The DOI matches its Crossref record; 63 of the 75 references it cites were found in a registry or an index; 18 of the 24 sources its claims cite were checked for support.
Temporal order of clinical and biomarker changes in familial frontotemporal dementia
Open accessAbstract
Unlike familial Alzheimer's disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects.
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56 Own result · 27 Own method · 17 Own interpretation · 6 Partly supported · 4 Supported · 3 No basis given · 2 Sources not found · 2 No full text of the sources · 2 Not checked yet · 1 Not supported · 1 Couldn’t confirm · accuracy not yet measured
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In the paper
“Experience from Alzheimer’s disease (AD), spinal muscular atrophy (SMA),5 and amyotrophic lateral sclerosis (ALS)6 suggests treating FTD will be most successful if treatment is initiated early in the disease course, ideally prior to the onset of symptoms.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Abstract
What the sources say
- Partly supportedcites [5] Mercuri, E. et al. Nusinersen versus sham control in later-onset spinal muscular atrophy. N. Engl. J. Med. 378, 625–635 (2018). sourceExperimental — accuracy not yet measured
The Discussion reports the greatest motor-function improvements in children with SMA who received nusinersen soon after symptom onset, supporting the early-treatment rationale. It does not establish a benefit from treatment before symptoms appear; applying the SMA finding to FTD is the citing authors’ inference. (LLM, conf=0.88)
- Could not verifycites [6] Miller, T. et al. Phase 1-2 trial of antisense oligonucleotide tofersen for SOD1 ALS. N. Engl. J. Med. 383, 109–119 (2020). sourceExperimental — accuracy not yet measured
The Characteristics of the Participants section says all trial participants had ALS symptoms at illness onset. The Exploratory Outcomes and discussion describe tofersen results but do not compare treatment started at different disease stages or address treatment before symptoms. Searches for presymptomatic and early treatment found no passage supporting the timing claim. (LLM, conf=0.76)
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In the paper
“For example, in GRN, familial age of onset only explains 14% of the variability in individual age at symptom onset.12”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Abstract
What the sources say
- Partly supportedcites [12] Moore, K. M. et al. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study. Lancet Neurol. 19, 145–156 (2020). sourceExperimental — accuracy not yet measured
The Results report that family membership explained 14% (95% CI 9–22) of the variability in age at symptom onset among people with GRN mutations. That is not the same as saying familial age at onset explained 14%: the paper analyzes mean family age at onset separately and reports a correlation of r=0.18 with individual age at onset (Abstract, Findings). (LLM, conf=0.88)
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In the paper
“In C9orf72, the thalamus and most other brain regions were smaller than controls 10 to 40 years prior to onset, supporting the hypothesis that C9orf72 repeat expansions may affect early brain development.19,20”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
What the sources say
- Supportedcites [19] Lee, S. E. et al. Network degeneration and dysfunction in presymptomatic C9ORF72 expansion carriers. NeuroImage Clin. 14, 286–297 (2017). sourceExperimental — accuracy not yet measured
Section 4.2 explicitly raises abnormal brain development as a possible explanation for the deficits in presymptomatic C9ORF72 expansion carriers. The paper presents this as a hypothesis, matching the claim’s cautious wording. (LLM, conf=0.93)
- Supportedcites [20] Caverzasi, E. et al. Gyrification abnormalities in presymptomatic c9orf72 expansion carriers. J. Neurol. Neurosurg. Psychiatry 90, 1005–1010 (2019). sourceExperimental — accuracy not yet measured
The Introduction says abnormalities in presymptomatic c9orf72 expansion carriers may reflect abnormal brain development, while acknowledging that early neurodegeneration remains possible. The section on low gyrification reports findings in carriers as young as their 30s and suggests the deficits may be neurodevelopmental, supporting the claim’s cautious wording. (LLM, conf=0.91)
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In the paper
“Known genetic modifiers of f-FTD disease progression were not included, such as specific mutations (for MAPT) and TMEM106B, a modifier of penetrance in GRN.2,40”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
What the sources say
- Partly supportedcites [2] Greaves, C. V. & Rohrer, J. D. An update on genetic frontotemporal dementia. J. Neurol. 266, 2075–2086 (2019). sourceExperimental — accuracy not yet measured
The Age at onset section (page unavailable) identifies TMEM106B as a genetic modifier in GRN carriers and suggests it may affect age-related penetrance. It does not identify specific MAPT mutations as modifiers of disease progression; instead, it says little is known about factors modifying age at onset in MAPT carriers. Whether the citing authors omitted these factors from their analysis is their own description, not a finding attributed to this review. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [40] Pottier, C. et al. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study. Lancet Neurol. 17, 548–558 (2018). source
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In the paper
“In C9orf72, MRI was the first biomarker to change (Figures 2, 3, & Extended Data Figure 1; Tables 2, S2-S5), with visual inspection of the DPM curves suggesting that brain volumes deviate from controls up to 40 years before expected onset.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“We found that the temporal ordering of clinical and biomarker progression differed by genotype.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Abstract
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In the paper
“When ALLFTD and GENFI participants were modeled separately, rates of progression were very similar between consortia on all measures (Figures 1, S1); subsequent models combined all participants.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“The insula was significantly atrophied compared to controls in the −40 to −10 epoch (Extended Data Figure 1, Table S5), and all ROIs had smaller mean volumes than controls in the −10 to 0 epoch, except the striatum (p=0.057).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“NfL concentrations become elevated by one SD compared to controls 4.9 years prior to onset (95%CI:-3.4,-7).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“The longitudinal rate of volume loss was relatively stable across the across epochs in C9orf72 compared to the other genetic groups (Table S4).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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“The frontal and temporal lobes were the first brain regions to differ from controls by one SD in the DPM (−1.1 and −1.2 years before estimated onset, respectively).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“For example, a two-year prevention trial requiring a DA within five years of onset would require sample sizes of 52 total participants for GRN (MRI Frontal), 108 for MAPT (MRI MTL), and 424 for C9orf72 (MRI Temporal) if MRI is used as an endpoint.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Application to Clinical Trials
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In the paper
“Visual inspection of the DPM curves suggested mean NfL values in C9orf72 begin to deviate from controls approximately 30 years before estimated onset.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“This revealed that in more severely impaired mutation carriers at later DA, there was more missing data, particularly MRI.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“Longitudinally, the medial temporal lobe (MTL), followed by the remainder of the temporal lobe, striatum, and insular regions were the regions to lose volume most rapidly in the symptomatic phase (Table S4).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“The remaining temporal regions and insula were the next regions to become atrophied by one SD compared to controls (Table S4), with overlapping credible intervals.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“In the symptomatic stage, NfL levels rose more than twice as fast in GRN than the other genetic groups.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“The largely overlapping credible intervals indicate these differences in temporal ordering are not statistically significant.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“Sample size estimates for prevention trials were generally lowest when using biomarkers (NfL or MRI) as the outcome.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Application to Clinical Trials
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In the paper
