Advances and controversies in frontotemporal dementia: diagnosis, biomarkers, and therapeutic considerations

There can be mimics of behavioural variant frontotemporal dementia.

“The fronto temporal dementia phenocopy syndrome also highlights that there can be mimics of behavioural variant frontotemporal dementia”

• cites [10] Valente, 2019, Phenocopy syndrome of behavioral variant frontotemporal dementia: a systematic review, Alzheimers Res Ther sourceSupported

Many of these patients develop parkinsonian features as their disease progresses.

“Moreover, many these patients develop parkinsonian features as their disease progresses.20”

• cites [20] Seckin, 2020, The evolution of parkinsonism in primary progressive apraxia of speech: a 6-year longitudinal study, Parkinsonism Relat Disord sourceSupported

Memory also declines with disease progression in behavioural variant frontotemporal dementia.

“Memory also declines with disease progression.37”

• cites [37] Ramanan, 2017, Longitudinal executive function and episodic memory profiles in behavioral-variant frontotemporal dementia and Alzheimer's disease, J Int Neuropsychol Soc sourceSupported

• AssumptionRests on an assumption: Diagnostic criteria for the behavioural variant of frontotemporal dementia emphasise executive dysfunction.

A mirror radiological variant with predominant right anterior temporal atrophy can present without aphasia, which has been termed the right temporal variant of frontotemporal dementia.

“A mirror radiological variant with predominant right anterior temporal atrophy can present without aphasia, which has been termed the right temporal variant of frontotemporal dementia (table 1, figure 2).25,26”

• cites [25] Ulugut Erkoyun, 2020, A clinical-radiological framework of the right temporal variant of frontotemporal dementia, Brain sourceSupported
• cites [26] Ulugut Erkoyun, 2021, The right temporal variant of frontotemporal dementia is not genetically sporadic: a case series, J Alzheimers Dis sourceSupported

One of the more controversial aspects of the primary progressive aphasia spectrum is the overlap and distinction between primary progressive apraxia of speech and non-fluent primary progressive aphasia.

“One of the more controversial aspects of the primary progressive aphasia spectrum is the overlap and distinction between people with a primary progressive apraxia of speech (ie, a motor speech disorder with no language problems) 18 and those with non-fluent primary progressive aphasia.”

• cites [18] Botha, 2019, Primary progressive aphasias and apraxia of speech, Continuum (Minneap Minn) sourceSupported

A group of patients present with features of multiple frontotemporal dementia phenotypes at the same time, with both behavioural variant frontotemporal dementia and progressive aphasia at onset.

“Notably, a group of patients present with features of multiple frontotemporal dementia phenotypes at the same time, with both behavioural variant fronto temporal dementia and progressive aphasia at onset.23”

• cites [23] Murley, 2020, Redefining the multidimensional clinical phenotypes of frontotemporal lobar degeneration syndromes, Brain sourcePartly supported

  The Results report that 62% of assessed patients met criteria for more than one syndrome, including 38 with overlapping bvFTD and svPPA. However, the Discussion says the clinical-feature assessment was cross-sectional, not a retrospective estimate of presenting features, so it does not establish that both phenotypes were present at onset. Page numbers were not supplied. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Episodic memory performance is variable in behavioural variant frontotemporal dementia, with some people showing considerable memory deficits, albeit usually to a lesser extent than in individuals with Alzheimer's disease.

“Episodic memory perfor mance is variable, with some people with behavioural variant frontotemporal dementia showing considerable memory deficits, albeit usually to a lesser extent than those seen in individuals with Alzheimer's disease.36”

• cites [36] Poos, 2018, Meta-analytic review of memory impairment in behavioral variant frontotemporal dementia, J Int Neuropsychol Soc sourceSupported

• AssumptionRests on an assumption: Diagnostic criteria for the behavioural variant of frontotemporal dementia emphasise executive dysfunction.

Based on these criteria, a degree of probability of underlying frontotemporal lobar degeneration can be attributed to cases presenting with at least three of five behavioural criteria and one cognitive criterion.

“Based on these criteria, a degree of probability of underlying frontotemporal lobar degeneration can be attributed to cases presenting with at least three of five behavioural criteria and one cognitive criterion.”

