There was a feeling in the air at the 7th International Conference on Frontotemporal Dementias, held 6-8 October 2010 in Indianapolis, Indiana, and it wasn’t that of fall in the Midwest. Quite the opposite—it was that the study of FTDs seems to have entered a season of growth. For many years, the frontotemporal dementias, also called frontotemporal lobar degeneration (FTLD), have languished in relative obscurity, overshadowed by the more common Alzheimer’s disease. But rapid progress in discovering the molecular underpinnings of FTD has energized the research, and it is now moving with a distinct spring in its step.

Frontotemporal dementias are a set of devastating, progressive diseases. They attack the parts of the brain responsible for judgment, empathy, and social behavior. People with FTD often develop personality changes, make ruinous financial decisions, become sexually inappropriate, or engage in compulsive behavior. Some patients with AD exhibit some of those behaviors, too; however, with FTDs they are front and center. Some forms of FTD rob people of normal speech, while others impair movement, similar to Parkinson’s disease and amyotrophic lateral sclerosis. FTD typically strikes at younger ages than does AD, often in a person’s late forties or fifties. It involves less memory loss than AD, but much worse behavior problems. One woman described how her 53-year-old husband, a computer engineer, urinates in public unashamedly (see story at The Globe and Mail). He has to be reminded to chew his food and wipe his nose, once wandered into the staff room at the mall and started rooting through the fridge, and shows no emotion. Other patients, in early stages of FTD, cheat on their spouses and find absolutely nothing wrong with that; FTD patients often seem indifferent to what would be a mortifying situation for a healthy person.

 

The disease is particularly devastating to families, said Susan Dickinson, who heads the Association for Frontotemporal Dementias, because it often goes unrecognized or misdiagnosed. Families, therefore, have no recourse if a spouse with FTD blows all his or her money on a sports car, or makes advances to a neighbor, since the spouse is not recognized as ill. Friends may withdraw because of the rude or disturbing behavior of the person with FTD. “Living with these diseases is incredibly isolating,” Dickinson said. “These families are losing their loved ones, and nobody will listen. We have a lot of people who get divorced.” Earlier diagnosis of the disease would help families to understand and cope with what is happening, Dickinson said. “As soon as there is a medical diagnosis, a lot of people get right back together to care for their spouse.”

FTDs are fairly rare. Scientists estimate as many as 20,000 Americans suffer from them, said David Knopman of the Mayo Clinic in Rochester, Minnesota, reviewing the findings of several recent papers. This is similar to the number of Americans with amyotrophic lateral sclerosis, but about 200-fold less than people with Alzheimer’s disease. FTD most often hits between 45 and 64 years old, and people typically survive six to nine years after diagnosis, Knopman said, similar to Alzheimer’s.

Frontotemporal dementia is an umbrella term that encompasses a large number of clinical syndromes and distinct pathologies. This includes a confusing lexicon of terms such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), primary progressive aphasia (PPA), behavioral variant FTD (bvFTD), and Pick’s disease. The distinctions among these syndromes are often hazy, and diagnosis can only be reliably made after death by examining brain tissue changes. Until quite recently, the fundamental biology at the root of many of these syndromes was a mystery.

At the 5th FTD Conference, held in 2006 in San Francisco, California, however, scientists announced the discovery that TAR DNA binding protein 43 (TDP-43) is the major component of protein deposits in about half of FTD patients (see ARF related news story), as well as the finding that mutations in the progranulin gene are responsible for many of these cases (see ARF related news story). And in 2009, scientists discovered that the fused in sarcoma (FUS) protein accumulates in inclusions in another 10 percent or so of FTD cases (see ARF related news story).

