Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update

Mackenzie, Ian R.; Neumann, Manuela; Bigio, Eileen H.; Cairns, Nigel J.; Alafuzoff, Irina; Kril, Jillian J.; Kovács, Gábor G.; Ghetti, Bernardino; Halliday, Glenda M.; Holm, Ida E.; Ince, Paul G.; Kamphorst, Wouter; Révész, Tamás; Rozemüller, Annemieke; Kumar‐Singh, Samir; Akiyama, Haruhiko; Baborie, Atik; Spina, Salvatore; Dickson, Dennis W.; Trojanowski, John Q.; Mann, David

doi:10.1007/s00401-009-0612-2

Cited by 844 publications

(757 citation statements)

References 14 publications

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“…Despite the fact that MFG‐E8 was increased in AD cases compared to both FTLD subtypes, it did not discriminate those clinical groups. Recent data has shown that A β can induce the release of MFG‐E8,46 and therefore, the higher levels of MFG‐E8 may reflect the higher amyloid load of AD patients that is rarely seen in FTLD cases 4…”

Section: Discussionmentioning

confidence: 99%

“…Two main pathological subtypes have been described based on the proteinopathy found in the brain: around half of the cases develop aggregates of the microtubule‐associated protein tau (FTLD‐Tau), while the other half are characterized by cytoplasmic inclusions of the transactivator regulatory DNA‐binding protein 43 (TDP43, FTLD‐TDP) 4. These two main pathologies likely require distinct pharmacological therapy, and thus, discrimination of both subtypes is strongly needed.…”

Section: Introductionmentioning

confidence: 99%

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Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Campo

Galimberti

Elias

et al. 2018

Ann Clin Transl Neurol

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ObjectiveFrontotemporal lobar degeneration (FTLD) is the second most prevalent dementia in young patients and is characterized by the presence of two main protein aggregates in the brain, tau (FTLD‐Tau) or TDP43 (FTLD‐TDP), which likely require distinct pharmacological therapy. However, specific diagnosis of FTLD and its subtypes remains challenging due to largely overlapping clinical phenotypes. Here, we aimed to assess the clinical performance of novel cerebrospinal fluid (CSF) biomarkers for discrimination of FTLD and its pathological subtypes.Methods YKL40, FABP4, MFG‐E8, and the activities of catalase and specific lysosomal enzymes were analyzed in patients with FTLD‐TDP (n = 30), FTLD‐Tau (n = 20), AD (n = 30), DLB (n = 29), and nondemented controls (n = 29) obtained from two different centers. Models were validated in an independent CSF cohort (n = 188).Results YKL40 and catalase activity were increased in FTLD‐TDP cases compared to controls. YKL40 levels were also higher in FTLD‐TDP compared to FTLD‐Tau. We identified biomarker models able to discriminate FTLD from nondemented controls (MFG‐E8, tTau, and Aβ 42; 78% sensitivity and 83% specificity) and non‐FTLD dementia (YKL40, pTau, p/tTau ratio, and age; 90% sensitivity, 78% specificity), which were validated in an independent cohort. In addition, we identified a biomarker model differentiating FTLD‐TDP from FTLD‐Tau (YKL40, MFGE‐8, βHexA together with βHexA/tHex and p/tTau ratios and age) with 80% sensitivity and 82% specificity.InterpretationThis study identifies CSF protein signatures distinguishing FTLD and the two main pathological subtypes with optimal accuracy (specificity/sensitivity > 80%). Validation of these models may allow appropriate selection of cases for clinical trials targeting the accumulation of Tau or TDP43, thereby increasing their efficiency and facilitating the development of successful therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Campo

Galimberti

Elias

et al. 2018

Ann Clin Transl Neurol

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“…Neuropathologic diagnosis was made using previously published neuropathologic criteria, including Braak stages,18, 19 Consortium to Establish a Registry for Alzheimer's Disease scores,19, 20 Thal A β phases,19, 21 LBD pathologic criteria,11 and FTLD classification22 by neuropathologists who were blinded to the 123 I‐FP‐CIT SPECT findings.…”

