Plasma Tau and Neurofilament Light in Frontotemporal Lobar Degeneration and Alzheimer Disease

Classified as probably not a substantial claim. May combine two claims.

Total tau is increased in pathology-confirmed AD and is considered a neurodegeneration biomarker in current research AD frameworks.

“Total tau (t-tau) is increased in pathology-confirmed AD and is considered a neurodegeneration biomarker in current research AD frameworks.3”

• cites [3] 3. Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement 2018;14:535-562. sourcePartly supported

  Section 9.4 places CSF total tau in the framework’s (N) neurodegeneration or neuronal-injury biomarker group. Section 9.3 discusses total tau in AD patients, but does not establish that it is increased specifically in pathology-confirmed AD; its reference to postmortem pathology concerns phosphorylated tau. Page numbers were not available in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Elevated CSF total tau and phosphorylated tau are regarded as markers of neurodegeneration and tau pathology in Alzheimer disease and are used clinically to raise diagnostic certainty; with CSF Aβ42 they are recommended in the Alzheimer's Association Appropriate Use Criteria for CSF testing in AD diagnosis.

“Elevated CSF levels of t-tau and p-tau are considered markers of neurodegeneration and tau pathology in AD and are used in the clinical setting to increase the diagnostic certainty of AD, 1 and together with CSF Aβ42 recommended for diagnostic use in the Alzheimer's Association Appropriate Use Criteria for CSF testing in the diagnosis of AD. 35”

• cites [1] 1. Lleo A, Irwin DJ, Illan-Gala I, et al. A 2-step cerebrospinal algorithm for the selection of frontotemporal lobar degeneration subtypes. JAMA Neurol 2018;75:738-745. sourcePartly supported

  Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [35] 35. Shaw LM, Arias J, Blennow K, et al. Appropriate use criteria for lumbar puncture and cerebrospinal fluid testing in the diagnosis of Alzheimer's disease. Alzheimers Dement 2018;14:1505-1521. sourcePartly supported

  Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable, 1 not checked. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

In that earlier study, plasma total tau was elevated in behavioral variant frontotemporal dementia, primary progressive aphasia, and symptomatic MAPT mutation carriers.

“In that study, plasma t-tau was elevated in bvFTD, PPA, and symptomatic MAPT mutation carriers”

• cites [38] 38. Foiani MS, Woollacott IO, Heller C, et al. Plasma tau is increased in frontotemporal dementia. J Neurol Neurosurg Psychiatry 2018;89:804-807. sourceSupported

May combine two claims.

The CSF total tau immunoassay used here employs monoclonal antibodies with epitopes in the mid-protein region, while the plasma total tau assay detects epitopes from the N-terminal region to amino acid 224.

“For example, the CSF t-tau immunoassay used here relies on a combination of monoclonal antibodies with epitopes in the mid-protein region.In contrast, the plasma t-tau assay detects epitopes going from the N-terminal region to the more distal amino acid 224.39”

• cites [39] 39. Cicognola C, Brinkmalm G, Wahlgren J, et al. Novel tau fragments in cerebrospinal fluid: relation to tangle pathology and cognitive decline in Alzheimer's disease. Acta Neuropathol 2019;137:279-296. sourcePartly supported

  The Introduction (page unavailable) says standard CSF t-tau immunoassays use monoclonal antibodies with mid-region epitopes. But the Materials and methods section describes the assay detecting fragments ending at amino acid 224 as a CSF assay using neat CSF samples, not a plasma t-tau assay; it also describes those fragments as N-terminally truncated. The plasma-assay portion is therefore unsupported by this paper. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

PET scans were read as positive or negative using a method previously described and validated against neuropathology.

“PET scans were read as positive or negative, as previously described and validated against neuropathology.27”

• cites [27] 27. La Joie R, Ayakta N, Seeley WW, et al. Multisite study of the relationships between antemortem [ 11 C]PIB-PET Centiloid values and postmortem measures of Alz- heimer's disease neuropathology. Alzheimers Dement 2019;15:205-216. sourcePartly supported

  The Results (Complementary analyses; page unavailable) describe clinicians reading PET scans as positive or negative. The Discussion (Pathology-based thresholds; page unavailable) validates a quantitative Centiloid threshold against neuropathology and compares it with visual reads, but does not establish that the visual-reading method itself was validated against neuropathology. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Tau hyperphosphorylation produces paired helical filaments that aggregate into neurofibrillary tangles, which are a defining pathologic feature of Alzheimer disease.