At this year’s conference, organized by Bernardino Ghetti of Indiana University, Indianapolis, an enthusiastic crowd of about 600 scientists from around the world showed each other the advances to which these discoveries have since led. These run the gamut from more accurate diagnosis and classification of FTD subtypes, to imaging news and the launch of a major biomarkers initiative and, finally, the creation of new animal models and deeper understanding of the molecular pathways involved in the disorder. At this meeting, but a handful of presenters discussed clinical trials or potential therapies. It’s too early for experimental therapies to have grown out of the new basic research yet, but many scientists said they believe a boom in trials is close at hand. Bruce Miller, a leading FTD expert at the University of California at San Francisco, summed up the mood when he said, “This is the most exciting time I’ve seen in this field.”

Clinically Diverse Tauopathies Present a Challenge for Diagnosis
One of the primary themes in Indianapolis was that a new understanding of the molecular basis of frontotemporal lobar degeneration will sharpen its diagnosis, which traditionally has been based on clinical symptoms. For example, about 40 percent of FTLD cases are characterized by tau pathology, but several subtypes exist, said Dennis Dickson of the Mayo Clinic in Jacksonville, Florida. In some variants of FTLD-tau, including most cases of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), the deposits consist of isoforms of tau with four microtubule binding repeats, Dickson said (see Dickson et al., 2010). In other tauopathies, such as Pick’s disease, the deposits contain isoforms of tau with three microtubule repeats, whereas in Alzheimer’s, both three-repeat and four-repeat tau are present in neurofibrillary tangles. Dickson pointed out, however, that the molecular nature of tau deposits carries less weight than where they form. The differing symptoms of PSP and CBD result from what brain areas and what cell types develop tau tangles, Dickson said. He emphasized that tauopathies form a disease spectrum with overlapping symptoms, and that current distinctions between these diseases may not help in the clinic. He said clinicians need a better classification system that will have greater prognostic and therapeutic significance.

Similarly, Brad Boeve of the Rochester Mayo Clinic showed that, for example, CBD underlies many different clinical diagnoses. The disorder often starts as a focal brain lesion in one hemisphere, Boeve said, and degeneration gradually spreads to surrounding regions, including the homologous region of the opposite hemisphere. As the damage spreads, the clinical symptoms change, depending on what brain areas are affected. This results in frequent misdiagnoses.

This clinical heterogeneity highlights the need for reliable biomarkers, such as brain imaging or protein levels in body fluids, in order to discern the underlying disease pathology, Boeve suggested. Boeve’s talk, and the FTD 2010 conference in general, showcased the well-known and knotty problem that clinical diagnoses of this group of diseases often match up poorly with subsequent postmortem pathological diagnosis. Thus far, classifying diseases by molecular genetic knowledge has not fully resolved the issue. For new imaging data to crack this nut, see Part 2.—Madolyn Bowman Rogers.

This is Part 1 of a four-part series. See also Part 2, Part 3, Part 4. View PDF of the entire series.

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References

News Citations

  1. New Ubiquitinated Inclusion Body Protein Identified
  2. Birds of a Feather…Mutations in Tau Gene Neighbor Progranulin Cause FTD
  3. London, Ontario: The Fuss About FUS at ALS Meeting
  4. Indianapolis: Neuroimaging Opens Window to Disease, Better Diagnosis
  5. Indianapolis: Dissecting the Pathways Behind Frontotemporal Dementia
  6. Indianapolis: Clinical Trials a Ripple, Scientists Hope for a Wave

Paper Citations

  1. . Neuropathology of variants of progressive supranuclear palsy. Curr Opin Neurol. 2010 Aug;23(4):394-400. PubMed.

Other Citations

  1. View PDF of the entire series.

External Citations

  1. 7th International Conference on Frontotemporal Dementias
  2. The Globe and Mail
  3. Association for Frontotemporal Dementias

Further Reading

News

  1. New Ubiquitinated Inclusion Body Protein Identified
  2. London, Ontario: The Fuss About FUS at ALS Meeting
  3. Birds of a Feather…Mutations in Tau Gene Neighbor Progranulin Cause FTD