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Progressive supranuclear palsy presenting as primary lateral sclerosis but lacking parkinsonism, gaze palsy, aphasia, or dementia
Journal of the Neurological Sciences 323 (2012) 147–153
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Progressive supranuclear palsy presenting as primary lateral sclerosis but lacking parkinsonism, gaze palsy, aphasia, or dementia Shigeto Nagao a, b, Osamu Yokota b,⁎, Reiko Nanba c, Hiroshi Takata d, Takashi Haraguchi a, Hideki Ishizu e, Chikako Ikeda b, Naoya Takeda b, Etsuko Oshima b, Katsuaki Sakane b, Seishi Terada b, Yuetsu Ihara a, Yosuke Uchitomi b a
Department of Neurology, National Hospital Organization Minami-Okayama Medical Center, Hayashima, Japan Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan c Nanba Clinic of Neurology, Hayashima, Japan d Department of Neurology, Kinashi Obayashi Hospital, Takamatsu, Japan e Department of Laboratory Medicine and Pathology, Zikei Institute of Psychiatry, Okayama, Japan b
a r t i c l e
i n f o
Article history: Received 27 June 2012 Received in revised form 10 September 2012 Accepted 11 September 2012 Available online 29 September 2012 Keywords: Motor neuron disease Primary lateral sclerosis Progressive supranuclear palsy Pseudobulbar palsy Pyramidal signs
a b s t r a c t We report an autopsy case of progressive supranuclear palsy (PSP) that clinically showed only slowly progressive and symmetric upper motor neuron syndrome over a disease course of 12 years. A female patient initially exhibited dysarthria at the age of 65, followed by gait disturbance and dysphagia. Neurological examination at age 67 disclosed pseudobulbar palsy, spastic gait, hyperreflexia, and presence of bilateral Hoffmann and Babinski signs. However, muscle atrophy, weakness, evidence of denervation on electromyography, vertical gaze palsy, parkinsonism, gait freezing, aphasia, speech apraxia, or dementia was not noted throughout the course. She was clinically diagnosed as having motor neuron disease consistent with so-called primary lateral sclerosis. Pathological examination disclosed histopathological features of PSP, including argyrophilic and tau-positive tufted astrocytes, neurofibrillary tangles, coiled bodies, and thread-like processes in the motor cortex and superior frontal gyrus, and to a lesser degree, in the basal ganglia and brain stem nuclei. In addition, severe fibrillary gliosis was noted in the precentral gyrus and corticospinal tract, being consistent with upper motor neuron syndrome observed in this case. No TAR-DNA binding protein 43-positive lesion, FUS pathology, Bunina body, or Lewy body-like hyaline inclusion was noted in the motor cortex or lower motor neurons. These findings suggest that when tau pathology is prominent in the motor cortex but is minimal in the basal ganglia and brain stem nuclei, a PSP case can lack all classic clinical features of PSP and show only slowly progressive upper motor syndrome, consistent with clinical picture of primary lateral sclerosis. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Progressive supranuclear palsy (PSP) is one of the tauopathies that is clinically characterized by dystonic posturing of the neck and axial rigidity, vertical gaze palsy, postural instability, gait disturbance with an ataxic quality, early falls, dysarthria, dysphasia, and poor L-dopa response [1]. Pathological hallmarks of PSP are argyrophilic neuronal and glial inclusions, including neurofibrillary tangles (NFTs), threads, tufted astrocytes, and coiled bodies, which develop mainly in the basal ganglia, brain stem nuclei, and frontal cortex. Although the pathological diagnosis of PSP is based on the topographical distribution and severity of NFTs and threads [2], presence of tufted astrocytes is also considered to have diagnostic value. In these neuronal and glial inclusions, four-repeat (4R) rather ⁎ Corresponding author at: Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700‐ 8558, Japan. Tel.: +81 86 235 7242; fax: +81 86 235 7246. E-mail address: [email protected] (O. Yokota). 0022-510X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2012.09.005
than three-repeat (3R) tau is more predominantly accumulated [3]. Recent clinicopathological studies have demonstrated that clinical presentation of PSP may not be as uniform as previously believed, and some cases can show L-dopa-responsive parkinsonism, pure akinesia with gait failure, frontotemporal dementia, corticobasal syndrome, progressive non-fluent aphasia, or speech apraxia [4–6]. It is considered that the variability in the clinical presentation in PSP is associated with the topographical distribution of tau pathology and synaptic loss [4,7–10]. Primary lateral sclerosis (PLS) is a rare clinical syndrome that was first proposed by Erb in 1875 [11]. The clinical picture of PLS is characterized by progressive involvement of upper motor neurons, which frequently occurs in the lower extremities [12]. Pathological features of PLS are neuronal loss in the precentral gyrus with corticospinal tract degeneration and preservation of the lower motor neurons. On the other hand, it was also reported that ubiquitin-positive neuronal cytoplasmic inclusions [13,14], TAR DNA-binding protein of 43 kDa (TDP-43)-positive inclusions [15], and Bunina bodies can be also found in the lower motor neurons as well as in the precentral gyrus
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in some clinically PLS cases [16–19]. Based on these findings, it is considered that at least some of the PLS cases may be a clinicopathological subtype of amyotrophic lateral sclerosis. However, as far as we know, fewer than ten autopsy cases of PLS showed only upper motor neuron findings and lacked other symptoms (e.g. parkinsonism, dementia) [12,20–22], and the detailed pathological bases in patients who present clinically with PLS remain unclear. We here present an autopsy case that clinically exhibited only progressive upper motor neuron signs throughout the clinical course, which is consistent with the clinical picture of PLS. However, unexpectedly, this case lacked TDP-43 or fused in sarcoma (FUS) pathology in the frontal cortex or lower motor neurons. Instead, argyrophilic and tau-positive neuronal and glial inclusions were found in the motor cortex, and, to a lesser degree, in the basal ganglia and brain stem nuclei. The morphological, topographical, and immunohistochemical features of the tau pathology were consistent with those observed in PSP, although its severity in the basal ganglia and brain stem nuclei was far milder than that in PSP cases showing typical clinical features. 2. Case report The patient was a 77-year-old Japanese woman at the time of death. She had no personal or family history of neurological or psychiatric disorders. She initially noticed speech difficulty at the age of 65 years. She developed gait difficulty at age 66, and difficulty in swallowing water at age 67. Neurological examination at this time at the department of neurology of a national hospital disclosed pseudobulbar palsy including attenuation of the palatal reflex, dysarthria, and dysphagia. She also showed hyperreflexia and spasticity predominantly affecting the lower extremities. Her gait was disturbed by spasticity. Jaw jerk was brisk. Hoffmann and Babinski signs were bilaterally positive. On the other hand, there was no muscle weakness, atrophy, or fasciculation in the tongue and four extremities. In addition, gaze palsy, rigidity in the neck or extremities, tremor, bradykinesia, postural instability, fall, gait freezing, asymmetric motor disturbance, aphasia, speech apraxia, personality change, and dementia were absent. Sensory disturbance or cerebellar sign was not seen. Electromyography revealed no active or chronic denervation in any four limbs or in masseter muscle. Magnetic resonance imaging did not reveal any abnormal finding that might be associated with dysarthria or gait disturbance. The progression of her neurological disturbances was very slow, and weakness in all four extremities was only mild during the course. Until five months before her death, she could walk shufflingly using crutches, and was able to eat pureed food just before death. Six months before her death, she showed a decrease in appetite, and endoscopy revealed gastric cancer. She died of gastric cancer at age 77 after a clinical course of 12 years. Vertical gaze palsy, parkinsonism, intellectual impairment, or psychiatric change was absent throughout the course. Her neurological symptoms could not be explained by paraneoplastic syndrome because the disease duration before gastric cancer was revealed was over 10 years. Due to the presence of upper motor neuron signs during the long course, the absence of lower motor neuron signs including electromyography, and the exclusion of other diseases by neuroimaging, final neurological diagnosis was motor neuron disease consistent with so-called primary lateral sclerosis. 3. Materials and methods 3.1. Conventional neuropathological examination Brain tissue samples were fixed post mortem with 10% formaldehyde and embedded in paraffin. Ten-μm-thick sections from the frontal, temporal, parietal, occipital, insular, and cingulate cortices, hippocampus, amygdala, basal ganglia, midbrain, pons, medulla oblongata, and cerebellum were prepared. The spinal cord was not available. These sections were stained by hematoxylin–eosin (H&E), Klüver–Barrera, Holzer, Gallyas–Braak silver, and modified Bielschowsky silver methods. Autopsy
