Association of Cognitive and Behavioral Features Between Adults With Tuberous Sclerosis and Frontotemporal Dementia

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

T-tau and Aβ42 levels in patients with FTD are similar to patients with normal cognition.

“Ljubenkov et al32 report that the T-tau and Aβ42 levels in patients with FTD are similar to patients with normal cognition.”

• cites [32] Ljubenkov PA, Staffaroni AM, Rojas JC, Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory. Ann Clin Transl Neurol. 2018; 5(10): 1250– 1263. doi: 10.1002/acn3.643 30349860 PMC6186942 sourceSupported

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

Frontotemporal dementia is caused by frontotemporal lobar degeneration (FTLD), which features abnormal aggregation of tau (FTLD-tau) or transactivating DNA-binding protein 43.

“Frontotemporal dementia is caused by frontotemporal lobar degeneration (FTLD), which features abnormal aggregation of the microtubule associated protein consisting of tau (FTLD-tau) or the transactivating DNA-binding protein 43.16,18–20”

• cites [16] Olney NT, Spina S, Miller BL. Frontotemporal dementia. Neurol Clin. 2017; 35(2): 339– 374. doi: 10.1016/j.ncl.2017.01.008 28410663 PMC5472209 sourceSupported
• cites [18] Cairns NJ, Bigio EH, Mackenzie IR,; Consortium for Frontotemporal Lobar Degeneration. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol. 2007; 114(1): 5– 22. doi: 10.1007/s00401-007-0237-2 17579875 PMC2827877 sourcePartly supported

  The Introduction (page not supplied) identifies FTD as the most common clinical presentation of FTLD. The Microscopy and Tau-positive inclusions sections describe TDP-43-positive and tau-positive FTLD pathology, respectively. But the Conclusions also recognize FTLD without tau-positive inclusions, so the sentence overstates the paper if it means that all FTLD features aggregation of one of those two proteins. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [19] Rascovsky K, Hodges JR, Knopman D, Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011; 134(pt 9): 2456– 2477. doi: 10.1093/brain/awr179 21810890 PMC3170532 sourcePartly supported

  The section headed “Development of the Proposed Classification of PPA and Its Variants” (page unavailable) identifies tau-positive and TDP-43-positive FTLD pathology, supporting the protein-pathology portion of the claim. It discusses primary progressive aphasia, however, and also identifies Alzheimer pathology as a possible cause; it does not establish that frontotemporal dementia as a whole is caused by FTLD or that these are its only pathological forms. (LLM, conf=0.79)

  Experimental — accuracy not yet measured
• cites [20] van Swieten J, Spillantini MG. Hereditary frontotemporal dementia caused by tau gene mutations. Brain Pathol. 2007; 17(1): 63– 73. doi: 10.1111/j.1750-3639.2007.00052.x 17493040 PMC8095608 sourcePartly supported

  The FRONTOTEMPORAL DEMENTIA section (around p. 64) describes FTD cases with abnormal tau inclusions, and the following passage reports TDP-43 in inclusions in familial FTD. But the paper also describes a third pathological subtype lacking distinctive histopathology; it does not establish tau or TDP-43 aggregation as a feature of every case. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

In the human central nervous system, P-tau exhibits a faster turnover rate, which likely explains the elevated CSF level of this protein in various neurodegenerative conditions.

“Sato et al36 report that in the human central nervous system, P-tau exhibits a faster turnover rate, which likely explains the elevated CSF level of this protein in various neurodegenerative conditions.”

• cites [36] Sato C, Barthélemy NR, Mawuenyega KG, Tau kinetics in neurons and the human central nervous system. Neuron. 2018; 97(6): 1284– 1298.e7. doi: 10.1016/j.neuron.2018.02.015 29566794 PMC6137722 sourcePartly supported

  The Results (Differential Tau Kinetics in iPSC-Derived Neurons; page unavailable) show faster turnover of phosphorylated tau peptides than corresponding unphosphorylated peptides, but this comparison was made in cultured neurons, not directly in the human CNS. The Discussion and Results (Tau Production Positively Correlates with Amyloidosis; pages unavailable) attribute elevated CSF tau in Alzheimer’s disease to increased production and release, not faster phosphorylated-tau turnover; they do not establish that explanation across various neurodegenerative conditions. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

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

Patients with FTD typically have elevated CSF levels of NfL when compared with control individuals.

“Additionally, Ljubenkov et al32 showed that patients with FTD typically have elevated CSF levels of NfL when compared with control individuals.”

• cites [32] Ljubenkov PA, Staffaroni AM, Rojas JC, Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory. Ann Clin Transl Neurol. 2018; 5(10): 1250– 1263. doi: 10.1002/acn3.643 30349860 PMC6186942 sourceSupported

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

Elevated NfL levels in the CSF implicate neuronal damage.

