Progressive Supranuclear Palsy and Corticobasal Degeneration

Neuropathology 2020; 40,57–67 doi:10.1111/neup.12590

Educational Review Chameleons and mimics: Progressive supranuclear palsy and corticobasal degeneration

Maya Mimuro and Mari Yoshida Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

Progressive supranuclear palsy (PSP) and corticobasal degen- CBD have extremely broad clinical spectra, and thus, it is eration (CBD) are neurodegenerative disorders that show difficult to diagnose atypical patients. In this study, we will parkinsonism as their main symptom. Both PSP and CBD discuss the critical clinicopathological findings to be noted are sporadic tauopathies associated with hyperphosphorylated while diagnosing PSP and CBD. four-repeat tau aggregation in neurons and glial cells. The characteristic pathologies of PSP are midbrain atrophy and PSP the appearance of tufted astrocytes and globose-type neurofi- Background brillary tangles. PSP shows severe degeneration in the globus pallidus, substantia nigra, subthalamic nucleus, and cerebellar PSP was first described by Steele, Richardson, and dentate nuclei. Conversely, the characteristic pathologies of Olszewski in 1964.1 They reported nine cases, including six CBD are cortical atrophy and the appearance of astrocytic autopsy-confirmed cases, of an “unusual syndrome” featur- plaques and argyrophilic threads. CBD is associated with ing postural instability, supranuclear gaze palsy, mild demen- severe degeneration in the cerebral white matter, substantia tia, and progressive axial rigidity and bulbar palsy. They nigra, and globus pallidus. Clinical symptoms depend on the reported that PSP involved heterogeneous degeneration of topographical distribution and severity of degeneration rather the brainstem, basal ganglia, and cerebellum. In 1996, the than on the type of aggregated protein or inclusions. PSP and criteria for defining PSP were published by the National CBD present clinically differential diagnostic difficulties Institute of Neurological Disorders and Stroke and the Soci- because of their overlapping pathological distributions. ety for PSP.3 Various clinical presentations have been described for patients with autopsy-confirmed PSP, including Key words: 4-repeat tauopathy, astrocytc plaque, cor- PSP-progressive nonfluent aphasia (PSP-PNFA)4 in 2003, ticobasal degeneration, progressive supranuclear palsy, PSP-parkinsonism (PSP-P)5 in 2005, PSP-corticobasal syn- tufted astrocyte. drome (PSP-CBS)6 in 2005, PSP-pure akinesia with gait freezing (PSP-PAGF)7 in 2007, and PSP with cerebellar INTRODUCTION ataxia8 (PSP-C) in 2009. The classical type is called PSP with Progressive supranuclear palsy (PSP)1 and corticobasal Richardson syndrome (PSP-RS), which is the most com- degeneration (CBD)2 are neurodegenerative disorders monly observed clinical phenotype of PSP. In 2017, new with extrapyramidal signs. Both the disorders are sporadic criteria for PSP including various subtypes were proposed 4-repeat (4R) tauopathies involving hyperphosphorylated by the International Parkinson and Movement Disorder 4R-tau aggregation in neurons and glial cells. Vertical Society (MDS)-endorsed the PSP Study Group.9 Various supranuclear gaze palsy or asymmetric rigidity and apraxia PSP clinical presentations appear to be in accordance with 10 are the most distinctive symptoms, and patients with these the pathological distribution of degenerative changes. symptoms are easily diagnosed. However, both PSP and Tau pathology of PSP PSP is defined as a major tauopathy featuring the intrace- Correspondence: Maya Mimuro, MD, PhD, Institute for Medical Sci- ence of Aging, Aichi Medical University, 1-1 Yazakokarimata, rebral aggregation of the abnormally phosphorylated Nagakute, Aichi 480-1195, Japan. Email: [email protected] microtubule-associated protein tau, predominantly involv- Presented at the Education Course (EC07) of the 60th Annual Meeting ing isoforms with four microtubule-binding repeats (4R- of the Japanese Society of Neurology on May 23, 2019, Osaka, Japan. tau), in neurons and glial cells.11,12 Immunoblotting of Received 28 June 2019; revised and accepted 05 July 2019; Sarkosyl-insoluble brain extracts revealed a predominant published online 12 September 2019. 