was carried out after informed consent was obtained from the family members, and all experiments in this study were approved by the ethical committees of the National Hospital Organization Minami-Okayama Medical Center and the Okayama University Graduate School of Medicine and Dentistry. 3.2. Immunohistochemistry Sections were immunostained by immunoperoxidase method using 3′3-diaminobenzidine tetrahydrochloride. Antibodies used were against phosphorylated tau (AT8, mouse, monoclonal, 1:3000, Innogenetics, Ghent, Belgium), 3R tau (RD3, mouse, monoclonal, 1:3000, Upstate Labs, Syracuse, NY) [23], 4R tau (RD4, mouse, monoclonal, 1:200, Upstate) [23], Aβ (11–28) (mouse, monoclonal, 1:4000, IBL, Fujioka, Japan), Aβ42 (Aβ42, rabbit, polyclonal, 1:100, IBL, Fujioka, Japan), phosphorylated α-synuclein (psyn#64, mouse, monoclonal, 1:1000, Wako Co. Ltd., Osaka, Japan), phosphorylated TDP-43 (pS409/ 410-2, rabbit, polyclonal, 1:5000, Cosmo Bio, Tokyo, Japan), phosphorylated neurofilament (SMI31, mouse, monoclonal, 1:1000, Sternberger, Lutherville, MD, USA), FUS (HPA008784, rabbit, polyclonal, 1:200, Sigma-Aldrich, St. Louis, MO, USA), glial fibrillary acidic protein (GFAP, rabbit, polyclonal, 1:5000, Dako, Glostrup, Denmark), CD68 (CD68 [KP1], monoclonal, mouse, 1:250, Dako, Glostrup, Denmark), and 3F4 (3F4, mouse monoclonal, Covance, San Diego, CA). When using anti-Aβ antibodies, the sections were pretreated with 70% formic acid for 10 min for antigen retrieval. When using psyn#64, pS409/410-2, GFAP, CD68, and HPA008784, the sections were pretreated with pressure cooker for 3 min. When using RD4, the sections were pretreated with 70% formic acid for 5 min and autoclaved for 10 min in 10 mM sodium citrate buffer at 121 °C. When using RD3, the sections were autoclaved, but not pretreated with formic acid. For PrP immunohistochemistry, deparaffinized sections were pretreated by hydrolytic autoclaving in 1.5 mM HCl at 121 °C for 10 min. 3.3. Semiquantitative assessment of histopathological lesions Neuronal loss associated with gliosis in the cerebral cortex was assessed on H&E- and Klüver–Barrera-stained sections according to the grading system used previously [24]: −, no histopathological alteration; +, slight neuronal loss and gliosis only in the superficial layers; ++, obvious neuronal loss and gliosis in the cortical layers II and III, often accompanied by status spongiosis and relative preservation of neurons in layers V and VI; +++, pronounced neuronal loss with gliosis in all cortical layers, and prominent fibrillary gliosis in adjacent subcortical white matter. The degree of neuronal loss and gliosis in the basal ganglia and brainstem nuclei was also assessed as follows [24]: −, no histopathological alteration; ±, mild gliosis, but neurons reduced in number; +, mild gliosis and neuronal loss; ++, moderate neuronal loss and gliosis, but no tissue rarefaction; +++, severe neuronal loss, severe gliosis, and tissue rarefaction. Degeneration of the corticospinal tract and frontopontine tract at the levels of the cerebral peduncle and medulla oblongata was indicated as follows [24]: −, no degeneration; +, mild degeneration with slight myelin loss and gliosis without atrophy of the tract; ++, moderate degeneration with evident myelin loss and gliosis with slight atrophy of the tract; +++, severe degeneration with evident myelin loss, gliosis, and severe atrophy of the tract. NFTs and tufted astrocytes were semiquantitatively evaluated with the following staging system using the Gallyas–Braak silver method and AT8 immunohistochemistry, respectively: −, no lesion; +, one inclusion in each anatomical region; ++, 2 or more inclusions in each anatomical region but less than one inclusion per × 200 visual field; +++, one inclusion per × 200 visual field; ++++, 2 to 10 inclusions per × 200 visual field; +++++, 11 or more inclusions per × 200 visual field. The threads were semiquantitatively assessed only in the regions recommended in the pathological criteria for PSP [2] on Gallyas–Braak
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silver-stained sections in a ×200 field as follows: −, none; +, low density; ++, high density. Argyrophilic grains were semiquantitatively assessed on Gallyas–Braak silver stained sections in a ×400 field as: −, no lesion; ±, 10 to 20; +, 20 to 50; ++, 50 to 100; +++, >100. 4. Results 4.1. Neuropathological findings The brain weighed 1042 g after fixation. Macroscopically, the frontal lobe was atrophic (Fig. 1a). The precentral gyrus was also mildly atrophic. The temporal lobe was relatively well spared. On coronal sections, thinning of the cerebral cortex in the motor cortex and superior frontal gyrus was noted (Fig. 1b and c). The hippocampus, amygdala, striatum, thalamus, subthalamic nucleus, tegmentum of the midbrain, pyramidal tract, and cerebellum were unremarkable. The substantia nigra and locus coeruleus were well pigmented (Fig. 1d). Microscopic examination disclosed tau-positive neuronal and glial inclusions with mild neuronal loss in the cerebral cortex, basal ganglia, and brain stem nuclei. The distribution and severity of these changes are shown in Table 1. On H&E and Klüver–Barrera-stained sections, neuronal loss in the frontal cortex was not evident. However, Holzer's stain demonstrated evident fibrillary gliosis in the precentral gyrus and superior frontal gyrus (Fig. 2a,b, and b inset). In the amygdala, although neuronal loss was mild, a few ballooned neurons immunopositive for phosphorylated neurofilament antibody were scattered (Fig. 3m). In the striatum, globus pallidus, thalamus, subthalamic nucleus, and nucleus basalis of Meynert, neuronal loss with gliosis was absent or minimal. Likewise, neuronal loss was not observed in the substantia nigra (Fig. 3e), oculomotor nucleus, pontine nucleus, hypoglossal nucleus (Fig. 3d), inferior olivary nucleus, or dentate nucleus in the cerebellum. In contrast, the pyramidal tract at the level of the medulla oblongata showed myelin pallor (Fig. 3a) with glial proliferation. In this region, Holzer's stain demonstrated severe fibrillary gliosis (Fig. 3b), while neither GFAP nor CD68 immunohistochemistry revealed an evident increase of the number of positive cells (Fig. 3c). The Gallyas–Braak silver method demonstrated argyrophilic glial lesions morphologically consistent with tufted astrocytes. They were most frequently observed in the motor cortex and superior frontal gyrus (Table 1, Fig. 2c,d,e,f). A few tufted astrocytes were also noted in the caudate nucleus and putamen (Fig. 3g and h). No tufted astrocyte was found in the other regions. A small number of NFTs were noted in the entorhinal cortex and hippocampal CA1, but were hardly seen in the temporal cortex, a distribution that corresponded to Braak NFT stage II. NFTs, threads, and coiled bodies were more frequently found in the frontal cortex including the motor cortex, subthalamic nucleus, and substantia nigra, and to a lesser frequency, in the striatum (Table 1, Fig. 3f and j). No argyrophilic lesion was found in the pontine nucleus, inferior olivary nucleus, or dentate nucleus in the cerebellum. Moderate numbers of argyrophilic grains, corresponding to Saito's stage II [25], were noted in the limbic region and adjacent temporal cortex (Table 1, Fig. 3i). An astrocytic plaque was not noted in any anatomical region. AT8 immunohistochemistry demonstrated tau-positive NFTs, threads, tufted astrocytes, and coiled bodies with more extensive distribution than that of argyrophilic lesions on Gallyas–Braak silver-stained sections (Table 1). Tufted astrocytes were most frequently noted in the motor cortex (Fig. 2g,h,i), and to a lesser frequency, in the caudate nucleus, putamen, globus pallidus, and subthalamic nucleus (Fig. 3k). The number of tufted astrocytes in the motor cortex demonstrated by tau immunohistochemistry was evidently larger than that demonstrated by the Gallyas–Braak silver method (Table 1). These tau pathologies were immunolabeled with RD4 rather than RD3 antibody, suggesting that this case had four-repeat tauopathies, including PSP. A few tau-positive neuronal and glial inclusions were also noted in the
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substantia nigra, pontine nucleus, inferior olivary nucleus, and dentate nucleus in the cerebellum (Fig. 3l). Like the Gallyas–Braak silver stain, tau immunohistochemistry did not demonstrate astrocytic plaques in any region. The quantity and distribution of tau-positive NFTs and threads fit the pathological diagnostic criteria of PSP [2], although those of argyrophilic lesions on Gallyas–Braak-stained sections were not sufficient for its diagnosis (Table 1). In the amygdala and temporal cortex, tau-positive argyrophilic grains and bush-like astrocytes [26] were seen. In this case, a few TDP-43-positive neuronal cytoplasmic inclusions and dystrophic neurites were also found in the amygdala and entorhinal cortex (Fig. 3n). However, no TDP-43-positive lesion was found in other regions, including the frontal and temporal cortices or motor neurons in the hypoglossal nuclei. Neither Bunina body nor Lewy body-like hyaline inclusion was noted. There were no Aβ deposits, Pick bodies,
Fig. 1. (a) Atrophy is noted in the frontal lobe. The precentral gyrus is also mildly atrophic. (b, c) On coronal sections, narrowing of the cortical ribbon in the superior frontal gyrus and motor cortex is noted (arrowheads). (d) The tegmentum of the midbrain and pons is not atrophic. The substantia nigra and locus coeruleus are well pigmented. All scale bars = 2 cm.
