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Progressive Supranuclear Palsy and Corticobasal Degeneration

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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 neu- rofibrillary 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 cau- date 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 degener- ation and 4R-tau-positive inclusions such as TAs and coiled bodies.20 In the brainstem, the superior colliculus, periaqueductal gray matter, brainstem tegmentum, oculo- motor 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 tegmen- tum including the pedunculopontine nucleus and lower pontine reticular formation, is closely correlated with ocu- lar motor dysfunction. The cerebellar dentate nuclei are moderately affected, and
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