Modelling the cascade of biomarker changes in <i>GRN</i>-related frontotemporal dementia

Panman, Jessica L.; Venkatraghavan, Vikram; Ende, Emma L. van der; Steketee, Rebecca M. E.; Jiskoot, Lize C.; Poos, Jackie M.; Dopper, Elise G.P.; Meeter, Lieke H.H.; Kaat, Laura Donker; Rombouts, Serge A.R.B.; Vernooij, Meike W.; Kievit, Anneke J.A.; Premi, Enrico; Cosseddu, Maura; Bonomi, Elisa; Olives, Jaume; Rohrer, Jonathan D.; Sánchez‐Valle, Raquel; Borroni, Barbara; Bron, Esther E.; Swieten, John C. van; Papma, Janne M.; Klein, Stefan

doi:10.1136/jnnp-2020-323541

Cited by 29 publications

(40 citation statements)

References 42 publications

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“…In keeping with these studies, low CSF PRGN and high CSF NfL levels predicted the presence of GRN variants. Measurement of PRGN is well established as a state marker for GRN -associated FTD, whereas NfL has only recently been introduced as a trait marker indicating the onset of the disease with an increase of levels 2–4 years before conversion [ 53 , 54 ]. Interestingly, in patients with variants in GRN , levels continuously increased, whereas in other genetic forms of FTD, levels remained stable after conversion.…”

Section: Discussionmentioning

confidence: 99%

Clinico-genetic findings in 509 frontotemporal dementia patients

et al. 2021

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Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. To which extent genetic aberrations dictate clinical presentation remains elusive. We investigated the spectrum of genetic causes and assessed the genotype-driven differences in biomarker profiles, disease severity and clinical manifestation by recruiting 509 FTD patients from different centers of the German FTLD consortium where individuals were clinically assessed including biomarker analysis. Exome sequencing as well as C9orf72 repeat analysis were performed in all patients. These genetic analyses resulted in a diagnostic yield of 18.1%. Pathogenic variants in C9orf72 (n = 47), GRN (n = 26), MAPT (n = 11), TBK1 (n = 5), FUS (n = 1), TARDBP (n = 1), and CTSF (n = 1) were identified across all clinical subtypes of FTD. TBK1-associated FTD was frequent accounting for 5.4% of solved cases. Detection of a homozygous missense variant verified CTSF as an FTD gene. ABCA7 was identified as a candidate gene for monogenic FTD. The distribution of APOE alleles did not differ significantly between FTD patients and the average population. Male sex was weakly associated with clinical manifestation of the behavioral variant of FTD. Age of onset was lowest in MAPT patients. Further, high CSF neurofilament light chain levels were found to be related to GRN-associated FTD. Our study provides large-scale retrospective clinico-genetic data such as on disease manifestation and progression of FTD. These data will be relevant for counseling patients and their families.

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Section: Discussionmentioning

confidence: 99%

Clinico-genetic findings in 509 frontotemporal dementia patients

et al. 2021

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“…As well as cognitive and behavioural changes, serum NfL levels have been shown to be valuable markers of disease severity in genetic and sporadic FTD [ 12 , 14 , 15 , 17 , 35 – 37 ]. In line with studies on genetic FTD, in this work we observed that serum NfL levels were significantly increased already in the prodromal phases of disease compared with healthy controls, but still considerably lower than patients with mild, moderate or severe FTD.…”

Section: Discussionmentioning

confidence: 99%

Prodromal frontotemporal dementia: clinical features and predictors of progression