“In the symptomatic stage, frontal, temporal and medial temporal, insular, and striatal regions showed the greatest degree of cross-sectional atrophy (Extended Data Figure 1, Figure S4, Table S5).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“This results in considerable uncertainty around exact DA in those furthest from expected onset (e.g., +/-14 years in the −40 to −10 epoch).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“In direct statistical comparison, C9orf72 expansion carriers performed worse than controls on Trails A and B at all DA epochs (Table S5).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“For example, within a population having a CDR®+NACC-FTLD-Global=1 or a DA within 2.5 years of onset in those with a CDR®+NACC-FTLD-Global<1, the estimated sample sizes using CDR®+NACC-FTLD-SB as the primary endpoint for a two-year trial were 68 total participants for GRN, 120 for MAPT, and 124 for C9orf72.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Application to Clinical Trials
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In the paper
“In addition to the thalamus, most ROIs were smaller than controls (Extended data figure 2, Tables S5) and other mutation carriers (Table S6) in the −40 to −10 epoch.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“The insula was significantly atrophied compared to controls in the −40 to −10 epoch (Extended Data Figure 1, Table S5), and all ROIs had smaller mean volumes than controls in the −10 to 0 epoch, except the striatum (p=0.057).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“Because the models incorporate both new and some previously analyzed historical data, we were able to replicate and extend the results of previous studies.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“In C9orf72, the thalamus and most other brain regions were smaller than controls 10 to 40 years prior to onset, supporting the hypothesis that C9orf72 repeat expansions may affect early brain development.19,20”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“In those furthest from onset, when most scores tend to be within normal limits, prior information about their age has a large influence on estimated DA.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“Third, using estimated DA to select high-risk presymptomatic participants for trial enrollment leads to a sizeable reduction in sample sizes.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“GRN also displayed the most rapid rates of NfL increase in the symptomatic epoch (Figures 1&2, Table S4).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“Neuropsychological changes typically occurred later, contemporaneous with the emergence of informant-reported symptoms (CDR®+NACC-FTLD-SB).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“Across all three FTD mutation carrier groups, regional brain atrophy and plasma NfL elevations were the first measurable manifestations of disease, potentially developing 10 to 40 years before the earliest clinical features.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“The medial temporal lobe was the only region with significant volume loss compared to controls in the presymptomatic phase (Extended Data Figure 1, Table S5).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“In C9orf72, MRI was the first biomarker to change (Figures 2, 3, & Extended Data Figure 1; Tables 2, S2-S5), with visual inspection of the DPM curves suggesting that brain volumes deviate from controls up to 40 years before expected onset.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“In mutation carriers with at least one post-baseline visit who were >10 years from expected onset, the average uncertainty of the DA estimate (95%CI) was +/−14.6 years.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“Paralleling the biomarker findings, global disease severity (CDR®+NACC-FTLD-SB) and neuropsychological measures declined more rapidly in GRN than C9orf72 or MAPT mutation carriers.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“Voxelwise quantification also underscored the early thalamic involvement (Extended Data Figure 2, Figure S2).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“Despite differences in analytic methods, and the inclusion of a much larger dataset, the DPMs developed in this study allowed us to replicate the findings of earlier, smaller analyses.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“Similar to the MRI results, GRN exhibited the most rapid CDR®+NACC-FTLD-SB changes following symptom onset (Figure 2, Table S4).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“Brain atrophy and plasma NfL elevations are measurable years prior to symptom onset, paving the way for using these biomarkers in clinical trials of agents that could prevent or delay the clinical manifestations of f-FTD.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In the current study, we verified that the genotype-related patterns of plasma NfL elevation that were measured in two different laboratories, in two independent f-FTD cohorts, were very similar and for the purposes of DPM, could be combined.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The striking concordance in disease progression between the two independent North American and European cohorts supports the validity of the models, suggesting that the natural history of the disease is strongly determined by pathogenic mutations and that global clinical trials of f-FTD therapies are feasible.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The striking concordance in disease progression between the two independent North American and European cohorts supports the validity of the models, suggesting that the natural history of the disease is strongly determined by pathogenic mutations and that global clinical trials of f-FTD therapies are feasible.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The genetic groups displayed differences in patterns of disease progression that are relevant for clinical care and clinical trial planning.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This suggests an important limitation to the use of MRI as an outcome in symptomatic mutation carriers: data may be missing because scans are harder to acquire in advanced patients, possibly because they either cannot travel to research centers or they cannot lie still in a MRI scanner.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Additional recruitment would be required for a C9orf72 prevention trial to be sufficiently powered to detect a 50% treatment effect.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Application to Clinical Trials
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“note that statistical comparisons of this measure should be interpreted with caution given that controls were defined as having a baseline CDR®+NACC-FTLD=0 (as is typical in most clinical dementia research studies) and thus have no variance due to this selection process.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We were also limited in the clinical measures that we could include in the analysis to those that were readily harmonizable between ALLFTD and GENFI, excluding a variety of promising novel measures that were not available in both cohorts.34,35”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The striking concordance in disease progression between the two independent North American and European cohorts supports the validity of the models, suggesting that the natural history of the disease is strongly determined by pathogenic mutations and that global clinical trials of f-FTD therapies are feasible.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The validity of our DPM models is supported by the results of previous studies focusing on individual biomarkers or clinical measures in f-FTD.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“First, using NfL and MRI biomarkers as surrogate endpoints for prevention trials would allow trials to be conducted with many fewer participants than clinical measures.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Finally, the current study is limited by the lack of racial and ethnic diversity of the sample.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The DPM curves suggest that clinical trial endpoint selection might differ by genetic group and disease stage (Figure 2).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Application to Clinical Trials
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The models also highlight the challenges of conducting adequately powered trials in rare f-FTD populations”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Brain atrophy and plasma NfL elevations are measurable years prior to symptom onset, paving the way for using these biomarkers in clinical trials of agents that could prevent or delay the clinical manifestations of f-FTD.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 26
- It may state two separate claims as one. 48
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“F-FTD is rare, with only hundreds of mutation carriers known to exist worldwide.12”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Abstract
What the sources say
- Disputedcites [12] Moore, K. M. et al. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study. Lancet Neurol. 19, 145–156 (2020). sourceExperimental — accuracy not yet measured
The Results report 3,403 symptomatic mutation carriers in this international cohort alone, contrary to the claim that only hundreds are known worldwide. The Discussion says the analysis did not include carriers who had not developed symptoms, so this count is not a worldwide total. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Disputed
Every source the paper cites for this claim was checked and supports it.