33 kDa band among low molecular weight tau © 2019 Japanese Society of Neuropathology 58 M Mimuro and M Yoshida fragments.13 Electron microscopic observation revealed abundant in CBD. Argyrophilic threads and coiled bodies thin straight tubules that were 7–15 nm in diameter.14 The were also immunopositive for 4R-tau. characteristic cellular tau pathologies of PSP included neurofibrillary tangles (NFTs) in neurons, coiled bodies and The pathology of PSP-RS cases threads in oligodendrocytes, and tufted astrocytes Macroscopic appearances (TAs) (Fig. 1). The brain weight of patients with PSP is well-preserved, NFTs but most typical cases of PSP involve mild frontal atrophy In PSP, filamentous tau aggregation is produced in the including the precentral gyrus, particularly in the convex- form of NFTs, which are often globose in shape (Fig. 1A). ity (Fig. 2A). The brainstem and cerebellum display mild NFTs in PSP are basophilic and 4R-tau-immunopositive. atrophy. The globus pallidus and subthalamic nucleus are NFTs are most frequently present in subcortical and generally brownish and atrophic (Fig. 2A). The third ven- brainstem nuclei than the cerebral cortices.15 tricle and Sylvian fissure may be dilated. The tectum from the midbrain to the pons exhibits atrophy (Fig. 2B). The TAs substantia nigra is discolored, whereas the locus coeruleus TAs of PSP (Fig. 1B) were first described as star-like tufts is often better preserved (Fig. 2B). The hilus of the cere- by Hauw et al.15 They observed star-like tufts dominantly bellar dentate nucleus (Fig. 2B) and the superior cerebel- in the first layer via Bodian staining as well as tau immu- lar peduncle are also atrophic in most cases. nocytochemistry. Double immunostaining of these paired nucleated cells with anti-glial fibrillary acid protein and Microscopic appearances Tau-2 antibodies established that tufts were astrocytic in The basic pathologies of PSP are neuronal loss and gliosis nature.16 On Gallyas–Braak staining using camera lucida with 4R-tau-immunopositive inclusions in the cerebral cor- drawings, TAs of PSP exhibited radial branching without tices, basal ganglia, thalamus, brainstem, and cerebellum. collaterals, and the branches exhibited a gradually The pathological subtypes of PSP are generally divided decreasing caliber and blunt ends.17 Immunoelectron into three representative categories according to the sever- microscopic analysis demonstrated that TAs were com- ity and distribution of affected areas: typical PSP type, posed of bundles of abnormal tubules in processes and pallido-nigro-luysian (PNL) type, and CBD-like type perikaryal cytoplasm of protoplasmic astrocytes.18 4R-tau- (Fig. 3).10 The severity of the degeneration and the positive TAs are more common in PSP. Therefore, TAs amount of tau deposition are usually correlated, and thus, are considered the pathognomonic hallmark of PSP.17,19 severely degenerated areas usually display large amounts of tau deposits. Coiled bodies and threads The most affected areas in the typical PSP type are the Coiled bodies are thin or thick, elongated, coil-shaped globus pallidus, subthalamic nucleus, and substantia structures in the cytoplasm and/or processes of the oligo- nigra.3,7,10 Severe neuronal loss, gliosis, and many NFTs dendroglia (Fig. 1C). Coiled bodies are observed in a rela- are found in these areas. The globus pallidus medial seg- tively wide number of patients with PSP as well as other ment and substantia nigra, which are the output parts of neurodegenerative disorders.18 Argyrophilic threads are the basal ganglia, are more affected than the striatum, partly kinked threads along the axonal direction mainly in which is the input part of the basal ganglia, in PSP. The the cerebral white matter and cortex (Fig. 1C).18 Both subthalamic nucleus and globus pallidus lateral segment, PSP and CBD feature these threads, but they are more which are the relay nuclei of the basal ganglia, are also

