Modelling the cascade of biomarker changes in progranulin‐related frontotemporal dementia

AbstractBackgroundProgranulin related frontotemporal dementia (FTD‐GRN) is a fast progressive disorder, in which pathophysiological changes precede overt clinical symptoms in only a short time period. Modelling the cascade of multimodal biomarker changes aids in understanding the etiology of this disease, enables monitoring of individual mutation carriers, and would give input for disease‐modifying treatments. In this cross‐sectional study, we estimated the temporal cascade of biomarker changes for FTD‐GRN, in a data‐driven way.MethodWe included 56 presymptomatic and 35 symptomatic GRN mutation carriers, and 35 healthy non‐carriers. Of the symptomatic subjects, 17 had behavioural variant FTD (bvFTD), 16 presented as non‐fluent variant primary progressive aphasia (nfvPPA). The selected biomarkers for establishing the cascade of changes were neurofilament light chain, regional grey matter volumes, fractional anisotropy of white matter tracts, and cognitive domains. We used a data‐driven analysis called discriminative event‐based modelling (Venkatraghavan, NeuroImage, 2019) with a novel modification to its Gaussian Mixture Model (GMM) called Siamese GMM, to estimate the cascade of biomarker changes for FTD‐GRN. Using cross‐validation, we estimated disease severities of individual mutation carriers in the test set based on their progression along the biomarker cascade established on the training set.ResultNeurofilament light chain and white matter tracts were the earliest biomarkers to become abnormal in FTD‐GRN mutation carriers. Attention and executive functioning were also affected early on in the disease process. Based on the estimated individual disease severities, presymptomatic mutation carriers could be distinguished from symptomatic mutation carriers with a sensitivity of 95% and specificity of 100% in the cross‐validation experiment. There was a high correlation (r=0.94, p<0.001) between estimated disease severity and years since symptom onset in nfvPPA, but not in bvFTD (r=0.33, p=0.46).ConclusionIn this study, we unravelled the temporal cascade of multimodal biomarker changes for FTD‐GRN. Our results suggest that axonal degeneration is one of the first disease events in FTD‐GRN, which calls for designing disease modifying treatments that strengthens the axons. We also demonstrated a good delineation between symptomatic and presymptomatic carriers using the estimated disease severities, which suggest that our model could enable monitoring of individual mutation carriers

A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors

Background: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. Methods: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. Results: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. Conclusions: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.</p

Progranulin Levels in Plasma and Cerebrospinal Fluid in Granulin Mutation Carriers

Background: Pathogenic mutations in the granulin gene (GRN) are causative in 5-10% of patients with frontotemporal dementia (FTD), mostly leading to reduced progranulin protein (PGRN) levels. Upcoming therapeutic trials focus on enhancing PGRN levels. Methods: Fluctuations in plasma PGRN (n = 41) and its relationship with cerebrospinal fluid (CSF, n = 32) and specific single nucleotide polymorphisms were investigated in pre- and symptomatic GRN mutation carriers and controls. Results: Plasma PGRN levels were lower in carriers than in controls and showed a mean coefficient of variation of 5.3% in carriers over 1 week. Although plasma PGRN correlated with CSF PGRN in carriers (r = 0.54, p = 0.02), plasma only explained 29% of the variability in CSF PGRN. rs5848, rs646776 and rs1990622 genotypes only partly explained the variability of PGRN levels between subjects. Conclusions: Plasma PGRN is relatively stable over 1 week and therefore seems suitable for treatment monitoring of PGRN-enhancing agents. Since plasma PGRN only moderately correlated with CSF PGRN, CSF sampling will additionally be needed in therapeutic trials

Clinical value of neurofilament and phospho-tau/tau ratio in the frontotemporal dementia spectrum