“Tau hyperphosphorylation leads to the formation of paired helical filaments that aggregate in neurofibrillary tangles, a defining pathologic hallmark of AD. 3”

• cites [3] 3. Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement 2018;14:535-562. sourcePartly supported

  Section 6 (Definition of AD; page unavailable) says paired helical filament (PHF) tau deposits are required, along with Aβ deposits, to meet neuropathologic criteria for AD. Section 9.2 (Tau PET; page unavailable) refers to PHF tangles, while section 9.3 (CSF T-tau and P-tau; page unavailable) associates phosphorylated tau with PHF formation. The paper does not state the claimed causal sequence that tau hyperphosphorylation produces filaments that then aggregate into tangles. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

t-tau and NfL reflect different aspects of neurodegeneration and provide different information from other neurodegeneration biomarkers such as FDG-PET or structural neuroimaging, and their longitudinal trajectories may be differently affected by demographic variables or disease stage.

“This adds to accumulating evidence supporting that t-tau and NfL reflect different aspects of neurodegeneration and provide different information compared to other neurodegeneration biomarkers, such as FDG-PET, or structural neuroimaging biomarkers, and that their longitudinal trajectories may be differently affected by demographic variables or disease stage.34”

• cites [34] 34. Illan-Gala I, Pegueroles J, Montal V, et al. Challenges associated with biomarker-based classification systems for Alzheimer's disease. Alzheimers Dement Amst Neth 2018; 10:346-357. sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Plasma NfL and t-tau concentrations were measured by board-certified laboratory technicians blinded to clinical data.

“Plasma NfL and plasma t-tau concentrations were determined with commercially available ultrasensitive Single molecule array technology using an HD-1 analyzer (Quanterix, Billerica, MA), by board-certified laboratory technicians blinded to clinical data, as previously described.5”

• cites [5] 5. Rojas JC, Karydas A, Bang J, et al. Plasma neurofilament light chain predicts pro- gression in progressive supranuclear palsy. Ann Clin Transl Neurol 2016;3:216-225. sourcePartly supported

  The Subjects and Methods section (Plasma and CSF analyses; page unavailable) says a board-certified laboratory technician measured plasma NfL using an assay transferred onto the Simoa platform. It does not say the technician was blinded to clinical data, and the paper reports total tau measurements in CSF, not plasma. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

High CSF total tau is associated with clinical progression in Alzheimer disease and frontotemporal lobar degeneration.

“High CSF t-tau relates to clinical progression in AD 36 and FTLD.37”

• cites [36] 36. Wattmo C, Blennow K, Hansson O. Cerebro-spinal fluid biomarker levels: phos- phorylated tau (T) and total tau (N) as markers for rate of progression in Alzheimer's disease. BMC Neurol 2020;20:10. sourceSupported
• cites [37] 37. Ljubenkov PA, Staffaroni AM, Rojas JC, et al. Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory. Ann Clin Transl Neurol 2018;5:1250-1263. sourcePartly supported

  The Results section, “Baseline NfL and total tau predict change in nfvPPA” (page unavailable), reports that higher CSF total tau predicted faster clinical worsening in patients with nfvPPA, an FTD variant. This supports the FTLD-related point cited to this paper, but the finding is specific to nfvPPA rather than FTLD generally. The citing sentence assigns the Alzheimer disease point to a different citation, so it is not judged here. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Consistent with this study, plasma total tau was unrelated to baseline severity, brain volume, or AD pathophysiology indexed by the CSF tau/Aβ1-42 ratio.

“In agreement with our results, no associations were found between plasma t-tau and baseline measures of disease severity or brain volume and AD pathophysiology (as measured by the CSF tau/Aβ 1-42 ratio).38”

• cites [38] 38. Foiani MS, Woollacott IO, Heller C, et al. Plasma tau is increased in frontotemporal dementia. J Neurol Neurosurg Psychiatry 2018;89:804-807. sourceSupported

May combine two claims.