In the paper
“Approximately 20–30% of FTD is caused by autosomal dominant mutations (familial, or f-FTD), usually in one of three genes: chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT).2”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Abstract
What the sources say
- Supportedcites [2] Greaves, C. V. & Rohrer, J. D. An update on genetic frontotemporal dementia. J. Neurol. 266, 2075–2086 (2019). source
The Genes section says about 30% of FTD is genetic and identifies C9orf72, GRN, and MAPT as the main genes with autosomal dominant mutations. It estimates that mutations in each of those three genes cause roughly 5–10% of all FTD, consistent with the claim’s approximate 20–30% range. No page number is available in our copy. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Although the clinical manifestations of the f-FTD mutations are similar, the biology and neuropathology associated with C9orf72, GRN, and MAPT mutations are vastly different.2”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Abstract
What the sources say
- Supportedcites [2] Greaves, C. V. & Rohrer, J. D. An update on genetic frontotemporal dementia. J. Neurol. 266, 2075–2086 (2019). source
The Phenotype section says bvFTD is the most common presentation in all three genetic groups, while describing differences among them. The Genes section distinguishes MAPT-associated tauopathy from the TDP-43 proteinopathies associated with GRN and C9orf72, including their differing TDP-43 types. Together, these passages support the paraphrase; page numbers are unavailable in our copy. (LLM, conf=0.86)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Prevention trials in DIAD have also been facilitated by fluid and molecular PET imaging biomarkers that allow for the measurement of treatment-related changes in AD pathologies and neurodegeneration.8”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Abstract
What the sources say
- Supportedcites [7] Bateman, R. J. et al. The DIAN-TU Next Generation Alzheimer’s prevention trial: adaptive design and disease progression model. Alzheimers Dement. 13, 8–19 (2017). source
Section 3.3 says fluid and imaging biomarkers are included to determine drug effects on amyloid and tau pathology and on markers of neurodegeneration. Section 3.3.2 also describes biomarkers as a way to measure treatment responses and increase the efficiency of AD prevention trials. Page numbers are not supplied in our copy. (LLM, conf=0.92)
- Supportedcites [8] Salloway, S. et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat. Med. 27, 1187–1196 (2021). source
The Methods (Primary and secondary outcomes; page unavailable) list PET and cerebrospinal-fluid biomarkers as trial outcomes. The Results (Biological measures; page unavailable) use those measures to report treatment-related changes in amyloid deposition, tau and neurofilament light chain, supporting the claim that biomarkers enabled measurement of pathology and neurodegeneration in this DIAD trial. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“in genetic f-FTD there are known founder effects for C9orf7245 and GRN mutations46 with European ancestry, leading to strong associations with particular racial and ethnic groups.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
What the sources say
- Partly supportedcites [45] Mok, K. et al. Chromosome 9 ALS and FTD locus is probably derived from a single founder. Neurobiol. Aging 33, 209.e3–8 (2012). sourceExperimental — accuracy not yet measured
The Discussion (page not provided) links a likely single founder haplotype spanning C9orf72 to ALS and FTD, with the strongest association in populations with Northern European and Scandinavian ancestry. But the Introduction says the causative mutation had not been identified, so this paper does not establish a founder effect for a specific C9orf72 mutation. The separate GRN citation is not assessed here. (LLM, conf=0.86)
- Partly supportedcites [46] van der Zee, J. et al. A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD. Brain 129, 841–852 (2006). sourceExperimental — accuracy not yet measured
The Introduction (page not provided) reports a founder haplotype associated with a substantial fraction of familial FTLD in Belgium, supporting the general founder-effect point. But the paper does not identify the causal mutation as GRN, and it does not establish strong associations with particular racial or ethnic groups. The GRN and racial/ethnic claims therefore are not supported by this source. (LLM, conf=0.85)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Not only was this measure statistically powerful for measuring change, but given that it reflects informant-reported clinical status, it could also be considered a clinically meaningful outcome and approvable endpoint from a regulatory perspective.15”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
What the sources say
- Could not verifycites [15] Rentz, D. M. et al. Building clinically relevant outcomes across the Alzheimer’s disease spectrum. Alzheimer’s Dement. Transl. Res. Clin. Interv. 7, e12181 (2021). sourceExperimental — accuracy not yet measured
The section on minimal clinically important differences discusses CDR-SB in Alzheimer’s disease, and the regulators’ perspective section gives general criteria for clinically meaningful outcomes. Neither addresses CDR+NACC-FTLD-SB or establishes its statistical power, informant-reported status, or suitability as an approvable endpoint (searched: FTLD, informant-reported clinical status, approvable endpoint). (LLM, conf=0.76)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Temporal lobe atrophy in presymptomatic MAPT has been consistently reported,16,18,23 and the insula may be a common region of early atrophy in MAPT.24”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
What the sources say
- Could not verifycites [16] Staffaroni, A. M. et al. Rates of brain atrophy across disease stages in familial frontotemporal dementia associated with MAPT, GRN, and C9orf72 pathogenic variants. JAMA Netw. Open 3, e2022847 (2020). sourceExperimental — accuracy not yet measured
Citation 24 is attached to the claim that the insula may be a common region of early atrophy in MAPT. The Results (Longitudinal Atrophy Rates; page unavailable) report presymptomatic temporal-lobe volume loss in MAPT carriers, but a search for “insula” found no passage addressing early insular atrophy. (LLM, conf=0.74)
- Could not verifycites [18] Chen, Q. et al. Rates of lobar atrophy in asymptomatic MAPT mutation carriers. Alzheimer’s Dement. Transl. Res. Clin. Interv. 5, 338–346 (2019). sourceExperimental — accuracy not yet measured
Citation 24 is attached to the claim about early insular atrophy. The Discussion and Results describe early temporal-lobe atrophy in MAPT carriers, but the passages retrieved when searching for “insula” and “insular cortex” do not address insular atrophy. Our copy therefore does not verify the point attributed to this citation. (LLM, conf=0.75)
- Supportedcites [24] Young, A. L. et al. Characterizing the clinical features and atrophy patterns of MAPT-related frontotemporal dementia with disease progression modeling. Neurology 97, e941–e952 (2021). source
The citation is attached to the claim that the insula may be a common region of early atrophy in MAPT. The Results (Subtype Progression Patterns) identify early anterior insula atrophy in both MAPT subtypes, and the Discussion likewise describes early anterior insula volume loss in both. (LLM, conf=0.94)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Based on these simulations, it would be feasible to power trials for all three genetic groups using the CDR®+NACC-FTLD-SB and neuropsychological tests, measures most likely to be approvable by regulatory bodies as clinically meaningful endpoints.15”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Application to Clinical Trials
What the sources say
- Partly supportedcites [15] Rentz, D. M. et al. Building clinically relevant outcomes across the Alzheimer’s disease spectrum. Alzheimer’s Dement. Transl. Res. Clin. Interv. 7, e12181 (2021). sourceExperimental — accuracy not yet measured
