Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration

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 microtubule-associated tau (MAPT) gene mutation, also called FTD with parkinsonism linked to chromosome 17 (FTDP-17)]. The proposed criteria take into account new disease entities and include the novel molecular pathology, TDP-43 proteinopathy, now recognized to be the most frequent histological finding in FTLD. TDP-43 is a major component of the pathologic inclusions of most sporadic and familial cases of FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Molecular genetic studies of familial cases of FTLD-U have shown that mutations in the progranulin (PGRN) gene are a major genetic cause of FTLD-U. Mutations in valosin-containing 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 FTLD-U. Thus, familial TDP-43 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 TDP-43 proteinopathies, there is also neuropathologic heterogeneity and there is a close relationship between genotype and FTLD-U subtype. In addition to these recent significant advances in the neuropathology of FTLD-U, novel FTLD entities have been further characterized, including neuronal intermediate filament inclusion disease. The proposed criteria incorporate up-to-date 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, clinico-pathologic, mechanistic studies and in vivo models of pathogenesis of FTLD.

Figures

Fig. 1

Frontotemporal lobar degeneration neuropathology algorithm flow chart. AD Alzheimer's disease, AGD argyrophilic grain disease, AMYG amygdala, BIBD basophilic inclusion body disease, CBD corticobasal degeneration, CBLM cerebellum including the dentate nucleus (DN), CHMP2B charged multivesicular body protein 2B gene, CG cingulate gyrus, DLB dementia with Lewy bodies, DLDH dementia lacking distinctive histologic features, also called FTLD according to McKhann et al. [4] criteria, FTLD frontotemporal lobar degeneration, FTLD-U FTLD with ubiquitin-positive, tau-negative inclusions, GP globus pallidus, H&E hematoxylin and eosin, HIP hippocampus, IHC immunohistochemistry, INAα-internexin, MAPT microtubule-associated protein tau gene, MED medulla oblongata, MFG middle frontal gyrus, MID midbrain including the substantia nigra, MND motor neuron disease, MSTD sporadic multiple system tauopathy with dementia, NIFID neuronal intermediate filament inclusion disease, NF neurofilament; neurofibrillary tangle dementia, also called tangle predominant form of senile dementia, NOS not otherwise specified, OL occipital lobe, PGRN progranulin gene, FL frontal lobe, PL parietal lobe, PSP progressive supranuclear palsy, SC spinal cord, STG superior temporal gyrus, STR striatum, TDP-43 TAR DNA-binding protein 43, THAL/SUBTN thalamus and subthalamic nucleus, Ub ubiquitin, VCP valosin-containing protein gene, 3R, 4R, or 3R and 4R tau isoforms containing 3, 4, or 3 and 4 microtubule-binding repeats

Fig. 2

Frontotemporal lobar degeneration with Pick bodies. Pick bodies (arrowheads) and a neurofibrillary tangle (arrow) in the subiculum (a) are immunolabeled by anti-phosphorylated tau antibodies (PHF1 immunohistochemistry). Pick bodies are not immunolabeled with anti-4R tau antibodies (arrowheads), while neurofibrillary tangles are immunolabeled (arrows) (b). Anti-3R tau antibodies clearly label Pick bodies (arrowheads) (c). b 4R tau (ET3) and c 3R tau (RD3) immunohistochemistry. Bars 10 μm

Fig. 3

Corticobasal degeneration. a A swollen achromatic neuron (arrow) in the middle frontal gyrus. Hematoxylin and eosin (HE). b Tau-positive neurofibrillary tangles in the pyramidal neurons of the CA1 hippocampal subfield. c A globose neurofibrillary tangle (arrow) in the locus coeruleus. d An astrocytic plaque (asterisk), coiled body (arrow), and threads (arrowhead) in the deep cortical laminae and white matter of the parietal lobe. b, c, d Anti-phosphorylated tau (PHF1) immunohistochemistry. Bars 10 μm

Fig. 4

Progressive supranuclear palsy. Neurofibrillary tangles in the subthalamic nucleus (a), occulomotor nucleus (b), and locus coeruleus (e). Tufted astrocytes in the putamen (c and d). a, b, c, e Anti-phosphorylated tau (PHF1) immunohistochemistry. d Gallyas silver impregnation. Scale bars a 50 μm, b, c, d, e 10 μm

Fig. 5

Argyrophilic grain disease. A swollen achromatic neuron (arrow) with pale center and more intense tau-immunoreactive periphery in the subiculum. Tau-immunoreactive grains in the neuropil and diffusely stained pyramidal neurons (arrow) indicating a preneurofibrillary tangle stage in the pyramidal layer of the hippocampus (b). A tau-immunoreactive astrocytic inclusion (arrowhead) and oligodendroglial cytoplasmic inclusions called coiled bodies (arrows) in the CA1 subfield of the hippocampus. (a, b, c) Anti-phosphorylated tau (PHF1) immunohistochemistry. Scale bars (a) 100 μm and (b and c) 50 μm

