The Use of Biomarkers and Genetic Screening to Diagnose Frontotemporal Dementia: Evidence and Clinical Implications

Abstract

Within the wide range of neurodegenerative brain diseases, the differential diagnosis of frontotemporal dementia (FTD) frequently poses a challenge. Often, signs and symptoms are not characteristic of the disease and may instead reflect atypical presentations. Consequently, the use of disease biomarkers is of importance to correctly identify the patients. Here, we describe how neuropsychological characteristics, neuroimaging and neurochemical biomarkers and screening for causal gene mutations can be used to differentiate FTD from other neurodegenerative diseases as well as to distinguish between FTD subtypes. Summarizing current evidence, we propose a stepwise approach in the diagnostic evaluation. Clinical consensus criteria that take into account a full neuropsychological examination have relatively good accuracy (sensitivity [se] 75–95%, specificity [sp] 82–95%) to diagnose FTD, although misdiagnosis (mostly AD) is common. Structural brain MRI (se 70–94%, sp 89–99%) and FDG PET (se 47–90%, sp 68–98%) or SPECT (se 36–100%, sp 41–100%) brain scans greatly increase diagnostic accuracy, showing greater involvement of frontal and anterior temporal lobes, with sparing of hippocampi and medial temporal lobes. If these results are inconclusive, we suggest detecting amyloid and tau cerebrospinal fluid (CSF) biomarkers that can indicate the presence of AD with good accuracy (se 74–100%, sp 82–97%). The use of P-tau 181 and the Aβ 1 – 42 /Aβ 1 – 40 ratio significantly increases the accuracy of correctly identifying FTD vs. AD. Alternatively, an amyloid brain PET scan can be performed to differentiate FTD from AD. When autosomal dominant inheritance is suspected, or in early onset dementia, mutation screening of causal genes is indicated and may also be offered to at-risk family members. We have summarized genotype–phenotype correlations for several genes that are known to cause familial frontotemporal lobar degeneration, which is the neuropathological substrate of FTD. The genes most commonly associated with this disease ( C9orf72, MAPT, GRN, TBK1 ) are discussed, as well as some less frequent ones ( CHMP2B, VCP ). Several other techniques, such as diffusion tensor imaging, tau PET imaging and measuring serum neurofilament levels, show promise for future implementation as diagnostic biomarkers.

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

“…Lack of specific and sensitive biomarkers are another roadblock in the development of therapies for FTD [40]. Importantly, appropriate biomarkers are useful for monitoring disease progression as well as assessing the efficacy of potential drugs.…”

“…Another roadblock in the development of therapies for FTD is a lack of specific and sensitive biomarkers [40]. The identification of reliable biomarkers is important to distinguish FTD from Alzheimer's disease or other neurodegenerative diseases.…”

Genetic study ofyoung‐onsetdementia using targeted gene panel sequencing in Taiwan

“…FTD is a clinically, genetically, and pathologically heterogeneous disorder that frequently overlaps with parkinsonism syndrome and motor neuron disorder (Gossye, Van Broeckhoven, & Engelborghs, 2019). The genetic causes of young‐onset FTD in our population were heterogeneous and different than in Caucasian populations.…”

Proton Magnetic Resonance Spectroscopy in Common Dementias—Current Status and Perspectives

“…More frequently than other common dementias, FTD shows a dominant inheritance pattern (10–23 % of the patients), with mutations in the MAPT gene (microtubule associated protein tau) being found in several affected families [for review see Gossye et al. ( 72 )]. In two studies, asymptomatic and symptomatic MAPT mutation carriers were investigated, providing insights into early metabolic changes in the brains of affected individuals.…”