Neurochemical biomarkers in the diagnosis of frontotemporal lobar degeneration: an update

Abstract

Frontotemporal lobar degeneration (FTLD) is a spectrum of rare neurodegenerative diseases with overlapping symptoms and neuropathology. It includes the behavioral variant of frontotemporal dementia (bvFTD), the semantic and non-fluent variant of primary progressive aphasia (svPPA and nfvPPA), FTD with motor neuron disease (FTD-MND), progressive supranuclear palsy, and corticobasal syndrome. The diagnosis of the FTLD spectrum of diseases is based on clinical symptoms which hampers the differentiation of the diseases among each other and with other disorders that show a similar clinical appearance resulting in a high rate of misdiagnoses.This highlights the need for objective and selective measures in the diagnostic criteria and there is extensive research on neurochemical biomarkers in FTLD as one option to address this unmet clinical need. Here, we review the advances in CSF biomarker research in FTLD in the last 2 years with regard to the validation of previously suggested and identification of new biomarker candidates for the differential diagnosis of FTLD. Keywords: biomarker, cerebrospinal fluid, corticobasal syndrome, frontotemporal dementia, frontotemporal lobar degeneration, progressive supranuclear palsy.This article is part of the Frontotemporal Dementia special issue.Frontotemporal lobar degeneration (FTLD) describes a group of neurodegenerative disorders with overlapping symptomatology and neuropathology. The common feature is the degeneration of the frontal and anterior temporal lobe, and at present, the following syndromes are assigned to the FTLD spectrum (Seltman and Matthews 2012): the three types of frontotemporal dementia (FTD) including the behavioral variant of frontotemporal dementia (bvFTD) and the semantic and non-fluent variant of primary progressive aphasia (svPPA and nfvPPA), FTD with motor neuron disease (FTD-MND), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). These syndromes can further be classified as behavioral variant (bvFTD), language variant (svPPA and nfvPPA), and motor variant (FTD-MND, PSP and CBS) of FTLD.FTD is the third most common subtype of neurodegenerative dementia after Alzheimer 0 s disease (AD) and dementia with Lewy bodies (DLB) with an estimated prevalence of 1-26 cases per 100 000 persons and bvFTD accounts for most cases (50-70%) (Bang et al. 2015). The prevalence of PSP is estimated to 4-9 cases per 100 000 persons in the age-group > 60 years (Savica et al. 2013).

ATN status in amnestic and non-amnestic Alzheimer’s disease and frontotemporal lobar degeneration

“…Diagnostic sensitivity and specificity to typical, amnestic AD is high for CSF Aβ1-42, p-tau, and t-tau (Shaw et al, 2009;Ewers et al, 2015;Palmqvist et al, 2015;Hampel et al, 2018), and studies have shown that the ratio of p-tau to is especially accurate at stratifying patients with AD pathology from another form of neurodegenerative disease, frontotemporal lobar degeneration (FTLD) (Struyfs et al, 2015;Oeckl et al, 2016;Lleó et al, 2018). Still, these studies demonstrate partial overlap in CSF levels between pathologic AD and FTLD.…”

Intrafamilial variable phenotype including corticobasal syndrome in a family with p.P301L mutation in the MAPT gene: first report in South America

“…FTLD shows overlapping symptoms including behavioral and personality changes, language impairment, deficits in executive functioning, variable combinations of hyperkinetic or hypokinetic movement disorders (parkinsonism) and/or motor –neuron disease (Pottier et al 2016; Mackenzie et al 2016; Oeckl et al 2016; Baizabal-Carvallo et al 2016). …”

“…In the last few years a number of different mutations in the MAPT , progranulin ( GRN ) and C9orf72 have been shown to cause autosomal dominant forms of FTLD (FTD, PSP and CBS) (Pottier C et al 2016; Mackenzie IR et al 2016; Oeckl Pet al 2016; Baizabal-Carvallo JF et al 2016). Although no clear genotype-phenotype correlation has been established for all, more than 55 mutations in MAPT have classically been assigned as causative of autosomal dominant FTD, primary progressive aphasia (PPA), and PSP.…”

Frontotemporal dementia: from molecular mechanisms to therapy

“…This highlights the need for the development of sensitive and selective biomarkers (Oeckl et al . ) as well as imaging technologies (Gordon et al . ) with the attempt to stratify sporadic FTD patients according to their underlying molecular subgroup over a lifetime and to develop markers for monitoring disease progression and staging for use in clinical trials.…”

“…Woollacott and Rohrer (Woollacott and Rohrer 2016) summarize the spectrum of clinical syndromes and features subsumed under the term FTD and discuss not only the clinical differences but also dramatic overlaps between the distinct neuropathological and genetic FTD forms. This highlights the need for the development of sensitive and selective biomarkers (Oeckl et al 2016) as well as imaging technologies (Gordon et al 2016) with the attempt to stratify sporadic FTD patients according to their underlying molecular subgroup over a lifetime and to develop markers for monitoring disease progression and staging for use in clinical trials. Similar to amyloid PET imaging for the in vivo monitoring of Ab pathology in AD, novel technologies such as selective tau or TDP-43 tracers for PET imaging will be of great value to enroll patients with a clear diagnosis into clinical trials.…”