Plasma NfL increases after neuronal injury and correlates with clinical progression and survival in FTLD-S and AD-S.

“Plasma NfL increases upon neuronal injury and correlates with clinical progression and survival in FTLD syndromes (FTLD-S) and AD syndromes (AD-S).[4][5][6][7][8]”

• cites [4] 4. Mattsson N, Andreasson U, Zetterberg H, Blennow K; for the Alzheimer's Disease Neuroimaging Initiative. Association of plasma neurofilament light with neuro- degeneration in patients with Alzheimer disease. JAMA Neurol 2017;74:557. sourcePartly supported

  The Discussion (page unavailable) describes plasma NfL as a marker of neuronal injury and reports associations with cognitive and imaging decline in AD. It notes elevated levels in frontotemporal dementia, but does not establish a correlation with clinical progression in FTLD syndromes; neither the Discussion nor the Results addresses survival in either syndrome. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [5] 5. Rojas JC, Karydas A, Bang J, et al. Plasma neurofilament light chain predicts pro- gression in progressive supranuclear palsy. Ann Clin Transl Neurol 2016;3:216-225. sourcePartly supported

  The Discussion (page unavailable) describes blood NfL as a marker of neuronal injury, and the Results and Discussion link higher baseline plasma NfL to faster clinical decline in PSP. This copy does not establish a plasma NfL association with progression and survival across FTLD-S and AD-S; its survival-related finding concerns ALS patients. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [6] 6. Bridel C, van Wieringen WN, Zetterberg H, et al. Diagnostic value of cerebrospinal fluid neurofilament light protein in neurology: a systematic review and meta-analysis. JAMA Neurol 2019;76:1035. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

In two large Alzheimer disease cohorts, plasma total tau was associated with faster clinical decline.

“Also in agreement with the present results are those from 2 large AD cohorts, in which plasma t-tau was associated with faster clinical decline.13”

• cites [13] 13. Mattsson N, Zetterberg H, Janelidze S, et al. Plasma tau in Alzheimer disease. Neu- rology 2016;87:1827-1835. sourcePartly supported

  The Results section reports that higher plasma tau was associated with accelerated cognitive decline in ADNI. The Methods section describes ADNI as prospectively followed but BioFINDER as cross-sectional, so the paper does not establish faster clinical decline in both cohorts. Page numbers were not available in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

NfL in blood shows a clear increase in AD and tracks neurofibrillary tangle load and cognitive decline.

“Whereas blood t-tau shows no diagnostic potential for AD, 13 NfL in blood shows a clear increase in AD, 4 and also tracks neurofibrillary tangle load and cognitive decline.14,15”

• cites [4] 4. Mattsson N, Andreasson U, Zetterberg H, Blennow K; for the Alzheimer's Disease Neuroimaging Initiative. Association of plasma neurofilament light with neuro- degeneration in patients with Alzheimer disease. JAMA Neurol 2017;74:557. sourcePartly supported

  The Results section on diagnostic groups reports higher plasma NfL in AD dementia than in controls, and the Results section on cognition reports an association with faster cognitive decline. The paper does not measure neurofibrillary tangle load. Its biochemical-marker results show a weak correlation with CSF phosphorylated tau in the full cohort, which does not establish that NfL tracks tangle load. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [14] 14. Ashton NJ, Leuzy A, Lim YM, et al. Increased plasma neurofilament light chain concentration correlates with severity of post-mortem neurofibrillary tangle pathol- ogy and neurodegeneration. Acta Neuropathol Commun 2019;7:5. sourceSupported
• cites [15] 15. Mattsson N, Cullen NC, Andreasson U, Zetterberg H, Blennow K. Association be- tween longitudinal plasma neurofilament light and neurodegeneration in patients with Alzheimer disease. JAMA Neurol 2019;76:791. sourcePartly supported

  The Abstract and Discussion report that changes in plasma NfL correlate with worsening cognition, and the Abstract reports associations with CSF tau biomarkers. The paper does not report measuring neurofibrillary tangle load, so the claim that NfL tracks tangle load is not established by this source. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

In Creutzfeldt-Jakob disease, plasma and CSF total tau correlate strongly, and both the concentration range and species diversity in these fluids exceed those in Alzheimer disease or frontotemporal lobar degeneration.

