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Cited by 40Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis Research

Diagnosing the frontal variant of Alzheimer’s disease: a clinician’s yellow brick road

Open access
Sawyer, Russell P., Rodriguez-Porcel, Federico, Hagen, Matthew, Shatz, Rhonna, Espay, Alberto J.·2017·Journal of Clinical Movement Disorders
DOI 10.1186/s40734-017-0052-4PMC PMC5333400
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Abstract

BACKGROUND: Disruption of the frontal lobes and its associated networks are a common consequence of neurodegenerative disorders. Given the wide range of cognitive, behavioral and motor processes in which the frontal lobes are involved, there can be a great variety of manifestations depending on the pathology distribution. The most common are the behavioral variant of frontotemporal dementia (bvFTD) and the frontal variant of Alzheimer's disease (fvAD), which are particularly challenging to disentangle. Recognizing fvAD from bvFTD-related pathologies is a diagnostic challenge and a critical need in the management and counseling of these patients. CASE PRESENTATION: Here we present three pathology-proven cases of Alzheimer's disease initially misdiagnosed as bvFTD and discuss the distinctive or less overlapping historical, examination, and laboratory findings of fvAD and bvFTD, deriving analogies for mnemonic endurance from the Wizard of Oz worldview. CONCLUSION: The Yellow Brick Road to diagnosing these disorders may be served by the metaphor of fvAD as the irritable, paranoid, and tremulous Scarecrow and bvFTD the heartless, ritualistic, and rigid Tin Man. An Oz-inspired creative license may help the clinician recognize the differential disease progression, caregiver burden, and treatment response of fvAD compared with bvFTD.

AI snapshot

Written from the paper’s full text.

TL;DR

This case series and review describes three patients with autopsy-proven Alzheimer’s disease who were initially misdiagnosed with behavioral variant frontotemporal dementia (bvFTD), and it proposes clinical features and a Wizard of Oz mnemonic to distinguish frontal variant AD (fvAD) from bvFTD. The authors argue that early memory impairment, semantic language deficits, and myoclonus favor fvAD, whereas early behavioral change, loss of empathy, hyperphagia, and early parkinsonism favor bvFTD.

Key findings

  • All three pathology-proven cases had high-level AD neuropathology by NIA-AA criteria but were diagnosed in life as possible or probable bvFTD; the authors highlight early memory involvement, impaired semantic fluency, paraphasic errors, and myoclonus as features that should have supported fvAD.
  • fvAD is reported as approximately 2–3% of AD, though AD pathology can be found in up to 25% of patients with a clinical diagnosis of bvFTD; memory impairment is the first abnormality in up to 85% of fvAD patients, with the remainder developing memory impairment within 3 years.
  • Cortical myoclonus is documented in about 50% of fvAD patients, while parkinsonism is present in 20–30% of bvFTD patients and may appear in up to 30% of AD patients later in the disease course.
  • CSF p-tau/Aβ42 ratio >0.21 is reported in fvAD compared with bvFTD with sensitivity and specificity of about 92%; in one small series, APOE ε4 carriers were 52% in fvAD, 19% in bvFTD, and 17% in controls.

Methods

  • Design: case presentation of three patients with pathology-proven AD initially misdiagnosed as bvFTD, followed by a narrative review of clinical, imaging, biomarker, and treatment differences between fvAD and bvFTD.
  • Data/sample: three autopsy-confirmed cases (72-year-old man, 79-year-old man, 78-year-old woman) with clinical histories, examinations, MRI findings, medication trials, and neuropathology.
  • Main analysis: descriptive clinicopathological correlation and literature synthesis, with a proposed mnemonic analogy from “The Wonderful Wizard of Oz”; no formal statistical analysis or randomized trial data are presented.

Limitations

  • Stated: the authors acknowledge the limitations of classic literature-based metaphors for a complex clinical dilemma; they note that the fvAD phenotype is less well delineated and heterogenous across case reports and series, and that no randomized clinical trials have been undertaken in fvAD.
  • Stated: disease-specific biomarkers remain elusive, and future clinical trials will require better patient selection and reliable serologic/imaging biomarkers.
  • Evident from the text: the study is limited to three cases, two cases lacked amyloid imaging and CSF biomarkers, diagnoses were confirmed only at autopsy, and comorbid cerebrovascular disease in cases #1 and #2 and Lewy body pathology in case #2 may have contributed to clinical features and confounded interpretation.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1186/s40734-017-0052-4

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

32 of 54 cited sources checked · 8 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    A corticobasal syndrome is more often due to AD pathology than corticobasal degeneration or other disorders.