Section: Methodsmentioning

confidence: 99%

Clinicopathological and ¹²³I‐FP‐CIT SPECT correlations in patients with dementia

Jung

Jordan

Lowe

et al. 2018

Ann Clin Transl Neurol

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The relationship between clinicopathologic diagnosis and 123I‐FP‐CIT SPECT in 18 patients with dementia (12 with Lewy body disease) from one center in the United States was assessed. The sensitivity and specificity of abnormal 123I‐FP‐CIT SPECT with reduced striatal uptake on visual inspection for predicting Lewy body disease were 91.7% and 83.3%, respectively. The mean calculated putamen to occipital ratio (mPOR) based on regions of interest was significantly reduced in Lewy body disease compared to non‐Lewy body disease cases (P = 0.002). In this study, abnormal 123I‐FP‐CIT SPECT was strongly associated with underlying Lewy body disease pathology, supporting the utility of 123I‐FP‐CIT SPECT in the clinical diagnosis of dementia with Lewy bodies.

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“…Historically, FTLD patients were subclassifi ed as tau-positive cases (FTLD-tau) and those with tau-negative, ubiquitin-positive inclusions (FTLD-U). In most FTLD-U cases, the ubiquitinated protein is TAR DNA-binding protein-43 (TDP-43) [7] and the term FTLD-TDP was recently introduced for this subgroup [8] , whereas in approximately 10 % of FTLD-U cases FUS (fused in sarcoma) protein pathology could be found [9,10] , and the term FTLD-FUS was introduced for this FTLD subtype [11] . TDP-43 and FUS pathology are also found in patients with ALS.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, as a specifi c feature of FTLD-FUS, but not of ALS-FUS, the co-accumulation of all members of the FET protein family that also includes Ewing ' s sarcoma protein (EWS), TATAbinding protein-associated factor 15 (TAF15) and the Drosophila ortholog Cabeza, was recently described by Neumann et al and proposed to be designated as FTLD-FET cases [12] . In a small subset of cases, inclusions are positive for proteins of the ubiquitin proteasome system, but negative for tau protein, TDP-43 and FUS (FTLD-UPS), suggesting that additional protein abnormalities will be found in FTLD [11] . The link between the protein tau and FTLD was further strengthened by the discovery that mutations in the microtubule-associated protein tau gene ( MAPT ) cause familial FTLD-tau [13] .…”

Section: Introductionmentioning

confidence: 99%

Recent biomarker approaches in the diagnosis of frontotemporal lobar degeneration/Neurochemische Ansätze in der Diagnose der Frontotemporalen Lobärdegeneration

Feneberg

Steinacker

Lehnert

et al. 2012

LaboratoriumsMedizin

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Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of syndromes with different symptoms. Frontotemporal lobar degeneration is mostly used as a clinical umbrella term for different diseases. In some clinical subtypes of the FTLD spectrum, a close correlation with underlying pathology can be found. Neuroimaging techniques, such as magnetic resonance imaging and position emission tomography help to detect neuroanatomical lesions and therefore obtain relevance for in vivo prediction of neurodegeneration. However, there is still a lack of neurochemical biomarkers helping to differentiate between underlying histopathologies. The following review gives an overview about present neurochemical biomarker studies and perspective approaches in the diagnosis of FTLD.

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Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update

Cited by 844 publications

References 14 publications

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Clinicopathological and ¹²³I‐FP‐CIT SPECT correlations in patients with dementia

Recent biomarker approaches in the diagnosis of frontotemporal lobar degeneration/Neurochemische Ansätze in der Diagnose der Frontotemporalen Lobärdegeneration

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Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update

Cited by 844 publications

References 14 publications

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Clinicopathological and 123I‐FP‐CIT SPECT correlations in patients with dementia

Recent biomarker approaches in the diagnosis of frontotemporal lobar degeneration/Neurochemische Ansätze in der Diagnose der Frontotemporalen Lobärdegeneration

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Clinicopathological and ¹²³I‐FP‐CIT SPECT correlations in patients with dementia