• cites [3] Rascovsky, 2011, Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia, Brain sourceCould not verify

  The passages supplied and returned for this DOI are labelled as sections of a paper on primary progressive aphasia, not the cited paper’s behavioural-variant frontotemporal dementia criteria. Searches for the three-of-five behavioural and one cognitive criterion, including possible and probable bvFTD criteria, found no passage in our copy that addresses the claimed threshold. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

• AssumptionRests on an assumption: In any given individual, the frontotemporal dementia syndrome is typically (but not always) due to frontotemporal lobar degeneration.

The clinical diagnosis of behavioural variant frontotemporal dementia is based on consensus diagnostic criteria derived from an international cohort of 406 pathologically verified cases of frontotemporal dementia.

“The clinical diagnosis of behavioural variant frontot emporal dementia is based on consensus diagnostic criteria that have been derived from an international cohort of 406 pathologically verified cases of frontotemporal dementia.3”

• cites [3] Rascovsky, 2011, Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia, Brain sourceCould not verify

  The retrieved copy is labelled as a paper on primary progressive aphasia, despite the index identifying it as the cited Rascovsky paper. Its Discussion and diagnostic-criteria passages do not address criteria for behavioural variant frontotemporal dementia derived from 406 pathologically verified cases. Searches for “406” and the claimed cohort found no relevant passage, so the claim cannot be judged from this copy. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

• AssumptionRests on an assumption: In any given individual, the frontotemporal dementia syndrome is typically (but not always) due to frontotemporal lobar degeneration.

Social cognition complements the assessment of behavioural features during clinical interview or via informant report, since behavioural features can be influenced both by the person's insight and the availability and knowledge of an informant.

“Social cognition complements the assessment of behavioural features (ie, apathy, disinhibition, stereo typical behaviours, and changes in eating behaviour) during clinical interview 2 or via informant report, since behavioural features can be influenced both by the person's insight and the availability and knowledge of an informant.”

• cites [2] Heuer, 2020, Comparison of sporadic and familial behavioral variant frontotemporal dementia (FTD) in a North American cohort, Alzheimers Dement 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

• AssumptionRests on an assumption: Diagnostic criteria for the behavioural variant of frontotemporal dementia emphasise executive dysfunction.

Growing evidence shows that tests of ventromedial prefrontal cortex function (such as error sensitivity, verbal fluency, inhibition, and decision-making and neuroeconomics derived tasks) are more sensitive than dorsolateral prefrontal tests (such as cognitive control and attention).

“Importantly, growing evidence shows that tests of ventromedial prefrontal cortex function (such as error sensitivity, 33 verbal fluency, 33 inhibition, 34 and decisionmaking and neuroeconomics derived tasks 35 ) are more sensitive than dorsolateral prefrontal tests (such as cognitive control and attention).33”

• cites [33] Ranasinghe, 2016, Cognition and neuropsychiatry in behavioral variant frontotemporal dementia by disease stage, Neurology sourcePartly supported

  The Domain-specific cognitive dysfunction section (page not supplied) reports that error insensitivity and verbal fluency were markedly impaired in early bvFTD, while cognitive control was low-average or normal; the Discussion also describes attention as intact. But the Discussion links error insensitivity to right lateral prefrontal networks, not specifically to ventromedial prefrontal cortex function. This paper therefore supports the early-test-sensitivity comparison, but not the claimed anatomical classification. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [34] Hughes, 2018, Reorganization of cortical oscillatory dynamics underlying disinhibition in frontotemporal dementia, Brain sourcePartly supported

  The citation to Hughes et al. is attached to “inhibition.” The Introduction says the study used a Go–NoGo task to assess inhibitory control, supporting that example. But the paper describes a network involving the right inferior frontal gyrus and preSMA; it does not identify the task as a test of ventromedial prefrontal function. The comparative sensitivity claim is separately cited to reference 33. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [35] Wong, 2017, Should I trust you? Learning and memory of social interactions in dementia, Neuropsychologia sourceSupported

• AssumptionRests on an assumption: Diagnostic criteria for the behavioural variant of frontotemporal dementia emphasise executive dysfunction.

FDG-PET findings are not 100% sensitive or specific for underlying frontotemporal lobar degeneration.

