July 11, 2007 

Second International FTD and ALS Conference: Challenges and Progress

The second international conference on frontotemporal dementia (FTD) and ALS convened in London, Ontario, Canada, June 10 through 13. Co-sponsored by The ALS Association in collaboration with the ALS Society of Canada, the meeting allowed clinicians and researchers involved in aspects of these two conditions to learn from each other and from invited outside experts. As ALS patients can develop cognitive and behavioral changes that resemble aspects of FTD, the participants sought to work toward consensus on how best to diagnose and treat the overlapping disorders and how to leverage what is being learned about both into effective therapy.

ALS, a motor neuron disease, is named for the obvious death of the motor neurons that reach from brain to spinal cord and cord to muscle. But areas in the brain, other than those directing movement, can be affected to some degree as well. As investigators learn more about these changes, they will uncover new potential therapies for ALS. These potential therapies were the focus of discussion at the meeting. A working group will now build upon and move recent findings into strategies that will aid patients and their families.

At the conference, ALS clinicians and the neuropsychologists who carry out cognitive and behavioral assessments of patients, discussed the tests that are likely to prove most useful for diagnosis and prediction. Pathologists who see the tissue damage in the disease contributed their perspective on the key features and emerging commonalities. Experts in Alzheimer’s disease shared their relevant experiences.

The following are highlights of the proceedings. A consensus paper will be published.

Motor Neuron Diseases and Genes

Stanley Appel, M.D., Methodist Neurological Institute, Houston, Texas, presented a rating scale he and colleagues have devised to measure disease progression: the angle of decline in function, as rated by the functional rating scale, is 90 percent predictive of how individuals will fare. He noted that ALS patients present with a primary site of onset, but as the disease progresses, one can describe each patient’s disease as primarily involving affected areas: onset may be in a limb, but the disease develops with primarily bulbar aspects. Recently published data from the myotrophin trial indicate, Appel said, that patient progression can differ between centers, and this produced the differences among the clinics participating in the trial rather than differences in evaluation between centers or in patient care.

His group, as have others, find mild cognitive impairment in about a third of patients, and about 20 percent have moderate to severe cognitive impairment (severe meeting the criteria for FTD). No one knows if every patient might become impaired if they live long enough.

Genome-wide studies in ALS are finding no single gene responsible, Appel said. In Alzheimer’s, by contrast, the gene called ApoE4 always comes up as linked with increased risk for the disease. A variety of genes being associated with risk for ALS likely reflect that a variety of processes are affected in the motor neuron disorder.

Leonard van den Berg, University Medical Center, Utrecht, The Netherlands, presented evidence that primary lateral sclerosis (PLS), a disorder of just the upper motor neurons from the brain to the spinal cord, may be a continuum of ALS. PLS appears to occasionally have frontal lobe involvement as well. The diagnosis cannot be given with certainty until four years pass with no lower motor neuron involvement (the neurons from cord to muscle; ALS by definition affects both upper and lower motor neurons). People with PLS can have family members with ALS.

John Fink, M.D., University of Michigan, Ann Arbor, spoke on the genetics in people with hereditary spastic paraplegia (HSP), a disease of the upper motor neurons.  More than 30 different causative genes have been identified. ALS may turn out to be similarly diverse genetically. HSP can produce brain involvement, such as mental retardation, or impaired cognition that gets worse as patients age; the latter can occur even in carriers of an HSP gene that do not have motor symptoms. ALS has occurred in families with HSP genes. The disease also can be worse in children compared to parents with the same gene, a phenomenon called genetic anticipation.

Ian Mackenzie, University of British Columbia, Vancouver, described the recent discovery of the mutation in the gene for the protein, progranulin, to explain many cases of inherited FTD. The protein is involved in wound repair and is linked to the blood vessel growth promoter, VEGF, this latter protein is implicated in ALS risk. Only one instance of progranulin mutation has so far been uncovered in someone with ALS. Swedish researcher Peter Anderson, Umea University, put forth the case that studies to date have not reliably stated the incidence of ALS. Familial ALS is defined by having two blood relatives affected, yet even with SOD1 mutations, not all produce the disease (incomplete penetrance). In general, he noted, the more stable the mutated SOD1 protein, the longer a patient will take to show signs of the disease. In these ways an inherited mutation may masquerade as sporadic ALS.