“This contrasts with a strong correlation of plasma and CSF t-tau concentration in Creutzfeldt-Jakob disease, in which the range of t-tau concentrations and species in plasma and CSF is higher than in AD or FTLD.40”

• cites [40] 40. Staffaroni AM, Kramer AO, Casey M, et al. Association of blood and cerebrospinal fluid tau level and other biomarkers with survival time in sporadic Creutzfeldt-Jakob disease. JAMA Neurol 2019;76:969-977. sourcePartly supported

  The Baseline Characteristics section reports a strong correlation between plasma and CSF total tau in sporadic CJD (r = 0.74). The Discussion mentions greater serum tau elevations in CJD than in other neurodegenerative conditions, but it does not establish that concentration ranges in both fluids exceed those in AD or FTLD. Our copy does not compare tau species diversity across these diseases. Page numbers were not available in the indexed passages. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

Plasma biomarkers are powerful diagnostic and prognostic clinical tools.

“Plasma biomarkers are powerful diagnostic and prognostic clinical tools. 1”

• cites [1] 1. Lleo A, Irwin DJ, Illan-Gala I, et al. A 2-step cerebrospinal algorithm for the selection of frontotemporal lobar degeneration subtypes. JAMA Neurol 2018;75:738-745. sourcePartly supported

  The Biofluid Collection and Analysis and Discussion sections describe cerebrospinal fluid (CSF) biomarkers and their diagnostic use in distinguishing neurodegenerative pathologies. The Discussion also notes that CSF neurofilament light correlates with disease progression, but the paper does not establish that plasma biomarkers are diagnostic or prognostic clinical tools. Page numbers are unavailable in our copy. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

May combine two claims.

Plasma total tau was slightly increased and tracked with greater longitudinal hypometabolism in Alzheimer disease patients versus controls.

“Plasma t-tau was weakly elevated and correlated with more severe longitudinal hypometabolism in patients with AD compared to controls.13”

• cites [13] 13. Mattsson N, Zetterberg H, Janelidze S, et al. Plasma tau in Alzheimer disease. Neu- rology 2016;87:1827-1835. sourceSupported

May combine two claims.

That earlier study had small effect sizes, lacked pathologic data, and did not test whether clinical scales, neuropsychological tests, or survival predicted progression.

“but the effect sizes were small, pathologic data were not available, and analyses for prediction of disease progression with clinical scales, neuropsychological testing, and survival were not conducted.”

• cites [38] 38. Foiani MS, Woollacott IO, Heller C, et al. Plasma tau is increased in frontotemporal dementia. J Neurol Neurosurg Psychiatry 2018;89:804-807. sourceSupported

May combine two claims.

In acute conditions like traumatic brain injury and hypoxic brain injury, plasma total tau measured by the same assay increases quickly, with an apparent half-life near 10 hours, while CSF total tau has a half-life near 20 days.

“In acute conditions, like traumatic brain injury and hypoxic brain injury, plasma t-tau concentrations measured using the same technology as the one employed here increase rapidly and show an apparent half-life of around 10 hours, 41 which contrasts with the half-life of CSF t-tau, which is about 20 days.42”

• cites [41] 41. Zetterberg H. Review: tau in biofluids: relation to pathology, imaging and clinical features. Neuropathol Appl Neurobiol 2017;43:194-199. sourcePartly supported

  The Plasma tau section reports rapid increases after hypoxic brain injury and concussion, and says tau’s half-life appears to be measured in hours in plasma versus weeks in CSF. It does not give the specific estimates of approximately 10 hours and 20 days. The section identifies Simoa as a blood-tau measurement platform, but does not establish that it is the same assay used by the citing authors. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [42] 42. Sato C, Barthélemy NR, Mawuenyega KG, et al. Tau kinetics in neurons and the human central nervous system. Neuron 2018;98:861-864. sourceNot checked — no full text of the source

May combine two claims.