Fig. 1 Characteristic cellular pathology of progressive supranuclear palsy, including globose-type neurofibrillary tangles visualized by immunohistochemistry with anti-phosphorylated tau antibody (AT8) (A), tufted astrocytes identified by Gallyas-Graak impregnation (B), and oligodendroglial coiled bodies and threads positively stained by AT8 (C). Scale bars: 10 μm (A-C). © 2019 Japanese Society of Neuropathology PSP and CBD 59

affected. These damages appear to be closely correlated with gait disturbance and rigidity. The putamen and caudate exhibit mild neuronal loss and gliosis, but TAs are prominent.17 The thalamus, especially the ventral anterior and lateral thalamic nuclei, has mild-to-moderate degeneration and 4R-tau-positive inclusions such as TAs and coiled bodies.20 In the brainstem, the superior colliculus, periaqueductal gray matter, brainstem tegmentum, oculomotor nuclei, locus coeruleus, pontine nuclei, and olivary nucleus are commonly affected, and tau-positive inclusions in both neurons and glial cells are also abundant in these areas. The superior colliculus, which projects from the substantia nigra, oculomotor nuclei, and pontine tegmentum including the pedunculopontine nucleus and lower pontine reticular formation, is closely correlated with ocular motor dysfunction. The cerebellar dentate nuclei are moderately affected, and they usually display grumose degeneration that is associated with clusters of degenerating presynaptic terminals around dentate neurons.21 The dentatorubrothalamic pathway consistently Fig. 2 Macroscopic findings of the typical progressive supra- exhibits fiber loss; in particular, the superior cerebellar nuclear palsy type. The coronal section at the subthalamic 22 nucleus level (A) reveals atrophy of the globus pallidus and sub- peduncles are moderately to severely atrophic (Fig. 4). thalamic nucleus (arrow). The sectioned area in the midbrain Conversely, Purkinje cells in the cerebellar cortex are rela- (B) exhibits atrophy of the tegmentum and loss of pigmentation tively preserved. Threads and coiled bodies are moder- in the substantia nigra (arrow). The locus coeruleus (arrow) dis- ately found in the cerebellar white matter. The frontal plays relatively preserved pigmentation in the pontine section (C). The sectioned area of the cerebellum (D) exhibits cortex, especially the premotor cortex and precentral atrophy of the dentate nucleus (arrow). Scale bars: 10 mm (A-D). gyrus in the convexity, are the most affected among the

Fig. 3 The pathological subtypes of progressive supranuclear palsy (PSP). The pathological subtypes of PSP are generally divided into three representative categories according to the distribution and severity of the lesions: typical PSP type, pallido-nigro-luysian (PNL) type, and corticobasal degeneration (CBD)-like type. The typical type features severe degeneration of the globus pallidus, subthalamic nucleus, substantia nigra, and brainstem tegmentum. The cerebellar dentate nuclei are moderately affected. The typical PSP type is clinically correlated with PSP with Richardson’s syndrome (PSP-RS). The spinocerebellar degeneration (SCD)-like type is associated with severe degeneration of the dentate nucleus, superior cerebellar peduncles, cerebellar cortex, white matter, and pontine tegmentum and base, which are frequently associated with frontal involvement. The SCD-like type is clinically correlated with PSP with predominant cerebellar ataxia (PSP-C). The PNL type displays relatively restricted changes in PNL lesions. The PNL type is clinically correlated with PSP-pure akinesia with gait freezing (PSP-PAGF) or PSP-parkinsonism (PSP-P). The CBD-like type is accompanied by more severe, asymmetrical cortical changes and variable degeneration of the basal ganglia, brainstem, and cerebellar dentate nucleus. The CBD-like type is clinically correlated with PSP-corticobasal syndrome (PSP-CBS). Reproduced from Yoshida10 with permission.