“Although the clinical and research utility of FDG-PET has been shown, 63 the findings are not 100% sensitive or specific for underlying frontotemporal lobar degeneration.69”

• cites [63] Bejanin, 2020, Longitudinal structural and metabolic changes in frontotemporal dementia, Neurology sourcePartly supported

  The Discussion (page not specified) says that hypometabolism patterns can overlap between FTD and Alzheimer disease and may lead to inaccurate FDG-PET interpretations, supporting a limitation in diagnostic specificity. But the study did not test associations with pathologic burden; it does not establish FDG-PET's sensitivity or specificity for underlying frontotemporal lobar degeneration. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [69] Vijverberg, 2016, Diagnostic accuracy of MRI and additional [18F]FDG-PET for behavioral variant frontotemporal dementia in patients with late onset behavioral changes, J Alzheimers Dis sourceNot checked — no full text of the source

Off-target binding can lead to false-positive tau PET scans in people with nontauopathies.

“Furthermore, off-target binding can lead to false-positive tau PET scans in people with nontauopathies.71,72”

• cites [71] Tsai, 2019, 18F-flortaucipir (AV-1451) tau PET in frontotemporal dementia syndromes, Alzheimers Res Ther sourceSupported
• cites [72] Makaretz, 2018, Flortaucipir tau PET imaging in semantic variant primary progressive aphasia, J Neurol Neurosurg Psychiatry sourceSupported

Family histories in C9orf72 mutation carriers can be negative or ambiguous due to the large variation in clinical phenotype, including psychiatric and other atypical presentations.

“It is well known, however, that family histories in C9orf72 mutation carriers can be negative or ambiguous due to the large variation in clinical phenotype, including psychiatric and other atypical presentations.61”

• cites [61] Khan, 2012, Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion, J Neurol Neurosurg Psychiatry sourceSupported

Total tau and amyloid β concentrations are not sensitive or specific for any of the frontotemporal lobar degeneration proteinopathies.

“Although total tau and amyloid β concentrations are not sensitive or specific for any of the frontotemporal lobar degeneration proteinopathies, elevated phosphorylated tau concentrations in either CSF or plasma suggest that underlying Alzheimer's disease pathology is likely to be the cause of the frontotemporal dementia clinical syndrome.49,55,56”

• cites [49] Thijssen, 2020, Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration, Nat Med sourcePartly supported

  The Discussion says CSF total tau has little diagnostic value for distinguishing FTLD from Alzheimer’s disease. The Results report that plasma Aβ42/40 did not differ between clinical diagnostic groups. These findings support limited diagnostic usefulness, but the paper does not establish that total tau and amyloid β concentrations lack sensitivity or specificity for every FTLD proteinopathy. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [55] Palmqvist, 2020, Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders, JAMA sourceCould not verify

  The Discussion (page unavailable) compares plasma phosphorylated tau with total tau for detecting Alzheimer disease, but does not assess whether total tau or amyloid-β concentrations identify frontotemporal lobar degeneration proteinopathies. Searches for that specific sensitivity-and-specificity claim found no passage addressing it. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [56] Thijssen, 2021, Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer's disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study, Lancet Neurol sourceCould not verify

  The Introduction discusses amyloid and tau measurements as established Alzheimer’s disease biomarkers, but does not assess whether total tau or amyloid-β concentrations identify FTLD proteinopathies. The Results compare phosphorylated tau across AD, FTLD-tau and FTLD-TDP; searches for total tau, amyloid-β concentrations and FTLD specificity found no passage establishing the quoted claim. Page numbers were not available in our copy. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

The histone deacetylase inhibitor FRM-0334 did not raise plasma progranulin concentrations in participants with GRN haploinsufficiency enrolled in a double-blind placebo-controlled trial.

“Histone deacetylase inhibitors substantially increase progranulin transcription, but the histone deacetylase inhibitor FRM-0334 did not raise plasma progranulin concentrations in participants with GRN haploinsufficiency enrolled in a double-blind placebo controlled trial.82”

• cites [82] Ljubenkov, 2021, Effect of the histone deacetylase inhibitor FRM-0334 on progranulin levels in patients with progranulin gene haploinsufficiency: a randomized clinical trial, JAMA Netw Open sourceSupported

Histone deacetylase inhibitors substantially increase progranulin transcription.

“Histone deacetylase inhibitors substantially increase progranulin transcription, but the histone deacetylase inhibitor FRM-0334 did not raise plasma progranulin concentrations in participants with GRN haploinsufficiency enrolled in a double-blind placebo controlled trial.82”

• cites [82] Ljubenkov, 2021, Effect of the histone deacetylase inhibitor FRM-0334 on progranulin levels in patients with progranulin gene haploinsufficiency: a randomized clinical trial, JAMA Netw Open sourceSupported

The AADvac1 vaccine has been shown to be safe and well tolerated in an open-label trial enrolling participants with Alzheimer's disease.