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Table 1 Distribution of pathological changes in the present case.
Superior frontal gyrus Middle frontal gyrus Inferior frontal gyrus Motor cortex Superior temporal gyrus Middle temporal gyrus Inferior temporal gyrus Cingulate cortex Insular cortex Hippocampal CA1 and subiculum Parahippocampal gyrus Amygdala Ambient gyrus Caudate nucleus Putamen Globus pallidus Thalamus Nucleus basalis of Meynert Subthalamic nucleus Oculomotor nucleus Substantia nigra Locus coeruleus Pontine nucleus Hypoglossal nucleus Dorsal vagal nucleus Inferior olivary nucleus Corticospinal tract At level of cerebral peduncle At level of medulla oblongata Cerebellum Dentate nucleus Cerebellar cortex
Neuronal loss with gliosis
Tufted astrocytes
Neurofibrillary tangles (/threads)a)
(H&E)
(AT8)
(GB)
(AT8)
(GB)
(GB)
+ − − + − − − − + − − + − − − + − − − − − − − − − −
+++ − ++ ++++ ++ + ++ − + − − − − ++ ++ ++ + + + + − − + − − −
+ − − ++ − − − − − − − − − + ++ − − − − − − − − − − −
+++ +++ ++ ++++ +++ ++++ +++++ ++++ ++++ +++++ +++++ +++++ ++++ +/+ −/+ ++/+ ++ ++++ +++/+ +/− ++/+ ++++ ++/+ − − +/−
++ ++ − +++ − − ++ +++ ++ +++++ ++++ +++ ++ −/+ −/+ −/− + ++ +++/− −/− ++/+ ++++ −/− − − −/−
− − − − ++b) + +++ ± + +++ + +++ +++ − − − − − − − − − − − − −
− ++
− −
− −
− −
− −
− −
− −
− −
− −
+++/+ −
−/− −
− −
Argyrophilic grains
Neuronal loss associated with gliosis: −, absent; +, slight neuronal loss with gliosis; ++, moderate neuronal loss with gliosis; +++, severe neuronal loss and gliosis with tissue rarefaction [24]. NFTs and tufted astrocytes were semiquantitatively evaluated using Gallyas–Braak silver stain and AT8 immunohistochemistry as follows, respectively: −, no lesion, +, one inclusion in each anatomical region, ++, 2 or more inclusions in each anatomical region but less than one inclusion per ×200 visual field; +++, one inclusion per ×200 visual field; ++++, 2 to 10 inclusions per ×200 visual field; +++++, 11 or more inclusions per ×200 visual field. Argyrophilic grains were semiquantitatively assessed on Gallyas–Braak-stained sections in a ×400 field as follows: −, no lesion, ±10 to 20; +, 20 to 50; ++, 50 to 100; +++, >100. H&E, hematoxylin–eosin; GB, Gallyas–Braak silver stain; tau, AT8 immunohistochemistry. a) The severity of argyrophilic or tau-positive threads was indicated only in anatomical regions recommended in the pathological criteria for PSP [2]: −, none; +, low density; ++, high density. b) The severity of argyrophilic grains in the anterior portion of the superior temporal gyrus is indicated.
α-synuclein pathology, FUS-positive lesions, astrocytic plaques, glial globular inclusions [27], or abnormal PrP accumulations in any region. Infiltration of adenocarcinoma as a thin layer in the subarachnoid space was often noted in the cerebellum. However, there was no solid metastatic tumor or cerebrovascular lesion that could be associated with motor disturbance. 5. Discussion The most prominent and solitary clinical feature in the present case was slowly progressive and symmetric upper motor neuron syndrome characterized by dysarthria and spastic gait, a clinical picture that was consistent with that in PLS. Parkinsonism, gaze palsy, falls, aphasia, and dementia were not noted during the course. However, pathological examination demonstrated histologic hallmarks of PSP, including tufted astrocytes, NFTs, coiled bodies, and thread-like structures, but not TDP-43 pathology, abnormal FUS accumulation, Bunina body, or Lewy body-like hyaline inclusion in lower motor neurons or motor cortex. The distribution of tau-positive lesions was consistent with that in PSP. However, while tau pathologies, especially glial lesions, were prominent in the motor cortex, tau pathology as well as neuronal loss in the basal ganglia and brain stem nuclei were far milder than those observed in typical PSP cases. Consistent with the distribution of these tau pathologies, fibrillary gliosis was evident in the motor cortex and adjacent white matter and corticospinal tract. Except for concomitant argyrophilic grains, no pathological change
suggesting other neurodegenerative diseases, such as corticobasal degeneration, prion disease, Lewy body disease, or Alzheimer's disease, was noted. Based on these findings, the present case was pathologically diagnosed as PSP with argyrophilic grain disease, and the progressive upper motor neuron syndrome observed in this case was well consistent with the topographical distribution of tau pathology. To our knowledge, this is the first pathologically-confirmed PSP case that presented clinically as PLS but lacked any typical symptom of PSP, such as parkinsonism, vertical gaze palsy, or early falls, throughout the course. Historically, it has been considered that PSP is clinically characterized by L-dopa-unresponsive symmetric axial rigidity, dystonic posture of the neck, vertical gaze palsy, dysarthria, dysphasia, gait disturbance with a variable degree of ataxic quality, and falls. However, recently, it is considered that a significant proportion of PSP cases show atypical clinical presentations, and that the clinical variability may be associated with the topographical distribution of tau pathology. Atypical clinical variants reported previously include PSP with L-dopa responsive parkinsonism (PSP–parkinsonism: PSP–P), PSP with pure akinesia and gait failure (PSP–PAGF), PSP with frontotemporal dementia (PSP–FTD), PSP with corticobasal syndrome (PSP–CBS), and PSP with progressive non-fluent aphasia or apraxia of speech (PSP–PNFA, PSP–AOS) [4–6]. Cases of PSP–FTD [8], PSP–CBS [7,9,10], PSP–PNFA, and PSP–AOS [28] tend to have more severe tau pathology in the cerebral cortex than typical PSP [4,7–10]; therefore, some researchers called these cases cortical predominant atypical variants of PSP [4]. Likewise,
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Fig. 2. (a, b) Severe fibrillary gliosis is found in the white matter in the superior frontal gyrus and motor cortex demonstrated by Holzer stain' (arrowheads). In these cortices, fibrillary astrocytes are often seen (b, inset). The sites showing gliosis in the frontal lobe are almost consistent with those with the narrowing of the cortical ribbon shown in Fig. 1. (c, d, e, f) Argyrophilic tufted astrocytes in the motor cortex. Gallyas–Braak silver stain. (g, h, i) Many tau-positive tufted astrocytes in the motor cortex revealed by AT8 immunohistochemistry. Labeled glial inclusions often surrounded vessel walls in the cerebral cortex (g). Scale bars = (a, b) 1 cm, (b inset) 100 μm, (c, d, e, f, i) 20 μm, (g, h) 100 μm.