Fig. 4 Semimacroscopic findings of the typical progressive supranuclear palsy (PSP) type (A), pallido-nigro-luysian (PNL) type) (B), and control (C). The brainstem tegmentum and cerebellar dentate nucleus are atrophic in the typical PSP type. By contrast, the brainstem tegmentum and superior cerebellar peduncles (arrows) are well preserved in the PNL type. Klüver-Barrera staining. cerebral cortices.15 The affected cortices exhibit large TAs and coiled bodies are prominent in the affected cere- numbers of NFTs and TAs and smaller numbers of bral cortices. The degeneration of the basal ganglia, threads and coiled bodies, although cell loss and gliosis brainstem, and cerebellar dentate nuclei is variable are relatively mild. The limbic system is commonly pre- (Fig. 6). The clinical phenotypes depend on the distribu- served in PSP, but cases of PSP involving Alzheimer’s tion of affected cerebral cortices. The cases involving pathology or argyrophilic grain disease have been severe degeneration of the frontoparietal lobe clinically described.23 The spinal cord, especially the cervical seg- correspond to PSP-CBS. Patients with cortical atrophy ment, usually exhibits NFTs and TAs in the medial divi- predominating in the perisylvian area exhibit PSP- sion of the anterior horn, posterior horn, and PNFA.26,27 intermediolateral nucleus.24,25

Clinicopathology of atypical PSP cases CBD PNL type Background PNL-type lesions are relatively confined to the pallidum, CBD was first described by Rebeiz et al. in 1968.2 They substantia nigra, and subthalamic nucleus. The degenera- reported three patients with an “unusual syndrome” fea- tion of the brainstem tegmentum, cerebral cortices, and turing slowness, awkwardness, and involuntary movements cerebellar dentate nuclei are usually mild (Figs 4, 5), and with laterality. They observed that CBD was a tau-positive inclusions in both neurons and glial cells are “corticodentatonigral degeneration” characterized by scant in these areas. Approximately 30% of patients with asymmetrical frontoparietal atrophy and neuronal loss the PNL type do not exhibit ocular motor dysfunction with achromasia. The cerebral cortex was chiefly affected, throughout the course of the disease. In addition, more but the substantia nigra and dentatorubrothalamic system than 50% of patients with the PNL type do not present were also involved. Gibb et al. reported three patients with predominant midbrain atrophy on magnetic reso- with focal dystonia and myoclonus of the arm, the “alien nance imaging, known as the “hummingbird sign,” hand” sign, or an akinetic-rigid syndrome as cases of because the brainstem tegmentum is well-preserved “CBD” in 1989.28 They found that CBD was pathologi- (Fig. 4). The initial symptoms are gait freezing or akinesia cally different from PSP. The three major clinical criteria in most cases of the PNL type, and thus, cases of PNL for CBD were published by Lang and Bergeron (Toronto type clinically correspond to PSP-PAGF or PSP-P. criteria) in 1994,29 by Boeve et al. (the Mayo Clinic criteria) in 2003,30 and by Bak and Hodges (Cambridge CBD-like type criteria) in 2009.31 The heterogeneity of the underlying The CBD-like type is associated with severe cortical pathology in autopsied cases of CBD has been reported lesions with laterality. Tau-positive glial inclusions such as since 1992.32,33 Conversely, patients with autopsy- © 2019 Japanese Society of Neuropathology PSP and CBD 61

Fig. 5 Phosphorylated tau immunohistochemistry with AT8 of the typical progressive supranuclear palsy (PSP) (A, B) and pallido-nigro-luysian (PNL) types (C, D). In the typical PSP type, the precentral gyrus (A) and superior colliculus (B) have many tufted astrocytes and a small number of neurofibrillary tangles (NFTs). By contrast, the precentral gyrus (C) in the PNL type has extremely few tau-positive inclusions. The subthalamic nucleus (D) in the PNL type has many NFTs. Scale bars: 100 μm (A, C), 50 μm (B, D). confirmed CBD have been gradually reported with vari- (FBS), a nonfluent/agrammatic variant of primary progres- ous clinical presentations.33 The term corticobasal syn- sive aphasia (naPPA), and PSP syndrome.35 The heteroge- drome (CBS) has been used for the patients with neity of the underlying pathology of CBS and the characteristic clinical features including progressive asym- existence of various clinical subtypes of CBD suggest that metrical rigidity and apraxia, and CBD has been used for clinical findings are in more accordance with the patholog- the histopathological disorder.30 The new clinical criteria ical distribution than the type of accumulated protein. for CBS including cognitive symptoms were proposed (modified Cambridge criteria) in 2012.34 The new criteria for pathologically confirmed CBD including four clinical Tau pathology of CBD subtypes were proposed by an international consortium of CBD is defined as a 4R tauopathy as is PSP, but CBD has behavioral neurology, neuropsychology, and movement a lower prevalence than PSP. On immunoblots of disorders specialists (Armstrong criteria) as follows: CBD- Sarkosyl-insoluble brain extracts, two closely associated CBS, CBD with frontal behavioral-spatial syndrome bands of approximately 37 kDa predominated among the