“The AADvac1 vaccine (containing the tau peptide aa 294-305-4R) has been shown to be safe and well tolerated in an open-label trial enrolling participants with Alzheimer's disease.89”

• cites [89] Novak, 2018, FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer's disease, Alzheimers Res Ther sourceSupported

NfL predicts future clinical progression during the prodromal stages of genetic frontotemporal lobar degeneration.

“NfL has been shown to predict future clinical progression during the prodromal stages of genetic frontotemporal lobar degeneration.51”

• cites [51] Rojas, 2021, Plasma neurofilament light for prediction of disease progression in familial frontotemporal lobar degeneration, Neurology sourceSupported

Internet-based speech and language therapy has been effective in people with primary progressive aphasia.

“Internet-based speech and language therapy has been effective in people with primary progressive aphasia, 78 but these findings need to be replicated in larger cohorts.”

• cites [78] Rogalski, 2018, A life participation approach to primary progressive aphasia intervention, Semin Speech Lang sourcePartly supported

  The section on the person-centered, multicomponent dyadic approach reports improved language performance and functional communication participation in the initial Communication Bridge study. The Conclusion says the telemedicine model was feasible for people with mild to moderate PPA, but the paper says a randomized trial was still assessing its effectiveness; it does not establish effectiveness as the claim states. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Substantial progress has been made to improve language symptoms in frontotemporal dementia.

“Substantial progress has been made to improve language symptoms.73”

• cites [73] Volkmer, 2020, Speech and language therapy approaches to managing primary progressive aphasia, Pract Neurol sourcePartly supported

  The Impairment-based approaches section reports improvements in word retrieval and speech production after therapy for people with primary progressive aphasia, and the Conclusion says the research literature is rapidly developing. The paper does not establish comparable progress for language symptoms across frontotemporal dementia generally; its treatment evidence concerns primary progressive aphasia, some cases of which have Alzheimer’s disease pathology (Introduction). (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Various pathogenic mechanisms have been proposed for C9orf72 repeat expansion toxicity, including toxic inclusions of abnormally expanded RNA, toxic gain of function from dipeptides abnormally transcribed from the expanded RNA, and haploinsufficiency.

“Various pathogenic mechanisms have been proposed for C9orf72 repeat expansion toxicity, including toxic inclusions of abnormally expanded RNA, toxic gain of function from dipeptides abnormally transcribed from the expanded RNA, and haploinsufficiency.84,85”

• cites [84] Todd, 2016, Insights into the pathogenic mechanisms of chromosome 9 open reading frame 72 (C9orf72) repeat expansions, J Neurochem sourceNot checked — no full text of the source
• cites [85] Jiang, 2016, Gain of toxicity from ALS/FTD-linked repeat expansions in C9ORF72 is alleviated by antisense oligonucleotides targeting GGGGCC-containing RNAs, Neuron sourcePartly supported

  The Introduction describes all three proposed mechanisms: C9ORF72 haploinsufficiency, toxicity from repeat-containing RNA foci, and toxicity from dipeptide-repeat proteins. It specifies that the dipeptide-repeat proteins are produced from the RNAs by RAN translation, not transcription, as the claim states. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Elevated phosphorylated tau concentrations in either CSF or plasma suggest that underlying Alzheimer's disease pathology is likely to be the cause of the frontotemporal dementia clinical syndrome.

“Although total tau and amyloid β concentrations are not sensitive or specific for any of the frontotemporal lobar degeneration proteinopathies, elevated phosphorylated tau concentrations in either CSF or plasma suggest that underlying Alzheimer's disease pathology is likely to be the cause of the frontotemporal dementia clinical syndrome.49,55,56”

• cites [49] Thijssen, 2020, Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration, Nat Med sourcePartly supported

  The Discussion (page not supplied) says elevated plasma pTau181 helps distinguish AD from FTLD, and the Results report higher CSF pTau181 in clinically diagnosed AD than in FTLD. But the Discussion also reports elevated plasma pTau181 in some MAPT-related FTLD without amyloid pathology. Thus elevation can suggest AD, but this paper does not establish that AD is likely to be the cause of every frontotemporal dementia syndrome with elevated pTau. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [55] Palmqvist, 2020, Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders, JAMA sourcePartly supported

