Pick’s disease

The use of the term has changed over the years, but the designation of Pick’s disease (PiD) is now usually restricted to cases in which the pathology is characterized by classical Pick bodies (see below). The clinical presentation is most often bvFTD or PNFA, with SD being somewhat less common. Rare cases present with an AD-like amnestic syndrome and motor deficits are less common than in most other FTLD subtypes. The typical gross pathology is severe circumscribed frontal and anterior temporal lobar atrophy, which may be asymmetric. Non-specific microscopic features of chronic degeneration, including neuronal loss, gliosis, and swollen neurons (sometimes referred to as Pick cells) are most severe in the frontal and temporal neocortices and limbic cortex, with variable involvement of the striatum and thalamus and relative sparing of the brainstem and cerebellum. The key diagnostic feature is the presence of large, well-demarcated, round or oval neuronal cytoplasmic inclusions that are lightly basophilic, argyrophilic (with Bielschowsky and Bodian but not Gallyas silver stains), and tau-immunoreactive. These Pick bodies are always numerous in the dentate granule cells (Figure 13.3A) and CA1 pyramidal neurons of the hippocampus and are consistently present in affected regions of neocortex [13]. They may also be found in lesser numbers in many subcortical regions. Pick bodies are largely or exclusively composed of 3R tau. Glial tau pathology is less abundant than in other FTLD-tau subtypes, and is represented by ramified astrocytes and tiny globular inclusions in oligodendrocytes.

Figure 13.3

Neuropathologic features of tauopathies. (A) Pick bodies in dentate granule cells of the hippocampus in Pick’s disease. (B) Globose neuronal tangle and (C) tufted astrocyte in progressive supranuclear palsy. (D) Astrocytic plaque in corticobasal degeneration. (E) Globular oligodendroglial inclusions in globular glial tauopathy. (F) Abundant neuronal and (G) glial inclusions in the hippocampus in a case of FTDP-17 MAPT with the S305I mutation. (H) Abundant grains in the hippocampal CA1 region in argyrophilic grain disease. (I) Prominent neurofibrillary degeneration in the hippocampal CA1 region in neurofibrillary tangle-predominant dementia. (A, C–G, I) immunohistochemistry using phospho-dependent tau antibody AT8, (B) hematoxylin and eosin, (H) Gallyas silver stain.

Progressive supranuclear palsy

The classic clinical presentation of PSP, known as Richardson’s syndrome, includes falls, postural instability, axial rigidity, bradykinesia, slow unsteady gait, and ophthalmoplegia. Other presentations, including asymmetric parkinsonism, pure akinesia with gait freezing, CBS, bvFTD, PNFA, apraxia of speech, and primary lateral sclerosis (PLS), are also described [14]. The degree and distribution of gross cerebral atrophy varies and correlates with the predominant clinical features. There is atrophy and discoloration of a variety of subcortical regions, which may include the subthalamic nucleus, globus pallidus, midbrain tectum/tegmentum, substantia nigra, basis pontis, cerebellar dentate nucleus, and cerebellar peduncles. Neuronal and glial cytoplasmic inclusions are best demonstrated with tau immunohistochemistry and Gallyas silver stain. The most characteristic neuronal inclusions are globose neurofibrillary tangles (NFTs) which predominate in subcortical nuclei (Figure 13.3B). Flame-shaped NFTs (similar to AD) may be present in small numbers in the cerebral cortex, and diffuse granular cytoplasmic tau-immunoreactive neuronal “pre-tangles” are present in cortical and subcortical regions. Glial inclusions are present in gray and white matter and include thread-like structures, oligodendroglial coiled bodies, and thorn-shaped astrocytes. However, the most disease-specific pathologic finding is the presence of tufted astrocytes in which tau immunohistochemistry and silver stain highlights a complex branching pattern of proximal and medial cell processes (Figure 13.3C). The neuropathologic diagnosis of PSP is based on demonstrating widespread involvement of subcortical regions by these various neuronal and glial inclusions, all of which are composed primarily of 4R tau. Grumose degeneration of the dentate nucleus of the cerebellum, in which neurons are surrounded by clusters of eosinophilic granular structures that result from the degeneration of presynaptic terminals, is a well-recognized but non-specific feature of PSP [15].