OBJECTIVE: To examine the clinical value of neurofilament light chain (NfL) and the phospho-tau/total tau ratio (p/t-tau) across the entire frontotemporal dementia (FTD) spectrum in a large, well-defined cohort. METHODS: CSF NfL and p/t-tau levels were studied in 361 patients with FTD: 179 behavioral variant FTD, 17 FTD with motor neuron disease (FTD-MND), 36 semantic variant primary progressive aphasia (PPA), 19 nonfluent variant PPA, 4 logopenic variant PPA (lvPPA), 42 corticobasal syndrome, and 64 progressive supranuclear palsy. Forty-five cognitively healthy controls were also included. Definite pathology was known in 68 patients (49 frontotemporal lobar degeneration [FTLD]-TDP, 18 FTLD-tau, 1 FTLD-FUS). RESULTS: NfL was higher in all diagnoses, except lvPPA (n = 4), than in controls, equally elevated in behavioral variant FTD, semantic variant PPA, nonfluent variant PPA, and corticobasal syndrome, and highest in FTD-MND. The p/t-tau was lower in all clinical groups, except lvPPA, than in controls and lowest in FTD-MND. NfL did not discriminate between TDP and tau pathology, while the p/t-tau ratio had a good specificity (76%) and moderate sensitivity (67%). Both high NfL and low p/t-tau were associated with poor survival (hazard ratio on tertiles 1.7 for NfL, 0.7 for p/t-tau). CONCLUSION: NfL and p/t-tau similarly discriminated FTD from controls, but not between clinical subtypes, apart from FTD-MND. Both markers predicted survival and are promising monitoring biomarkers for clinical trials. Of note, p/t-tau, but not NfL, was specific to discriminate TDP from tau pathology in vivo. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with cognitive issues, CSF NfL and p/t-tau levels discriminate between those with and without FTD spectrum disorders

Sex hormone-binding globulin (SHBG) in cerebrospinal fluid does not discriminate between the main FTLD pathological subtypes but correlates with cognitive decline in FTLD tauopathies

Biomarkers to discriminate the main pathologies underlying frontotemporal lobar degeneration (FTLD-Tau, FTLD-TDP) are lacking. Our previous FTLD cerebrospinal fluid (CSF) proteome study revealed that sex hormone-binding globulin (SHBG) was specifically increased in FTLD-Tau patients. Here we investigated the potential of CSF SHBG as a novel biomarker discriminating the main FTLD pathological subtypes. SHBG was measured in CSF samples from patients with FTLD-Tau (n = 23), FTLD-TDP (n = 29) and controls (n = 33) using an automated electro-chemiluminescent immunoassay. Differences in CSF SHBG levels across groups, as well as its association with CSF YKL40, pTau181/total-Tau ratio and cognitive function were analyzed. CSF SHBG did not differ across groups, though a trend towards elevated levels in FTLD-Tau cases compared to FTLD-TDP and controls was observed. CSF SHBG levels were not associated with either CSF YKL40 or the p/tTau ratio. They, however, inversely correlated with the MMSE score (r = −0.307, p = 0.011), an association likely driven by the FTLD-Tau group (r FTLD-Tau = −0.38; r FTLD-TDP = −0.02). CSF SHBG is not a suitable biomarker to discriminate FTLD-Tau from FTLD-TDP.</p

Clinical value of cerebrospinal fluid neurofilament light chain in semantic dementia

Background: Semantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of disease-modifying agents may be facilitated by the relative clinical and pathological homogeneity of SD, but we need robust monitoring biomarkers to measure their efficacy. In different FTLD subtypes, neurofilament light chain (NfL) is a promising marker, therefore we investigated the utility of cerebrospinal fluid (CSF) NfL in SD. Methods: This large retrospective multicentre study compared cross-sectional CSF NfL levels of 162 patients with SD with 65 controls. CSF NfL levels of patients were correlated with clinical parameters (including survival), neuropsychological test scores and regional grey matter atrophy (including longitudinal data in a subset). Results: CSF NfL levels were significantly higher in patients with SD (median: 2326 pg/mL, IQR: 1628-3593) than in controls (577 (446-766), p&lt;0.001). Higher CSF NfL levels were moderately associated with naming impairment as measured by the Boston Naming Test (rs=-0.32, p=0.002) and with smaller grey matter volume of the parahippocampal gyri (rs=-0.31, p=0.004). However, cross-sectional CSF NfL levels were not associated with progression of grey matter atrophy and did not predict survival. Conclusion: CSF NfL is a promising biomarker in the diagnostic process of SD, although it has limited cross-sectional monitoring or prognostic abilities.ImPhys/Quantitative Imagin