Other mutations linked to ALS include changes to genes for the proteins abbreviated as CHMP-2B (Charged multivesicular body protein 2b), VAPB (vesicle-associated membrane protein)-associated protein B), and angiogenin. Bryan Traynor, M.D., of the National Institute on Aging presented the possibility of a mutation in families with ALS and FTD linked to a region of chromosome 9 but cautioned that this location so far only holds up for one family. Paul Valdmanis, a graduate student working with Guy Rouleau, discussed the problems to pin down an exact gene identified by linkage studies. His group has also failed to find a causative mutation at the chromosome 9 location.

Imaging of Motor Neuron Disease

Eric Pioro, M.D., Ph.D., Cleveland Clinic, presented an update on imaging ALS. Until recently, imaging was used to rule out other treatable causes of motor function loss. Efforts are underway to harness imaging to be diagnostic and predictive; that is to serve as a biomarker of the specific processes in ALS. White areas in a scan, called hyperintensity, indicate degeneration. The nerve fiber tract from the motor area of the brain descending toward the spinal cord appears as a white funnel shape, but this damage to the fiber tracts can show up in other conditions of spasticity. Diffusion tensor imaging shows the diffusion of water along nerve tracts. If tracts are damaged, this will alter the signal, which may become useful in ALS. PET scanning might also be able to identify a biomarker linked to the pathology of ALS.

Where is the Damage?

Atrophy or shrinking of the frontal and temporal areas of brain can precede or coincide with cognitive change in ALS. Yet frontal atrophy to a certain extent is a normal sign of aging, according to Tiffany Chow, M.D., of the University of Toronto. Jillian Krill of the University of Sidney, Australia, showed the atrophy that appears with FTD and defined stages of the damage. Early on one finds a defect to the hippocampus, an area also affected in Alzheimer’s disease. But it is the shrinking of the temporal cortex (the region behind the temples) that is a monitor of the disorder’s progress in FTD, since hippocampal damage does not become severe (as it does in Alzheimer’s). Perhaps these changes might serve on imaging to see if a treatment has success, Krill suggested. Presenters seemed to agree that the hippocampus, a memory center, is a site of early change in ALS with cognitive involvement—and even without it—but that the change is subtle.

Pathologists provided a look at the cellular changes in brain that will help to diagnose the overlap between motor neuron diseases and FTD. Arthur Hays, M.D., at Columbia University in New York City, noted that so-called bunina bodies present in neurons in ALS contain the proteins cystatin C and transferrin (these proteins are also among a set of proposed biomarkers for ALS that need to be verified by larger studies). Bunina bodies, abnormal deposits found in ALS, are not present in SOD1 mutation, and the newly discovered, common link between ALS and FTD, the protein called TDP-43, may also not be involved in ALS patients with SOD1 mutation.

Japanese researcher Tetsuaki Arai, M.D., Ph.D., of Tokyo Institute of Psychiatry, recounted his discovery of the common presence of TDP-43 in ALS and FTD patients about the same time as the report by Virginia Lee and colleagues at the University of Pennsylvania.  He noted the abundance of TDP-43 in the fiber tracts, which turns out to be specifically in the cells that wrap around nerve fibers, the oligodendroglia.

Michael Strong, M.D., of the University of Western Ontario reported that the microtubule associated tau protein has increased amount of phosphate molecules in ALS. So even though the tau protein is not mutated, it may be changed in the disease.

Tests for Cognitive Change

Morris Freedman, M.D., University of Toronto, developed a test of frontal lobe function based on discerning patterns. People with frontal lobe damage cannot figure out the pattern. Chow suggested other quick tests for FTD changes such as reciprocal tapping as well as hiding a coin and changing the pattern of which hand has it. She noted a change in personality is the hallmark of frontal defect and that patients should be reviewed again for cognitive change after a year. Chow said it is important to have a caregiver available to question as lack of insight is another hallmark of FTD. Cognitive tests must accommodate for the motor and speech impairment of ALS.

Chow, Freedman, Keith Josephs, M.D., of Mayo Clinic, Rochester, and Thomas Bak of the University of Edinburgh, described the range of cognitive and behavioral changes in FTD, which can include obsessive rituals, hoarding, and behavioral rigidity. Socially incorrect behavior and loss of normal caution with strangers also can occur. Some patients lose ability to name objects or recognize faces, but other aspects of memory are intact. Bak discussed the families on the island of Guam who can show different aspects of the diseases ALS, Parkinson’s and Alzheimer’s. Dementia now predominates in affected families on the island where decades earlier, ALS and Parkinson’s features were more prevalent. The cause of this disease on Guam is still unknown.

