13 Mar 2021

The term frontotemporal lobar degeneration encompasses a broad spectrum of diseases that, to the researcher’s eye, seem marked by inexplicable, and maddening, variability at every turn. From the genetic mutations that cause it, to the neuropathology that damages the brain, to its clinical expressions, FTLD is sinister—and utterly bewildering—in its diversity. And yet, thanks to international cohort studies launched in recent years, researchers are finally gaining a handle on this syndrome. Starting in 2012 with the Genetic FTD Initiative (GENFI) in Europe and Eastern Canada, and followed in 2015 by the Advancing Research and Treatment for Frontotemporal Lobar Degeneration and the Longitudinal Evaluation of Familial FTD Subjects (ARTFL/LEFFTDS), scientists have collaborated on an unprecedented scale. They are charting the clinical progression of the disease and pegging imaging and fluid markers that track its onset and progression. They have tailored cognitive and functional tests to encompass the many symptoms of FTD, and devised physiological measures that link complex social and emotional deficits to faltering circuitry in the brain.

In addition to dozens of papers published in recent months, researchers shared the fruits of their efforts at the International Conference on FTD (ICFTD), held virtually March 3–5. This news series summarizes their progress, starting with the not-so-simple feat of charting the natural course of the disease. Parts 2 to 5 of this series will cover advances in fluid and neuroimaging biomarkers, along with cognitive, functional, and physiological measures that are primed for use in clinical trials. A newly formed international uber-consortium readies participants to enter trials and collaborates with industry to design studies. Clinical trials for carriers of mutations in progranulin are furthest along, with trials aimed at FTD caused by mutations in other genes close behind.

First, a refresher on FTLD or, in clinical parlance, frontotemporal dementia (FTD). In this spectrum of diseases, neurodegeneration afflicts the frontal and/or the temporal lobes of a person’s brain. The specific frontotemporal regions that are affected vary among the syndromes, indeed even among people with the same syndrome. On one end of the spectrum lies behavioral variant FTD. People with bvFTD develop social and emotional problems. They become apathetic, impulsive, loose empathy. Other people develop language disorders, grouped under the umbrella of primary progressive aphasia. They no longer can call up words, or they speak haltingly. Still others develop semantic dementia, where they no longer understand the meaning of words or situations. Movement disorders also lie along the spectrum, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS), a motor neuron disease. The lines between these syndromes can be maddeningly blurry, and some people, such as those with bvFTD-ALS, suffer from a combination of them.

With an estimated prevalence of 11 in 100,000 people, FTD is far less common than AD or vascular dementia (Coyle-Gilchrist et al., 2016).  Autosomal-dominant mutations are responsible for 25–30 percent of FTD cases. For bvFTD, roughly 40 percent of people harbor a pathogenic mutation, while the majority of PPA, CBD, and PSP cases are sporadic. Therefore, bvFTD patients make up the lion’s share of participants in familial studies of FTD. Of the familial cases, 95 percent carry a pathogenic variant in one of three genes: progranulin (GRN), tau (MAPT), or C9ORF72, while the remaining few carry a pathogenic variant in a handful of other genes. While MAPT mutation carriers accumulate neurofibrillary tangles of tau, carriers of GRN or C9ORF72 mutations are predominantly burdened by deposits of TDP-43. bvFTD can arise from variants in any of the three genes, while MAPT mutations can also cause PSP, GRN mutations can trigger PPA, and hexanucleotide expansions in C9ORF72 can lead to ALS.

There. Sound complicated? Rest assured, it’s not just you.

Amid this seemingly intractable complexity, Jonathan Rohrer of University College London initiated the Genetic FTD Initiative (GENFI). By 2012, Rohrer had been caring for many families with the disease, watching as adult children of his patients approached their own onset. Year after year, family members asked, “Will there be a treatment for me when I develop symptoms?” Until recently, the answer had always been no. “Now, I can actually point to clinical trials on the horizon, or even some that are already enrolling,” Rohrer said.

