costs, Galvin suggested.

Several scientists were impressed by how this analysis quantified the social and economic burden of the disease. Boeve called the data “enlightening.” Boxer, noting that researchers need to define what trial outcomes would be clinically meaningful for each FTD patient group, called Galvin’s analysis a starting point.—Madolyn Bowman Rogers


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News Citations

  1. Drug Trials in Frontotemporal Dementia: Can Field Push Forward Together?
  2. First Round of FTD Therapeutics Fell Short, But Many More Are Up and Running
  3. Fluid NfL Shines, Tau PET Dims, in the Hunt for FTD Biomarkers
  4. Tests of Social Cognition Hold Potential as FTD Outcome Measures
  5. FTD Gene Hunt Turns Up CYLD and Modifying Factors
  6. New Data Reinforces Concept of Protein Propagation
  7. Scientists Strategize With Regulators for Frontal Assault on FTD
  8. Meet the Artful Leftie: NIH Jump-Starts U.S.-Canadian FTLD Cohorts
  9. First Data from GENFI1: Brain’s Insula Region Shrinks A Decade Before FTD

External Citations

  1. FTD Disorders Registry
  2. Association for Frontotemporal Degeneration

Further Reading