Corticobasal degeneration

The classic clinical presentation of CBD is the corticobasal syndrome, which includes asymmetric ideomotor apraxia, rigidity, dystonia, myoclonus, cortical sensory signs, and alien limb phenomenon. Additional clinical syndromes may include Richardson’s syndrome, posterior cortical atrophy syndrome, bvFTD, and PNFA [16]. Cerebral atrophy is often asymmetric and focal with the distribution correlating with the clinical features. Gross atrophy of subcortical structures is usually not as widespread as in PSP, with the globus pallidus and substantia nigra most often affected. The histopathologic features of CBD overlap with those of PSP and other 4R tauopathies and are best demonstrated with tau immunohistochemistry and Gallyas silver stain. Neuronal inclusions include diffuse granular cytoplasmic tau immunoreactivity, small NFT, globose tangles (sometimes referred to as corticobasal bodies), and occasional small Pick body-like spherical inclusions. Thread-like structures tend to be abundant in the gray and white matter and there are variable numbers of oligodendroglial coiled bodies and thorn-shaped astrocytes. However, the most disease-specific type of inclusion in CBD is the astrocytic plaque, which appears as a circular or ring-shaped collection of short argyrophilic, tau-immunoreactive cell processes that bear a vague resemblance to the neuritic plaque of AD (Figure 13.3D). Unlike the tufted astrocytes of PSP, which involve the more proximal and medial cell processes, astrocytic plaques result from the accumulation of pathologic tau in the distal segments of astrocytic processes, and the associated cell body and nucleus are often not apparent. An additional pathologic feature that was stressed in early descriptions of CBD is the presence of ballooned, achromatic neurons in the cerebral cortex [15]. These are readily apparent on hematoxylin and eosin stained sections and highlighted with immunohistochemistry for neurofilament (NF) proteins and αB-crystallin, but are only weakly argyrophilic and variably tau-positive. Although achromatic neurons may be found in limbic regions in many neurodegenerative conditions, their presence in the neocortex is diagnostically helpful but not specific for CBD.

Globular glial tauopathies

Globular glial tauopathies (GGT) is the term that has recently been recommended for a group of uncommon 4R-predominant tauopathies that are characterized by distinctive and widespread tau-positive globular glial inclusions (GGI) [17]. These cases were previously included in reports of atypical tauopathies under a variety of different terminologies, including “sporadic multiple system tauopathy with dementia.” The clinical presentations include bvFTD with or without extrapyramidal features, PLS, or a combination of FTD and PLS [17]. The distinguishing neuropathologic feature is the globular morphology of cytoplasmic inclusions that occur in both oligodendroglia and astrocytes (Figure 13.3E). While the oligodendroglial inclusions are argyrophilic with Gallyas method, the astrocytic tau deposits are generally silver-negative. Neuronal tau pathology is mainly represented by diffuse cytoplasmic immunoreactivity or globular inclusions, which are also composed primarily of the 4R isoform. Involvement of the white matter is always more prominent than in other tauopathies.

FTD and parkinsonism caused by MAPT mutations

More than 40 different MAPT mutations have been identified in over 100 families with an autosomal dominant inheritance of FTD and parkinsonism (FTDP-17 MAPT), representing approximately 10% of familial FTD cases (http://www.molgen.ua.ac.be/FTDMutations/). Most of the pathogenic mutations are either missense or deletions in exons 1 or 9–13 or mutations in the intron that follows exon 10. The clinical and pathologic features of FTDP-17 MAPT vary significantly, with some degree of correlation with the specific mutation (see below) [18]. The phenotype usually includes some combination of behavior and personality change, cognitive deficits, and atypical parkinsonism. Language deficits, pyramidal dysfunction, and other motor features may also occur but are less common. The neuropathology is characterized by neuronal and glial inclusions (Figure 13.3F–G) composed of hyperphosphorylated, filamentous tau in cortical and subcortical gray and white matter. The anatomical distribution, inclusion morphology, and biochemistry overlap with the sporadic tauopathies. In general, mutations which affect the alternate splicing of exon 10 result in a relative increase in 4R tau and are associated with neuronal and glial pathology that resembles that of sporadic 4R tauopathies (PSP and CBD). In contrast, mutations in exons 9, 11, 12, and 13 result in a predominance of neuronal inclusions; either Pick bodies associated with a 3R-predominant insoluble tau banding pattern or NFT with the same three bands as is found in AD, indicating both 3R and 4R tau isoforms.

Other tauopathies

In addition to atypical and overlapping forms of PSP and CBD, there are reports of sporadic tauopathies that do not fit into current classifications and present as FTD [13, 19]. Various terminologies have been recommended for cases with similar clinical and pathologic features; however, these designations often overlap and are not yet widely accepted. Moreover, comprehensive studies of the aging brain have revealed complex constellations of tau pathologies that involve the frontal and temporal cortices as well as limbic and subcortical structures with various neuronal and glial inclusions, often combined with some AD pathology and even some transactive response DNA-binding protein 43 (TDP-43) proteinopathy [20].