The Conclusions (page unavailable) say regulators consider cognition a meaningful endpoint in Alzheimer's prevention trials, which supports the general point about cognitive measures. The paper does not report simulations showing that trials in three genetic groups could be powered using the CDR®+NACC-FTLD-SB and neuropsychological tests, or assess regulatory acceptance of those specific measures. (LLM, conf=0.81)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Medial temporal atrophy was the first observed biomarker change in MAPT, diverging from controls ~10 years before symptoms based on visual inspection (Figure 2), and reaching one SD below controls 1.8 years before onset (95%CI:-3.2,-0.5).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Visual inspections of the curves indicated that neuropsychological and Revised Self-Monitoring Scale (RSMS) impairments relative to controls were generally observed only after symptom onset for all genetic groups (Figure 2 & Table S5), and no measure reached one SD worse than controls until after symptom onset (Table S4).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Similar to the previous study, we detected medial temporal atrophy in MAPT 15 years prior to onset followed by atrophy of the insula.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Examining cases that the model estimated to be presymptomatic (DA<0) despite a CDR®+NACC-FTLD-SB>0, these participants tend to perform in the average range across other measures and stay stable or show improvements over time.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Baseline plasma NfL concentrations in GRN were significantly elevated relative to controls in all DA epochs (Figure 3, Table S5) and elevated compared to all other genetic groups in the symptomatic phase (Table S6).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“DA estimates at baseline ranged from −40 to 21.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“NfL levels began to diverge from controls closer to symptom onset in MAPT than C9orf72 or GRN, with mean values showing significant elevations during the symptomatic but not presymptomatic epochs (Extended Data Figure 1, Tables S5-6), and average values did not reach one SD above controls until 4.6 years after estimated symptom onset (95%CI:7.1,2.4).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For those −10 to 0 years from onset, this uncertainty decreased to +/−5.5 years, and after onset, the average uncertainty of the estimate was +/−0.9 years.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“With increasing DA, performance is increasingly impaired across multiple measures, and there is a greater tendency for progressive impairment from baseline to final observations.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GRN performed worse than controls on Trails A at all epochs, and worse than controls on Trails B in the −10 to 0 epoch.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“However, individuals furthest from onset are typically within normal limits on all contributing measures forcing the model to rely heavily on prior information about participants’ chronological age to estimate DA.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“NfL levels in C9orf72 were significantly higher than controls in all DA epochs and became elevated one SD above controls three years before estimated onset (95%CI:-0.7,-5.8).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the symptomatic stage, volume loss in all ROIs was more rapid than the other genetic groups, with the frontal, temporal, medial temporal, insular, and striatal ROIs losing volume most rapidly (Figure S3, Table S4).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“The precision of individual DA estimates depends on the proximity to symptom onset and follow-up duration.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“Visual inspection of the curves revealed a rapid CDR®+NACC-FTLD-SB increase after symptom onset, and all genetic groups had cross-sectional elevations in CDR®+NACC-FTLD-SB prior to symptom onset (Figure 3, Table S5);”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“Thalamic volume in C9orf72 was significantly lower than controls in the −40 to −10 epoch, with the largest effect size of all regions of interest (ROIs) (Extended Data Figure 1 & Table S5).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“Also consistent with prior work, the most rapid rates of atrophy occurred in GRN with widespread brain involvement within 10 years of onset.21,22”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“Fourth, clinical measures perform very well in the early symptomatic trial simulations, and sample sizes for trials using the CDR®+NACC-FTLD-SB as a primary outcome are feasible for all three genetic groups.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“Longitudinally, the most rapid change in the symptomatic stage relative to controls was observed for Trails A & B in C9orf72, Trails A, MINT, and Benson Copy in GRN, and the MINT and Trails B in MAPT (Table S4).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“In subjects estimated to be within 10 years of symptom onset, the accuracy is +/- 5.5 years, which approaches the accuracy of familial age of onset-based estimates which are useful in DIAD,43 but not possible in most f-FTD syndromes.12”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“Neuropsychological impairments relative to age-matched controls were typically observed after symptom onset in all groups, although abnormalities on a few measures were detected in the presymptomatic stages.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“Consistent with previous MRI studies demonstrating brain atrophy can be detected in presymptomatic f-FTD,16–19 MRI-measured brain atrophy was the first biomarker to change in C9orf72 and MAPT, but our models revealed that NfL elevations preceded atrophy by a few years in GRN.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“In GRN, visual inspection suggested NfL begins to deviate from controls about 15 years prior to symptom onset, followed by MRI 5–10 years prior to onset (Figures 2, S1).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“MAPT mutation carriers exhibited impairments in the Figure Copy in the −10 to 0 epoch, with a trend towards impairment on the Multilingual Naming Test (MINT) in this epoch.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“In the −10 to 0 epoch, the temporal lobe showed the largest effect size (Extended Data Figure 1), and it was the first ROI to deviate from controls (Table S4; deviated at DA = −6.1, 95%CI:−9.4,−3.2) by one standard deviation (SD), followed closely by parietal (DA = −6.1, 95%CI:−9.2,−3.2) and frontal (DA = −4.9, 95%CI:−7.5,−2.7) lobes.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“In rare neurogenetic diseases such as f-FTD, the FDA has promoted the use of innovative approaches such as disease progression models (DPM) for selecting clinical trial endpoints, determining enrollment criteria, and analyzing the effects of novel interventions that might lead to deviations from expected disease progression,14”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Abstract
What the sources say
- Not matchedcites [14] U.S. Food & Drug Administration. Human Gene Therapy for Neurodegenerative Diseases. Draft Guidance for Industry. FDA-2020-D-2101 (2021).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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In the paper
“Also, the age at which symptoms present is variable even within a family (e.g., onset in the thirties vs. seventies in one family),11 making it difficult to identify the individuals in late presymptomatic stages most likely to benefit from therapies.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Abstract
What the sources say
- Not checked — no full text of the sourcecites [11] Leverenz, J. B. et al. A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology. Brain 130, 1360–1374 (2007). source
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In the paper
“Such informative missing data also impacts the DPMs, potentially biasing the models towards a smaller standard deviation from normal; this is a limitation and a direction for future research.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“Based on the estimated number of eligible participants from the FPI dataset (assuming no additional recruitment efforts), two-year trials appear to be feasible for GRN if MRI is used as the outcome, whereas a four-year trial would be required for MAPT.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Application to Clinical Trials
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- The authors state this as an assumption: The number of eligible participants in the FPI dataset, assuming no additional recruitment, represents the pool available for f-FTD prevention trials.