Fig. 6 Semimacroscopic findings of corticobasal degeneration (CBD)-like type progressive supranuclear palsy (PSP) (A, B) and CBD with PSP syndrome (C, D). CBD-like type PSP exhibits left side-predominant degeneration of the cerebral cortices and basal ganglia. Klüver-Barrera staining (A, C), Holzer staining (B, D). Scale bars: 2 cm (A-D). © 2019 Japanese Society of Neuropathology 62 M Mimuro and M Yoshida low molecular weight tau fragments.13 Electron micro- The pathology of typical CBD (CBD-CBS) cases scopic observation revealed thin twisted ribbon-like fila- Macroscopic appearances ments of 10–25 nm in diameter with 140–180 nm The brain weight of patients with CBD is relatively pre- periodicity.14 The characteristic cellular tau pathologies of served. Focal cortical atrophy and hemiatrophy are sug- CBD are pretangles and NFTs in neurons, coiled bodies gestive findings for CBD (Fig. 8A), but they are not and threads in oligodendrocytes, and astrocytic plaques always necessary. Cortical atrophy predominates in the (APs) (Fig. 7). frontoparietal lobe, especially in the perirolandic area, or the perisylvian area. The brainstem and cerebellum display variable atrophy. Coronal sections exhibit cortical Pretangles and NFTs atrophy and subcortical white matter atrophy in the Many neurons display diffuse or granular cytoplasmic tau affected areas (Fig. 8B). The corpus callosum is sometimes immunoreactivity at the affected cortices in CBD. Small thin.38 The temporal and occipital lobes are usually neurons in the upper cortical layers are most vulnerable.36 spared. The basal ganglia display variable atrophy. The Most tau-positive neurons are less filamentous, different substantia nigra is severely discolored (Fig. 8C), whereas from NFTs, and thus, they are called “pretangles” the locus coeruleus is often better preserved. The hilus of (Fig. 7A).37 Pretangles and NFTs in CBD are 4R-tau- the cerebellar dentate nucleus exhibits variable atrophy. positive. APs Microscopic appearances APs (Fig. 7B) are the most characteristic tau-positive The basic pathologies of CBD are neuronal loss and astrocytic inclusions in CBD. APs were first described by gliosis with 4R-tau-positive inclusions in the cerebral cor- Feany and Dickson using double immunohistochemistry tex and white matter, basal ganglia, thalamus, brainstem, and laser confocal microscopy.38 They found that APs and cerebellum. The pathological subtypes of CBD are exhibit annularly distributed tau aggregation in the most generally divided into three representative categories distal portion of the astrocytic processes. APs often have based on the severity and distribution of affected areas: the collateral appearance of distal astrocytic processes typical CBD type, basal ganglia-predominant type, and because some filaments in APs are located in a narrow PSP-like type (Fig. 9).10 hollow near synaptic structures.10,14,38 The most affected areas in the typical CBD type are the cerebral cortices and subcortical white matter, especially in the frontoparietal lobe (Fig. 10).10,36 Severe neuronal loss Coiled bodies and threads and gliosis are common in affected cortices. The cerebral Argyrophilic threads, glial tau-immunoreactive thread-like white matter near the affected cortices displays myelin loss processes, are usually abundant in the affected areas of (Fig. 10A). Gliosis is predominant in the superficial cortical gray and white matter in CBD.38 Coiled bodies following layers and subcortical white matter (Fig. 10B). One of the a curved course are also observed in white matter underly- characteristic pathological findings of CBD is swollen, ach- ing the affected cortices in CBD, albeit at a relatively romatic, or ballooned neurons (BNs) (Fig. 11A, D).2 BNs small number (Fig. 7C). Coiled bodies and argyrophilic have swollen cytoplasm and eccentrically located nuclei threads are also immunopositive for 4R-tau. Argyrophilic without Nissl bodies. In CBD, BNs are distributed in threads and APs are useful features for differentiating affected cortices, especially the precentral cortex, superior CBD from other degenerative disorders.39 frontal cortex, and cingulate cortex.40 However, in limbic