    “On the other hand, a corticobasal syndrome (asymmetric parkinsonism with limb dystonia, apraxia, and cortical sensory loss) is more often due to AD pathology than corticobasal degeneration or other disorders [31].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [31] Lee SE, Rabinovici GD, Mayo MC, Wilson SM, Seeley WW, DeArmond SJ, Huang EJ, Trojanowski JQ, Growdon ME, Jang JY, et al. Clinicopathological correlations in corticobasal degeneration. Ann Neurol. 2011;70:327–40. source

      The Abstract (Results) reports that CBD was the most common pathological cause of clinical corticobasal syndrome (35%), followed by AD (23%). The Results (Subjects: Histopathology) likewise lists 14 CBD cases versus 9 AD cases, contrary to the claim that AD was more common. (LLM, conf=0.94)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Memantine has shown no benefit in patients with bvFTD.

    “Likewise memantine, an NMDA receptor antagonist, approved for moderate to severe AD, has shown no benefit in patients with bvFTD [38].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [38] Boxer AL, Knopman DS, Kaufer DI, Grossman M, Onyike C, Graf-Radford N, Mendez M, Kerwin D, Lerner A, Wu CK, et al. Memantine in patients with frontotemporal lobar degeneration: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2013;12:149–56. source
  • Premisecitation

    The clinical distinction between fvAD and bvFTD has implications for prognosis, treatment, disease progression, and caregiver burden.

    “The appropriate clinical distinction between fvAD and bvFTD has implications for prognosis, treatment, disease progression, and caregiver burden [11–15].”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [11] Neary D, Snowden JS, Mann DM. Classification and description of frontotemporal dementias. Ann N Y Acad Sci. 2000;920:46–51. source
    • cites [12] Peters ME, Schwartz S, Han D, Rabins PV, Steinberg M, Tschanz JT, Lyketsos CG. Neuropsychiatric symptoms as predictors of progression to severe Alzheimer’s dementia and death: the cache county dementia progression study. Am J Psychiatry. 2015;172:460–5. source

      The Discussion (page unavailable) reports that early agitation/aggression in Alzheimer’s dementia predicted accelerated progression and mortality, supporting the general point that symptoms matter for prognosis. The paper does not address the clinical distinction between fvAD and bvFTD or show that making that distinction affects treatment or caregiver burden. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [13] Li Y, Hai S, Zhou Y, Dong BR. Cholinesterase inhibitors for rarer dementias associated with neurological conditions. Cochrane Database Syst Rev. 2015;3:Cd009444. source

      The Description of the intervention section says cholinesterase inhibitors are first-line medicines for Alzheimer’s disease, while the Authors’ conclusions say their efficacy in FTD is unclear. That supports a treatment-related reason to distinguish the conditions. The review does not discuss fvAD specifically or establish implications of distinguishing it from bvFTD for prognosis, disease progression, or caregiver burden; page numbers are unavailable in our copy. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [14] Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev. 2006;25:Cd005593.

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

    • cites [15] Adelman RD, Tmanova LL, Delgado D, Dion S, Lachs MS. Caregiver burden: a clinical review. JAMA. 2014;311:1052–60. source
  • Premisecitation

    In fvAD there is greater temporal than frontal atrophy, particularly in the perisylvian area compared to bvFTD.

    “In fvAD there is greater temporal than frontal atrophy, particularly in the perisylvian area compared to bvFTD [21, 33].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [21] Ossenkoppele R, Pijnenburg YA, Perry DC, Cohn-Sheehy BI, Scheltens NM, Vogel JW, Kramer JH, van der Vlies AE, Joie RL, Rosen HJ, et al. The behavioural/dysexecutive variant of Alzheimer’s disease: clinical, neuroimaging and pathological features. Brain. 2015;138:2732–49. source

