Precision Medicine for Frontotemporal Dementia

Abstract

Frontotemporal dementia (FTD) is a common young-onset dementia presenting with heterogeneous and distinct syndromes. It is characterized by progressive deficits in behavior, language, and executive function. The disease may exhibit similar characteristics to many psychiatric disorders owing to its prominent behavioral features. The concept of precision medicine has recently emerged, and it involves neurodegenerative disease treatment that is personalized to match an individual's specific pattern of neuroimaging, neuropathology, and genetic variability. In this paper, the pathophysiology underlying FTD, which is characterized by the selective degeneration of the frontal and temporal cortices, is reviewed. We also discuss recent advancements in FTD research from the perspectives of clinical, imaging, molecular characterizations, and treatment. This review focuses on the approach of precision medicine to manage the clinical and biological complexities of FTD.

Case Report: Early-Onset Behavioral Variant Frontotemporal Dementia in Patient With Retrotransposed Full-Length Transcript of Matrin-3 Variant 5

“…There are three clinical presentations of FTD: behavioral variant (bvFTD) and two forms of primary progressive aphasia, wherein non-fluent or fluent aphasia are the key neurologic deficits ( 4 , 5 ). In addition, FTD can overlap with other neurodegenerative disease motor deficits including: corticobasal degeneration, progressive supranuclear palsy, and amyotrophic lateral sclerosis (ALS) ( 6 ). Approximately 30–50% of FTD cases have some family history of dementia, parkinsonism or ALS ( 7 ), and in 10–20% a genetic cause is found ( 8 ).…”

“…FTLD-tau accounts for ~45% of all cases, followed by FTLD-FUS in <5% of cases ( 13 ). The majority of individuals with FTLD-FUS are diagnosed with sporadic, early-onset bvFTD ( 6 ).…”

Research advances in neuroimaging and genetic characteristics of the non-fluent/agrammatic variant of primary progressive aphasia

“…In the human brain, alternative mRNA splicing of the microtubule-associated protein tau gene produces six tau isoforms, each of which exhibits either three or four repeat domains in the C-terminal part (3R and 4R tau). [ 11 , 12 ] Three microtubule repeats (3R) is associated with Pick disease, while the presence of four microtubule repeats (4R) is associated with PSP and CBD. 3R and 4R tauopathies are also strongly associated with naPPA.…”

“…Patients with progranulin ( GRN ) gene mutations exhibit type A, although both the behavioral variant of frontotemporal dementia and naPPA can occur even without GRN mutations. [ 12 ] Most naPPA-3R-tau patients on neuroimaging analysis show gray matter atrophy found in the insula, frontal lobe, the precentral gyrus, and bilateral orbitofrontal cortex. White matter atrophy involves bilaterally the superior longitudinal fasciculus and anterior corona radiata, but with prevalence in the left hemisphere.…”

Language impairment as diagnostic clue to lvPPA in a young-onset dementia patient mimicking bvFTD

“…The neuropsychiatric symptoms are relatively infrequently early (Modirrousta et al, 2013). On the contrary, patients with behavior variant frontotemporal dementia (bvFTD) have prominent behavior symptoms, but less language deficits than patients with primary progressive aphasia (PPA) (Liu et al, 2019). It is challenging to differentiate lvPPA from bvFTD in patients with prominent behavioral symptoms with subtle language deficit at the beginning of the illness, and an accurate diagnosis could potentially alter treatment strategy.…”