Fig. 7 Characteristic cellular pathology of corticobasal degeneration (CBD), including pretangles visualized by by immunohistochemistry with anti-phosphorylated tau antibody (AT8) (A), typical astrocytic plaques identified by Gallyas-Braak impregnation (B), and oligodendroglial coiled bodies and threads positively stained by AT8. Scale bars: 10 μm (A-C). © 2019 Japanese Society of Neuropathology PSP and CBD 63

commonly preserved in CBD, but pretangles are more common in the dentate fascia due to argyrophilic grain pathology.42 The tau-positive inclusions are most conspicu- ous after Gallyas–Braak silver staining. The topographical distribution of affected cortices is correlated to clinical “higher cortical features” as follows: posterior frontoparietal or perisylvian cortical lesions correspond to CBD with clinical CBS, anterior frontal cortical lesions correspond to CBD with clinical FBS, and superior temporal or perisylvian cortical lesions correspond to CBD with naPPA.43 The substantia nigra also displays severe neuronal loss Fig. 8 Macroscopic findings of the typical corticobasal degeneration type. The brain (A) displays focal atrophy (arrow). The cor- and gliosis in the typical CBD type. The globus pallidus and onal section at the subthalamic nucleus level (B) reveals subthalamic nucleus exhibit variable neuron loss and gliosis hemiatrophy on the right side, and the corpus callosum is thin. with small numbers of NFTs. The subthalamic nucleus, puta- The sectioned area of the midbrain (C) exhibits mild atrophy and men, and caudate nucleus display mild neuronal loss and loss of pigments in the substantia nigra (arrow). Scale bars: 10 mm (A-C). gliosis, but many APs and pretangles are observed in the striatum, especially in the caudate nucleus.44 The locus coeruleus and tegmental area in the brainstem have mild and paralimbic areas, BNs appear in several disorders such neuronal loss, gliosis, and tau-positive inclusion-like ’ as argyrophilic grain disease, Pick s disease, and PSP. BNs pretangles, but the degeneration of these areas is usually not in the convexity cortical areas have much greater diagnostic 36 marked. The cerebellar dentate nuclei are variably affected, importance for CBD. CBD is characterized by wide- and neuronal loss, if present, is usually not marked. Purkinje spread hyperphosphorylated 4R-tau pathology in both neu- cells in the cerebellar cortex are relatively preserved. rons and glial cells.41 Numerous threads, coiled bodies, and pretangles are present in wider areas than the affected cortices. APs are most abundant in the prefrontal and The clinicopathology of atypical CBD cases premotor areas in the cerebral cortex, although the number PSP-like type of APs is variable according to the degree and extent of The PSP-like type features severe involvement of the damage in the affected cortices. The limbic system is basal ganglia, brainstem (Fig. 11F), and cerebellar dentate

Fig. 9 The pathological subtypes of corticobasal degeneration (CBD). The pathological subtypes of CBD are generally divided into three representative categories according to the distribution and severity of the lesions: typical CBD type, basal ganglia-predominant type, and progressive supranuclear palsy (PSP)-like type. The typical CBD type exhibits cortical-dominant involvement with laterality in the posterior frontoparietal or perisylvian areas. Some cases involve anterior frontal-predominant cortical degeneration, such as frontotemporal lobar degeneration. The typical CBD type is clinically correlated with CBD with corticobasal syndrome (CBD-CBS). The basal ganglia-predominant type features the severe involvement of the globus pallidus and subthalamic nucleus, with relatively mild cortical degeneration without distinct laterality. The basal ganglia-predominant type is clinically correlated with CBD with progressive supranuclear palsy syndrome (CBD-PSPS) or CBD with parkinsonism (CBD-P). The PSP-like type features severe degeneration of the brainstem and dentate nucleus similar to that observed in PSP, in addition to variable cortical involvement. The PSP-like type is clinically correlated with CBD-PSPS. Reproduced from Yoshida10 with permission. © 2019 Japanese Society of Neuropathology 64 M Mimuro and M Yoshida