Both t-tau and NfL may be useful for the diagnosis and prognosis of FTLD.

“The combination of CSF t-tau and NfL discriminated between early onset AD and FTLD, 9 and both analytes may be useful for the diagnosis and prognosis of FTLD.1,[10][11][12]”

• cites [1] 1. Lleo A, Irwin DJ, Illan-Gala I, et al. A 2-step cerebrospinal algorithm for the selection of frontotemporal lobar degeneration subtypes. JAMA Neurol 2018;75:738-745. sourcePartly supported

  The Discussion (page unavailable) says NfL is elevated in FTD and correlates with disease progression, supporting its potential prognostic use, but cautions that it lacks disease specificity. The paper uses t-tau among biomarkers that help exclude AD in FTLD-related syndromes; it does not establish t-tau as a prognostic marker for FTLD. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [10] 10. Irwin DJ, Lleo A, Xie SX, et al. Ante mortem cerebrospinal fluid tau levels correlate with postmortem tau pathology in frontotemporal lobar degeneration. Ann Neurol 2017;82:247-258. sourcePartly supported

  The Introduction (page unavailable) reports possible diagnostic utility for a CSF p-tau-to-t-tau ratio in distinguishing FTLD subtypes, which offers limited support for a role for t-tau. The Results and Discussion assess diagnostic accuracy for p-tau, not t-tau alone. Our copy does not establish diagnostic or prognostic utility for NfL, or prognostic utility for t-tau. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [11] 11. Grossman M, Elman L, McCluskey L, et al. Phosphorylated tau as a candidate bio- marker for amyotrophic lateral sclerosis. JAMA Neurol 2014;71:442-448. sourcePartly supported

  The Results (page unavailable) report that CSF t-tau distinguished ALS from a four-repeat-tau comparison group, which offers limited support for diagnostic usefulness within the FTLD spectrum. The paper does not evaluate NfL, and its Results state that CSF levels were not related to progression rate; it therefore does not support the claim that both analytes may aid FTLD diagnosis and prognosis. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Plasma total tau's weak performance may stem from assay limitations, while phosphorylated tau forms may have better clinical utility.

“These results may be related to limitations of the methodology to measure plasma t-tau, and the measurement of phosphorylated species of tau may have better clinical performance, as suggested by recent studies.44”

• cites [44] 44. Blennow K, Chen C, Cicognola C, et al. Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology. Brain 2020;143:650-660. sourceCould not verify

  The Introduction and CSF collection and biomarker analyses sections discuss assays for cerebrospinal-fluid tau, not plasma tau. The Discussion compares CSF tau measures with tau PET, but does not say that limitations in measuring plasma total tau explain its performance or that plasma phosphorylated tau has better clinical performance. Searches for plasma assay limitations and plasma p-tau found no passage addressing those claims; page numbers were unavailable in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

May combine two claims.

In Alzheimer disease, elevated plasma neurofilament light tracks with quicker global cognitive decline and faster atrophy.

“This study also replicated the findings of previous investigations supporting that, in AD, high plasma NfL correlates with faster worsening in global cognition and faster atrophy rates.4,15”

• cites [4] 4. Mattsson N, Andreasson U, Zetterberg H, Blennow K; for the Alzheimer's Disease Neuroimaging Initiative. Association of plasma neurofilament light with neuro- degeneration in patients with Alzheimer disease. JAMA Neurol 2017;74:557. sourceSupported
• cites [15] 15. Mattsson N, Cullen NC, Andreasson U, Zetterberg H, Blennow K. Association be- tween longitudinal plasma neurofilament light and neurodegeneration in patients with Alzheimer disease. JAMA Neurol 2019;76:791. sourceSupported

May combine two claims.

Most pathology-confirmed FTLD cases had at least some degree of AD co-pathology, but this did not influence the performance of plasma t-tau or NfL.

“Most pathology-confirmed FTLD cases had at least some degree of AD co-pathology, but this did not influence the performance of plasma t-tau or NfL.”

May combine two claims.