the term brain stem-predominant atypical PSP is used to refer to PSP–P and PSP–PAGF [4]. In general, tau-positive lesions in the cerebral cortex in PSP cases tend to be severe in the dorsal portion of the frontoparietal lobe, and this topographical feature may be associated with the occurrence of variable focal cortical dysfunctions. Our PSP case had clinical and pathological features commonly observed in cortical predominant variants, such as relatively severe tau pathology in the cerebral cortex, a distinct clinical presentation that can be explained by the distribution of cortical tau pathology, and minimal tau pathology and neuronal loss in the basal ganglia and brain stem nuclei. Therefore, we considered that our case may be classified as cortical predominant atypical PSP. However, this case did not fall into any of the variants reported previously due to the absence of parkinsonism, gait freezing, asymmetric
motor disturbance, aphasia, speech apraxia, personality change, or dementia. Our case seems to be clinically similar to cases reported as ‘atypical PSP with corticospinal tract degeneration’ by Josephs et al. [29]. They reported 12 PSP cases having pathological evidence of corticospinal tract degeneration, and 11 (92%) showed an upper motor neuron pattern of weakness, spasticity, hyperactive tendon reflexes, or Babinski sign. However, they also noted that, except for one case in which detailed data were not available, extrapyramidal signs (e.g., rigidity, bradykinesia, postural instability, and/or facial hypomimia) were also observed in all of the 11 cases with upper motor neuron findings during the course. The initial symptoms in these cases included fall (n= 2), difficulty with right or left hand or leg movements (n= 6), slowness of
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Fig. 3. (a, b, c) The pyramidal tract at the level of the medulla oblongata. (a) Loss of myelin is noted. Klüver–Barrera stain. (b) Severe fibrillary gliosis demonstrated by Holzer's stain. (c) CD68 immunohistochemistry did not demonstrate an increase of labeled cells in the pyramidal tract. (d) Motor neurons in the hypoglossal nuclei were preserved in number, and no gliosis was found. (e) Pigmented neurons in the substantia nigra were spared in number, and gliosis was not found. (f) A small number of argyrophilic threads scattered in the putamen. (g, h) A small number of argyrophilic tufted astrocytes noted in the caudate nucleus (g) and putamen (h). (i) Many argyrophilic grains in the ambient gyrus. (j) An argyrophilic NFT in the subthalamic nucleus. (k, l) Tau-positive NFTs in the globus pallidus (k) and inferior olivary nucleus (l). (m) A phosphorylated neurofilament-positive ballooned neuron in the amygdala. (n) A TDP-43-positive neuronal cytoplasmic inclusion in the entorhinal cortex. Scale bars = (a, b, c) 1 mm, (d) 250 μm, (e) 100 μm, (f) 50 μm, (g, h) 20 μm, (i) 50 μm , (j, k, l) 10 μm, (m, n) 20 μm. (a) Klüver–Barrera stain, (b) Holzer stain', (c) CD68 immunohistochemistry, (d, e) hematoxylin–eosin stain, (f, g, h, I, j) Gallyas–Braak silver stain, (k, l) AT8 immunohistochemistry, (m) SMI31 immunohistochemistry, (n) TDP-43 immunohistochemistry.
movement (n = 1), cognitive impairment (n = 2), light sensitivity (n = 1), and/or aphasia (n = 1). Nine of the 12 cases showed asymmetric motor disturbance. As noted by Josephs et al. [29], these clinical features (i.e., the presence of parkinsonism and asymmetric motor disturbance) were not consistent with the clinical picture of pure PLS without any complication [30], like the clinical picture of the present case [12,31]. Previously, the term PSP with primary lateral sclerosis (PSP–PLS) was used to refer to such cases showing not only pyramidal signs but also parkinsonism [4,29,32]. However, considering that upper motor neuron signs can be observed in some cases of PSP with various clinical variants, such as PSP–FTD [8], PSP–CBS [9], and PSP–PNFA [33], it might be more appropriate to use the term PSP–PLS to refer to PSP cases that exhibit only upper motor neuron syndrome. Nevertheless, it is noteworthy that both our case and the cases reported by Josephs et al. shared several distinct pathological features: relatively mild tau pathology in the basal ganglia and brain stem nuclei and rare Gallyas-positive tufted astrocytes. Although circumscribed cortical atrophy in the dorsal portion of the frontal cortex including the motor cortex was often
observed in Josephs et al.'s cases, our case had non-circumscribed mild frontal atrophy. These findings led us to consider that the clinical picture observed in our case might be one of the clinical presentations that can develop when PSP pathology is extremely restricted in distribution throughout the course. Available clinicopathological data regarding the involvement of pyramidal tract in PSP cases are very limited. In several PSP autopsy series, various frequencies of pyramidal signs were reported, ranging 14% to 70% [34–37]. It was reported that the frequency of pyramidal signs was 15.6% in PSP–P, and 17.0% in typical PSP [37]. Although the frequency of pyramidal signs by each clinical variant is unclear, pyramidal signs were also reported to be observed in cases of several cortical predominant variants of PSP, such as PSP–FTD [8], PSP–CBS [10], or PSP–PNFA [28]. As far as we know, the frequency of such atypical cases showing only progressive upper motor neuron syndrome in all cases of pathologically-confirmed PSP is unclear, and there are also no data regarding the frequency of pathological PSP cases in patients who presented clinically with PLS. Dickson et al. [4] suggested that, because some PSP–CBS cases have tau pathology
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that is rather sharply circumscribed in the motor cortex, the degeneration of the corticospinal tract in PSP cases may be Wallerian degeneration [4]. Considering the distribution of tau pathology, it is likely that pyramidal signs are more frequent in cortical-predominant variants than in brain stem-predominant variants; however, this view should be confirmed by further clinicopathological studies. In conclusion, the present case suggests that progressive upper motor neuron syndrome can develop as a solitary symptom in patients having pathological features of PSP. Clinicians should be aware that, although probably rare, PSP is one of the histological bases in patients showing PLS. For more precise prediction of underlying pathologies in patients with upper motor neuron syndrome, further accumulation of clinicopathological findings, as well as development of biomarkers, is awaited. Conflict of interest None of the authors have any conflict of interest. Acknowledgment We would like to thank Ms. Onbe (Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences) for her excellent technical assistance. Brain tissues were obtained from the Research Resource Network, which is supported by a research grant from the Neurological and Mental Disorders from the Ministry of Health, Labour and Welfare, Japan. This work was supported in part by grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology (No. 21591517, No. 23591708), and the Zikei Institute of Psychiatry. References [1] Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch Neurol 1964;10: 333-59. [2] Hauw JJ, Daniel SE, Dickson D, Horoupian DS, Jellinger K, Lantos PL. Preliminary NINDS neuropathologic criteria for Steele–Richardson–Olszewski syndrome (progressive supranuclear palsy). Neurology 1994;44:2015-9. [3] Arai T, Ikeda K, Akiyama H, Shikamoto Y, Tsuchiya K, Yagishita S, et al. Distinct isoforms of tau aggregated in neurons and glial cells in brains of patients with Pick's disease, corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol 2001;101:167-73. [4] Dickson DW, Ahmed Z, Algom AA, Tsuboi Y, Josephs KA. Neuropathology of variants of progressive supranuclear palsy. Curr Opin Neurol 2010;23:394-400. [5] Williams DR, Holton JL, Strand C, Pittman A, de Silva R, Lees AJ, et al. Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson's syndrome. Brain 2007;130:1566-76. [6] Williams DR, Lees AJ. Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges. Lancet Neurol 2009;8:270-9. [7] Bergeron C, Pollanen MS, Weyer L, Lang AE. Cortical degeneration in progressive supranuclear palsy. A comparison with cortical-basal ganglionic degeneration. J Neuropathol Exp Neurol 1997;56:726-34. [8] Bigio EH, Vono MB, Satumtira S, Adamson J, Sontag E, Hynan LS, et al. Cortical synapse loss in progressive supranuclear palsy. J Neuropathol Exp Neurol 2001;60:403-10. [9] Oide T, Ohara S, Yazawa M, Inoue K, Itoh N, Tokuda T, et al. Progressive supranuclear palsy with asymmetric tau pathology presenting with unilateral limb dystonia. Acta Neuropathol 2002;104:209-14. [10] Tsuboi Y, Josephs KA, Boeve BF, Litvan I, Caselli RJ, Caviness JN, et al. Increased tau burden in the cortices of progressive supranuclear palsy presenting with corticobasal syndrome. Mov Disord 2005;20:982-8. [11] Erb WH. Über einen wenig bekannten spinalen Symptomenkomplex. Klin Wochenschr 1875;12:357-9. [12] Pringle CE, Hudson AJ, Munoz DG, Kiernan JA, Brown WF, Ebers GC. Primary lateral sclerosis. Clinical features, neuropathology and diagnostic criteria. Brain 1992;115: 495-520.