Fig. 10 Semimacroscopic findings in the typical corticobasal degeneration (CBD) type. The coronal sections (A) reveal focal atrophy of the perirolandic and perisylvian areas. The cerebral white matter near the affected cortices exhibits myelin loss on Klüver- Barrera staining (A). The white matter, globus pallidus, and the medial thalamus display gliosis on Holzer staining (B). Arrows: precentral sulcus. Scale bars: 20mm (A, B). nucleus. Tau-positive glial inclusion-like argyrophilic distributions. Their many clinical similarities make the clini- threads and coiled bodies are prominent in the affected cal differentiation of the two diseases difficult. areas. The degeneration of the cerebral cortices is variable In PSP, the cerebellar dentate nucleus and without obvious laterality (Figs 7, 11E). Patients with the dentatorubrothalamic pathway are frequently affected. PSP-like type clinically exhibit CBD-PSPS.45 The cerebral cortex and white matter are relatively spared. Conversely, CBD is linked to severe cerebral and subcortical white matter degeneration. White matter Differential diagnosis lesions, including U-fibers, start at the early disease stage and progress rapidly. The atrophy of basal ganglia and The biochemical characterizations of pathological tau rev- neuronal loss in the substantia nigra are severe. Both PSP ealed that PSP and CBD are different disease entities with and CBD are known to have the concurrent pathologies distinct tau species. However, the clinical symptoms depend of cerebrovascular disease, argyrophilic grain disease,45 on the topographical distribution and degree of degenera- Lewy body disease, and Alzheimer’s disease, although the – tion opposed to the type of aggregated protein or inclu- coexistence of PSP and CBD is rare.46 48 The existence of sions. PSP and CBD exhibit wide pathological spectra, and concomitant pathologies makes their clinicopathological these two diseases frequently display similar pathological diagnosis complicated.

Fig. 11 Microscopic findings in the typical corticobasal degeneration (CBD) type (A–C) and progressive supranuclear palsy (PSP)-like type (D–F). Both types feature ballooned neurons in affected cortices (A, D). In the typical CBD type, the precentral gyrus (B) has a larger number of pretangles, threads, and astrocytic plaques than the brainstem tegmentum (C). By contrast, the precentral gyrus (E) has relatively fewer tau-positive inclusions than the brainstem tegmentum (F) and basal ganglia in the PSP-like type. Hematoxylin-eosin staining (A, D), immunohistochemical staining with AT8 (B, C, E, F). Scale bars: 20 μm(A,D),50μm (B, C, E, F). © 2019 Japanese Society of Neuropathology PSP and CBD 65