      The voxel-based morphometry results (p. 9) describe predominant temporoparietal atrophy with limited frontal atrophy in behavioural Alzheimer’s disease. The neuroimaging comparison (p. 14) contrasts this posterior pattern with the anterior atrophy seen in bvFTD. Our copy does not identify the perisylvian area as a particular focus of the difference. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [33] Ossenkoppele R, Cohn-Sheehy BI, La Joie R, Vogel JW, Moller C, Lehmann M, Van Berckel BN, Seeley WW, Pijnenburg YA, Gorno-Tempini ML, et al. Atrophy patterns in early clinical stages across distinct phenotypes of Alzheimer’s disease. Hum Brain Mapp. 2015;36:4421–37. source

      The Results (Voxel Based Morphometry: AD Variants Versus Controls; page unavailable) describe temporal and temporoparietal atrophy in the AD phenotypes studied, but do not examine frontal-variant AD (fvAD) or compare it with bvFTD. Searches for fvAD, bvFTD, perisylvian atrophy, and the frontal-versus-temporal comparison found no passage addressing the cited claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Findingcitation

    Case #3 autopsy revealed high level AD neuropathology per NIA-AA criteria.

    “By NIA-AA criteria, the findings met criteria for “high level” AD neuropathology [3–7].”
    Quote in the paperSubstantial claim1 of 5 sources checked
    • cites [3] Braak H, Braak E. Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging. 1995;16:271–8. discussion 278–284. source
    • cites [4] Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 2012;8:1–13. source
    • cites [5] Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, Van Belle G, Berg L. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology. 1991;41:479–86. source
    • cites [6] Thal DR, Rub U, Orantes M, Braak H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58:1791–800. source
    • cites [7] Braak H, Del Tredici K, Rub U, De Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24:197–211. source
  • Classified as probably not a substantial claim. 5
  • May combine two claims. 16

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

    Premisecitation

    Parkinsonian features may be present in up to 30% of patients with AD, and these appear later in the disease course.

    “While parkinsonian features may be present in up to 30% of patients with AD, [32] these appear later in the disease course [32].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [32] Portet F, Scarmeas N, Cosentino S, Helzner EP, Stern Y. Extrapyramidal signs before and after diagnosis of incident Alzheimer disease in a prospective population study. Arch Neurol. 2009;66:1120–6. source

      The Discussion says extrapyramidal signs were present in very early AD, even before the diagnosis was confirmed, contrary to the claim that they appear later in the disease course. The Abstract Results report 12.3% at first evaluation and 22.6% at last evaluation, supporting their presence in a substantial minority but not the claimed timing. Our copy provides no page numbers for these passages. (LLM, conf=0.87)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

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

    Premisecitation

    bvFTD is most often caused by FTLD proteinopathies: tauopathies, TDP-43 proteinopathies, and less frequently FUS proteinopathies.

    “bvFTD is most often caused by frontotemporal lobar degeneration (FTLD) proteinopathies, namely tauopathies (of which microtubule-associated protein tau (MAPT) gene mutations are the most common genetic causes), TDP-43 proteinopathies (of which chromosome 9 open reading frame 72 (C9orf72) and progranulin (GRN) gene mutations, in order of frequency, are most common), and less frequently, fused in s”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Sieben A, Van Langenhove T, Engelborghs S, Martin JJ, Boon P, Cras P, De Deyn PP, Santens P, Van Broeckhoven C, Cruts M. The genetics and neuropathology of frontotemporal lobar degeneration. Acta Neuropathol. 2012;124:353–72. source

  • May combine two claims.

    Premisecitation

    In bvFTD, language dysfunction is initially absent, unlike other frontotemporal dementia phenotypes (progressive nonfluent aphasia and semantic dementia).

    “In bvFTD, language dysfunction is initially absent, unlike other frontotemporal dementia phenotypes, namely progressive nonfluent aphasia and semantic dementia [17].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [17] Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, Van Swieten JC, Seelaar H, Dopper EG, Onyike CU, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134:2456–77. source

      The indexed section headed “Classification of primary progressive aphasia and its variants” describes language impairments in the nonfluent and semantic variants (page not provided). It does not establish that language dysfunction is initially absent in bvFTD, which is the central contrast in the citing sentence. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

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

    Premisecitation

    fvAD accounts for approximately 2-3% of AD.