Laura Goldstein, Ph.D., of King’s College, London, finds that a test of verbal fluency is most sensitive of changes in ALS patients. Also she finds that patients with bulbar symptoms, including exaggerated or inappropriate emotions, are more likely to have cognitive change. Susan Woolley-Levine, Ph.D., of Forbes Norris center in San Francisco, finds that patients with bulbar involvement are more likely to show apathy and changes in social judgment. She suggests that behavioral impairment be defined as a change in at least two measures.

No one knows if ALS patients get worse on cognitive tests as their disease progresses. Joseph Orange, Ph.D., of the University of Western Ontario, will be following patients over time with tests of language ability. Zachary Simmons, M.D., at Penn State Hershey, said cognitive function appears to decline over time in some patients but not others. The challenge is to find quick effective screening tests that will fit into a demanding clinic visit.

Simmons pointed out that the effort to diagnose cognitive change in ALS brings together specialists that do not usually deal with the respective problems: neuromuscular clinicians don’t do cognitive testing, and neuropsychologists don’t look for motor defects. He said it takes longer for ALS patients to think of the appropriate words, independent of their motor skills.  Masayuki Satoh, M.D., Ph.D., of Mie St. Cross Hospital, Japan, described the way Japanese ALS patients will drop characters when writing words in the script in which each character stands for a syllable. These abbreviated words are similar to the sparse wording used by English speaking ALS patients. Woolley-Levine noted this could simply represent a telegraphic writing style developed over time by patients who must write to communicate.

Jennifer Murphy, Ph.D., with colleagues at the University of California, San Francisco, has developed a 20 minute test that measures depression and emotional instability as well as irritability, a simple screening test confirmed at Baylor to predict the outcome of more extensive neuropsychological testing. Murphy pointed out why it matters to determine a patient’s cognitive status: more patients with cognitive impairment refuse choices of breathing and feeding aids and are more likely to have falls and choking episodes. The noncompliance produces distress for caregivers. These patients are assumed to be participating in decisions as competent individuals when their judgment may in fact be impaired.

Vladimir Hachinski, M.D., of the University of Western Ontario, shared the perspective of cognitive testing to detect vascular reasons for cognitive impairment—from small strokes. He said that a similar diagnosis dichotomy exists as with FTD and ALS in that Alzheimer’s clinicians are not stroke experts and vice versa. It is difficult to distinguish mixed dementia, in which both vascular damage and Alzheimer’s can co-exist. He has developed a test that measures executive function, not captured well by existing cognitive tests.

Andrew Kertesz, M.D., also at the University of Western Ontario, who helped devise the Neary critieria to diagnose FTD, cautioned against subdividing the disorder too much according to subtle pathology and cognitive versus behavioral criteria. He described the tests that best capture FTD, including the Frontal Behavioral Inventory, although this test also detects impairment that can come with vascular damage. Listening to the caregiver’s description of changes in behavior is critical, he noted.

Treatment Options

Richard Caselli, M.D., of Mayo Clinic, Scottsdale, Ariz., emphasized that any treatment of FTD is off label use. He also cautioned that some conditions can look a lot like FTD but can be cured. Detecting motor neuron disease in the elderly is difficult. Normal aging brings motor and cognitive consequences.

Richard Smith, M.D., of the Center for Neurologic Study in La Jolla, Calif., described the exaggerated emotional responses in many people with motor neuron diseases and reviewed the effect of the combination of dextromethorphan and quinidine to help in this aspect. The drug combination has not been approved by the FDA due to concern over potential of the quinidine to adversely affect the heart.

Future Directions

Howard Feldman of the University of British Columbia shared the pitfalls encountered by researchers in the field of mild cognitive impairment (MCI). No useful findings have emerged from a huge investment of research effort toward identifying which people with MCI may progress to Alzheimer’s disease, and the field is moving away from the concept. Instead, Feldman said, researchers need an objective footprint of the disease, and this is similar to the issues faced in FTD. The ApoE4 gene variant appears to be a valid risk factor for Alzheimer’s disease. Perhaps the progranulin gene change can serve for FTD, he suggested. People who have the gene change can be studied early to see what might predict FTD, and a paper has been submitted for publication that details symptoms in 31 cases studied from families with progranulin mutation.

Consensus needs to be achieved in which cognitive tests and which pathology hallmarks can best help diagnose the changes in behavior and mental processes that can accompany ALS. Through the fruitful discussions that took place around the formal presentations at this meeting, tools will soon be developed that will aid clinicians and guide caregivers in how to meet the challenges posed by this complex disorder.