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Progressive supranuclear palsy presenting as primary lateral sclerosis but lacking parkinsonism, gaze palsy, aphasia, or dementia Shigeto Nagao a, b, Osamu Yokota b,⁎, Reiko Nanba c, Hiroshi Takata d, Takashi Haraguchi a, Hideki Ishizu e, Chikako Ikeda b, Naoya Takeda b, Etsuko Oshima b, Katsuaki Sakane b, Seishi Terada b, Yuetsu Ihara a, Yosuke Uchitomi b a
Department of Neurology, National Hospital Organization Minami-Okayama Medical Center, Hayashima, Japan Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan c Nanba Clinic of Neurology, Hayashima, Japan d Department of Neurology, Kinashi Obayashi Hospital, Takamatsu, Japan e Department of Laboratory Medicine and Pathology, Zikei Institute of Psychiatry, Okayama, Japan b
a r t i c l e
i n f o
Article history: Received 27 June 2012 Received in revised form 10 September 2012 Accepted 11 September 2012 Available online 29 September 2012 Keywords: Motor neuron disease Primary lateral sclerosis Progressive supranuclear palsy Pseudobulbar palsy Pyramidal signs
a b s t r a c t We report an autopsy case of progressive supranuclear palsy (PSP) that clinically showed only slowly progressive and symmetric upper motor neuron syndrome over a disease course of 12 years. A female patient initially exhibited dysarthria at the age of 65, followed by gait disturbance and dysphagia. Neurological examination at age 67 disclosed pseudobulbar palsy, spastic gait, hyperreflexia, and presence of bilateral Hoffmann and Babinski signs. However, muscle atrophy, weakness, evidence of denervation on electromyography, vertical gaze palsy, parkinsonism, gait freezing, aphasia, speech apraxia, or dementia was not noted throughout the course. She was clinically diagnosed as having motor neuron disease consistent with so-called primary lateral sclerosis. Pathological examination disclosed histopathological features of PSP, including argyrophilic and tau-positive tufted astrocytes, neurofibrillary tangles, coiled bodies, and thread-like processes in the motor cortex and superior frontal gyrus, and to a lesser degree, in the basal ganglia and brain stem nuclei. In addition, severe fibrillary gliosis was noted in the precentral gyrus and corticospinal tract, being consistent with upper motor neuron syndrome observed in this case. No TAR-DNA binding protein 43-positive lesion, FUS pathology, Bunina body, or Lewy body-like hyaline inclusion was noted in the motor cortex or lower motor neurons. These findings suggest that when tau pathology is prominent in the motor cortex but is minimal in the basal ganglia and brain stem nuclei, a PSP case can lack all classic clinical features of PSP and show only slowly progressive upper motor syndrome, consistent with clinical picture of primary lateral sclerosis. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Progressive supranuclear palsy (PSP) is one of the tauopathies that is clinically characterized by dystonic posturing of the neck and axial rigidity, vertical gaze palsy, postural instability, gait disturbance with an ataxic quality, early falls, dysarthria, dysphasia, and poor L-dopa response [1]. Pathological hallmarks of PSP are argyrophilic neuronal and glial inclusions, including neurofibrillary tangles (NFTs), threads, tufted astrocytes, and coiled bodies, which develop mainly in the basal ganglia, brain stem nuclei, and frontal cortex. Although the pathological diagnosis of PSP is based on the topographical distribution and severity of NFTs and threads [2], presence of tufted astrocytes is also considered to have diagnostic value. In these neuronal and glial inclusions, four-repeat (4R) rather ⁎ Corresponding author at: Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700‐ 8558, Japan. Tel.: +81 86 235 7242; fax: +81 86 235 7246. E-mail address: [email protected] (O. Yokota). 0022-510X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2012.09.005
than three-repeat (3R) tau is more predominantly accumulated [3]. Recent clinicopathological studies have demonstrated that clinical presentation of PSP may not be as uniform as previously believed, and some cases can show L-dopa-responsive parkinsonism, pure akinesia with gait failure, frontotemporal dementia, corticobasal syndrome, progressive non-fluent aphasia, or speech apraxia [4–6]. It is considered that the variability in the clinical presentation in PSP is associated with the topographical distribution of tau pathology and synaptic loss [4,7–10]. Primary lateral sclerosis (PLS) is a rare clinical syndrome that was first proposed by Erb in 1875 [11]. The clinical picture of PLS is characterized by progressive involvement of upper motor neurons, which frequently occurs in the lower extremities [12]. Pathological features of PLS are neuronal loss in the precentral gyrus with corticospinal tract degeneration and preservation of the lower motor neurons. On the other hand, it was also reported that ubiquitin-positive neuronal cytoplasmic inclusions [13,14], TAR DNA-binding protein of 43 kDa (TDP-43)-positive inclusions [15], and Bunina bodies can be also found in the lower motor neurons as well as in the precentral gyrus
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in some clinically PLS cases [16–19]. Based on these findings, it is considered that at least some of the PLS cases may be a clinicopathological subtype of amyotrophic lateral sclerosis. However, as far as we know, fewer than ten autopsy cases of PLS showed only upper motor neuron findings and lacked other symptoms (e.g. parkinsonism, dementia) [12,20–22], and the detailed pathological bases in patients who present clinically with PLS remain unclear. We here present an autopsy case that clinically exhibited only progressive upper motor neuron signs throughout the clinical course, which is consistent with the clinical picture of PLS. However, unexpectedly, this case lacked TDP-43 or fused in sarcoma (FUS) pathology in the frontal cortex or lower motor neurons. Instead, argyrophilic and tau-positive neuronal and glial inclusions were found in the motor cortex, and, to a lesser degree, in the basal ganglia and brain stem nuclei. The morphological, topographical, and immunohistochemical features of the tau pathology were consistent with those observed in PSP, although its severity in the basal ganglia and brain stem nuclei was far milder than that in PSP cases showing typical clinical features. 