FTLD-S participants without a mutation had plasma NfL concentrations similar to GRN and MAPT mutation carriers but lower than C9orf72 repeat expansion carriers.

“participants in the FTLD-S group without a mutation had similar plasma NfL concentrations (46.1 ± 23 pg/mL) compared to GRN (88.1 ± 60 pg/mL, p = 0.43) and MAPT (30.1 ± 17 pg/mL, p = 0.89) mutation carriers, but lower than those with a C9orf72 repeat expansion (88.1 ± 57, p = 0.049).”

May combine two claims.

In the whole sample, plasma NfL correlated with MMSE, language and executive cognitive composites, and CDR+NACC/FTLD-SB scores.

“In the whole sample, plasma NfL correlated with MMSE (r = -0.26,p < 0.001), the language and executive cognitive composites (r = -0.22 and r = -0.22,respectively, all p < 0.001), and CDR+NACC/FTLD-SB (r = 0.41, p < 0.001) scores.”

May combine two claims.

The relationship between baseline NfL and worse disease severity was significant in all FTLD-S subgroups except nfvPPA and CBS and in both typical amnestic and nonamnestic AD presentations.

“The relationship between baseline NfL and worse disease severity was significant in all FTLD-S subgroups (except for nfvPPA and CBS) and both typical amnestic and nonamnestic AD presentations (supplementary table e-4, 10.5061/dryad.12jm63xvv).”

May combine two claims.

Baseline plasma t-tau concentrations were associated with worse decline in FTLD-S, but only in the bvFTD and PSP subgroups, and not in AD-S.

“In FTLD-S, baseline plasma t-tau concentrations were associated with worse decline (3.7 points change in CDR+NACC/FTLD-SB score per log t-tau pg/mL increase per year, 95% CI 1.4 to 6.0, p = 0.006).”

• Also stated in: § Relationship Between Baseline Plasma Biomarkers and Clinical Progression · plain

  “However, this effect was evident only in the bvFTD and PSP FTLD-S subgroups (3.6 points change in CDR+NACC/FTLD-SB, 95% CI 0. 1-7.1, p = 0.015 and 11.8 points change in CDR+NACC/FTLD-SB, 95% CI 0.3-23.3,p = 0.023) and was not observed in the AD-S group.”

May combine two claims.

Plasma NfL showed strong correlations with cortical thickness in frontal regions in FTLD-S and in right lateral temporal, right inferior parietal, and left superior frontal regions in AD-S.

“In contrast, plasma NfL showed strong correlations with cortical thickness in frontal regions in FTLD-S and the right lateral temporal lobe, right inferior parietal, and left superior frontal in the AD-S group (figure 4, E and F).”

May combine two claims.

Neither plasma t-tau nor plasma NfL predicted survival in AD-S.

“Neither plasma t-tau nor plasma NfL predicted survival in the AD-S group (table 2).”

May combine two claims.

Plasma NfL, but not plasma t-tau, predicted clinical decline in both FTLD-S and AD-S.

“Plasma NfL, but not plasma t-tau, predicted clinical decline and survival and correlated with regional cortical thickness in both FTLD-S and AD-S.”

• Also stated in: § Relationship Between Baseline Plasma Biomarkers and Clinical Progression · plain

  “baseline plasma NfL concentrations related to faster annual worsening in both FTLD-S (2.4 point change per log NfL ng/mL increase per year, 95% CI 0.78-2.4,p < 0.001) and AD-S (4.6 points change per log NfL ng/mL increase per year, 95% CI 1.2-5.5, p = 0.002).”

May combine two claims.

Age and plasma NfL were moderately correlated in AD-S and healthy controls but not in FTLD-S.

“In contrast, age and plasma NfL were moderately correlated in AD-S and HC (r = 0.51 and r = 0.63, respectively, all p < 0.001), but not in FTLD-S (r = 0.02, p = 0.79).”

Classified as probably not a substantial claim.

The final sample included 265 participants: 167 with FTLD-S, 43 with AD-S, and 55 healthy controls.