    “Some studies have suggested that fvAD accounts for approximately 2–3% of AD, [1, 2]”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [1] Alladi S, Xuereb J, Bak T, Nestor P, Knibb J, Patterson K, Hodges JR. Focal cortical presentations of Alzheimer’s disease. Brain. 2007;130:2636–45. source
    • cites [2] Lam B, Masellis M, Freedman M, Stuss DT, Black SE. Clinical, imaging, and pathological heterogeneity of the Alzheimer’s disease syndrome. Alzheimers Res Ther. 2013;5:1. source

      The ‘Frontal (executive) variant’ section reports 2 cases among 100 AD cases in one series, consistent with the lower end of the claimed range. It also reports 3 among 63 in another series—about 5%—and does not establish that fvAD accounts for 2–3% of AD overall. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    While semantic (category) fluency is usually impaired to a greater degree in fvAD, phonemic (letter) fluency is more affected in bvFTD.

    “While semantic (category) fluency is usually impaired to a greater degree in fvAD, phonemic (letter) fluency is more affected in bvFTD [17].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [17] Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, Van Swieten JC, Seelaar H, Dopper EG, Onyike CU, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134:2456–77. source

      The passages returned from our indexed copy are labeled as a section on primary progressive aphasia, despite the supplied source title. Its discussion of semantic and phonological language deficits does not compare category and letter fluency in fvAD and bvFTD. Searches for both fluency types and the fvAD–bvFTD comparison found no passage addressing the claim. (LLM, conf=0.71)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Clinical diagnosis of bvFTD is based on behavioral changes antedating cognitive deficits, with sensitivity 76-95% and specificity 82-95%.

    “The clinical diagnosis of bvFTD is currently based on the presence of behavioral changes antedating cognitive deficits with a sensitivity of 76–95% and specificity of 82–95% [16, 17].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [16] Harris JM, Gall C, Thompson JC, Richardson AM, Neary D, Du Plessis D, Pal P, Mann DM, Snowden JS, Jones M. Sensitivity and specificity of FTDC criteria for behavioral variant frontotemporal dementia. Neurology. 2013;80:1881–7. source
    • cites [17] Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, Van Swieten JC, Seelaar H, Dopper EG, Onyike CU, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134:2456–77. source

      The supplied passages and further indexed results are labeled as a classification of primary progressive aphasia, not as the cited bvFTD study. Searches for the claimed sequence of behavioural and cognitive changes and for the 76–95% sensitivity and 82–95% specificity ranges found no passage addressing them. The apparent mismatch in the indexed copy prevents verification of this citation. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    bvFTD patients may exhibit compulsive perseverative thoughts or behaviors, including collecting, hoarding, and hyperphagia, while these compulsive changes are typically absent in fvAD.

    “Relatedly, bvFTD patients may exhibit compulsive perseverative thoughts or behaviors, including collecting, hoarding, and hyperphagia, while these compulsive changes are typically absent in fvAD [27].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [27] Leger GC, Banks SJ. Neuropsychiatric symptom profile differs based on pathology in patients with clinically diagnosed behavioral variant frontotemporal dementia. Dement Geriatr Cogn Disord. 2014;37:104–12. source

      The Introduction (page not available) reports that stereotypic behaviors and changes in eating are more characteristic of clinically diagnosed bvFTD than AD. The Discussion (page not available) likewise reports more appetite and eating changes in bvFTD, but only suggests that some patients with AD pathology might have frontal-variant AD. The paper does not establish that compulsive changes are typically absent in fvAD or specifically document collecting and hoarding. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Personality changes are more common in patients with bvFTD than fvAD, with differences in the nature of the personality change shedding light on the underlying diagnosis.

    “Personality changes are more common in patients with bvFTD than fvAD, with differences in the nature of the personality change shedding light on the underlying diagnosis [10, 22].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [10] Forman MS, Farmer J, Johnson JK, Clark CM, Arnold SE, Coslett HB, Chatterjee A, Hurtig HI, Karlawish JH, Rosen HJ, et al. Frontotemporal dementia: clinicopathological correlations. Ann Neurol. 2006;59:952–62. source

      The Results describe early personality changes in the frontal or social/dysexecutive variant of FTLD, and the Discussion says early clinical features can help distinguish pathological subgroups statistically. But the Results do not establish that personality changes are more common in bvFTD than in frontal-variant AD or identify differing types of personality change between them; they report that behavioral/social dysfunction alone was not significantly different among the pathological groups. Our copy provides no page numbers for these passages. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [22] Mendez MF, Joshi A, Tassniyom K, Teng E, Shapira JS. Clinicopathologic differences among patients with behavioral variant frontotemporal dementia. Neurology. 2013;80:561–8. source

      The Results passage (indexed under GLOSSARY; page not provided) reports significantly more personality change in patients with bvFTD-FTLD than in those clinically diagnosed with bvFTD who had AD pathology. This supports a related diagnostic distinction, but the study did not directly compare bvFTD with a separately defined fvAD group or characterize differences in the nature of personality change between those groups. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A higher p-tau/Aβ42 ratio (>0.21) is observed in fvAD compared to bvFTD, with sensitivity and specificity of about 92%.