The shift became possible when Rohrer and other researchers realized that multicenter, international collaborations were the only way to properly investigate FTD—and because patients and their families joined. Today, GENFI includes centers in the U.K., Netherlands, Belgium, France, Spain, Portugal, Italy, Germany, Sweden, Finland, and Canada. It involves more than 100 investigators and 1,000 participants.

On the heels of GENFI, researchers in North America started two similar studies of their own. Called, awkwardly, Advancing Research and Treatment for Frontotemporal Lobar Degeneration and the Longitudinal Evaluation of Familial FTD Subjects, ARTFL created a network of 19 centers to study both sporadic and familial forms of FTLD, while LEFFTDS tapped eight of those centers to more deeply phenotype people with familial forms (Nov 2014 conference news). In 2019, the two merged into one cooperative study, called ALLFTD. Bradley Boeve at the Mayo Clinic in Rochester, Minnesota, and Adam Boxer and Howard Rosen at the University of California, San Francisco, co-direct ALLFTD. At ICFTD , Boeve reported that ALLFTD currently includes more than 1,500 participants who have been evaluated at a total of 2,293 visits.

After GENFI and ALLFTD, other multicenter, longitudinal cohort studies sprang up, such as the Dominantly Inherited Non-Alzheimer’s Disease (DINAD) study in Australia, the New Zealand FTD Genetic Study (FTDGeNZ), and the Research Dementia Latin America (ReDLat) in South America. Recently, these national or regional studies have joined forces in the Frontotemporal Dementia Prevention Initiative (FPI), an effort that will create a global registry of potential clinical trial participants, and collaborate with industry to plan and execute effective clinical trials (see Part 4 of this series for more on FPI).

Nine years and more than 30 publications later, what has GENFI achieved? Take a recent paper that charted the natural history of bvFTD. In the most comprehensive of such studies to date, GENFI researchers led by Barbara Borroni of the University of Brescia, Italy, tracked the progression of behavioral and neuropsychiatric symptoms among 232 people with different genetic forms of the disease (Benussi et al., 2021). 

Between 2012 and 2019, 101 of the participants had had at least one follow-up visit, and 35 came for at least two. A handful of participants showed up for seven visits, making for a total of 400 evaluations across the cohort. Because people’s apathy, disinhibition, and lack of insight worsen as their disease progresses, both clinicians and caregivers face an uphill battle getting participants to return to the clinic once they are symptomatic, said co-author John Van Swieten of Erasmus University in Rotterdam. In light of those challenges and the scarcity of people with the disease, those 400 evaluations are hard-won.

Charting Devastation. Rows show how prevalent nine different symptoms became over time among people with bvFTD, tracked separately for 115 carriers of C9ORF72 hexanucleotide expansions, 78 GRN mutation carriers, and 39 MAPT mutation carriers. [Courtesy of Benussi et al., JAMA Network Open, 2021.]

At each visit, study staff assessed participants’ core behavioral and neuropsychiatric symptoms of bvFTD. All core behavioral symptoms—apathy, disinhibition, loss of empathy, compulsive behavior, and hyperorality—emerged across mutation carriers, with apathy being the most common.

Patients with MAPT variants had the most—and the most severe—behavioral disturbances, especially disinhibition and compulsion. Some began to have neuropsychiatric episodes, with anxiety and depression most common among MAPT and GRN carriers, and hallucinations among C9ORF72 carriers. How severe these were, and how that changed over a person’s progression, also differed between the genetic forms. For example, while participants with C9ORF72 expansions became steadily less depressed in their late stages, depression grew more profound in GRN carriers. This suggests that individuals go down different symptom trajectories in the different genetic forms of the disease. This is important to know to estimate a patient’s prognosis, and eventually for clinical trials that gauge the effects of treatments on different mutation groups.

Just as the progression of a person’s disease varies depending on his or her genetic cause, so does the first symptom that crops up. “For one person, it might be an awkward elevator conversation. Someone else might start stealing, while another gets pulled over for speeding,” said Elizabeth Finger of Western University in London, Ontario, at ICFTD. Some people withdraw from conversations with their loved ones, while others voraciously chat up strangers, perhaps even going to far as to caress them on the back, as one woman’s video of her husband revealed.