Fig. 6

Sporadic multiple system tauopathy with dementia. Neuronal and glial globular inclusions at the gray/white junction. Anti-phosphorylated tau (PHF1) immunohistochemistry. Scale bar 100 μm

Fig. 7

Neurofibrillary tangle dementia. a, b Numerous neurofibrillary tangles in the upper and lower pyramidal neurons of the occipitotemporal cortex; no neuritic plaques or amyloid deposits are present. a Gallyas silver impregnation. b Anti-phosphorylated tau (PHF1) immunohistochemistry. Scale bars 50 μm

Fig. 8

Frontotemporal lobar degeneration (FTLD) with MAPT mutation. Inclusions in FTLD with MAPT G389R mutation (a) and FTLD with MAPT intron 10 + 16 mutation (b–g). a Numerous tau-immuno-reactive Pick body-like inclusions in the granule neurons of the dentate fascia. b A swollen achromatic neuron in the superior temporal gyrus. c A swollen neuron with a central area of pale anti-tau immunoreactivity surrounded by more intense staining. Fibrillary material surrounds the nucleus and extends into the apical dendrite. d An intraneuronal inclusion resembling a Pick body in the superior frontal gyrus. e A neurofibrillary tangle-like inclusion in layer V of the superior frontal gyrus. f A globose neurofibrillary tangle-like inclusion in the dorsal raphé nucleus. g An astrocytic fibrillary inclusion (a) and a coiled body (b) in an oligodendrocyte in the white matter of the frontal lobe. b Hematoxylin and eosin (HE); (a, c–g) anti-phosphorylated tau (AT8) immunohistochemistry. Scale bars 10 μm. (Adapted from Ref. [44]; reproduced with permission)

Fig. 9

Frontotemporal lobar degeneration (FTLD)-U with or without MND: spectrum of TDP-43 pathology. Adjacent sections of superficial frontal neocortex showing neuronal cytoplasmic inclusions (NCIs), dystrophic neurites (DNs), and isolated neuronal intranuclear inclusions (NIIs) stain for both ubiquitin (a) and TDP-43 (b). NCI in the dentate granule cells stain for ubiquitin (c) and TDP-43 (d). Neuronal and glial inclusions include NCI (e), round and lentiform NIIs (f, g); skein-like (h), and compact round (i) NCI in the lower motor neurons; and glial cytoplasmic inclusion (GCI) (j). (a and c) ubiquitin immunohistochemisty (b, d, e–j TDP-43 immunohistochemistry). Scale bars 10 μm (a–d); 5 μm (e–j) (Adapted from Ref. [16]; reproduced with permission)

Fig. 10

Frontotemporal lobar degeneration-U with MND. Diffuse perinuclear staining in a motor neuron (arrow). TDP-43 immunohistochemistry. Scale bar 10 μm

Fig. 11

Frontotemporal lobar degeneration-U, subtypes 1–4. a–d Type 1 is characterized by long and tortuous dystrophic neurites (DNs) in lamiae II/III with relatively few neuronal cytoplasmic inclusions (NCIs) and no neuronal intranuclear inclusion (NII). b Type 2 has numerous NCIs, relatively few DNs, and no NII is present. c Type 3 has numerous NCIs and DNs and an occasional NII in lamina II. d Type 4 pathology in a case of FTD with VCP mutation is characterized by numerous NII and DN, but few NCI. TDP-43 immunohistochemistry. Scale bar 10 μm (a–d). (Adapted from Ref. [14]; reproduced with permission)

Fig. 12

Frontotemporal lobar degeneration with CHMP2B mutation. a Sparse ubiquitin-immunoreactive NCIs (arrows) in the granule neurons of the dentate fascia. The NCIs are not labeled with anti-TDP-43 antibodies (b). Ubiquitin-positive neuropil aggregates and a sparse NCI (arrow) in the frontal lobe of an affected 61-year-old female (c). Scale bars a, b 50 μm, c 10 μm

Fig. 13

Basophilic inclusion body disease. a A basophilic inclusion (BI) in the precentral gyrus (motor cortex), with a similar, weakly ubiquitin-immunoreactive inclusion in (b). c Neurons with basophilic inclusions showing fine granular perikaryal TDP-43 positivity in neurons with BIs on the left and negative in neurons with BIs on the right. a Hematoxylin and eosin; b ubiquitin, and c TDP-43 immunohisto-chemistry. Scale bars 20 μm

Fig. 14

Neuronal intermediate filament inclusion disease. a Eosinophilic Lewy body-like NCI in a pyramidal neuron of the CA1 subfield of the hippocampus. b α-Internexin immunoreactive NCIs in layer III of the superior temporal gyrus. c Numerous α-internexin immunoreactive NCIs in the granule neurons of the dentate fascia. a Hematoxylin and eosin; b, c α-internexin immunohistochemistry. Scale bars 10 μm