- Rests on an assumption: The FPI dataset provides a reliable estimate of the number of eligible participants for f-FTD prevention trials.
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In the paper
“Raw values were modeled. The same pattern of findings was observed (Figure S5) in a sensitivity analysis adjusting for nuisance covariates (details in online methods).”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“These findings add to prior studies suggesting that cognitive changes can be detected in the presymptomatic phases of f-FTD and that there are genotype-specific cognitive profiles.34–37”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“The DPMs produced for the current study have additional limitations related to less informative clinical data at early stages of disease and missing data at late stages of disease.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“We conducted a voxelwise sensitivity analysis in each DA epoch to complement the coarse-grained ROIs used in the DPMs and to illustrate the findings were not dependent on the DPMs. Results of this sensitivity analysis (Extended Data Figure 2, Figures S2-S4) supported the patterns observed using ROIs.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
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In the paper
“Second, prevention trials appear most feasible for MAPT and GRN relative to the estimated number of eligible participants based on our dataset, however, given that C9orf72 is the most common mutation causing FTD and ALS, recruiting the estimated sample sizes may be feasible.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“These results extend previous fluid biomarker studies showing NfL concentrations become elevated early in f-FTD, are harbingers of symptom onset, and rise most rapidly in GRN.25,27,30–32”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“We and others have previously shown that NfL concentrations are elevated in the plasma25–27 and CSF28,29 of symptomatic FTD patients compared to other neurological conditions.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
What the sources say
- Not checked — no full text of the sourcecites [25] van der Ende, E. L. et al. Serum neurofilament light chain in genetic frontotemporal dementia: a longitudinal, multicentre cohort study. Lancet Neurol. 18, 1103–1111 (2019). source
- Not checked — no full text of the sourcecites [28] Bridel, C. et al. Diagnostic value of cerebrospinal fluid neurofilament light protein in neurology: a systematic review and meta-analysis. JAMA Neurol. 76, 1035–1048 (2019). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Because disease onset was defined as CDR®+NACC-FTLD-SB=0.5, non-carrier controls by definition had CDR®+NACC-FTLD-SB=0 at baseline, which reduced the variance in this measure, thereby potentially overestimating the effect size relative to other measures where there was more variance in the controls.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This reduction in sample size must be balanced against the reduction in number of eligible participants (of that DA), but these simulations show that GRN and MAPT trials enrolling presymptomatic participants within five years of estimated onset would be feasible based on the estimated number of eligible participants from our current dataset.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- The authors state this as an assumption: The number of eligible participants in the FPI dataset, assuming no additional recruitment, represents the pool available for f-FTD prevention trials.
- Rests on an assumption: The FPI dataset provides a reliable estimate of the number of eligible participants for f-FTD prevention trials.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All available data were included in the statistical analyses. Complete cases were not required, and no imputation was conducted.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Online Methods > Statistical Analyses
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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In the paper
“The same image processing steps were performed on ALLFTD and GENFI data.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Online Methods > Neuroimaging
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Probably not a substantial claim.
In the paper
“In conclusion, these DPMs will facilitate the planning of f-FTD clinical trials, including selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects.14”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
What the sources say
- Not matchedcites [14] U.S. Food & Drug Administration. Human Gene Therapy for Neurodegenerative Diseases. Draft Guidance for Industry. FDA-2020-D-2101 (2021).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
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- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and provide a roadmap for development of new biomarkers and clinical endpoints that may improve power to detect effects in presymptomatic stages of disease”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
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In the paper
“A standard imaging protocol was used across all centers, managed, and reviewed for quality by a core group at the Mayo Clinic, Rochester.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Online Methods > Neuroimaging
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Before any prepossessing of the images, all T1-weighted images were visually inspected for quality control. Images with excessive motion or image artifact were excluded.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Online Methods > Neuroimaging
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Across all assays, the percent coefficient of variations of the mean NfL concentration for the inter-assay controls were below 10%.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Online Methods > Plasma Neurofilament Light Chain (NfL)
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Multiple comparisons were controlled for using the Tukey method.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Online Methods > Statistical Analyses
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Therefore, the W-score represents the gray matter content at that voxel as the number of standard deviations away from the expected mean for a reference group, accounting for TIV and scanner platform.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Online Methods > Neuroimaging
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Results from the disease progression model can be used to create evidence-based assumptions about rates of progression and variability of progression of each endpoint for a target population.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Online Methods > Statistical Analyses
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
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In the paper
“Every step of the transformation was carefully inspected from the native space to the group template.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Online Methods > Neuroimaging
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“All scans were quality checked and those with movements or artifacts were removed.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Online Methods > Neuroimaging
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
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In the paper
“All samples were quantifiable within the dynamic range of 0.69 to 2,000 pg/mL and with an average coefficient of variation below 10%.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Online Methods > Plasma Neurofilament Light Chain (NfL)
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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In the paper
“Instrument operators were blinded to clinical and genetic information.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Online Methods > Plasma Neurofilament Light Chain (NfL)
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, if any participants displayed moderate to severe vascular disease or any other brain lesions, they were also excluded from the analysis.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Online Methods > Neuroimaging
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Probably not a substantial claim.
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In the paper
“Visual inspection suggested sufficient alignment between disease progression of all endpoints across the two consortia and subsequent models combined both cohorts within a single analysis.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Online Methods > Statistical Analyses
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition to the two quality control samples provided with the kit, all assays included five inter-assay controls.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Online Methods > Plasma Neurofilament Light Chain (NfL)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Measures were completed in duplicate over a total of six batches, each with an eight-point calibration curve tested in triplicate and two controls tested in duplicate.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Online Methods > Plasma Neurofilament Light Chain (NfL)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Samples were tested in duplicate using kits from the same lot.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Online Methods > Plasma Neurofilament Light Chain (NfL)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This study is the first comprehensive effort to combine clinical, imaging, and plasma biomarker data across consortia.”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Online Methods > Prior publications
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The authors state this as an assumption.