“It is also well established that elevated NfL levels in the CSF implicate a neuronal damage.34”

• cites [34] Khalil M, Teunissen CE, Otto M, Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol. 2018; 14(10): 577– 589. doi: 10.1038/s41582-018-0058-z 30171200 sourceSupported

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

The TAND checklist serves as a clinical screening tool to assess neuropsychiatric difficulties that include the behavioral, cognitive and psychiatric domains.

“The TAND checklist serves as a clinical screening tool to assess neuropsychiatric difficulties that include the behavioral, cognitive and psychiatric domains.11”

• cites [11] de Vries PJ, Whittemore VH, Leclezio L, Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND checklist. Pediatr Neurol. 2015; 52(1): 25– 35. doi: 10.1016/j.pediatrneurol.2014.10.004 25532776 PMC4427347 sourceSupported

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

The CSF biomarker levels reported in the FTD and HC cohorts overlapped with the data reported by Ljubenkov et al in 2018.

“The CSF biomarker levels reported in the FTD and HC cohorts overlapped with the data reported by Ljubenkov et al32 in 2018.”

• cites [32] Ljubenkov PA, Staffaroni AM, Rojas JC, Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory. Ann Clin Transl Neurol. 2018; 5(10): 1250– 1263. doi: 10.1002/acn3.643 30349860 PMC6186942 sourceSupported

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

High CSF NfL levels are associated with more severe cognitive impairment and shorter survival time in patients with FTD.

“Neurofilament light chain was chosen because in 2014 several groups reported that high CSF NfL levels were associated with more severe cognitive impairment and shorter survival time in patients with FTD.32,33”

• cites [32] Ljubenkov PA, Staffaroni AM, Rojas JC, Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory. Ann Clin Transl Neurol. 2018; 5(10): 1250– 1263. doi: 10.1002/acn3.643 30349860 PMC6186942 sourcePartly supported

  The Results (Baseline NfL and p-tau predict longitudinal change in bvFTD) report that higher CSF NfL predicted faster worsening on cognitive measures, and the Discussion reports faster clinical decline in bvFTD and nfvPPA, but not svPPA. These findings concern subsequent decline, rather than necessarily more severe impairment at baseline. The passages do not report shorter survival or substantiate the sentence’s attribution to several groups in 2014. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [33] Skillbäck T, Farahmand B, Bartlett JW, CSF neurofilament light differs in neurodegenerative diseases and predicts severity and survival. Neurology. 2014; 83(21): 1945– 1953. doi: 10.1212/WNL.0000000000001015 25339208 sourceNot checked — no full text of the source

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

Elevated CSF P-tau, with a mean level of 31 pg/mL, is seen in FTD owing to a genetic variant in the MAPT gene.

“It was reported that elevated levels of CSF P-tau, with a mean level of 31 pg/mL, is seen in FTD owing to a genetic variant in the MAPT gene,46 which produces the protein product tau.”

• cites [46] Jack CR Jr, Lowe VJ, Senjem ML, 11C PiB and structural MRI provide complementary information in imaging of Alzheimer’s disease and amnestic mild cognitive impairment. Brain. 2008; 131(pt 3): 665– 680. doi: 10.1093/brain/awm336 18263627 PMC2730157 sourceCould not verify

  The Introduction discusses CSF amyloid beta 42 and PiB binding in frontotemporal dementia, but not CSF P-tau levels in FTD. Searches for the reported 31 pg/mL mean and for MAPT-related FTD found no passage addressing either point in our copy. (LLM, conf=0.75)

  Experimental — accuracy not yet measured

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

Tuberous sclerosis-associated neuropsychiatric disorders have been reported in the pediatric and adult TSC populations.

“Tuberous sclerosis–associated neuropsychiatric disorders have been reported in the pediatric and adult TSC populations.13,14”

• cites [13] Kingswood JC, d’Augères GB, Belousova E,; TOSCA consortium and TOSCA investigators. Tuberous Sclerosis registry to increase disease Awareness (TOSCA): baseline data on 2093 patients. Orphanet J Rare Dis. 2017; 12(1): 2. doi: 10.1186/s13023-016-0553-5 28057044 PMC5217262 sourceSupported
• cites [14] Peron A, Vignoli A, Briola F,; TSC Study Group of the San Paolo Hospital of Milan. Deep phenotyping of patients with Tuberous Sclerosis Complex and no mutation identified in TSC1 and TSC2. Eur J Med Genet. 2018; 61(7): 403– 410. doi: 10.1016/j.ejmg.2018.02.005 29432982 sourceNot checked — no full text of the source

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

Development of the TAND checklist was necessary because 90% of patients with TSC endorsed neuropsychiatric symptoms, yet only 20% received treatment.