  The Discussion reports that plasma P-tau217 was elevated in Alzheimer disease but not in other neurodegenerative diseases, and that its association with tau pathology was seen only when amyloid pathology was evident. The diagnostic-accuracy section includes a frontotemporal dementia/primary progressive aphasia group. However, the paper does not establish that elevated phosphorylated tau in a person with a frontotemporal dementia clinical syndrome means Alzheimer pathology is the likely cause of that syndrome; its direct findings also concern plasma P-tau217, not phosphorylated tau generally in either CSF or plasma. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [56] Thijssen, 2021, Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer's disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study, Lancet Neurol sourcePartly supported

  The Results report higher plasma P-tau217 and P-tau181 in autopsy-confirmed Alzheimer’s disease than in FTLD, and the Discussion describes patients with a clinical FTLD-spectrum syndrome whose elevated plasma P-tau accompanied Alzheimer’s pathology at autopsy. The Introduction calls CSF tau measurements established Alzheimer’s biomarkers, but our copy does not establish the more specific claim about elevated phosphorylated tau in CSF in this clinical setting. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Therapeutic trials of intrathecal antisense oligonucleotides designed to target expanded C9orf72 transcripts have only recruited people with an amyotrophic lateral sclerosis phenotype.

“So far, therapeutic trials of intrathecal antisense oligonucleotides designed to target expanded C9orf72 transcripts (including BIIB078 and afinersen 86 ) have only recruited people with an amyotrophic lateral sclerosis phenotype.”

• cites [86] Tran, 2021, Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide, Nat Med sourcePartly supported

  The Results section (page unavailable) reports intrathecal afinersen treatment in one person with a C9ORF72 expansion and atypical motor neuron dysfunction. The paper supports that example, but it does not establish that all such trials—including BIIB078—recruited only people with an ALS phenotype. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Sentence reading, sentence ordering, and aspects of dictation are more impaired in individuals with non-fluent primary progressive aphasia than in those with semantic variant primary progressive aphasia.

“Conversely, sentence reading, sentence ordering, and aspects of dictation are more impaired in individuals with non-fluent primary progressive aphasia than in those with semantic variant primary progressive aphasia.44”

• cites [44] Harris, 2019, Neuropsychological differentiation of progressive aphasic disorders, J Neuropsychol sourcePartly supported

  The Results (Group comparisons; page not available in our copy) report poorer performance in nfvPPA than in all other patient groups on the reading and dictation conditions of the Manchester sentence ordering test. But on the standard sentence-ordering condition, nfvPPA scores were not poorer than those of the semantic dementia group, which the paper identifies as broadly corresponding to svPPA. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

NfL has been highlighted as a biomarker for differential diagnosis between behavioural variant frontotemporal dementia and primary psychiatric disorders, with areas under the curve between 0.84 and 0.94.

“A few studies have highlighted the use of NfL as a biomarker for differential diagnosis between behavioural variant fronto temporal dementia and primary psychiatric disorders, with areas under the curve between 0•84 and 0•94.53,54”

• cites [53] Eratne, 2020, A pilot study of the utility of cerebrospinal fluid neurofilament light chain in differentiating neurodegenerative from psychiatric disorders: a ‘C-reactive protein’ for psychiatrists and neurologists?, Aust N Z J Psychiatry sourceNot checked — no full text of the source
• cites [54] Katisko, 2020, Serum neurofilament light chain is a discriminative biomarker between frontotemporal lobar degeneration and primary psychiatric disorders, J Neurol sourcePartly supported

  The Results report that serum NfL discriminated bvFTD from primary psychiatric disorders, supporting its proposed diagnostic use. But the reported AUC for that comparison is 0.820 (0.830 in the Abstract), below the claimed range of 0.84–0.94; the Results’ AUC of 0.850 compares the broader FTLD group with psychiatric disorders. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

The potential of tau PET imaging to differentiate tauopathy from nontauopathy among individuals with underlying frontotemporal lobar degeneration has not been substantiated.