The number of eligible participants in the FPI dataset, assuming no additional recruitment, represents the pool available for f-FTD prevention trials.
“assuming no additional recruitment efforts”
The authors state this as an assumption.
Abnormal global status in controls may reflect other brain pathologies that could obscure important findings.
“Because abnormal global status may reflect other brain pathologies in the controls that could potentially obscure important findings, we believe that the requirement for CDR®+NACC-FTLD-SB=0 in controls was appropriate.”
The paper relies on this without support.
The FPI dataset provides a reliable estimate of the number of eligible participants for f-FTD prevention trials.
“Based on the estimated number of eligible participants from the FPI dataset”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Results > Disease Progression Models
“Medial temporal atrophy was the first observed biomarker change in MAPT, diverging from controls ~10 years before symptoms based on visual inspection (Figure 2)”
§ Temporal order of clinical and biomarker changes in familial frontotemporal dementia > Discussion
“Similar to the previous study, we detected medial temporal atrophy in MAPT 15 years prior to onset followed by atrophy of the insula.”
Citations
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Metadata
- Authors
- Staffaroni, A. M., Quintana, M., Wendelberger, B., Heuer, H. W., Russell, L. L., Cobigo, Y., Wolf, A., Goh, S.-Y. M., Petrucelli, L., Gendron, T. F., Heller, C., Clark, A. L., Taylor, J. C., Wise, A., Ong, E., Forsberg, L., Brushaber, D., Rojas, J. C., VandeVrede, L., Ljubenkov, P., Kramer, J., Casaletto, K. B., Appleby, B., Bordelon, Y., Botha, H., Dickerson, B. C., Domoto-Reilly, K., Fields, J. A., Foroud, T., Gavrilova, R., Geschwind, D., Ghoshal, N., Goldman, J., Graff-Radford, J., Graff-Radford, N., Grossman, M., Hall, M. G. H., Hsiung, G.-Y., Huey, E. D., Irwin, D., Jones, D. T., Kantarci, K., Kaufer, D., Knopman, D., Kremers, W., Lago, A. L., Lapid, M. I., Litvan, I., Lucente, D., Mackenzie, I. R., Mendez, M. F., Mester, C., Miller, B. L., Onyike, C. U., Rademakers, R., Ramanan, V. K., Ramos, E. M., Rao, M., Rascovsky, K., Rankin, K. P., Roberson, E. D., Savica, R., Tartaglia, M. C., Weintraub, S., Wong, B., Cash, D. M., Bouzigues, A., Swift, I. J., Peakman, G., Bocchetta, M., Todd, E. G., Convery, R. S., Rowe, J. B., Borroni, B., Galimberti, D., Tiraboschi, P., Masellis, M., Finger, E., van Swieten, J. C., Seelaar, H., Jiskoot, L. C., Sorbi, S., Butler, C. R., Graff, C., Gerhard, A., Langheinrich, T., Laforce, R., Sanchez-Valle, R., de Mendonça, A., Moreno, F., Synofzik, M., Vandenberghe, R., Ducharme, S., Le Ber, I., Levin, J., Danek, A., Otto, M., Pasquier, F., Santana, I., Kornak, J., Boeve, B. F., Rosen, H. J., Rohrer, J. D., Boxer, A. L., Frontotemporal Dementia Prevention Initiative (FPI) Investigators, ALLFTD Investigators, Apostolova, L., Barmada, S., Boeve, B., Boxer, A. L., Bozoki, A., Clark, D., Coppola, G., Darby, R., Dickson, D., Faber, K., Fagan, A., Galasko, D. R., Grant, I. M., Huang, E., Kerwin, D., Lapid, M., Lee, S., Leger, G., Masdeux, J. C., McGinnis, S., Mendez, M., Onyike, C., Pascual, M. B., Pressman, P., Rademakers, R., Ramanan, V., Ritter, A., Seeley, W. W., Syrjanen, J., Taylor, J. C., Weintraub, S., GENFI Investigators, Esteve, A. S., Nelson, A., Greaves, C. V., Thomas, D. L., Benotmane, H., Zetterberg, H., Nicholas, J., Samra, K., Shafei, R., Timberlake, C., Cope, T., Rittman, T., Benussi, A., Premi, E., Gasparotti, R., Archetti, S., Gazzina, S., Cantoni, V., Arighi, A., Fenoglio, C., Scarpini, E., Fumagalli, G., Borracci, V., Rossi, G., Giaccone, G., Di Fede, G., Caroppo, P., Prioni, S., Redaelli, V., Tang-Wai, D., Rogaeva, E., Castelo-Branco, M., Freedman, M., Keren, R., Black, S., Mitchell, S., Shoesmith, C., Bartha, R., Poos, J., Papma, J. M., Giannini, L., van Minkelen, R., Pijnenburg, Y., Nacmias, B., Ferrari, C., Polito, C., Lombardi, G., Bessi, V., Veldsman, M., Andersson, C., Thonberg, H., Öijerstedt, L., Jelic, V., Thompson, P., Lladó, A., Antonell, A., Olives, J., Balasa, M., Bargalló, N., Borrego-Ecija, S., Verdelho, A., Maruta, C., Ferreira, C. B., Miltenberger, G., Simões do Couto, F., Gabilondo, A., Gorostidi, A., Villanua, J., Cañada, M., Tainta, M., Zulaica, M., Barandiaran, M., Alves, P., Bender, B., Wilke, C., Graf, L., Vogels, A., Vandenbulcke, M., Van Damme, P., Bruffaerts, R., Poesen, K., Rosa-Neto, P., Gauthier, S., Camuzat, A., Brice, A., Bertrand, A., Funkiewiez, A., Rinaldi, D., Saracino, D., Colliot, O., Sayah, S., Prix, C., Wlasich, E., Wagemann, O., Loosli, S., Schönecker, S., Hoegen, T., Lombardi, J., Anderl-Straub, S., Rollin, A., Kuchcinski, G., Bertoux, M., Lebouvier, T., Deramecourt, V., Santiago, B., Duro, D., Leitão, M. J., Almeida, M. R., Tábuas-Pereira, M., & Afonso, S.