Finger and colleagues catalogued and categorized these types of initial symptoms among 185 symptomatic GENFI participants, and among more than 1,200 asymptomatic family members, about half of whom carried a pathogenic mutation (Tavares et al., 2020). Caregivers retrospectively reported first symptoms in their symptomatic loved ones. Apathy was the most common initial symptom, followed by disinhibition, memory impairment, and language problems.

Strikingly, even relatives who carried the same mutation often had different first symptoms. Even so, some themes emerged. For example, MAPT mutation carriers tended to lose normal social inhibitions first, while GRN carriers first tended to stumble over language. During the preclinical stage, i.e., in presymptomatic carriers, people with tau mutations were more likely to be moody and wake up a lot at night, while C9ORF72 mutation carriers were slightly more likely to become socially awkward or show odd behaviors, and GRN carriers seemed to have trouble with everyday skills, such as cooking, using appliances, or paying bills.

Notably, none of these early symptoms would warrant a trip to the neurologist, Finger said. This is especially true for people with sporadic forms of the disease who have no indication they are at risk. People without a known family history of FTD typically do not find their way to a neurologist until the disease has progressed well into the symptomatic stage. Instead, the mood and behavior problems drive people to therapists, marriage counselors, or psychiatrists. Like the nurse (with unrecognized FTD) who one day asked a patient to lend her cash, many people with FTD have a history of losing their jobs due to odd behavior or inefficiency at work. “When enough of these events accumulate over the years, that’s when we finally see them in the clinic,” Finger said.

The puzzling range of early symptoms, and their likelihood of being misinterpreted, makes finding objective biomarkers for the disease essential, Finger and other researchers emphasized. In fact, finding and developing robust fluid, neuroimaging, and other types of markers is a central goal of GENFI and ALLFTD. For progress on this front, read Part 2 of this series.—Jessica Shugart

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References

News Citations

1. Meet the Artful Leftie: NIH Jump-Starts U.S.-Canadian FTLD Cohorts 12 Nov 2014
2. FTD Fluid Markers for Degeneration: Check. For Pathology: Not Yet. 16 Mar 2021

Paper Citations

1. Coyle-Gilchrist IT, Dick KM, Patterson K, Vázquez Rodríquez P, Wehmann E, Wilcox A, Lansdall CJ, Dawson KE, Wiggins J, Mead S, Brayne C, Rowe JB. Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes. Neurology. 2016 May 3;86(18):1736-43. Epub 2016 Apr 1 PubMed.
2. Benussi A, Premi E, Gazzina S, Brattini C, Bonomi E, Alberici A, Jiskoot L, van Swieten JC, Sanchez-Valle R, Moreno F, Laforce R, Graff C, Synofzik M, Galimberti D, Masellis M, Tartaglia C, Rowe JB, Finger E, Vandenberghe R, de Mendonça A, Tagliavini F, Santana I, Ducharme S, Butler CR, Gerhard A, Levin J, Danek A, Otto M, Frisoni G, Ghidoni R, Sorbi S, Le Ber I, Pasquier F, Peakman G, Todd E, Bocchetta M, Rohrer JD, Borroni B, Genetic FTD Initiative (GENFI). Progression of Behavioral Disturbances and Neuropsychiatric Symptoms in Patients With Genetic Frontotemporal Dementia. JAMA Netw Open. 2021 Jan 4;4(1):e2030194. PubMed.
3. Tavares TP, Mitchell DG, Coleman KK, Coleman BL, Shoesmith CL, Butler CR, Santana I, Danek A, Gerhard A, de Mendonca A, Borroni B, Tartaglia MC, Graff C, Galimberti D, Tagliavini F, Moreno F, Frisoni G, Rowe JB, Levin J, Van Swieten JC, Otto M, Synofzik M, Sanchez-Valle R, Vandenberghe R, Laforce RJ, Ghidoni R, Sorbi S, Ducharme S, Masellis M, Rohrer J, Finger E. Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration. J Neurol Neurosurg Psychiatry. 2020 Sep;91(9):975-984. Epub 2020 Aug 7 PubMed.

External Citations

1. FPI

Further Reading

No Available Further Reading