Nomenclature and nosology for neuropathologic subt

Authors: Ian R A Mackenzie Manuela Neumann Eileen H Bigio Nigel J Cairns Irina Alafuzoff Jillian Kril Gabor G Kovacs Bernardino Ghetti Glenda Halliday Ida E Holm Paul G Ince Wouter Kamphorst Tamas Revesz Annemieke J M Rozemuller Samir KumarSingh Haruhiko Akiyama Atik Baborie Salvatore Spina Dennis W Dickson John Q Trojanowski David M A Mann

Publish Date: 2009/11/19

Volume: 119, Issue: 1, Pages: 1-

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Abstract

One year ago in this journal we published a recommended nomenclature for the neuropathologic subtypes of frontotemporal lobar degeneration FTLD 7 A major impetus behind this was to resolve the confusion that had arisen around the use of the term “FTLD with ubiquitinated inclusions” FTLDU following the discovery that the molecular pathology of these cases was heterogeneous with most but not all being characterized by pathological TDP43 6 11 In addition a system of nosology was introduced that grouped the FTLD subtypes into broad categories based on the molecular defect that is most characteristic according to current evidence This system provided a concise and consistent terminology that has now been widely adopted in the literature Another anticipated advantage was the ability to readily accommodate new discoveries At the time we did not anticipate how quickly this attribute would be put to useAlthough most FTLDs are characterized by cellular inclusion bodies composed of either tau FTLDtau or TDP43 FTLDTDP approximately 10–15 of cases remain that include a number of uncommon FTLD subtypes in which the pathologic protein is unknown Recently two studies identified mutations in the gene encoding the fused in sarcoma FUS protein also known as translocated in liposarcoma TLS as the cause of familial amyotrophic lateral sclerosis ALS type 6 5 14 The recognized clinical genetic and pathological overlap between ALS and FTD and the high degree of functional homology between FUS and TDP43 prompted a number of subsequent studies that demonstrated that the inclusions of several of the tau/TDP43negative FTLDs are immunoreactive ir for FUS 8 9 10 One such group are those cases with TDP43negative FTLDU pathology originally referred to as atypical FTLDU aFTLDU 6 11 According to the previous nomenclature recommendations the neuropathology of these cases was designated as FTLDUPS because the inclusions were only detectable with immunohistochemistry against proteins of the ubiquitin proteasome system UPS 7 However based on the discovery that all the ubiquitinpositive pathology in these cases is immunoreactive for FUS we now recommend that they should be reclassified as FTLDFUS 9 In addition the characteristic neuronal cytoplasmic inclusions of basophilic inclusions body disease BIBD previously of unknown biochemical composition have also been shown to be consistently FUSir 8 Perhaps most surprising has been the identification of abundant FUSpositive pathology in cases of neuronal intermediate filament inclusion disease NIFID 10 The diagnostic criterion for NIFID is the presence of neuronal inclusions that are negative for tau αsynuclein and TDP43 but immunoreactive for class IV intermediate filaments IF 1 and therefore the term FTLDIF was designated in the previous nomenclature recommendations 7 However the finding that only a minority of the inclusions in NIFID are IFir the absence of any identifiable genetic or molecular abnormality of IF in these cases and the recognition that immunohistochemistry for IF is not specific for this condition is consistent with the possibility that another protein may be more central to the pathogenesis The recent demonstration that a much larger proportion of the inclusions in NIFID are FUSir that all the cells with IFir inclusions also contain pathological FUS and that there are widespread FUSir glial inclusions suggests that the abnormal accumulation of FUS may be more fundamental in the disease process and that IF pathology probably develops as a secondary process 10

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