Art depiction of a brain inside a human head

The Frontotemporal Dementia and Related Disorders Laboratory of Rosa Rademakers, Ph.D., at Mayo Clinic in Florida, focuses on the identification of novel causal genes and genetic risk factors for early-onset dementias and related disorders to improve the diagnosis and treatment of people with these disorders.

One of these types of early-onset dementia, frontotemporal lobar degeneration (FTLD), is the second most common form after Alzheimer's disease (AD), accounting for 5 to 10 percent of all dementia patients and 10 to 20 percent of patients with an onset of dementia before the age of 65. Up to 50 percent of FTLD patients report a family history of dementia, suggesting a strong genetic component to the disease. FTLD usually affects patients in midlife, but onset of symptoms can vary between the ages of 35 and 75 years.

The most common clinical manifestation of FTLD is frontotemporal dementia (FTD), whereby people have an early alteration in personality and social conduct, characterized by inertia, loss of volition and disinhibition, followed by more general cognitive decline, eventually leading to dementia. Sometimes FTD is accompanied by signs of parkinsonism or by amyotrophic lateral sclerosis. The neuropathology associated with most people who have FTD is characterized by atrophy of the frontal and temporal lobes and the presence of abnormal intracellular protein aggregates of the tau protein or the TAR DNA-binding protein 43. Interestingly, the same protein is deposited in the spinal cord of people affected with amyotrophic lateral sclerosis (ALS).

Using classical linkage analyses in extended multigenerational families, enormous progress has been made in the last decade with respect to the identification of novel FTLD and ALS disease genes. Despite these advances, the cause of 50 percent of familial FTLD and 40 percent of familial ALS and the majority of all sporadic FTLD and ALS cases is still unknown. However, multigenerational families without mutations in the known genes have become rare, and the majority of people in which the genetic cause is currently unexplained have a complex disease inheritance.

The Frontotemporal Dementia and Related Disorders Laboratory has therefore started the use of exome and whole-genome sequencing to identify novel genetic causes. Understanding the genetic factors responsible for the extensive clinical variability observed in people with known disease mutations is an additional focus of research.

While there are currently no treatments to slow or stop the progression of FTLD and related disorders, the identification of mutations in the microtubule associated protein tau, progranulin (GRN) and repeat expansions in the chromosome 9 open reading frame 72 gene (C9orf72) have yielded an important understanding of the pathogenic mechanisms underlying these devastating diseases and enabled the generation of transgenic models. Additional research in the laboratory is in improving the understanding of the regulation of GRN and C9orf72 expression, with the goal to identify novel molecular targets for disease therapy.