A harmonized classification system for FTLD-TDP pathology

Mackenzie, Ian R.; Neumann, Manuela; Baborie, Atik; Sampathu, Deepak M.; Plessis, Daniel du; Jaros, Evelyn; Perry, Robert H.; Trojanowski, John Q.; Mann, David; Lee, Virginia M.‐Y.

doi:10.1007/s00401-011-0845-8

Cited by 865 publications

(953 citation statements)

References 11 publications

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“…However, in two cases (patients 1 and 2) there was only rare TDP‐43‐positive NCI within the hippocampus dentate gyrus, and very sparse TDP‐43 immunopositive pathological changes, mostly as short neurites with only rare, or no, NCI, within frontal and temporal cortex. These two cases were diagnosed with FTLD‐TDP, suggestive of type A [20]. Another case (patient 3) bore more abundant TDP‐43 immunopositive NCI in hippocampus and cortex and conformed to FTLD‐TDP type B [20].…”

Section: Discussionmentioning

confidence: 86%

“…A pathological diagnosis of FTLD‐TDP, suggestive of type A [20], was ascribed to both. Newcastle patient 3 showed a few ubiquitin/TDP‐43‐positive NCI in the dentate gyrus, and in frontal and temporal lobes, with rare scattered neurites in these latter regions; a pathological diagnosis of FTLD‐TDP, suggestive of type B was ascribed (Tables 1 and 2).…”

Section: Resultsmentioning

confidence: 99%

“…Pathologically, of the 22 Newcastle cases, 19 had FTLD‐TDP (nine with type A histology, four with type B histology and six with type C histology), one had FTLD‐FUS (NIFID) and two were pathologically unclassifiable, but were possibly FTLD‐UPS [20]. Among the 13 Manchester C9ORF72 expansion bearers, eight patients had FTLD‐TDP type A histology, whereas five patients had FTLD‐TDP type B histology [20].…”

Section: Methodsmentioning

confidence: 99%

“…Among the 13 Manchester C9ORF72 expansion bearers, eight patients had FTLD‐TDP type A histology, whereas five patients had FTLD‐TDP type B histology [20].…”

Section: Methodsmentioning

confidence: 99%

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Accumulation of dipeptide repeat proteins predates that of TDP‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene

Baborie

Griffiths

Jaros

et al. 2015

Neuropathology Appl Neurobio

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AimsFrontotemporal lobar degeneration (FTLD) and motor neurone disease are linked by the possession of a hexanucleotide repeat expansion in C9ORF72, and both show neuronal cytoplasmic inclusions within cerebellar and hippocampal neurones which are TDP‐43 negative but immunoreactive for p62 and dipeptide repeat proteins (DPR), these being generated by a non‐ATG RAN translation of the expanded region of the gene.MethodsTwenty‐two cases of FTLD from Newcastle were analysed for an expansion in C9ORF72 by repeat primed PCR and Southern blot. Detailed case note analysis was performed, and blinded retrospective clinical impressions were achieved by review of clinical histories. Sections from all major brain regions were immunostained for TDP‐43, p62 and DPR. The extent of TDP‐43 and DPR pathology in expansion bearers was compared with that in 13 other previously identified cases from the Manchester Brain Bank with established disease.ResultsThree Newcastle patients bearing an expansion in C9ORF72 were identified. These three patients died prematurely, two from bronchopneumonia within 10 months and 3 years of onset, and one from myocardial infarction 3 years after onset. In all three, DPR were plentiful throughout all cerebral cortical regions, hippocampus and cerebellum, but TDP‐43 pathological changes were sparse. The severity of DPR pathological changes in these three patients was similar to that in the Manchester series, although the extent of TDP‐43 pathology was significantly less.ConclusionWidespread accumulation of DPR within nerve cells may occur much earlier than that of TDP‐43 in patients with FTLD bearing expansion in C9ORF72.

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Section: Discussionmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Among the 13 Manchester C9ORF72 expansion bearers, eight patients had FTLD‐TDP type A histology, whereas five patients had FTLD‐TDP type B histology [20].…”

Section: Methodsmentioning

confidence: 99%

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Accumulation of dipeptide repeat proteins predates that of TDP‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene

Baborie

Griffiths

Jaros

et al. 2015

Neuropathology Appl Neurobio

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“…In this report, we describe [ 18 F]AV‐1451 binding in a patient with a clear familial case of frontotemporal dementia (FTD) due to a hexanucleotide repeat expansion in the C9orf72 gene. This is the commonest genetic cause of FTD14 and it is strongly associated with TDP‐43 pathology15 without the presence of any tau. We examine not only the magnitude of the [ 18 F]AV‐1451 binding, but also the pattern of regional distribution across cortical and subcortical structures.…”

Section: Introductionmentioning

confidence: 99%

[¹⁸F]AV‐1451 binding is increased in frontotemporal dementia due to C9orf72 expansion

Bevan-Jones

Cope

Jones

et al. 2018

Ann Clin Transl Neurol

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The PET ligand [18F]AV‐1451 was developed to bind tau pathology in Alzheimer's disease, but increased binding has been shown in both genetic tauopathies and in semantic dementia, a disease strongly associated with TDP‐43 pathology. Here we assessed [18F]AV‐1451 binding in behavioral variant frontotemporal dementia due to a hexanucleotide repeat expansion in C9orf72, characterized by TDP‐43 pathology. We show that the C9orf72 mutation increases binding in frontotemporal cortex, with a distinctive distribution of binding compared with healthy controls.

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Progranulin Mutations as Risk Factors for Alzheimer Disease

Perry¹,

Lehmann²,

Yokoyama³

et al. 2013

JAMA Neurol

118

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Importance: Mutations in the progranulin gene are known to cause diverse clinical syndromes, all attributed to frontotemporal lobar degeneration. We describe 2 patients with progranulin gene mutations and evidence of Alzheimer disease (AD) pathology. We also conducted a literature review.Observations: This study focused on case reports of 2 unrelated patients with progranulin mutations at the University of California, San Francisco, Memory and Aging Center. One patient presented at age 65 years with a clinical syndrome suggestive of AD and showed evidence of amyloid aggregation on positron emission tomography. Another patient presented at age 54 years with logopenic progressive aphasia and, at autopsy, showed both frontotemporal lobar degeneration with TDP-43 inclusions and AD. Conclusions and Relevance:In addition to autosomaldominant frontotemporal lobar degeneration, mutations in the progranulin gene may be a risk factor for AD clinical phenotypes and neuropathology.

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A harmonized classification system for FTLD-TDP pathology

Cited by 865 publications

References 11 publications

Accumulation of dipeptide repeat proteins predates that of TDP‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene

Accumulation of dipeptide repeat proteins predates that of TDP‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene

[¹⁸F]AV‐1451 binding is increased in frontotemporal dementia due to C9orf72 expansion

Progranulin Mutations as Risk Factors for Alzheimer Disease

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A harmonized classification system for FTLD-TDP pathology

Cited by 865 publications

References 11 publications

Accumulation of dipeptide repeat proteins predates that of TDP‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene

Accumulation of dipeptide repeat proteins predates that of TDP‐43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene

[18F]AV‐1451 binding is increased in frontotemporal dementia due to C9orf72 expansion

Progranulin Mutations as Risk Factors for Alzheimer Disease

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[¹⁸F]AV‐1451 binding is increased in frontotemporal dementia due to C9orf72 expansion