2. Case report The patient was a 77-year-old Japanese woman at the time of death. She had no personal or family history of neurological or psychiatric disorders. She initially noticed speech difficulty at the age of 65 years. She developed gait difficulty at age 66, and difficulty in swallowing water at age 67. Neurological examination at this time at the department of neurology of a national hospital disclosed pseudobulbar palsy including attenuation of the palatal reflex, dysarthria, and dysphagia. She also showed hyperreflexia and spasticity predominantly affecting the lower extremities. Her gait was disturbed by spasticity. Jaw jerk was brisk. Hoffmann and Babinski signs were bilaterally positive. On the other hand, there was no muscle weakness, atrophy, or fasciculation in the tongue and four extremities. In addition, gaze palsy, rigidity in the neck or extremities, tremor, bradykinesia, postural instability, fall, gait freezing, asymmetric motor disturbance, aphasia, speech apraxia, personality change, and dementia were absent. Sensory disturbance or cerebellar sign was not seen. Electromyography revealed no active or chronic denervation in any four limbs or in masseter muscle. Magnetic resonance imaging did not reveal any abnormal finding that might be associated with dysarthria or gait disturbance. The progression of her neurological disturbances was very slow, and weakness in all four extremities was only mild during the course. Until five months before her death, she could walk shufflingly using crutches, and was able to eat pureed food just before death. Six months before her death, she showed a decrease in appetite, and endoscopy revealed gastric cancer. She died of gastric cancer at age 77 after a clinical course of 12 years. Vertical gaze palsy, parkinsonism, intellectual impairment, or psychiatric change was absent throughout the course. Her neurological symptoms could not be explained by paraneoplastic syndrome because the disease duration before gastric cancer was revealed was over 10 years. Due to the presence of upper motor neuron signs during the long course, the absence of lower motor neuron signs including electromyography, and the exclusion of other diseases by neuroimaging, final neurological diagnosis was motor neuron disease consistent with so-called primary lateral sclerosis. 3. Materials and methods 3.1. Conventional neuropathological examination Brain tissue samples were fixed post mortem with 10% formaldehyde and embedded in paraffin. Ten-μm-thick sections from the frontal, temporal, parietal, occipital, insular, and cingulate cortices, hippocampus, amygdala, basal ganglia, midbrain, pons, medulla oblongata, and cerebellum were prepared. The spinal cord was not available. These sections were stained by hematoxylin–eosin (H&E), Klüver–Barrera, Holzer, Gallyas–Braak silver, and modified Bielschowsky silver methods. Autopsy
was carried out after informed consent was obtained from the family members, and all experiments in this study were approved by the ethical committees of the National Hospital Organization Minami-Okayama Medical Center and the Okayama University Graduate School of Medicine and Dentistry. 3.2. Immunohistochemistry Sections were immunostained by immunoperoxidase method using 3′3-diaminobenzidine tetrahydrochloride. Antibodies used were against phosphorylated tau (AT8, mouse, monoclonal, 1:3000, Innogenetics, Ghent, Belgium), 3R tau (RD3, mouse, monoclonal, 1:3000, Upstate Labs, Syracuse, NY) [23], 4R tau (RD4, mouse, monoclonal, 1:200, Upstate) [23], Aβ (11–28) (mouse, monoclonal, 1:4000, IBL, Fujioka, Japan), Aβ42 (Aβ42, rabbit, polyclonal, 1:100, IBL, Fujioka, Japan), phosphorylated α-synuclein (psyn#64, mouse, monoclonal, 1:1000, Wako Co. Ltd., Osaka, Japan), phosphorylated TDP-43 (pS409/ 410-2, rabbit, polyclonal, 1:5000, Cosmo Bio, Tokyo, Japan), phosphorylated neurofilament (SMI31, mouse, monoclonal, 1:1000, Sternberger, Lutherville, MD, USA), FUS (HPA008784, rabbit, polyclonal, 1:200, Sigma-Aldrich, St. Louis, MO, USA), glial fibrillary acidic protein (GFAP, rabbit, polyclonal, 1:5000, Dako, Glostrup, Denmark), CD68 (CD68 [KP1], monoclonal, mouse, 1:250, Dako, Glostrup, Denmark), and 3F4 (3F4, mouse monoclonal, Covance, San Diego, CA). When using anti-Aβ antibodies, the sections were pretreated with 70% formic acid for 10 min for antigen retrieval. When using psyn#64, pS409/410-2, GFAP, CD68, and HPA008784, the sections were pretreated with pressure cooker for 3 min. When using RD4, the sections were pretreated with 70% formic acid for 5 min and autoclaved for 10 min in 10 mM sodium citrate buffer at 121 °C. When using RD3, the sections were autoclaved, but not pretreated with formic acid. For PrP immunohistochemistry, deparaffinized sections were pretreated by hydrolytic autoclaving in 1.5 mM HCl at 121 °C for 10 min. 3.3. Semiquantitative assessment of histopathological lesions Neuronal loss associated with gliosis in the cerebral cortex was assessed on H&E- and Klüver–Barrera-stained sections according to the grading system used previously [24]: −, no histopathological alteration; +, slight neuronal loss and gliosis only in the superficial layers; ++, obvious neuronal loss and gliosis in the cortical layers II and III, often accompanied by status spongiosis and relative preservation of neurons in layers V and VI; +++, pronounced neuronal loss with gliosis in all cortical layers, and prominent fibrillary gliosis in adjacent subcortical white matter. The degree of neuronal loss and gliosis in the basal ganglia and brainstem nuclei was also assessed as follows [24]: −, no histopathological alteration; ±, mild gliosis, but neurons reduced in number; +, mild gliosis and neuronal loss; ++, moderate neuronal loss and gliosis, but no tissue rarefaction; +++, severe neuronal loss, severe gliosis, and tissue rarefaction. Degeneration of the corticospinal tract and frontopontine tract at the levels of the cerebral peduncle and medulla oblongata was indicated as follows [24]: −, no degeneration; +, mild degeneration with slight myelin loss and gliosis without atrophy of the tract; ++, moderate degeneration with evident myelin loss and gliosis with slight atrophy of the tract; +++, severe degeneration with evident myelin loss, gliosis, and severe atrophy of the tract. NFTs and tufted astrocytes were semiquantitatively evaluated with the following staging system using the Gallyas–Braak silver method and AT8 immunohistochemistry, respectively: −, no lesion; +, one inclusion in each anatomical region; ++, 2 or more inclusions in each anatomical region but less than one inclusion per × 200 visual field; +++, one inclusion per × 200 visual field; ++++, 2 to 10 inclusions per × 200 visual field; +++++, 11 or more inclusions per × 200 visual field. The threads were semiquantitatively assessed only in the regions recommended in the pathological criteria for PSP [2] on Gallyas–Braak