“Tau PET imaging was initially considered to be a potential major breakthrough in differentiating tauopathy from nontauopathy among individuals with underlying frontotemporal lobar degeneration, but this potential has not been substantiated.71”

• cites [71] Tsai, 2019, 18F-flortaucipir (AV-1451) tau PET in frontotemporal dementia syndromes, Alzheimers Res Ther sourcePartly supported

  The Conclusions (page unavailable) report that 18F-flortaucipir showed limited sensitivity and specificity in patients with FTD and predicted tau or TDP-43 pathology, supporting the concern about distinguishing these pathologies. The claim extends that finding from one tracer to tau PET imaging generally; the paper says more sensitive and specific tracers are needed, not that their potential has been ruled out. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Nimodipine did not raise progranulin concentrations in participants with GRN haploinsufficiency enrolled in an 8-week, open-label trial.

“The calcium channel blocker nimodipine did not raise progranulin concentrations in participants with GRN haploinsufficiency enrolled in an 8-week, open-label trial.81”

• cites [81] Sha, 2017, An 8-week, open-label, dose-finding study of nimodipine for the treatment of progranulin insufficiency from GRN gene mutations, Alzheimers Dement (N Y) sourceSupported

Irregular word reading, word-picture matching, and semantic association are more impaired in people with semantic variant primary progressive aphasia than in those with non-fluent primary progressive aphasia.

“Irregular word reading, word-picture matching, and semantic association are more impaired in people with semantic variant primary progressive aphasia than in those with non-fluent primary progressive aphasia.43”

• cites [43] Staffaroni, 2021, Uniform data set language measures for bvFTD and PPA diagnosis and monitoring, Alzheimers Dement (Amst) sourceSupported

Atrophy in the frontal or temporal lobes supports the clinical suspicion of frontotemporal dementia.

“Atrophy in the frontal or temporal lobes, which can be either symmetrical or very focal or asymmetrical, supports the clinical suspicion of frontotemporal dementia.3,4”

• cites [3] Rascovsky, 2011, Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia, Brain sourceCould not verify

  The retrieved copy’s diagnostic-criteria passages concern primary progressive aphasia: they describe frontal or temporal atrophy as supporting diagnoses of particular aphasia variants, not clinical suspicion of frontotemporal dementia generally. Searches for the behavioural-variant criteria and for the stated atrophy patterns did not retrieve a passage addressing the attributed claim; the indexed text appears to belong to a different paper. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [4] Gorno-Tempini, 2011, Classification of primary progressive aphasia and its variants, Neurology sourcePartly supported

  The development and diagnostic-features sections (page not provided) use frontal and temporal atrophy patterns to support diagnoses of specific primary progressive aphasia variants. They do not establish that frontal or temporal atrophy generally supports suspicion of frontotemporal dementia, or address the sentence’s symmetrical, focal, and asymmetrical patterns. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Plasma NfL concentrations correlate well with CSF NfL concentrations.

“NfL concentrations in plasma correlate well with those in CSF.47,50”

• cites [47] Meeter, 2016, Neurofilament light chain: a biomarker for genetic frontotemporal dementia, Ann Clin Transl Neurol sourcePartly supported

  The Results section (“Correlation between CSF and serum NfL”) reports a strong correlation between CSF and serum NfL (rₛ = 0.87, P < 0.001). The cited study measured serum, not plasma, so it does not directly establish the claim for plasma concentrations. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [50] Illan-Gala, 2021, Plasma tau and neurofilament light in frontotemporal lobar degeneration and Alzheimer disease, Neurology sourceSupported

In familial frontotemporal dementia mutation carriers, greater intensity of physical and cognitive activities is associated with slower clinical decline and rate of atrophy on MRI.

“Evidence suggests that in familial frontotemporal dementia mutation carriers, greater intensity of physical and cognitive activities are associated with slower clinical decline and rate of atrophy on MRI.80”

• cites [80] Casaletto, 2020, Active lifestyles moderate clinical outcomes in autosomal dominant frontotemporal degeneration, Alzheimers Dement sourcePartly supported

  The Results section reports that greater baseline physical and cognitive activity were associated with slower clinical decline in mutation carriers. It does not establish slower MRI-measured atrophy: associations with longitudinal brain-volume change did not reach statistical significance. The reported atrophy interactions concern cognitive performance despite comparable volume loss, not a reduced rate of atrophy. Page numbers were not supplied in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Plasma phosphorylated tau at residues 181 or 217 has similar diagnostic accuracy to amyloid and tau PET or CSF measures for the differential diagnosis from Alzheimer's disease.