Although argyrophilic grain disease (AGD) and NFT-dementia each rarely present with clinical features of FTD, they are worth mentioning in this context because their pathology often overlaps and may coexist with other forms of FTLD-tau. AGD is a sporadic 4R-predominant tauopathy that usually presents as a late-onset progressive dementia with relatively mild features that are similar to AD [21]. Personality and emotional changes are common but only rarely do patients present as typical bvFTD. Diffuse frontotemporal atrophy is usually mild; however, severe atrophy of the ambient gyrus is frequently documented and it is involved early in disease according to a proposed staging paradigm [22]. The key histopathologic feature is the presence of small dot-like spindle-shaped structures (grains) that are argyrophilic and immunoreactive for tau, ubiquitin, and p62 and thought to represent degenerating dendrites (Figure 13.3H). Grains are most abundant in the amygdala and limbic cortex of the mesial temporal lobe and may extend into the adjacent temporal neocortex. Additional pathologic changes that occur in affected limbic regions include oligodendroglial coiled bodies and silver-negative, tau-positive pre-tangles. Most cases of AGD also have some AD pathology, usually NFT in a Braak stage I–III distribution, and it has been suggested that the presence of argyrophilic grains may lower the threshold for AD-type dementia. A degree of argyrophilic grain pathology has also been reported in a wide variety of other tauopathies (particularly other 4R tauopathies), non-tau-based neurodegenerative diseases, and very old non-demented subjects [21].

A subset of late-onset dementia cases, termed NFT-dementia, is found to have abundant AD-type neurofibrillary pathology (3R- and 4R-positive) that is restricted to the allocortex (Braak stage IV) (Figure 13.3I) with only minimal involvement of the isocortex and without significant numbers of neuritic senile plaques [23]. The clinical presentation is usually relatively mild, slowly progressive dementia that resembles AD and not FTD. Although astrocytic tau pathology is rare, argyrophilic grains and oligodendroglial coiled bodies are often present, suggesting that NFT-dementia and AGD may represent overlapping, age-related conditions.

Normal TDP-43 expression and function

TDP-43 is a 414-amino acid protein encoded by the TARDBP gene on chromosome 1, consisting of two RNA recognition motifs, a glycine-rich C-terminal region, and a nuclear localization and nuclear export signal that allows TDP-43 to continuously shuttle between the nucleus and the cytoplasm (Figure 13.4). It is a highly conserved, ubiquitously expressed protein predominantly localized to the nucleus, and expression levels are very tightly regulated by an autoregulatory mechanism. TDP-43 is involved in multiple steps of RNA processing including transcription, splicing, transport, and stabilization [28]. However, the precise functions of TDP-43, particularly in the central nervous system (CNS), are not fully elucidated.

Figure 13.4

Schematic representation of the TDP-43 protein. GRR, glycine-rich region; RRM, RNA recognition motif; NLS, nuclear localization signal; NES, nuclear export sequence.

TDP-43 in disease

The hallmark lesions of FTLD-TDP are neuronal cytoplasmic inclusions (NCI) and dystrophic neurites (DN) that are immunoreactive for TDP-43, as well as ubiquitin and p62, but negative for other neurodegenerative disease-related proteins, such as tau, α-synuclein, β-amyloid, and fused in sarcoma (FUS) [27]. NCI and DN are characteristically abundant in the frontotemporal neocortex and the dentate granule cells of the hippocampus (Figure 13.5A–G); however, notable differences exist in the morphology and laminar distribution patterns among FTLD-TDP cases, allowing the delineation of four subtypes (see below) (Table 13.2). In a subset of cases, particularly those with a positive family history, neuronal intranuclear inclusions (NII) are also present (Figure 13.5E). Most cases also show TDP-43 pathology in many subcortical regions, including the amygdala, striatum (Figure 13.5H), thalamus, substantia nigra, midbrain tectum and tegmentum, inferior olives, brainstem motor nuclei, and ventral gray matter of the spinal cord (Figure 13.5I). In addition, TDP-43 immunohistochemistry demonstrates previously unrecognized ubiquitin-negative pathology, including diffuse neuronal cytoplasmic staining (“pre-inclusions”) (Figure 13.5J), delicate neurites in the CA1 region in a subset of FTLD-TDP (Figure 13.5K), and glial cytoplasmic inclusions (GCI) in cells of presumed oligodendroglial lineage (Figure 13.5L), that are most abundant in frontotemporal white matter, brainstem, and spinal cord [29].