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silver-stained sections in a ×200 field as follows: −, none; +, low density; ++, high density. Argyrophilic grains were semiquantitatively assessed on Gallyas–Braak silver stained sections in a ×400 field as: −, no lesion; ±, 10 to 20; +, 20 to 50; ++, 50 to 100; +++, >100. 4. Results 4.1. Neuropathological findings The brain weighed 1042 g after fixation. Macroscopically, the frontal lobe was atrophic (Fig. 1a). The precentral gyrus was also mildly atrophic. The temporal lobe was relatively well spared. On coronal sections, thinning of the cerebral cortex in the motor cortex and superior frontal gyrus was noted (Fig. 1b and c). The hippocampus, amygdala, striatum, thalamus, subthalamic nucleus, tegmentum of the midbrain, pyramidal tract, and cerebellum were unremarkable. The substantia nigra and locus coeruleus were well pigmented (Fig. 1d). Microscopic examination disclosed tau-positive neuronal and glial inclusions with mild neuronal loss in the cerebral cortex, basal ganglia, and brain stem nuclei. The distribution and severity of these changes are shown in Table 1. On H&E and Klüver–Barrera-stained sections, neuronal loss in the frontal cortex was not evident. However, Holzer's stain demonstrated evident fibrillary gliosis in the precentral gyrus and superior frontal gyrus (Fig. 2a,b, and b inset). In the amygdala, although neuronal loss was mild, a few ballooned neurons immunopositive for phosphorylated neurofilament antibody were scattered (Fig. 3m). In the striatum, globus pallidus, thalamus, subthalamic nucleus, and nucleus basalis of Meynert, neuronal loss with gliosis was absent or minimal. Likewise, neuronal loss was not observed in the substantia nigra (Fig. 3e), oculomotor nucleus, pontine nucleus, hypoglossal nucleus (Fig. 3d), inferior olivary nucleus, or dentate nucleus in the cerebellum. In contrast, the pyramidal tract at the level of the medulla oblongata showed myelin pallor (Fig. 3a) with glial proliferation. In this region, Holzer's stain demonstrated severe fibrillary gliosis (Fig. 3b), while neither GFAP nor CD68 immunohistochemistry revealed an evident increase of the number of positive cells (Fig. 3c). The Gallyas–Braak silver method demonstrated argyrophilic glial lesions morphologically consistent with tufted astrocytes. They were most frequently observed in the motor cortex and superior frontal gyrus (Table 1, Fig. 2c,d,e,f). A few tufted astrocytes were also noted in the caudate nucleus and putamen (Fig. 3g and h). No tufted astrocyte was found in the other regions. A small number of NFTs were noted in the entorhinal cortex and hippocampal CA1, but were hardly seen in the temporal cortex, a distribution that corresponded to Braak NFT stage II. NFTs, threads, and coiled bodies were more frequently found in the frontal cortex including the motor cortex, subthalamic nucleus, and substantia nigra, and to a lesser frequency, in the striatum (Table 1, Fig. 3f and j). No argyrophilic lesion was found in the pontine nucleus, inferior olivary nucleus, or dentate nucleus in the cerebellum. Moderate numbers of argyrophilic grains, corresponding to Saito's stage II [25], were noted in the limbic region and adjacent temporal cortex (Table 1, Fig. 3i). An astrocytic plaque was not noted in any anatomical region. AT8 immunohistochemistry demonstrated tau-positive NFTs, threads, tufted astrocytes, and coiled bodies with more extensive distribution than that of argyrophilic lesions on Gallyas–Braak silver-stained sections (Table 1). Tufted astrocytes were most frequently noted in the motor cortex (Fig. 2g,h,i), and to a lesser frequency, in the caudate nucleus, putamen, globus pallidus, and subthalamic nucleus (Fig. 3k). The number of tufted astrocytes in the motor cortex demonstrated by tau immunohistochemistry was evidently larger than that demonstrated by the Gallyas–Braak silver method (Table 1). These tau pathologies were immunolabeled with RD4 rather than RD3 antibody, suggesting that this case had four-repeat tauopathies, including PSP. A few tau-positive neuronal and glial inclusions were also noted in the
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substantia nigra, pontine nucleus, inferior olivary nucleus, and dentate nucleus in the cerebellum (Fig. 3l). Like the Gallyas–Braak silver stain, tau immunohistochemistry did not demonstrate astrocytic plaques in any region. The quantity and distribution of tau-positive NFTs and threads fit the pathological diagnostic criteria of PSP [2], although those of argyrophilic lesions on Gallyas–Braak-stained sections were not sufficient for its diagnosis (Table 1). In the amygdala and temporal cortex, tau-positive argyrophilic grains and bush-like astrocytes [26] were seen. In this case, a few TDP-43-positive neuronal cytoplasmic inclusions and dystrophic neurites were also found in the amygdala and entorhinal cortex (Fig. 3n). However, no TDP-43-positive lesion was found in other regions, including the frontal and temporal cortices or motor neurons in the hypoglossal nuclei. Neither Bunina body nor Lewy body-like hyaline inclusion was noted. There were no Aβ deposits, Pick bodies,
Fig. 1. (a) Atrophy is noted in the frontal lobe. The precentral gyrus is also mildly atrophic. (b, c) On coronal sections, narrowing of the cortical ribbon in the superior frontal gyrus and motor cortex is noted (arrowheads). (d) The tegmentum of the midbrain and pons is not atrophic. The substantia nigra and locus coeruleus are well pigmented. All scale bars = 2 cm.
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Table 1 Distribution of pathological changes in the present case.
Superior frontal gyrus Middle frontal gyrus Inferior frontal gyrus Motor cortex Superior temporal gyrus Middle temporal gyrus Inferior temporal gyrus Cingulate cortex Insular cortex Hippocampal CA1 and subiculum Parahippocampal gyrus Amygdala Ambient gyrus Caudate nucleus Putamen Globus pallidus Thalamus Nucleus basalis of Meynert Subthalamic nucleus Oculomotor nucleus Substantia nigra Locus coeruleus Pontine nucleus Hypoglossal nucleus Dorsal vagal nucleus Inferior olivary nucleus Corticospinal tract At level of cerebral peduncle At level of medulla oblongata Cerebellum Dentate nucleus Cerebellar cortex
Neuronal loss with gliosis
Tufted astrocytes
Neurofibrillary tangles (/threads)a)
(H&E)
(AT8)
(GB)
(AT8)
(GB)
(GB)
+ − − + − − − − + − − + − − − + − − − − − − − − − −
+++ − ++ ++++ ++ + ++ − + − − − − ++ ++ ++ + + + + − − + − − −
+ − − ++ − − − − − − − − − + ++ − − − − − − − − − − −
+++ +++ ++ ++++ +++ ++++ +++++ ++++ ++++ +++++ +++++ +++++ ++++ +/+ −/+ ++/+ ++ ++++ +++/+ +/− ++/+ ++++ ++/+ − − +/−
++ ++ − +++ − − ++ +++ ++ +++++ ++++ +++ ++ −/+ −/+ −/− + ++ +++/− −/− ++/+ ++++ −/− − − −/−
− − − − ++b) + +++ ± + +++ + +++ +++ − − − − − − − − − − − − −
− ++
− −
− −
− −
− −
− −
− −
− −
− −
+++/+ −
−/− −
− −
Argyrophilic grains
Neuronal loss associated with gliosis: −, absent; +, slight neuronal loss with gliosis; ++, moderate neuronal loss with gliosis; +++, severe neuronal loss and gliosis with tissue rarefaction [24]. NFTs and tufted astrocytes were semiquantitatively evaluated using Gallyas–Braak silver stain and AT8 immunohistochemistry as follows, respectively: −, no lesion, +, one inclusion in each anatomical region, ++, 2 or more inclusions in each anatomical region but less than one inclusion per ×200 visual field; +++, one inclusion per ×200 visual field; ++++, 2 to 10 inclusions per ×200 visual field; +++++, 11 or more inclusions per ×200 visual field. Argyrophilic grains were semiquantitatively assessed on Gallyas–Braak-stained sections in a ×400 field as follows: −, no lesion, ±10 to 20; +, 20 to 50; ++, 50 to 100; +++, >100. H&E, hematoxylin–eosin; GB, Gallyas–Braak silver stain; tau, AT8 immunohistochemistry. a) The severity of argyrophilic or tau-positive threads was indicated only in anatomical regions recommended in the pathological criteria for PSP [2]: −, none; +, low density; ++, high density. b) The severity of argyrophilic grains in the anterior portion of the superior temporal gyrus is indicated.