“The final sample included 265 participants: 167 FTLD-S (43 bvFTD, 28 nfvPPA, 18 svPPA, 36 PSP, 32 CBS, and 10 ALS-FTD), 43 AD-S, and 55 HC.”

May combine two claims.

In FTLD-S, only clinical phenotype was independently associated with shorter survival; in AD-S, only CDR+NACC/FTLD-SB was independently associated with shorter survival.

“As shown in table 2, in FTLD-S, only the clinical phenotype was independently associated with shorter survival, whereas in AD-S, only the CDR+NACC/FTLD-SB score was independently associated with shorter survival.”

May combine two claims.

Plasma total tau was not associated with survival in FTLD-S or AD-S.

“Plasma t-tau | 0.80 (0.40-1.60) | 0.514 | 0.98 (0.12-7.71) | 0.984”

May combine two claims.

Plasma neurofilament light lacks specificity and discriminates poorly between frontotemporal lobar degeneration and Alzheimer disease, or among frontotemporal lobar degeneration subtypes.

“but it is nonspecific and has weak discriminatory power between FTLD and AD or between FTLD clinical subtypes.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Survival analyses controlled for age at diagnosis, sex, disease severity at symptom onset, and primary clinical phenotype in FTLD-S.

“We applied Cox regression analyses to estimate survival, controlling for age at diagnosis, sex, disease severity at symptom onset, and primary clinical phenotype (only in the FTLD-S group).”

May combine two claims.

These differences may also explain the weak plasma-CSF total tau correlation and the poor diagnostic performance of plasma total tau in chronic neurodegeneration.

“This may also explain the weak correlation of plasma and CSF t-tau and the poor diagnostic performance of plasma t-tau in chronic neurodegeneration.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The combination of CSF t-tau and NfL discriminated between early onset AD and FTLD.

“The combination of CSF t-tau and NfL discriminated between early onset AD and FTLD, 9 and both analytes may be useful for the diagnosis and prognosis of FTLD.1,[10][11][12]”

• cites [9] 9. Sjogren M, Rosengren L, Minthon L, Davidsson P, Blennow K, Wallin A. Cyto- skeleton proteins in CSF distinguish frontotemporal dementia from AD. Neurology 2000;54:1960-1964. sourceNot checked — no full text of the source

May combine two claims.

Age at plasma sampling, education, MMSE, and CDR+NACC/FTLD-SB were similar in FTLD-S and AD-S, while the healthy control group was younger than both disease groups.

“Age at plasma sampling, education, MMSE, and CDR+NACC/FTLD-SB was similar in FTLD-S and AD-S.The HC group, however, was younger than both disease groups (table 1).”

May combine two claims.

Tau is implicated in the pathophysiology of AD and FTLD and can be measured in plasma with ultrasensitive immunoassays.

“The microtubule-associated protein tau has been implicated in the pathophysiology of Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) and can be measured in plasma with ultrasensitive immunoassays.2”

• cites [2] 2. Randall J, Mörtberg E, Provuncher GK, et al. Tau proteins in serum predict neuro- logical outcome after hypoxic brain injury from cardiac arrest: results of a pilot study. Resuscitation 2013;84:351-356. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Fluid biomarker concentrations were log-transformed using the natural log to satisfy the normal distribution assumption.

“Fluid biomarker concentrations were log-transformed using the natural log to fulfill the normal distribution assumption.”

Probably not a substantial claim: may not pass S3 (load-bearing).

All participants gave written informed consent.

“All participants gave their written informed consent to participate in the study.”

May combine two claims.

Plasma NfL is superior to plasma t-tau for diagnosing and predicting clinical progression in FTLD-S and AD-S.

“Plasma NfL is superior to plasma t-tau for the diagnosis and prediction of clinical progression of FTLD-S and AD-S.”

• Also stated in: § Discussion · plain

  “The main findings of this study are that (1) only plasma NfL provided between-group clinical discrimination, predicted disease progression and survival, and correlated with neuroimage measures of neurodegeneration; and”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The study was approved by the UCSF Institutional Review Board and conducted following the Declaration of Helsinki.

“The study was approved by the UCSF Institutional Review Board and was conducted following the Declaration of Helsinki.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Fifteen MRIs were excluded from final neuroimaging analyses because of low image quality or because they were performed on a different scanner.