et al. 2021

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Background The prodromal phase of frontotemporal dementia (FTD) is still not well characterized, and conversion rates to dementia and predictors of progression at 1-year follow-up are currently unknown. Methods In this retrospective study, disease severity was assessed using the global CDR plus NACC FTLD. Prodromal FTD was defined to reflect mild cognitive or behavioural impairment with relatively preserved functional independence (global CDR plus NACC = 0.5) as well as mild, moderate and severe dementia (classified as global CDR plus NACC = 1, 2, 3, respectively). Disease progression at 1-year follow-up and serum NfL measurements were acquired in a subgroup of patients. Results Of 563 participants, 138 were classified as prodromal FTD, 130 as mild, 175 as moderate and 120 as severe FTD. In the prodromal and mild phases, we observed an early increase in serum NfL levels followed by behavioural disturbances and deficits in executive functions. Negative symptoms, such as apathy, inflexibility and loss of insight, predominated in the prodromal phase. Serum NfL levels were significantly increased in the prodromal phase compared with healthy controls (average difference 14.5, 95% CI 2.9 to 26.1 pg/mL), but lower than in patients with mild FTD (average difference -15.5, 95% CI -28.4 to -2.7 pg/mL). At 1-year follow-up, 51.2% of patients in the prodromal phase had converted to dementia. Serum NfL measurements at baseline were the strongest predictors of disease progression at 1-year follow-up (OR 1.07, 95% CI 1.03 to 1.11, p < 0.001). Conclusions Prodromal FTD is a mutable stage with high rate of progression to fully symptomatic disease at 1-year follow-up. High serum NfL levels may support prodromal FTD diagnosis and represent a helpful marker to assess disease progression.

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“…Not surprisingly, the rate of serum NFL increase during follow-up was higher in converters compared with non-converting presymptomatic carriers (van der Ende et al, 2019). A very recent study of the GENFI including presymptomatic and symptomatic GRN mutation carriers investigating the temporal cascade of multimodal biomarkers by means of discriminative event-based modeling (DEBM) demonstrated that, both in bvFTD and in nfvPPA, serum NFL is-together with language-the first biomarker to become abnormal in this genetic form of FTD (Panman et al, 2021). Heller et al (2020b) investigated plasma NFL in a large cohort comprising 196 presymptomatic and 90 symptomatic carriers of GRN and MAPT mutations and the C9orf72 HRE as well as 183 neurologically healthy non-carriers belonging to the same families.…”

Section: Nfl In Genetic Forms Of Ftdmentioning

confidence: 99%

Neurofilament Light Chain as Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

2021

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related currently incurable neurodegenerative diseases. ALS is characterized by degeneration of upper and lower motor neurons causing relentless paralysis of voluntary muscles, whereas in FTD, progressive atrophy of the frontal and temporal lobes of the brain results in deterioration of cognitive functions, language, personality, and behavior. In contrast to Alzheimer’s disease (AD), ALS and FTD still lack a specific neurochemical biomarker reflecting neuropathology ex vivo. However, in the past 10 years, considerable progress has been made in the characterization of neurofilament light chain (NFL) as cerebrospinal fluid (CSF) and blood biomarker for both diseases. NFL is a structural component of the axonal cytoskeleton and is released into the CSF as a consequence of axonal damage or degeneration, thus behaving in general as a relatively non-specific marker of neuroaxonal pathology. However, in ALS, the elevation of its CSF levels exceeds that observed in most other neurological diseases, making it useful for the discrimination from mimic conditions and potentially worthy of consideration for introduction into diagnostic criteria. Moreover, NFL correlates with disease progression rate and is negatively associated with survival, thus providing prognostic information. In FTD patients, CSF NFL is elevated compared with healthy individuals and, to a lesser extent, patients with other forms of dementia, but the latter difference is not sufficient to enable a satisfying diagnostic performance at individual patient level. However, also in FTD, CSF NFL correlates with several measures of disease severity. Due to technological progress, NFL can now be quantified also in peripheral blood, where it is present at much lower concentrations compared with CSF, thus allowing less invasive sampling, scalability, and longitudinal measurements. The latter has promoted innovative studies demonstrating longitudinal kinetics of NFL in presymptomatic individuals harboring gene mutations causing ALS and FTD. Especially in ALS, NFL levels are generally stable over time, which, together with their correlation with progression rate, makes NFL an ideal pharmacodynamic biomarker for therapeutic trials. In this review, we illustrate the significance of NFL as biomarker for ALS and FTD and discuss unsolved issues and potential for future developments.

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Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia

Cited by 29 publications

References 42 publications

Clinico-genetic findings in 509 frontotemporal dementia patients

Clinico-genetic findings in 509 frontotemporal dementia patients

Prodromal frontotemporal dementia: clinical features and predictors of progression

Neurofilament Light Chain as Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

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