    “A higher p-tau/Aβ42 ratio (>0.21) is observed in fvAD compared to bvFTD (sensitivity and specificity of about 92%) [25].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [25] Bertoux MK Aurélie, Azuar C, Lamari F, Cruz de Souza L, Sarazin M, Samri D, Funkiewiez A, Dubois B, Odile HM. Frontal presentation of Alzheimer’s disease. A series of patients with biological evidence by CSF biomarkers. Dementia & Neuropsychologia. 2013;7(1):66–74. source

      The Methods define the frontal AD group by a P-Tau/Aβ42 ratio above 0.21 and the bvFTD comparison group by a ratio below 0.21. They also report 91.2% sensitivity and 92.6% specificity for distinguishing AD from bvFTD, but do not establish those figures specifically for distinguishing frontal-variant AD from bvFTD. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    bvFTD patients may have mild difficulty with free recall early, but recognition memory is typically intact and they are able to recognize items with cueing, consistent with a retrieval-predominant deficit.

    “While bvFTD patients may have mild difficulty with free recall early in the disease, recognition memory is typically intact and thus patients are able to recognize items with cueing, consistent with a retrieval-predominant deficit [24].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [24] Karantzoulis S, Galvin JE. Distinguishing Alzheimer’s disease from other major forms of dementia. Expert Rev Neurother. 2011;11:1579–91. source

  • May combine two claims.

    Interpretationcitation

    The proportion of fvAD is likely higher because AD pathology can be found in up to 25% of patients with a clinical diagnosis of bvFTD.

    “although this figure is likely higher because AD pathology can be found in up to 25% of patients with a clinical diagnosis of bvFTD [9, 10].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [9] Kertesz A, McMonagle P, Blair M, Davidson W, Munoz DG. The evolution and pathology of frontotemporal dementia. Brain. 2005;128:1996–2005. source
    • cites [10] Forman MS, Farmer J, Johnson JK, Clark CM, Arnold SE, Coslett HB, Chatterjee A, Hurtig HI, Karlawish JH, Rosen HJ, et al. Frontotemporal dementia: clinicopathological correlations. Ann Neurol. 2006;59:952–62. source

      The Discussion reports AD pathology in 16.7% of patients clinically diagnosed with FTLD, supporting the general point that AD can underlie a frontotemporal clinical presentation. It does not give a rate of up to 25% specifically for behavioral-variant FTD (bvFTD), and it does not establish that the proportion of frontal-variant AD is higher. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In fvAD, memory impairment is the first abnormality in up to 85% of patients, with the remainder developing memory impairment within 3 years from symptom onset.

    “Conversely, in fvAD memory impairment is the first abnormality in up to 85% of patients (Fig. 4), with the remainder developing memory impairment within 3 years from symptom onset [1, 22, 23].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [1] Alladi S, Xuereb J, Bak T, Nestor P, Knibb J, Patterson K, Hodges JR. Focal cortical presentations of Alzheimer’s disease. Brain. 2007;130:2636–45. source
    • cites [22] Mendez MF, Joshi A, Tassniyom K, Teng E, Shapira JS. Clinicopathologic differences among patients with behavioral variant frontotemporal dementia. Neurology. 2013;80:561–8. source

      The Results (“First and current symptoms”; page not given) report that memory deficits were the first cognitive symptom in 8 of 21 patients with bvFTD and Alzheimer pathology (38.1%). This supports memory impairment as an initial symptom in some patients, but not the claimed figure of up to 85%; our copy also does not establish that the remainder developed it within three years of symptom onset. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [23] Ossenkoppele R, Cohn-Sheehy BI, La Joie R, Vogel JW, Möller C, Lehmann M, van Berckel BN, Seeley WW, Pijnenburg YA, Gorno-Tempini ML, Kramer JH, Barkhof F, Rosen HJ, van der Flier WM, Jagust WJ, Miller BL, Scheltens P, Rabinovici GD. Atrophy patterns in early clinical stages across distinct phenotypes of Alzheimer's disease. Hum Brain Mapp. 2015;36(11):4421-37. doi: 10.1002/hbm.22927 . source

