Neuropathologic diagnostic and nosologic criteria

Authors: Nigel J Cairns Eileen H Bigio Ian R A Mackenzie Manuela Neumann Virginia MY Lee Kimmo J Hatanpaa Charles L White Julie A Schneider Lea Tenenholz Grinberg Glenda Halliday Charles Duyckaerts James S Lowe Ida E Holm Markus Tolnay Koichi Okamoto Hideaki Yokoo Shigeo Murayama John Woulfe David G Munoz Dennis W Dickson Paul G Ince John Q Trojanowski David M A Mann

Publish Date: 2007/06/20

Volume: 114, Issue: 1, Pages: 5-22

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Abstract

The aim of this study was to improve the neuropathologic recognition and provide criteria for the pathological diagnosis in the neurodegenerative diseases grouped as frontotemporal lobar degeneration FTLD revised criteria are proposed Recent advances in molecular genetics biochemistry and neuropathology of FTLD prompted the Midwest Consortium for Frontotemporal Lobar Degeneration and experts at other centers to review and revise the existing neuropathologic diagnostic criteria for FTLD The proposed criteria for FTLD are based on existing criteria which include the tauopathies FTLD with Pick bodies corticobasal degeneration progressive supranuclear palsy sporadic multiple system tauopathy with dementia argyrophilic grain disease neurofibrillary tangle dementia and FTD with microtubuleassociated tau MAPT gene mutation also called FTD with parkinsonism linked to chromosome 17 FTDP17 The proposed criteria take into account new disease entities and include the novel molecular pathology TDP43 proteinopathy now recognized to be the most frequent histological finding in FTLD TDP43 is a major component of the pathologic inclusions of most sporadic and familial cases of FTLD with ubiquitinpositive taunegative inclusions FTLDU with or without motor neuron disease MND Molecular genetic studies of familial cases of FTLDU have shown that mutations in the progranulin PGRN gene are a major genetic cause of FTLDU Mutations in valosincontaining protein VCP gene are present in rare familial forms of FTD and some families with FTD and/or MND have been linked to chromosome 9p and both are types of FTLDU Thus familial TDP43 proteinopathy is associated with defects in multiple genes and molecular genetics is required in these cases to correctly identify the causative gene defect In addition to genetic heterogeneity amongst the TDP43 proteinopathies there is also neuropathologic heterogeneity and there is a close relationship between genotype and FTLDU subtype In addition to these recent significant advances in the neuropathology of FTLDU novel FTLD entities have been further characterized including neuronal intermediate filament inclusion disease The proposed criteria incorporate uptodate neuropathology of FTLD in the light of recent immunohistochemical biochemical and genetic advances These criteria will be of value to the practicing neuropathologist and provide a foundation for clinical clinicopathologic mechanistic studies and in vivo models of pathogenesis of FTLDIn this paper we follow the convention that FTLD is an umbrella term that groups several different neurodegenerative diseases characterized by predominant destruction of the frontal and temporal lobes After Alzheimer disease AD and dementia with Lewy bodies DLB frontotemporal lobar degeneration FTLD is the third most common neurodegenerative cause of dementia in industrialized countries 59 60 69 Most commonly patients with FTLD present with frontotemporal dementia FTD a change in personal and social conduct often associated with disinhibition with gradual and progressive changes in language 53 Other patients falling under the diagnostic umbrella of FTLD may present with early and progressive changes in language function and two syndromes have been recognized semantic dementia SD and primary progressive nonfluent aphasia PNFA 40 43 53 65 67 78 In later stages of these particular syndromes both behavioral and language dysfunction may be present A proportion of patients with FTLD present with or develop parkinsonism as part of their disease process Clinical amyotrophic lateral sclerosis/motor neuron disease ALS/MND may also be found in a proportion of patients with FTLD especially those with FTD indicating a spectrum of clinical phenotypes that relate to common neuropathologic lesions 3 61 69FTD SD or PNFA refer to the main clinical syndromes linked to the FTLD group Typically at least in the early course of the disease patients with FTD do not have an amnestic syndrome which distinguishes them clinically from AD 46 53 but there are exceptions 29 Although no presymptomatic biomarkers have been identified at least in sporadic cases clinical assessment neuropsychology and neuroimaging may help to distinguish FTD and the related disorders of SD and PNFA from other neurodegenerative causes of dementia 12 43 46 The diagnosis of FTD SD or PNFA may only be considered when other potential causes of dementia including other nervous system diseases eg small and large vessel disease systemic conditions eg hypothyroidism tumors and substance abuse have been excludedThe apolipoprotein E APOE gene ε4 allele is a major risk factor for AD though this is not the case in most association studies of FTLD but see ref 71 and none of the autosomal dominant mutations in genes associated with some familial cases of AD amyloid precursor protein APP presenilin 1 PS1 and presenilin 2 PS2 acts as a risk factor for FTLDRecent developments in the molecular pathology and genetics of FTLD now dictate that a minimal panel of pathological investigations is required for correct diagnosis in this group of diseases Standardization of nomenclature and approach will facilitate better understanding of clinicopathologic correlations provide insights into pathogenesis and guide the construction and validation of in vivo modelsWith the exception of those cases in which a gene defect has been identified examination of the brain and neuropathology are essential in order to determine the disease entity underlying FTLD Even in those cases that have been genetically characterized it is not uncommon to find coexisting neurodegenerative disease and other pathology which may have contributed to the clinical picture to a varying degree The neuropathology of the brain either on autopsy or rarely on biopsy remains the “gold standard” for determining the neuropathologic diagnosis Although most cases seen by a neuropathologist are likely to be cases of advanced disease there is an increasing awareness that the molecular pathology of all neurodegenerative disease is present often several years prior to the onset of clinical symptoms and this knowledge will inform the neuropathologist of preclinical FTLD in an otherwise cognitively and behaviorally normal subjectExamination of the brain of a patient with FTLD typically shows symmetrical focal atrophy of the frontal or temporal lobes or both In some patients there is asymmetry of atrophy typically reflected in perisylvian loss on one side of the brain Macroscopic atrophy of the basal ganglia and loss of pigmentation from the substantia nigra are seen in a proportion of cases This focal atrophy is not infrequently the most dramatic in all of neuropathology Conversely in some individuals for example those who die at an earlier stage the brain is unremarkable The pattern of atrophy may assist in staging disease severity 11 39 41In most forms of FTLD examination of the cerebral cortex with HE staining shows microvacuolation and neuronal loss In many cases this is most evident around layer II of the affected cortical regions In advanced cases there is transcortical microvacuolation and neuronal loss Swollen cortical neurons may be seen and highlighted with immunostaining for alpha Bcrystallin however they are not specific for any disease subtype White matter myelin loss and astrocytic gliosis may be seen There may be significant neuronal loss from the basal ganglia and substantia nigra in some cases

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