α-synuclein pathology, FUS-positive lesions, astrocytic plaques, glial globular inclusions [27], or abnormal PrP accumulations in any region. Infiltration of adenocarcinoma as a thin layer in the subarachnoid space was often noted in the cerebellum. However, there was no solid metastatic tumor or cerebrovascular lesion that could be associated with motor disturbance. 5. Discussion The most prominent and solitary clinical feature in the present case was slowly progressive and symmetric upper motor neuron syndrome characterized by dysarthria and spastic gait, a clinical picture that was consistent with that in PLS. Parkinsonism, gaze palsy, falls, aphasia, and dementia were not noted during the course. However, pathological examination demonstrated histologic hallmarks of PSP, including tufted astrocytes, NFTs, coiled bodies, and thread-like structures, but not TDP-43 pathology, abnormal FUS accumulation, Bunina body, or Lewy body-like hyaline inclusion in lower motor neurons or motor cortex. The distribution of tau-positive lesions was consistent with that in PSP. However, while tau pathologies, especially glial lesions, were prominent in the motor cortex, tau pathology as well as neuronal loss in the basal ganglia and brain stem nuclei were far milder than those observed in typical PSP cases. Consistent with the distribution of these tau pathologies, fibrillary gliosis was evident in the motor cortex and adjacent white matter and corticospinal tract. Except for concomitant argyrophilic grains, no pathological change
suggesting other neurodegenerative diseases, such as corticobasal degeneration, prion disease, Lewy body disease, or Alzheimer's disease, was noted. Based on these findings, the present case was pathologically diagnosed as PSP with argyrophilic grain disease, and the progressive upper motor neuron syndrome observed in this case was well consistent with the topographical distribution of tau pathology. To our knowledge, this is the first pathologically-confirmed PSP case that presented clinically as PLS but lacked any typical symptom of PSP, such as parkinsonism, vertical gaze palsy, or early falls, throughout the course. Historically, it has been considered that PSP is clinically characterized by L-dopa-unresponsive symmetric axial rigidity, dystonic posture of the neck, vertical gaze palsy, dysarthria, dysphasia, gait disturbance with a variable degree of ataxic quality, and falls. However, recently, it is considered that a significant proportion of PSP cases show atypical clinical presentations, and that the clinical variability may be associated with the topographical distribution of tau pathology. Atypical clinical variants reported previously include PSP with L-dopa responsive parkinsonism (PSP–parkinsonism: PSP–P), PSP with pure akinesia and gait failure (PSP–PAGF), PSP with frontotemporal dementia (PSP–FTD), PSP with corticobasal syndrome (PSP–CBS), and PSP with progressive non-fluent aphasia or apraxia of speech (PSP–PNFA, PSP–AOS) [4–6]. Cases of PSP–FTD [8], PSP–CBS [7,9,10], PSP–PNFA, and PSP–AOS [28] tend to have more severe tau pathology in the cerebral cortex than typical PSP [4,7–10]; therefore, some researchers called these cases cortical predominant atypical variants of PSP [4]. Likewise,
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Fig. 2. (a, b) Severe fibrillary gliosis is found in the white matter in the superior frontal gyrus and motor cortex demonstrated by Holzer stain' (arrowheads). In these cortices, fibrillary astrocytes are often seen (b, inset). The sites showing gliosis in the frontal lobe are almost consistent with those with the narrowing of the cortical ribbon shown in Fig. 1. (c, d, e, f) Argyrophilic tufted astrocytes in the motor cortex. Gallyas–Braak silver stain. (g, h, i) Many tau-positive tufted astrocytes in the motor cortex revealed by AT8 immunohistochemistry. Labeled glial inclusions often surrounded vessel walls in the cerebral cortex (g). Scale bars = (a, b) 1 cm, (b inset) 100 μm, (c, d, e, f, i) 20 μm, (g, h) 100 μm.
the term brain stem-predominant atypical PSP is used to refer to PSP–P and PSP–PAGF [4]. In general, tau-positive lesions in the cerebral cortex in PSP cases tend to be severe in the dorsal portion of the frontoparietal lobe, and this topographical feature may be associated with the occurrence of variable focal cortical dysfunctions. Our PSP case had clinical and pathological features commonly observed in cortical predominant variants, such as relatively severe tau pathology in the cerebral cortex, a distinct clinical presentation that can be explained by the distribution of cortical tau pathology, and minimal tau pathology and neuronal loss in the basal ganglia and brain stem nuclei. Therefore, we considered that our case may be classified as cortical predominant atypical PSP. However, this case did not fall into any of the variants reported previously due to the absence of parkinsonism, gait freezing, asymmetric
motor disturbance, aphasia, speech apraxia, personality change, or dementia. Our case seems to be clinically similar to cases reported as ‘atypical PSP with corticospinal tract degeneration’ by Josephs et al. [29]. They reported 12 PSP cases having pathological evidence of corticospinal tract degeneration, and 11 (92%) showed an upper motor neuron pattern of weakness, spasticity, hyperactive tendon reflexes, or Babinski sign. However, they also noted that, except for one case in which detailed data were not available, extrapyramidal signs (e.g., rigidity, bradykinesia, postural instability, and/or facial hypomimia) were also observed in all of the 11 cases with upper motor neuron findings during the course. The initial symptoms in these cases included fall (n= 2), difficulty with right or left hand or leg movements (n= 6), slowness of
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Fig. 3. (a, b, c) The pyramidal tract at the level of the medulla oblongata. (a) Loss of myelin is noted. Klüver–Barrera stain. (b) Severe fibrillary gliosis demonstrated by Holzer's stain. (c) CD68 immunohistochemistry did not demonstrate an increase of labeled cells in the pyramidal tract. (d) Motor neurons in the hypoglossal nuclei were preserved in number, and no gliosis was found. (e) Pigmented neurons in the substantia nigra were spared in number, and gliosis was not found. (f) A small number of argyrophilic threads scattered in the putamen. (g, h) A small number of argyrophilic tufted astrocytes noted in the caudate nucleus (g) and putamen (h). (i) Many argyrophilic grains in the ambient gyrus. (j) An argyrophilic NFT in the subthalamic nucleus. (k, l) Tau-positive NFTs in the globus pallidus (k) and inferior olivary nucleus (l). (m) A phosphorylated neurofilament-positive ballooned neuron in the amygdala. (n) A TDP-43-positive neuronal cytoplasmic inclusion in the entorhinal cortex. Scale bars = (a, b, c) 1 mm, (d) 250 μm, (e) 100 μm, (f) 50 μm, (g, h) 20 μm, (i) 50 μm , (j, k, l) 10 μm, (m, n) 20 μm. (a) Klüver–Barrera stain, (b) Holzer stain', (c) CD68 immunohistochemistry, (d, e) hematoxylin–eosin stain, (f, g, h, I, j) Gallyas–Braak silver stain, (k, l) AT8 immunohistochemistry, (m) SMI31 immunohistochemistry, (n) TDP-43 immunohistochemistry.
movement (n = 1), cognitive impairment (n = 2), light sensitivity (n = 1), and/or aphasia (n = 1). Nine of the 12 cases showed asymmetric motor disturbance. As noted by Josephs et al. [29], these clinical features (i.e., the presence of parkinsonism and asymmetric motor disturbance) were not consistent with the clinical picture of pure PLS without any complication [30], like the clinical picture of the present case [12,31]. Previously, the term PSP with primary lateral sclerosis (PSP–PLS) was used to refer to such cases showing not only pyramidal signs but also parkinsonism [4,29,32]. However, considering that upper motor neuron signs can be observed in some cases of PSP with various clinical variants, such as PSP–FTD [8], PSP–CBS [9], and PSP–PNFA [33], it might be more appropriate to use the term PSP–PLS to refer to PSP cases that exhibit only upper motor neuron syndrome. Nevertheless, it is noteworthy that both our case and the cases reported by Josephs et al. shared several distinct pathological features: relatively mild tau pathology in the basal ganglia and brain stem nuclei and rare Gallyas-positive tufted astrocytes. Although circumscribed cortical atrophy in the dorsal portion of the frontal cortex including the motor cortex was often
observed in Josephs et al.'s cases, our case had non-circumscribed mild frontal atrophy. These findings led us to consider that the clinical picture observed in our case might be one of the clinical presentations that can develop when PSP pathology is extremely restricted in distribution throughout the course. Available clinicopathological data regarding the involvement of pyramidal tract in PSP cases are very limited. In several PSP autopsy series, various frequencies of pyramidal signs were reported, ranging 14% to 70% [34–37]. It was reported that the frequency of pyramidal signs was 15.6% in PSP–P, and 17.0% in typical PSP [37]. Although the frequency of pyramidal signs by each clinical variant is unclear, pyramidal signs were also reported to be observed in cases of several cortical predominant variants of PSP, such as PSP–FTD [8], PSP–CBS [10], or PSP–PNFA [28]. As far as we know, the frequency of such atypical cases showing only progressive upper motor neuron syndrome in all cases of pathologically-confirmed PSP is unclear, and there are also no data regarding the frequency of pathological PSP cases in patients who presented clinically with PLS. Dickson et al. [4] suggested that, because some PSP–CBS cases have tau pathology
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