      The Introduction says amnesia is the most common presenting symptom of Alzheimer’s disease generally, but the paper studies PCA, lvPPA, EOAD and LOAD—not fvAD. Searches for fvAD, the 85% figure and memory impairment within three years found no passage addressing those claims in our copy; section pages were not provided. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

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

    Findingreasoning

    Case #3 was initially diagnosed with possible bvFTD associated with parkinsonism.

    “the patient was diagnosed with possible bvFTD associated with parkinsonism.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Case #1 was initially diagnosed with possible bvFTD with parkinsonism based on apathy, poor personal hygiene, and predominantly executive dysfunction.

    “A diagnosis of possible bvFTD with parkinsonism was made based on apathy, poor personal hygiene, and predominantly executive dysfunction on cognitive testing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    In the authors' patients, cueing was of no benefit because memory was not formed, which was a missed clue to the underlying pathology.

    “As memory is not formed, cueing is of no benefit, which was the case in our patients –a missed clue as to the underlying pathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Our cases highlight several features which in hindsight should have supported a diagnostic revision to fvAD from bvFTD: early memory involvement, impaired semantic fluency, paraphasic errors and myoclonus.

    “Our cases highlight several features, which in hindsight should have supported a diagnostic revision to fvAD from bvFTD: early memory involvement, impaired semantic fluency, paraphasic errors and myoclonus (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Distinguishing between fvAD and bvFTD may be challenging for the clinician, as evidenced by our three cases initially diagnosed with bvFTD but found to have primarily AD pathology.

    “Distinguishing between fvAD and bvFTD may be challenging for the clinician, as evidenced by our three cases whom were initially diagnosed with bvFTD but were found to have primarily AD pathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The parkinsonian features of Case #2 were likely contributed to by Lewy body pathology, which not uncommonly co-occurs with AD.

    “The parkinsonian features of Case #2, however, were likely contributed to by Lewy body pathology, which not uncommonly co-occurs with AD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cortical myoclonus is documented in about 50% of patients with fvAD, and its presence favors fvAD over bvFTD.

    “As cortical myoclonus is documented in about 50% of patients with fvAD, [28] its presence favors fvAD over bvFTD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Snowden JS, Stopford CL, Julien CL, Thompson JC, Davidson Y, Gibbons L, Pritchard A, Lendon CL, Richardson AM, Varma A, et al. Cognitive phenotypes in Alzheimer’s disease and genetic risk. Cortex. 2007;43:835–45. source

  • May combine two claims.

    Premisecitation

    Acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) have been shown to be effective in classic AD but not in bvFTD.

    “While no randomized clinical trials have been undertaken in fvAD, acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) have been shown to be effective in classic AD but not in bvFTD [36].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Kertesz A, Morlog D, Light M, Blair M, Davidson W, Jesso S, Brashear R. Galantamine in frontotemporal dementia and primary progressive aphasia. Dement Geriatr Cogn Disord. 2008;25:178–85. source
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  • The paper relies on this without support.

    The phenotype of fvAD is less well delineated and heterogeneous.

    “Unlike bvFTD, the phenotype in fvAD is less well delineated, with heterogenous clinical descriptions from case reports and case series.”

  • The paper relies on this without support.

    Vascular pathology may confound the evaluation of frontal lobe syndromes, including fvAD and bvFTD.

    “In addition, vascular pathology may confound the evaluation of frontal lobe syndromes, including fvAD and bvFTD.”

  • The paper relies on this without support.

    Patients with bvFTD tend to present with behavioral changes first, followed by executive dysfunction and language disturbances.

    “Patients with bvFTD tend to present with behavioral changes first, which are followed by executive dysfunction and language disturbances (Fig. 3).”

  • The paper relies on this without support.

    Progressive language deterioration may occur late in bvFTD.

    “Progressive language deterioration may occur late in bvFTD.”

  • The paper relies on this without support.

    fvAD may more often present with word-finding difficulties, anomia, and semantic paraphasias.

    “The fvAD Scarecrow, “who lacks a brain”, may more often present with word-finding difficulties, anomia, and semantic paraphasias.”