“Fifteen MRIs were excluded from final neuroimaging analyses: 8 because of low image quality (i.e., significant movement artifact) or preprocessing errors and 7 because they were performed in a different MRI scanner.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Partial correlations between neuropsychology testing variables and plasma biomarkers adjusted for age and education to account for their effect on cognitive performance.

“Then, we studied the correlation between neuropsychology testing variables and plasma biomarkers with partial correlations adjusting for age and education, to account for the well-known effect of these variables on cognitive performance.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The lack of plasma-CSF total tau association may arise from compartment-specific tau species or from differing assay sensitivities.

“This may be related to differential expression of tau species in each compartment or different sensitivities of the techniques used for detection.”

Classified as probably not a substantial claim.

Clinical diagnosis was made by clinicians who were blinded to fluid biomarker results.

“Clinical diagnosis was made by clinicians blinded to fluid biomarker results.”

Classified as probably not a substantial claim.

Longitudinal changes in plasma biomarkers were analyzed with linear mixed-effects models controlling for age, sex, CDR+NACC/FTLD-SB, and time between samples.

“To study longitudinal changes in plasma biomarkers, we used linear mixed-effects models controlling for age, sex, CDR+NACC/FTLD-SB, and time between samples in the subset of participants with 2 plasma samples (n = 123, mean time between samples = 1.2 ± 0.4 years).”

Classified as probably not a substantial claim.

The proportionality-of-hazards assumption was checked and fulfilled.

“Of note, we checked that the assumption of proportionality of hazards was fulfilled.”

May combine two claims.

The FTLD-S cohort was sizable and had pathologic data for 70 cases, 42% of the sample.

“We studied a sizeable FTLD-S cohort with available pathologic data (i.e., 70 cases or 42% of the FTLD-S sample).”

• AssumptionRests on an assumption: The analyses of frontotemporal lobar degeneration pathologic subtypes assume that the 70 cases with available pathologic data are representative of the entire frontotemporal lobar degeneration syndrome cohort.

May combine two claims.

Plasma and CSF neurofilament light may yield similar prognostic information, with plasma offering greater clinical convenience.

“and that plasma and CSF NfL may provide equivalent prognostic information, with the added value of plasma being more convenient for clinical use.”

May combine two claims.

Plasma total tau may differ from other blood neurodegeneration biomarkers, a point relevant to refining biomarker-based classification.

“Plasma t-tau may not be equivalent to other blood-based neurodegeneration biomarkers, which should be considered for the refinement of biomarker-based classification schemes.”

Classified as probably not a substantial claim.

Neurofilament light is recognized as a nonspecific CSF and plasma marker of neuronal injury across degenerative and nondegenerative conditions.

“NfL has emerged as a nonspecific CSF and plasma biomarker of neuronal injury in degenerative and nondegenerative disorders.6”

• cites [6] 6. Bridel C, van Wieringen WN, Zetterberg H, et al. Diagnostic value of cerebrospinal fluid neurofilament light protein in neurology: a systematic review and meta-analysis. JAMA Neurol 2019;76:1035. sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

AD-S findings warrant caution given the group's small size and lack of preclinical AD cases.

“However, our results in the AD-S group should be interpreted cautiously due to its relatively small size and the lack of AD participants at the preclinical stage.”

Probably not a substantial claim: may not pass S3 (load-bearing).

These findings align with a recent European multicenter study of plasma NfL in genetic FTLD.

“Our results, however, are in line with a recent European multicenter study of plasma NfL in genetic FTLD.50”

• cites [50] 50. van der Ende EL, Meeter LH, Poos JM, et al. Serum neurofilament light chain in genetic frontotemporal dementia: a longitudinal, multicentre cohort study. Lancet Neurol 2019;18:1103-1111. sourceNot checked — no full text of the source

May combine two claims.

The cohort does not represent genetic FTLD, as it had few genetic cases and no prodromal forms.

“The study is not representative of genetic FTLD forms, because it included only a small number of participants with genetic FTLD and did not include prodromal forms of disease.”