Three VCP Mutations in Patients with Frontotemporal Dementia

Valosin-containing protein (VCP) is involved in multiple cellular activities. Mutations in VCP lead to heterogeneous clinical presentations including inclusion body myopathy with Paget's disease of the bone, frontotemporal dementia and amyotrophic lateral sclerosis, even in patients carrying the same mutation. We screened a cohort of 48 patients with familial frontotemporal dementia (FTD) negative for MAPT, GRN, and C9orf72 mutations for other known FTD genes by using whole exome sequencing. In addition, we carried out targeted sequencing of a cohort of 37 patients with frontotemporal lobar degeneration with Transactive response DNA-binding protein 43 (TDP-43) subtype from the Netherlands Brain bank. Two novel (p.Thr262Ser and p.Arg159Ser) and one reported (p.Met158Val) VCP mutations in three patients with a clinical diagnosis of FTD were identified, and were absence in population-match controls. All three patients presented with behavioral changes, with additional semantic deficits in one. No signs of Paget or muscle disease were observed. Pathological examination of the patient with VCP p.Arg159Ser mutation showed numerous TDP-43 immunoreactive (IR) neuronal intranuclear inclusions (NII) and dystrophic neurites (DN), while a lower number of NII and DN were observed in the patient with the VCP p.Thr262Ser mutation. Pathological findings of both patients were consistent with FTLD-TDP subtype D. Furthermore, only rare VCP-IR NII was observed in both cases. Our study expands the clinical heterogeneity of VCP mutations carriers, and indicates that other additional factors, such as genetic modifiers, may determine the clinical phenotype

EIF2AK3 variants in Dutch patients with Alzheimer's disease

Next-generation sequencing has contributed to our understanding of the genetics of Alzheimer's disease (AD) and has explained a substantial part of the missing heritability of familial AD. We sequenced 19 exomes from 8 Dutch families with a high AD burden and identified EIF2AK3, encoding for protein kinase RNA-like endoplasmic reticulum kinase (PERK), as a candidate gene. Gene-based burden analysis in a Dutch AD exome cohort containing 547 cases and 1070 controls showed a significant association of EIF2AK3 with AD (OR 1.84 [95% CI 1.07–3.17], p-value 0.03), mainly driven by the variant p.R240H. Genotyping of this variant in an additional cohort from the Rotterdam Study showed a trend toward association with AD (p-value 0.1). Immunohistochemical staining with pPERK and peIF2α of 3 EIF2AK3 AD carriers showed an increase in hippocampal neuronal cells expressing these proteins compared with nondemented controls, but no difference was observed in AD noncarriers. This study suggests that rare variants in EIF2AK3 may be associated with disease risk in AD.Pattern Recognition and Bioinformatic

Cognitive profiles discriminate between genetic variants of behavioral frontotemporal dementia

Introduction: Trials to test disease-modifying treatments for frontotemporal dementia are eagerly awaited and sensitive instruments to assess potential treatment effects are increasingly urgent, yet lacking thus far. We aimed to identify gene-specific instruments assessing clinical onset and disease progression by comparing cognitive functioning between bvFTD patients across genetic mutations. Methods: We examined differences in 7 cognitive domains between bvFTD patients with GRN (n = 20), MAPT (n = 29) or C9orf72 (n = 31) mutations, and non-carriers (n = 24), and described longitudinal (M = 22.6 months, SD = 16.6) data in a subsample (n = 27). Results: Patients showed overall cognitive impairment, except memory recall, working memory and visuoconstruction. GRN patients performed lower on executive function (mean difference − 2.1; 95%CI − 4.1 to − 0.5) compared to MAPT and lower on attention compared to MAPT (mean difference − 2.5; 95%CI − 4.7 to − 0.3) and C9orf72 (mean difference − 2.4; 95%CI − 4.5 to − 0.3). Only MAPT patients were impaired on delayed recall (mean difference − 1.4; 95%CI − 2.1 to − 0.7). GRN patients declined rapidly on attention and memory, MAPT declined in confrontation naming, whereas C9orf72 patients were globally impaired but remained relatively stable over time on all cognitive domains. Discussion: This study shows gene-specific cognitive profiles in bvFTD, which underlines the value of neuropsychological tests as outcome measures in upcoming trials for genetic bvFTD

Correction to: Cognitive profiles discriminate between genetic variants of behavioral frontotemporal dementia (Journal of Neurology, (2020), 267, 6, (1603-1612), 10.1007/s00415-020-09738-y)

The original version of this article unfortunately contained a mistake. The presentation of Table 1 was incorrect. The original article has been corrected. The corrected Table 1 is given below. (Table presented.)