Recently, animal studies of tau propagation supported 5. Williams DR, deSilva R, Paviour DC et al. Character- the notion that PSP and CBD have distinct tau strains and istics of two distinct clinical phenotypes in pathologi- represent different pathological processes.49,50 The injec- cally proven progressive supranuclear palsy: tion of brain homogenates leads to their subsequent Richardson’s syndrome and PSP-parkinsonism. Brain spread to distant brain regions connected by specific neu- 2005; 128: 1247–1258. ral networks. PSP and CBD are based on a prion-like 6. Tuboi Y, Josephs KA, Boeve BF et al. Increased tau templating mechanism that is central to tau propagation burden in the cortices of progressive supranuclear and disease propagation. However, PSP and CBD display palsy presenting with corticobasal syndrome. Mov Dis- different distributions of tau aggregation in individual ord 2005; 20: 982–988. cases, and the distributions of neuronal and glial inclusions 7. Williams DR, Lees AJ. Progressive supranuclear differ. Continued investigation is necessary to clarify the palsy: Clinicopathological concepts and diagnostic disease pathogenesis. challenges. Lancet Neurol 2009; 8: 270–279. 8. Kanazawa M, Shimohata T, Toyoshima Y et al. Cere- bellar involvement in progressive supranuclear palsy: ACKNOWLEDGMENTS A clinicopathological study. Mov Disord 2009; 24: This work was presented in part at the 60th Annual Meet- 1312–1318. ing of the Japanese Society of Neurology (Osaka, Japan, 9. Höglinger GU, Respondek G, Stamelou M et al. Clini- 2019), and supported by AMED under Grant Numbers cal diagnosis of progressive supranuclear palsy: The JP18dm0107105 (M. Yoshida) and JP16kk0205009 movement disorder society criteria. Mov Disord 2017; (M. Yoshida) and by Grants-in Aid from the Research 32: 853–864. Committee of CNS Degenerative Diseases, Research on 10. Yoshida M. Astrocytic inclusions in progressive supra- Policy Planning and Evaluation for Rare and Intractable nuclear palsy and corticobasal degeneration. Diseases, Health, Labour and Welfare Sciences Research Neuropahology 2014; 34: 555–570. Grants, the Ministry of Health, Labour and Welfare, 11. Dickson DW. Neuropathologic differentiation of pro- Japan (M. Yoshida). The authors acknowledge gressive supranuclear palsy and corticobasal degenera- Dr. A. Akagi, Dr. Y. Riku, Dr. H. Miyahara, and tion. J Neurol 1999; 246: II6–II15. Dr. Y. Iwasaki, and also thanks K. Koutani, T. Mizuno, 12. Kovacs GG. Neuropathology of tauopathies: Principles C. Sano and C. Uno for excellent technical assistance. and practice. Neuropathol Appl Neurobiol 2015; 41:3–23. 13. Arai T, Ikeda K, Akiyama H et al. Tau fragments that distinguish progressive supranuclear palsy from cor- DISCLOSURE ticobasal degeneration. Ann Neurol 2004; 55:72–79. Authors declare no conflict of interests for this article. 14. Taniguchi-Watanabe S, Arai T, Kametani F et al. Bio- chemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of REFERENCES sarkosyl-insoluble and trypsin-resistant tau. Acta Neu- 1. Steel JC, Richardson JC, Olszewski J. Progressive ropathol 2016; 131: 267–280. supranuclear palsy. A heterogeneous degeneration 15. Hauw JJ, Verny M, Delaère P, Cervera P, He Y, involving the brainstem, basal ganglia and cerebellum Duyckaerts C. Constant neurofibrillary changes in the with vertical gaze and pseudobulbar palsy, nucha dys- neocortex in progressive supranuclear palsy. Basic dif- tonia and dementia. Arch Neurol 1964; 10: 333–359. ferences with Alzheimer’s disease and aging. Neurosci 2. Rebeiz JJ, Kolodny EH, Richardson EP Jr. Lett 1990; 119: 182–186. Corticodentatonigral degeneration with neuronal 16. Yamada T, McGeer PL, McGeer EG. Appearance of achromasia. Arch Neurol 1968; 18:20–33. paired nucleated, tau-positive glia in patients with pro- 3. Litvan I, Agid y, Calne D et al. Clinical research gressive supranulear palsy brain tissue. Neurosci Lett criteria for the diagnosis of progressive supranuclear 1990; 119: 182–186. palsy (Steel-Richardson-Olszewski syndrome): Report 17. Komori T, Arai N, Oda M et al. Astrocytic plaque and of the NINDS-SPSP international workshop. Neurol- tufts of abnormal fibers do not coexist in corticobasal ogy 1996; 47:1–9. degeneration and progressive supranuclear palsy. Acta 4. Mochizuki A, Ueda Y, Komatsuzaki Y, Tsuchiya K, Neuropathol 1998; 96: 401–408. Arai T, Shoji S. Progressive supranuclear palsy presenting 18. Arima K. Ultrastructural characteristics of tau fila- with primary progressive aphasia-clinicopathological ments in tauopathies: Immuno-electron microscopic report of an autopsy case. Acta Neuropathol 2003; demonstration of tau filaments in tauopathies. Neuro- 105:610–614. pathology 2006; 26: 475–483. © 2019 Japanese Society of Neuropathology 66 M Mimuro and M Yoshida

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