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Individuals under the age of 65 years are as likely to be afflicted by frontotemporal dementia (FTD) as by Alzheimer's disease (AD). While FTD onset can occur as early as age 45, it also progresses more rapidly than AD and causes far more severe burdens on caregivers and families. Yet, FTD continues to be understudied, and it also is often poorly diagnosed and mismanaged.
“FTD has received scant attention although it is a very significant cause of dementia,” said Lennart Mucke, director of the Gladstone Institute of Neurological Disease (GIND). “For example, relatively few papers cite animal models related to FTD, even though animal models have been critical for our studies of AD.” The GIND has made significant contributions to the understanding of AD, Huntington's disease, Parkinson’s disease, and other neurodegenerative disorders.
New FTD Collaboration
Now Gladstone and UCSF's Memory and Aging Center have embarked on a bold new initiative to find a cure or better treatments for FTD in 10 years. The Richards Investigators Consortium for Frontotemporal Dementia Research was established in memory of the late Alice Richards, who died of FTD last year and the Richards family is funding the research. Her son-in-law and Gladstone investigator Robert Farese, Jr., says the Consortium will take a “Manhattan Project” approach to tackle the devastating disease. “We have focused the expertise of a small group of highly interactive investigators on this condition, reducing bureaucracy to enable rapid exchange of information, reagents, and processes,” Dr. Farese said.
“This is a unique opportunity to regain lost time in addressing FTD,” said Dr. Mucke. “While we know it may be closely connected to the origins of other neurological disease, research is needed to make the connections and find pathways to treatment.”
Progressive Personality Changes
The clinical diagnosis of FTD is based on progressive personality change and language impairment related to atrophy of frontotemporal brain regions. Patients often experience changes in behavior associated with a lack of inhibition, resulting in impulsive, inappropriate, or even self-destructive behavior.
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In other cases, patients experience progressive changes in their ability to use language even though other cognitive functions remain intact. Over time, patients use less and less language, eventually becoming essentially mute.
The cause of FTD is unclear. “There seems to be a genetic component in about 40% of cases,” said Erik Roberson, Gladstone staff scientist. A proportion of familial FTD results from mutations in the gene for the microtubule-associated protein tau. The most common pathological features associated with FTD are neuronal cytoplasmic inclusions and neurites that are immunoreactive for another protein called ubiquitin but not for tau, yielding a form of FTD called FTDU-17.
Progranulin Holds a Key
FTDU-17 is likely caused by mutations in the gene for progranulin. Progranulin is a growth factor that participates in many physiological and pathological processes, including inflammation. Interestingly, all familial mutations lead to reduced progranulin levels, probably because the mutant transcripts are degraded. These observations suggest that a reduction in the levels of progranulin leads to neurodegeneration, but the mechanism is unknown.
In the brain, progranulin is expressed in both neurons and microglia. In FTD brains, microglia are often activated and secrete toxic factors that may injure neurons. These processes involve a careful balance of a cascade of factors. Intact progranulin is an anti-inflammatory: it inhibits tumor necrosis factor. However, cleavage of progranulin by an enzyme called elastase generates the proteolytic fragments called epithelins, which stimulate the production of inflammatory cytokines, such as interleukin 8. The elastase activity is counteracted by its endogenous inhibitor, secretory leukocyte protease inhibitor, which blocks the inflammatory response of macrophage and monocytes to microbial products.
“FTD is likely to be as challenging as AD has been,” said Dr. Farese. “But I am excited about the surge of interest in this little-studied disease here at Gladstone, where so much progress has been made against AD.”
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