“Plasma measures of phos phorylated tau at residues 181 or 217 have similar diagnostic accuracy to amyloid and tau PET or CSF measures for the differential diagnosis from Alzheimer's disease, and plasma phosphorylated tau measures might eventually supplant these”

• cites [49] Thijssen, 2020, Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration, Nat Med sourcePartly supported

  The Discussion says plasma pTau181 differentiated Alzheimer’s disease from frontotemporal lobar degeneration with accuracy similar to previously reported amyloid-PET accuracy, and reports accuracy similar to CSF pTau181. The paper also relates pTau181 to tau-PET findings, but the cited passages do not establish similar differential-diagnostic accuracy to tau PET. It studies pTau181, not pTau217; no page numbers are available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [55] Palmqvist, 2020, Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders, JAMA sourcePartly supported

  The Discussion (page not provided) says plasma P-tau217 did not perform significantly differently from tau-PET or CSF P-tau measures in distinguishing Alzheimer dementia from other neurodegenerative disorders. It also reports significantly higher diagnostic accuracy for plasma P-tau217 than plasma P-tau181. The paper therefore does not support extending the comparable-accuracy finding to both plasma measures, and it does not establish a comparable differential-diagnosis result against amyloid PET. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Several neuropsychological tests have been developed that are tailored for primary progressive aphasia.

“Several neuropsychological tests have been developed that are tailored for primary progressive aphasia.42”

• cites [42] Henry, 2018, Assessment of individuals with primary progressive aphasia, Semin Speech Lang sourceSupported

People with C9orf72 expansions can have a Huntington's disease-like hyperkinetic disorder.

“For example, people with C9orf72 expansions can have a Huntington's disease-like hyper kinetic disorder.24”

• cites [24] Ida, 2018, C9orf72 repeat expansion frequency among patients with Huntington disease genetic testing, Neurodegener Dis sourceNot checked — no full text of the source

Accurate and early diagnosis of frontotemporal dementia is now a possibility due to development of neuropsychological measures with a special focus on social cognition.

“Accurate and early diagnosis of frontotemporal dementia is now a possibility due to development of neuropsychological measures with a special focus on social cognition.”

Many individuals with both primary progressive apraxia of speech and mixed primary progressive apraxia of speech and non-fluent primary progressive aphasia could also have tau pathology at post mortem, similar to patients with progressive supranuclear palsy, corticobasal degeneration, or Pick's disease.

“Many individuals with both primary progressive apraxia of speech and mixed primary progressive apraxia of speech and the non-fluent primary progressive aphasia could also have tau pathology at post mortem, similar to patients with progressive supranuclear palsy, corticobasal degeneration, or Pick's disease.”

A change in speech or language functioning would be expected in individuals with evolving primary progressive aphasia.

“Similarly, a change in speech or language functioning would be expected in individuals with evolving primary progressive aphasia.”

• AssumptionRests on an assumption: In any given individual, the frontotemporal dementia syndrome is typically (but not always) due to frontotemporal lobar degeneration.

Quantifiable features such as reading prosody and quantifiable non-speech features such as working memory and visuospatial function are useful when classifying individuals with the non-fluent versus logopenic variant.

“Quantifiable features (such as reading prosody), 16 and quantifiable non-speech features (such as working memory and visuospatial function), 17 are therefore useful when classifying these individuals.”

• cites [16] Matias-Guiu, 2020, Reading prosody in the non-fluent and logopenic variants of primary progressive aphasia, Cortex sourceNot checked — no full text of the source
• cites [17] Kamath, 2020, A meta-analysis of neuropsychological functioning in the logopenic variant of primary progressive aphasia: comparison with the semantic and non-fluent variants, J Int Neuropsychol Soc sourceNot checked — no full text of the source

These features might still be part of the same pathological spectrum.

“Nonetheless, these features might still be part of the same pathological spectrum.”

The primary proteinopathies associated with frontotemporal lobar degeneration include tau (often termed tauopathies), TDP43, and FET-related proteins.

“The primary proteinopathies associated with frontotemporal lobar degeneration include tau (often termed tauopathies), TDP43, and FET-related proteins (appendix pp 2-3).27”

• cites [27] Neumann, 2019, Review: neuropathology of non-tau frontotemporal lobar degeneration, Neuropathol Appl Neurobiol sourceNot checked — no full text of the source

Mixed phenotypes or expanded clinical phenotypes occur in people with underlying Alzheimer's disease.

