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The neuropathology associated with the clinical entities frontotemporal dementia (FTD, behavioral variant FTD), progressive non-Xuent aphasia (PNFA) and semantic dementia (SD), is heterogeneous with the common feature being a relatively selective degeneration of the frontal and temporal lobes (frontotemporal lobar degeneration, FTLD). As in other neurodegenerative conditions, most pathological subtypes of FTLD are characterized by specific kinds of intracellular protein inclusions. In the past few decades, the biochemical composition of many of these inclusion bodies has been determined. There is a growing trend to classify FTLD based on the presumed molecular defect, in the belief that this most closely reflects the underlying pathogenic process and because many of the eponymous and descriptively named syndromes of the past are now known to have imperfect clinicopathological correlation.
A comprehensive consensus paper on the neuropathologic diagnostic and nosologic criteria for FTLD was recently published in this journal . These criteria incorporate several important recent advances in our understanding of the molecular genetics and pathology of FTLD; specifically, the discovery of several new FTLD-associated gene abnormalities and the identification of TDP-43 as the pathological protein in most tau-negative FTLD. The criteria employ a protein-based approach for the neuropathologic diagnosis and classification of FTLD; however, the nomenclature for individual conditions has not been revised to reXect this.
Further advances in our understanding of the disease specificity and sensitivity of TDP-43 pathology have resulted in confusion around the use of the term “frontotemporal lobar degeneration with ubiquitinated inclusions” (FTLD-U). “FTLD-U” was originally developed for cases in which the characteristic inclusions are only visible with ubiquitin immunohistochemistry. It was anticipated that the ubiquitinated protein (or proteins) would eventually be identified and that this would allow more specific nomenclature and reclassification. Accordingly, when a small subset of cases was discovered to have inclusions that were also immunoreactive for class IV intermediate filaments, these were given a new designation (neuronal intermediate filament inclusion disease, NIFID) and removed from the FTLD-U category. However, when TDP-43 was recently identified as the pathological protein in most of the remaining cases of FTLD-U [2, 9], this convention was not immediately followed. FTLD-U has continued to be used with the assumption that all the remaining genetic and pathologic subtypes of FTLD-U are TDP-43 proteinopathies. However, recent studies have demonstrated that this is not the case; at least one familial subtype [the Danish kindred with autosomal dominant FTD linked to chromosome 3 (FTD-3), caused by a CHMP2B mutation] and a significant proportion of sporadic FTLD-U cases, do not have signatory pathological TDP-43 [4, 5, 7, 10]. Therefore, the group currently designated as FTLD-U appears to include several distinct entities, the largest of which (TDP-43-positive) no longer satisfies the original definition of the term.
A second area of uncertainty relates to the disease specificity of TDP-43 pathology. Although the initial reports suggested that pathological TDP-43 was specific for FTLD-U and ALS, several recent studies have found TDP-43-positive inclusions in a significant proportion of cases with other neurodegenerative conditions, such as Alzheimer’s disease (AD), Lewy body disease and some primary tauopathies [1, 8, 12]. This TDP-43 pathology had not been recognized previously because ubiquitin immunohistochemistry does not distinguish it from the other coexisting (tau or α-synuclein) pathology. Although the concomitant TDP-43 pathology is usually restricted to limbic structures of the mesial temporal lobe, it sometimes extends into the neocortex and can closely resemble FTLD-U. It is currently not known if this represents a coincidental primary pathological process, which contributes to the clinical phenotype, or a secondary change of little pathogenic significance, occurring in susceptible neuronal populations. Furthermore, there are currently no neuropathologic criteria for FTLD-U that define the extent and anatomic distribution of pathology needed for the diagnosis. Therefore, pending further clinicopathological correlative studies, it is uncertain whether or not a diagnosis of FTLD-U should be made when TDP-43 pathology is found in conjunction with other neurodegenerative processes.
The following recommendations are meant to serve two purposes. First, to introduce a protein-based nomenclature for FTLD that is simple, consistent and transparent, and one that can easily accommodate future discoveries. Second, to modify existing terminology to address the specific issues related to FTLD-U and TDP-43 pathology, described above.
These recommendations provide a simple system of nomenclature that reflects our current understanding of the molecular pathology of FTLD and that can easily accommodate future discoveries. The terminology will allow neuropathologists to communicate their findings in a concise and unambiguous fashion. Terms that have become obsolete (i.e., FTLD-U) have been eliminated, while other traditional names for specific patterns of pathology within these broad protein-based categories can still be used without contradiction. This also provides a neuropathologic nosology that can be correlated with molecular genetic and clinical features. The next logical step will be to convene a meeting of international experts to update the clinical and pathological diagnostic criteria for FTLD and to develop an integrated classification scheme that reflects the many recent advances in the field.
Ian R. A. Mackenzie, Department of Pathology and Laboratory Medicine, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada.
Manuela Neumann, Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
Eileen H. Bigio, Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Nigel J. Cairns, Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
Irina Alafuzoff, Section of Neuropathology, Kuopio University, Kuopio, Finland.
Jillian Kril, Department of Pathology, The University of Sydney, Sydney, NSW, Australia.
Gabor G. Kovacs, Institute of Neurology, Medical University of Vienna, Vienna, Austria.
Bernardino Ghetti, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Glenda Halliday, Prince of Wales Medical Research Institute, University of New South Wales, Sydney, NSW, Australia.
Ida E. Holm, Department of Pathology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.
Paul G. Ince, Neuropathology Group, University of SheYeld Medical School, SheYeld, UK.
Wouter Kamphorst, Department of Pathology, Vrije University Medical Centre, Amsterdam, The Netherlands.
Tamas Revesz, Department of Molecular Neuroscience, Queen Square, London, UK.
Annemieke J. M. Rozemuller, Department of Pathology, Vrije University Medical Centre, Amsterdam, The Netherlands.
Samir Kumar-Singh, Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.
Haruhiko Akiyama, Tokyo Institute of Psychiatry, Tokyo, Japan.
Atik Baborie, Neuropathology, The Walton Centre for Neurology and Neurosurgery, Liverpool, UK.
Salvatore Spina, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Dennis W. Dickson, Neuropathology Laboratory, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
John Q. Trojanowski, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
David M. A. Mann, Clinical Neuroscience Research Group, Greater Manchester Neurosciences Centre, University of Manchester, Salford, UK.