Temporal order of clinical and biomarker changes in familial frontotemporal dementia

In the paper

“F-FTD is rare, with only hundreds of mutation carriers known to exist worldwide.12”

What the sources say

• Disputed

  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.

  cites [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

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”

What the sources say

• Supported

  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)

  cites [2] Greaves, C. V. & Rohrer, J. D. An update on genetic frontotemporal dementia. J. Neurol. 266, 2075–2086 (2019). source

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”

What the sources say

• Supported

  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)

  cites [2] Greaves, C. V. & Rohrer, J. D. An update on genetic frontotemporal dementia. J. Neurol. 266, 2075–2086 (2019). source

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”

What the sources say

• Supported

  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)

  cites [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
• Supported

  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)

  cites [8] Salloway, S. et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat. Med. 27, 1187–1196 (2021). source

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.”

What the sources say

• Partly supported

  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)

  cites [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
• Partly supported

  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)

  cites [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

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”

What the sources say

• ?Could not verify

  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)

  cites [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

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”

What the sources say

• ?Could not verify

  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)

  cites [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
• ?Could not verify

  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)

  cites [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
• Supported

  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)

  cites [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

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”

What the sources say

• Partly supported

  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)

  cites [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

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).”

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).”

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.”

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.”

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).”

In the paper

“DA estimates at baseline ranged from −40 to 21.”

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).”

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.”

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.”

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.”

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.”

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).”

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).”

In the paper

“The precision of individual DA estimates depends on the proximity to symptom onset and follow-up duration.”

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);”

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).”

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”

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.”

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).”

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”

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.”

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.”

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).”

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.”

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.”

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”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [14] U.S. Food & Drug Administration. Human Gene Therapy for Neurodegenerative Diseases. Draft Guidance for Industry. FDA-2020-D-2101 (2021).

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.”

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

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.”

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.”

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).”

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”

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.”

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.”

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.”

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”

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.”

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

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.”

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.”

In the paper

“All available data were included in the statistical analyses. Complete cases were not required, and no imputation was conducted.”

In the paper

“The same image processing steps were performed on ALLFTD and GENFI data.”

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”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [14] U.S. Food & Drug Administration. Human Gene Therapy for Neurodegenerative Diseases. Draft Guidance for Industry. FDA-2020-D-2101 (2021).

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”

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.”

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.”

In the paper

“Across all assays, the percent coefficient of variations of the mean NfL concentration for the inter-assay controls were below 10%.”

In the paper

“Multiple comparisons were controlled for using the Tukey method.”

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.”

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.”

In the paper

“Every step of the transformation was carefully inspected from the native space to the group template.”

In the paper

“All scans were quality checked and those with movements or artifacts were removed.”

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%.”

In the paper

“Instrument operators were blinded to clinical and genetic information.”

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.”

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.”

In the paper

“In addition to the two quality control samples provided with the kit, all assays included five inter-assay controls.”

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.”

In the paper

“Samples were tested in duplicate using kits from the same lot.”

In the paper

“This study is the first comprehensive effort to combine clinical, imaging, and plasma biomarker data across consortia.”