- Affiliations
- University of California, San Francisco (US)
- Berry Consultants, LLC (United States) (US)
- National Hospital for Neurology and Neurosurgery (GB)
- Mayo Clinic in Florida (US)
- Mayo Clinic (US)
- Case Western Reserve University (US)
- University of California, Los Angeles (US)
- Harvard University (US)
- Indiana University School of Medicine (US)
- Washington University in St. Louis (US)
- Columbia University (US)
- University of Pennsylvania (US)
- University of British Columbia (CA)
- University of North Carolina at Chapel Hill (US)
- University of California San Diego (US)
- University of Alabama at Birmingham (US)
- University of Toronto (CA)
- MRC Cognition and Brain Sciences Unit (GB)
- University of Brescia (IT)
- University of Milan (IT)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Sunnybrook Health Science Centre (CA)
- Western University (CA)
- Erasmus MC (NL)
- Don Carlo Gnocchi Foundation (IT)
- Karolinska University Hospital (SE)
- University of Manchester (GB)
- Salford Royal NHS Foundation Trust (GB)
- Centre hospitalier universitaire de Québec (CA)
- German Center for Neurodegenerative Diseases (DE)
- Universitair Ziekenhuis Leuven (BE)
- Montreal Neurological Institute and Hospital (CA)
- Munich Cluster for Systems Neurology (DE)
- Ludwig-Maximilians-Universität München (DE)
- Universität Ulm (DE)
- Inserm (FR)
- Unidade Local de Saúde de Coimbra (PT)
- Indiana University Indianapolis (US)
- University of Michigan (US)
- Vanderbilt University (US)
- Northwestern University (US)
- Houston Methodist (US)
- Cleveland Clinic (US)
- UK Dementia Research Institute (GB)
- London School of Hygiene & Tropical Medicine (GB)
- Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- University Health Network (CA)
- Amsterdam University Medical Centers (NL)
- University of Florence (IT)
- University of Oxford (GB)
- Karolinska Institutet (SE)
- Hospital Clínic de Barcelona (ES)
- University of Lisbon (PT)
- Donostiako Unibertsitate Ospitalea (ES)
- Biogipuzkoa Health Research Institute (ES)
- University of Tübingen (DE)
- University of Antwerp (BE)
- Centre National de la Recherche Scientifique (FR)
- LabEx DISTALZ (FR)
- Université de Lille (FR)
- Centro de Neurociências e Biologia Celular (PT)
- Corresponding author
- Staffaroni, Adam M.
- ORCID
- Staffaroni, Adam M.
- Quintana, Melanie
- Wendelberger, Barbara
- Heuer, Hilary W.
- Russell, Lucy L.
- Cobigo, Yann
- Wolf, Amy
- Petrucelli, Leonard
- Gendron, Tania F.
- Heller, Carolin
- Clark, Annie L.
- Taylor, Jack Carson
- Wise, Amy
- Forsberg, Leah
- Brushaber, Danielle
- Rojas, Julio C.
- VandeVrede, Lawren
- Ljubenkov, Peter
- Kramer, Joel
- Casaletto, Kaitlin B.
- Appleby, Brian
- Bordelon, Yvette
- Botha, Hugo
- Dickerson, Bradford C.
- Domoto-Reilly, Kimiko
- Fields, Julie A.
- Foroud, Tatiana
- Gavrilova, Ralitza
- Geschwind, Daniel
- Ghoshal, Nupur
- Goldman, Jill
- Grossman, Murray
- Hall, Matthew G. H.
- Hsiung, Ging-Yuek
- Huey, Edward D.
- Irwin, David
- Jones, David T.
- Kantarci, Kejal
- Kaufer, Daniel
- Knopman, David
- Kremers, Walter
- Lago, Argentina Lario
- Lapid, Maria I.
- Litvan, Irene
- Lucente, Diane
- Mackenzie, Ian R.
- Mendez, Mario F.
- Mester, Carly
- Miller, Bruce L.
- Ramanan, Vijay K.
- Ramos, Eliana Marisa
- Rao, Meghana
- Rankin, Katherine P.
- Roberson, Erik D.
- Savica, Rodolfo
- Tartaglia, M. Carmela
- Wong, Bonnie
- Cash, David M.
- Bouzigues, Arabella
- Swift, Imogen J.
- Peakman, Georgia
- Bocchetta, Martina
- Todd, Emily G.
- Convery, Rhian S.
- Rowe, James B.
- Borroni, Barbara
- Galimberti, Daniela
- Tiraboschi, Pietro
- Masellis, Mario
- Finger, Elizabeth
- Seelaar, Harro
- Jiskoot, Lize C.
- Sorbi, Sandro
- Graff, Caroline
- Gerhard, Alexander
- Langheinrich, Tobias
- Laforce, Robert
- Sanchez-Valle, Raquel
- Synofzik, Matthis
- Vandenberghe, Rik
- Ducharme, Simon
- Levin, Johannes
- Danek, Adrian
- Otto, Markus
- Pasquier, Florence
- Santana, Isabel
- Kornak, John
- Boeve, Bradley F.
- Rosen, Howard J.
- Rohrer, Jonathan D.
- Apostolova, Liana
- Barmada, Sami
- Boeve, Bradley
- Bozoki, Andrea
- Clark, David
- Coppola, Giovanni
- Dickson, Dennis
- Faber, Kelley
- Fagan, Anne
- Galasko, Douglas R.
- Grant, Ian M.
- Huang, Eric
- Kerwin, Diana
- Lapid, Maria
- Lee, Suzee
- Mendez, Mario
- Pressman, Peter
- Ramanan, Vijay
- Seeley, William W.
- Syrjanen, Jeremy
- Taylor, Jack C.
- Greaves, Caroline V.
- Thomas, David L.
- Zetterberg, Henrik
- Nicholas, Jennifer
- Samra, Kiran
- Shafei, Rachelle
- Cope, Thomas
- Rittman, Timothy
- Benussi, Alberto
- Premi, Enrico
- Gasparotti, Roberto
- Gazzina, Stefano
- Cantoni, Valentina
- Arighi, Andrea
- Fenoglio, Chiara
- Fumagalli, Giorgio
- Borracci, Vittoria
- Rossi, Giacomina
- Giaccone, Giorgio
- Caroppo, Paola
- Prioni, Sara
- Redaelli, Veronica
- Rogaeva, Ekaterina
- Castelo-Branco, Miguel
- Freedman, Morris
- Keren, Ron
- Black, Sandra
- Shoesmith, Christen
- Poos, Jackie
- Papma, Janne M.
- Pijnenburg, Yolande
- Nacmias, Benedetta
- Ferrari, Camilla
- Polito, Cristina
- Lombardi, Gemma
- Bessi, Valentina
- Veldsman, Michele
- Öijerstedt, Linn
- Thompson, Paul
- Lladó, Albert
- Antonell, Anna
- Olives, Jaume
- Balasa, Mircea
- Verdelho, Ana
- Maruta, Carolina
- Ferreira, Catarina B.