Figure 13.5

TDP-43-immunoreactive neuropathologic changes in FTLD-TDP. FTLD-TDP is characterized by neuronal cytoplasmic inclusions (NCI), neuronal intranuclear inclusions (NII), and dystrophic neurites (DN) in the frontotemporal neocortex (A–E) and dentate granule cell layer of the hippocampus (F and G) that are immunoreactive for TDP-43. Cases can be subclassified into FTLD-TDP type A in which both NCI and DN are numerous in layer II neocortex (A), FTLD-TDP type B with a predominance of NCI (B), FTLD-TDP type C with a predominance of elongated DN (C), and FTLD-TDP type D characterized by numerous DN and lentiform NII (D and E). Lesser numbers of NII are usually present in FTLD TDP type A cases and are a consistent finding of cases with progranulin gene mutations. NCI in the dentate granule cells of the hippocampus may be granular (F) or compact (G). TDP-43 pathology may be found in many subcortical regions such as the striatum (H) and may be present in lower motor neurons, even in the absence of clinical motor neuron disease (I). Neurons with diffuse granular cytoplasmic reactivity for TDP-43 (pre-inclusions) are most common in cases with type B pathology and a consistent feature in FTD cases with motor neuron disease and those with C9orf72 mutations (J). Numerous delicate DN in the CA1 region of the hippocampus may be associated with severe neuronal loss (hippocampal sclerosis) (K). TDP-43-immunoreactive glial cytoplasmic inclusions are present in cells with oligodendroglial morphology (L). TDP-43 immunohistochemistry.

FTLD-TDP is associated with several pathologic changes of TDP-43. The formation of TDP-43-positive inclusion bodies (either cytoplasmic or nuclear) is consistently associated with a dramatic reduction of the normally diffuse nuclear staining (Figure 13.6A) [27]. By immunoblot analysis, a distinct biochemical pattern of TDP-43 is seen in insoluble protein fractions isolated from post-mortem CNS tissue with the presence of FTLD-TDP specific bands at approximately 25 kDa and 45 kDa and a high molecular smear, in addition to the normal 43 kDa band (Figure 13.6B). The pathologic forms of TDP-43 show evidence of abnormal processing with hyperphosphorylation, ubiquitination, and N-terminal truncation [27]. Antibodies raised against phosphorylated epitopes of TDP-43 have further facilitated the detection of pathologic TDP-43 species, since they label only abnormal TDP-43 enriched in inclusions, but not the physiologic TDP-43 (Figure 13.6B–C) [30]. Notable differences are also present in the composition of inclusions with respect to the ratio of full-length TDP-43 versus N-terminally truncated TDP-43 species; while cortical inclusions are selectively enriched for hyperphosphorylated C-terminal TDP-43 fragments, spinal cord inclusions contain more full-length TDP-43 [30, 31].

Figure 13.6

TDP-43 in FTLD-TDP. (A) Cytoplasmic accumulation of TDP-43 is associated with a dramatic decrease of the normal nuclear staining in inclusion-bearing cells, demonstrated with immunohistochemistry using a phosphorylation independent TDP-43 antibody. (B) Immunoblot analysis of urea fractions isolated from brain tissue show the highly characteristic biochemical signature of TDP-43 in FTLD-TDP, with pathologic bands of approximately 25 kDa (*) and 45 kDa (**), and a high-molecular-weight smear (***) that are not detected in controls. The arrow indicates the wild-type 43 kDa TDP-43 band present in controls and in FTLD-TDP patients. With a phosphorylation-specific TDP-43 antibody against phosphorylated serine residues 409 and 410, only pathologic TDP-43 species are detected on immunoblot (B) and in tissue sections (C).

Pathologic subtypes of FTLD-TDP

Prior to the identification of TDP-43 as pathologic protein in FTLD-U, it was noted in two independent studies that FTLD-U cases show a heterogeneous picture with respect to the morphology and laminar distribution of ubiquitin-positive inclusions in the frontotemporal neocortex and three distinct subtypes were delineated (Table 13.2) [32, 33]. Following the identification of TDP-43, and the confirmation that the vast majority of FTLD-U cases have TDP-43 pathology, the same criteria as described in the original ubiquitin immunohistochemistry-based studies were commonly used to subclassify FTLD-TDP cases [34]. Subsequently, a fourth subtype was added, corresponding to the unique pattern of ubiquitin and TDP-43 pathology in VCP mutation carriers [35]. While the findings in both initial typing studies were very similar, different numbering systems were used [32, 33]. To avoid confusion, a harmonized classification scheme was recently introduced, in which the previous numerical subtypes were replaced with subtypes A to D (Table 13.2) [36]. The relevance of the four distinct FTLD-TDP subtypes is supported by relatively specific correlations between the various patterns of pathology, the clinical phenotypes, and the known genetic causes in inherited forms of FTLD-TDP (Table 13.1).

Familial FTLD-TDP

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