“Development of the TAND checklist was necessary because 90% of patients with TSC endorsed neuropsychiatric symptoms, yet only 20% received treatment.11”

• cites [11] de Vries PJ, Whittemore VH, Leclezio L, Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND checklist. Pediatr Neurol. 2015; 52(1): 25– 35. doi: 10.1016/j.pediatrneurol.2014.10.004 25532776 PMC4427347 sourcePartly supported

  The Introduction links development of the TAND Checklist to a substantial treatment gap: more than 90% of individuals with TSC were likely to have relevant challenges, while only 18% of surveyed families had ever received recommended evaluations or treatments. It does not say that 90% of patients endorsed symptoms or that 20% received treatment; those figures change both what was measured and who was counted. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Susceptibility-weighted imaging and low-dose CT showed no evidence of calcifications in the tubers or other cortical malformations; thus, binding to calcifications appears less likely.

“These sequences showed no evidence of calcifications in the tubers or other cortical malformations; thus, binding to calcifications appears to be less likely.”

May combine two claims.

All 3 TSC patients who had tau-PET scans also underwent PiB-PET scans for amyloid β deposition, which were negative.

“All 3 patients with TSC who had tau-PET scans also underwent PiB-PET scans for amyloid β deposition, which were negative (data not shown).”

May combine two claims.

Both TSC and FTD TAND severity scores in the behavioral and cognitive domains were significantly higher than HC individuals.

“Both TSC and FTD severity scores in these domains were significantly higher when compared with HC individuals (Table 2).”

May combine two claims.

When the total TAND severity score was compared, the TSC group occupied an intermediate space between FTD and HC cohorts, although it was not significantly different from either group.

“When the total severity score was compared, the TSC group occupied an intermediate space between FTD and HC cohorts, although it was not significantly different from either group (eTable 2 in the Supplement).”

May combine two claims.

The TAND checklist and neuropsychological test results were not significantly different when the TSC and FTD cohorts were compared.

“The tuberous sclerosis–associated neuropsychiatric disorders checklist and neuropsychological test results were not significantly different when the tuberous sclerosis complex and frontotemporal dementia cohorts were compared.”

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

There is a higher risk of a type 1 error owing to the small sample size.

“There is a higher risk of a type 1 error owing to the small sample size.”

May combine two claims.

Inclusion criteria for this study required that the patients with TSC be able to complete neuropsychological testing; subsequently, the results may not be generalizable to all patients with TSC.

“Inclusion criteria for this study required that the patients with TSC be able to complete neuropsychological testing. Subsequently, the results from this study may not be generalizable to all patients with TSC.”

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

All CSF samples were run in duplicate and had to pass quality control criteria.

“Samples were thawed at 4°C for approximately 3 hours prior to analysis, and all were run in duplicate. For all assays, values had to pass quality control criteria, including coefficients of variation (calculated as standard deviation × 100/mean) 25% or less, kit controls within the expected range as defined by the manufacturer (where applicable), and measurement consistency of 2 common pooled CSF”

May combine two claims.

The low-dose CT scans are of low quality, and sensitivity to capture calcification in two-thirds of the cases was low.

“However, the low-dose CT scans are of low quality, and therefore, our sensitivity to capture calcification in two-thirds of the cases was low.”

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

The patients with FTD and HC participants who provided CSF results were not the same patients with FTD and HC participants who completed clinical measurements.

“Lastly, the patients with FTD and HC participants who provided CSF results were not the same patients with FTD and HC participants who completed clinical measurements.”

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

To achieve an adequate study group for comparison to the patients with TSC, different patients with FTD were used for cognitive testing and CSF biomarker analysis.

“An additional limitation of this study is that to achieve an adequate study group for comparison to the patients with TSC, we used different patients with FTD for cognitive testing and CSF biomarker analysis.”

May combine two claims.

Our data suggest a clinical overlap and therefore potential association between TAND and the neurodegenerative disease FTD, in particular, where the latter is associated with the accumulation of pathological tau.

“Our data suggest a clinical overlap and therefore potential association between TAND and the neurodegenerative disease FTD, in particular, where the latter is associated with the accumulation of pathological tau.”

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

Institutional review board approval was obtained from the University of California Human Research Protection Program, and written informed consent was obtained from all study participants or their surrogates.

“Institutional review board approval was obtained from the University of California Human Research Protection Program, and written informed consent was obtained from all study participants or their surrogates.”

May combine two claims.

The FTP PET ligand is not specific for tau pathology and can show elevated binding unrelated to tau in normal individuals and in patients with non-tau-related neurodegeneration.

“Additionally, the FTP PET ligand is not specific for tau pathology and can show elevated binding unrelated to tau in normal individuals and in patients with non–tau-related neueodegeneration.42”

• cites [42] Baker SL, Harrison TM, Maass A, La Joie R, Jagust WJ. Effect of off-target binding on 18F-flortaucipir variability in healthy controls across the lifespan. J Nucl Med. 2019; 60(10): 1444– 1451. doi: 10.2967/jnumed.118.224113 30877180 PMC6785795 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

Linear regression models covarying for age, sex, and genotype determined group differences in the neuropsychologic composite scores.

“Linear regression models covarying for age, sex, and genotype determined group differences in the neuropsychologic composite scores.”