  • The paper relies on this without support.

    Unlike fvAD, bvFTD patients may be cold, more apathetic and less empathetic, creating tension with caregivers.

    “Moreover, unlike fvAD “Scarecrows”, bvFTD “Tin Men” may be cold, more apathetic and less empathetic, creating tension with caregivers.”

  • The paper relies on this without support.

    Irritability and depression, as in Case #2, and emotional lability, as in Case #3, may be more common in fvAD, whereas constricted affect and apathy are more typical in bvFTD.

    “Whereas irritability and depression, as in Case #2, and emotional lability, as in Case #3, may be more common in fvAD, constricted affect and apathy are more typical in bvFTD.”

  • The paper relies on this without support.

    The bvFTD “Tin Man” is more emotionally constrained, whereas the fvAD “Scarecrow” is often depressed and may be overburdened by delusions and aggressive behaviors.

    “The bvFTD “Tin Man” is more emotionally constrained, whereas the fvAD “Scarecrow” is often depressed and may be overburdened by delusions and aggressive behaviors.”

  • The paper relies on this without support.

    bvFTD patients' eating habits may be significantly altered, with hyperphagia and food rituals, and a tendency to seek out and eat one type of food, such as high-carbohydrate meals, with resultant weight gain.

    “bvFTD patients eating habits may be significantly altered, with hyperphagia and food rituals, and a tendency to seek out and eat one type of food, such as high-carbohydrate meals, with resultant weight gain.”

  • The paper relies on this without support.

    Weight loss is typical of fvAD patients.

    “This contrasts with the weight loss typical of fvAD patients.”

  • The paper relies on this without support.

    Because of disinhibition and lack of empathy, bvFTD patients have poor table manners, and may engage in eating off tablemates’ plates or uncouthly eating with their hands.

    “Lastly, because of disinhibition and lack of empathy, bvFTD patients have poor table manners, and may engage in eating off tablemates’ plates or uncouthly eating with their hands.”

  • The paper relies on this without support.

    Parkinsonism is present in 20–30% of patients with bvFTD.

    “Parkinsonism is indeed present in 20–30% of patients with bvFTD.”

  • The paper relies on this without support.

    A symmetric tremorless parkinsonism with axial rigidity and supranuclear gaze palsy is highly predictive of progressive supranuclear palsy pathology due to MAPT or, less commonly, C9orf72 mutations.

    “A symmetric tremorless parkinsonism with axial rigidity and supranuclear gaze palsy has been shown to be highly predictive of progressive supranuclear palsy pathology due to MAPT or, less commonly, C9orf72 mutations.”

  • The paper relies on this without support.

    No randomized clinical trials have been undertaken in fvAD.

    “While no randomized clinical trials have been undertaken in fvAD”

  • The paper relies on this without support.

    Disease-specific biomarkers remain elusive.

    “While disease-specific biomarkers remain elusive”
15 of 15

Cites

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Research works printed but not linked: 1

  1. Ossenkoppele R, Cohn-Sheehy BI, La Joie R, Vogel JW, Moller C, Lehmann M, Van Berckel BN, Seeley WW, Pijnenburg YA, Gorno-Tempini ML, et al. Atrophy patterns in early clinical stages across distinct phenotypes of Alzheimer’s disease. Hum Brain Mapp. 2015;36:4421–37. · DOI · Paper page

Cited by

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Related

Authors
Sawyer, R. P., Rodriguez-Porcel, F., Hagen, M., Shatz, R., & Espay, A. J.
Affiliations
University of Cincinnati (US)
Corresponding author
Sawyer, Russell P.
ORCID
Venue
Journal of Clinical Movement Disorders
Publisher
Springer Science and Business Media LLC
Published
2017-03-02
Volume
4
Issue
1
Pages
2-2
ISSN
2054-7072 (ISSN-L)
DOI
10.1186/s40734-017-0052-4
PMC
PMC5333400
OpenAlex
W2587748142
Cited by
40
References
38
Citations by year
2026: 3 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 7 · 2021: 12 · 2020: 2 · 2019: 1 · 2018: 3
FWCI
0.25
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Clinical Movement Disorders (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
behavioral variant frontotemporal dementia, differential diagnosis, misdiagnosis, frontal lobe dysfunction, neurodegenerative diseases, caregiver burden, treatment response

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