- Gabilondo, Alazne
- Gorostidi, Ana
- Tainta, Mikel
- Zulaica, Miren
- Bender, Benjamin
- Wilke, Carlo
- Graf, Lisa
- Vogels, Annick
- Vandenbulcke, Mathieu
- Bruffaerts, Rose
- Poesen, Koen
- Gauthier, Serge
- Brice, Alexis
- Bertrand, Anne
- Saracino, Dario
- Colliot, Olivier
- Sayah, Sabrina
- Prix, Catharina
- Wlasich, Elisabeth
- Wagemann, Olivia
- Loosli, Sandra
- Schönecker, Sonja
- Lombardi, Jolina
- Bertoux, Maxime
- Lebouvier, Thibaud
- Deramecourt, Vincent
- Santiago, Beatriz
- Duro, Diana
- Leitão, Maria João
- Venue
- Nature Medicine
- Published
- 2022-09-22
- Volume
- 28
- Issue
- 10
- Pages
- 2194-2206
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC9951811
- OpenAlex
- W4296690345
- Cited by
- 140
- References
- 75
- Citations by year
- 2026: 29 · 2025: 44 · 2024: 39 · 2023: 26 · 2022: 2
- FWCI
- 18.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature Medicine (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Brunel University Research Archive (BURA) (Brunel University London) (acceptedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- HAL (submittedVersion)
- ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Florence Research (University of Florence) (submittedVersion, other-oa)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- Institutional Research Information System (Università degli Studi di Trento) (submittedVersion, other-oa)
- Lirias (KU Leuven) (submittedVersion)
- DZNE Pub (submittedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by)
- Funders
- U.S. Department of Defense
- Alzheimer's Association (U24AG021886, P30 AG062422)
- Larry L. Hillblom Foundation (2018-A-025-FEL)
- National Ataxia Foundation
- Bristol-Myers Squibb
- Association for Frontotemporal Degeneration
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Novartis
- Biogen
- Teva Pharmaceutical Industries
- Vanderbilt University
- University of Pennsylvania
- Northwestern University
- Cleveland Clinic
- University of Washington
- Université Laval
- Johns Hopkins University
- University of Texas Southwestern Medical Center
- CurePSP
- McGill University
- Fondation Brain Canada
- London School of Hygiene and Tropical Medicine
- University Health Network
- Wellcome Trust (220258, BRC-1215-20014, 220258/Z/20/Z)
- Sunnybrook Research Institute
- Università degli Studi di Milano
- Weston Brain Institute
- EU Joint Programme – Neurodegenerative Disease Research (2019-02248, 739510)
- Ionis Pharmaceuticals
- Brain Research UK (202021-32)
- Buck Institute for Research on Aging
- ACADIA Pharmaceuticals
- Global Brain Health Institute
- Université de Lille
- National Brain Appeal (290173, RCN 290173)
- Rainwater Charitable Foundation
- Alzheimer's Society (AS-JF-19a-004-517)
- Puma Biotechnology
- TauRx Pharmaceuticals
- National Institute for Health and Care Research (BRC1215-20014, BRC149/NS/MH, CL-2018-14-007)
- Department of Health and Social Care
- University of Cambridge (BRC-1215-20014)
- Imperial College London
- University College London
- University of Oxford
- Wolfson Foundation (20143810)
- Deutsche Forschungsgemeinschaft (EXC 2145, EXC 2145SyNergy, 774/5‐1, 390857198, SCHR 774/5‐1)
- Agence Nationale de la Recherche (ANR-11-LABX-0009)
- Institut National de la Santé et de la Recherche Médicale
- Toronto Rehabilitation Institute
- Eberhard Karls Universität Tübingen
- Bundesministerium für Bildung und Forschung (FKZ O1GI1007A, O1GI1007A)
- Cambridge University Hospitals
- Ministero della Salute (2018-)
- University of Toronto
- Eisai
- KU Leuven
- Karolinska Institutet
- Stockholms Läns Landsting
- Vetenskapsrådet (2018-, 2015-02926, 2018-02754)
- Università degli Studi di Firenze
- Centre National de la Recherche Scientifique
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- Universidade de Coimbra
- Göteborgs Universitet
- Universidade de Lisboa
- Universitat de Barcelona
- Università degli Studi di Brescia
- Universiteit Antwerpen
- Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
- Universität Ulm
- H. Lundbeck A/S
- FONDATION ALZHEIMER
- UK Dementia Research Institute
- Sorbonne Université
- National Institutes of Health (1r21ns114764-01a1, AG016976, AG019724, AG063911, AG062677, NS092089)
- Genentech
- University of California, Los Angeles
- University of North Carolina at Chapel Hill
- University of California, San Diego
- University of California, San Francisco (AG019724)
- Parkinsonfonden
- School of Medicine, Indiana University
- Faculté de Médecine, Université Laval
- Houston Methodist Research Institute
- Bayer Vital
- Tau Consortium
- Canadian Institutes of Health Research (20143810, 175242_1)
- Medical Research Council (SUAG092 G116768, MR/M023664/1, G116768, MR/T046015/1, MR/M008525/1, MR/K010395/1, BRC-1215-20014)
- Instituto de Salud Carlos III (20143810, PI20/00448)
- Sahlgrenska Akademin
- Robarts Research Institute
- NIHR Cambridge Biomedical Research Centre ((BRC-1215-20014), BRC149/NS/MH)
- National Institute on Aging (AG032306, AG 016976, R01AG058233, R01AG029577, K23AG059888, AG058233, U01AG016976, K23AG061253, RF1AG029577, L30 AG069301, NS092089, U01AG045390, R01AG032306, AG019724, AG062422, AG045390, AG021886, K24AG045333, R01AG038791, AG038791, U19AG063911, P01AG019724, P30AG062422, K23AG073514, P30AG062677, P30AG066509, U24AG072122, P30AG072977, U24AG021886)
- National Institute of Neurological Disorders and Stroke (U01NS080818, U54NS092089, R25NS098999, U01NS100610)
- National Center for Advancing Translational Sciences
- Janssen Pharmaceuticals
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD001459)
- David Geffen School of Medicine, University of California, Los Angeles
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- familial frontotemporal dementia, presymptomatic mutation carriers, C9orf72, gene regulatory networks, MAPT, neurofilament light chain, brain atrophy, disease progression modeling, prevention trials, sample size determination, biomarkers, neuropsychological decline
- MeSH terms
- C9orf72 Protein, Clinical Trials as Topic, Humans, Mutation, Biomarkers, tau Proteins, Disease Progression, Frontotemporal Dementia
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-09-28, under version 3 of the claim definition (prompt extract-v3).
A second model labelled each claim on 2026-09-28 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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