“In particular, mixed phenotypes or expanded clinical phenotypes occur in people with underlying Alzheimer's disease.15”

• cites [15] Louwersheimer, 2016, Heterogeneous language profiles in patients with primary progressive aphasia due to Alzheimer's disease, J Alzheimers Dis sourceNot checked — no full text of the source

In two well-powered phase 2 trials, antibodies directed against N-terminal tau epitopes (gosuranemab and tilavonemab) did not affect the rate of clinical progression in people with progressive supranuclear palsy.

“In two well powered phase 2 trials, antibodies directed against N-terminal tau epitopes (namely, gosuranemab and tilavonemab) did not affect the rate of clinical progression in people with progressive supranuclear palsy (NCT03413319, NCT03068468).”

• cites NCT03413319Not matched

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

• cites NCT03068468Not matched

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

A frontotemporal dementia-like clinical presentation associated with intracranial hypotension, termed frontotemporal brain sagging syndrome, can be reversible in contrast to frontotemporal dementia.

“One mimic that has been described (and is important to consider) is a frontotemporal dementialike clinical presentation associated with intracranial hypotension, termed by some as frontotemporal brain sagging syndrome, 68 which (in contrast to frontotemporal dementia) can be reversible.”

• cites [68] Schievink, 2018, Behavioral variant frontotemporal dementia as a serious complication of spontaneous intracranial hypotension, Oper Neurosurg (Hagerstown) sourceNot checked — no full text of the source

Enriched encoding might enhance generalisation to other exemplars and situations.

“Although generalisation of training is variable and tends to be context dependent, 74 enriched encoding might enhance generalisation to other exemplars and situations.75”

• cites [75] Suarez-Gonzalez, 2018, Successful short-term re-learning and generalisation of concepts in semantic dementia, Neuropsychol Rehabil sourceNot checked — no full text of the source

Current first-generation tau ligands do not have sufficient clinical or research utility in frontotemporal dementia.

“Therefore, the current first-generation tau ligands do not have sufficient clinical or research utility in frontotemporal dementia.”

Performance on nonlanguage cognitive tests is more impaired in people with logopenic variant primary progressive aphasia than in those with non-fluent primary progressive aphasia.

“Performance on nonlanguage cognitive tests is more impaired in people with logopenic variant primary progressive aphasia than in those with non-fluent primary progressive aphasia (table 1).”

• cites table 1Not matched

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

The presence of social cognition impairment and behavioural changes might assist with differential diagnosis from logopenic variant primary progressive aphasia.

“Social cognition impairment and behavioural changes are also present in individuals with semantic variant primary progressive aphasia, 45 and to a lesser extent in those with non-fluent primary progressive aphasia, 46 which might assist with differential diagnosis from logopenic variant primary progressive aphasia.”

Stopping the gosuranemab testing programme in people with progressive supranuclear palsy led to early termination of the phase 1 basket trial of gosuranemab, into which participants were enrolled with corticobasal syndrome, non-fluent primary progressive aphasia, MAPT mutations, or traumatic encephalopathy.

“Stopping the gosuranemab testing programme in people with progressive supranuclear palsy led to early termination of the phase 1 basket trial of gosuranemab, into which participants were enrolled with corticobasal syndrome, non-fluent primary progressive aphasia, MAPT mutations, or traumatic encephalopathy (NCT03658135).”

• cites NCT03658135Not matched

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

Together with GENFI and ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration, these studies have formed the FTD Prevention Initiative.

“together with GENFI and ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration, these studies have formed the FTD Prevention Initiative.”

The formation of large international study cohorts has enabled researchers to define intermediate stages between onset of symptomatology and overt frontotemporal dementia.

“and to define intermediate stages between onset of symptomatology and overt frontotemporal dementia.”

The formation of large international study cohorts has enabled researchers to identify the earliest clinical, biomarker, and neuroimaging changes in presymptomatic mutation carriers.

“enabling researchers to identify the earliest clinical, biomarker, and neuroimaging changes in presymptomatic mutation carriers”

The major achievements in frontotemporal dementia and frontotemporal lobar degeneration research over the past decade include the formation of large international study cohorts.

“The major achievements in frontotemporal dementia and frontotemporal lobar degeneration research over the past decade include the formation of large international study cohorts”