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Chorea as a clinical feature of the basophilic inclusion body disease subtype of fused-in-sarcoma-associated frontotemporal lobar degeneration

Chorea as a clinical feature of the basophilic inclusion body disease subtype of... Choreoathetoid involuntary movements are rarely reported in patients with frontotemporal lobar degeneration (FTLD), suggesting their exclusion as a supportive feature in clinical diagnostic criteria for FTLD. Here, we identified three cases of the behavioral variant of frontotemporal dementia (bvFTD) that display chorea with fused in sarcoma (FUS)-positive inclusions (FTLD-FUS) and the basophilic inclusion body disease (BIBD) subtype. We determined the behavioral and cognitive features in this group that were distinct from other FTLD-FUS cases. We also reviewed the clinical records of 72 FTLD cases, and clarified additional clinical features that are predictive of the BIBD pathology. Symptom onset in the three patients with chorea was at 44.0 years of age (±12.0 years), and occurred in the absence of a family history of dementia. The cases were consistent with a clinical form of FTD known as bvFTD, as well as reduced neurological muscle tone in addition to chorea. The three patients showed no or mild parkinsonism, which by contrast, increased substantially in the other FTLD cases until a later stage of disease. The three patients exhibited severe caudate atrophy, which has previously been reported as a histological feature distinguishing FTLD-FUS from FTLD-tau or FTLD-TAR DNA-binding protein 43. Thus, our findings suggest that the clinical feature of choreoathetosis in bvFTD might be associated with FTLD-FUS, and in particular, with the BIBD subtype. Keywords: FTLD-FUS, BIBD, bvFTD, Chorea, Involuntary movement, Parkinsonism Introduction picture in the early disease stage are currently referred Frontotemporal lobar degeneration (FTLD) is a neurode- to as having a behavioral variant of FTD (bvFTD) [3]. generative disease that commonly causes dementia [1]. The neuropathology of FTLD is as complex as the In clinical practice, FTLD is considered a syndrome and clinical syndrome. Virtually all patients with FTLD have is presently classified by the consensus criteria of Neary abnormal intracellular accumulations of disease-specific and colleagues [2] into three subtypes: frontotemporal molecules. These molecules include tau, TAR DNA- dementia (FTD), progressive nonfluent aphasia, and se- binding protein 43 (TDP-43), and fused in sarcoma mantic dementia. Most patients with progressive nonflu- (FUS) [4, 5]. FTLD cases are now assigned to one of ent aphasia and semantic dementia show some features three major molecular subgroups based on histopatho- of FTD (e.g., behavioral symptoms), later on in their dis- logical findings: FTLD-tau, FTLD-TDP, or FTLD-FUS ease course. Those with FTD as the dominant clinical [5]. Before the discovery of TDP-43 in 2006 [6, 7], most cases of tau-negative FTLD were collectively termed FTLD-U because their inclusions were ubiquitin- * Correspondence: kawakami-it@igakuken.or.jp 1 positive. Subsequently, it became apparent that the ma- Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan jority of FTLD-U cases were in fact FTLD-TDP, (i.e., Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital (TMMH), FTLD with TDP-43 inclusions), with 10 to 20 % of Tokyo, Japan FTLD-U cases remaining as tau-negative and TDP-43- Full list of author information is available at the end of the article © 2016 Kawakami et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 2 of 15 negative FTLD. In 2009, FUS was identified as one of Huntington’s disease (HD), an inherited neurodegenera- the genes for familial amyotrophic lateral sclerosis tive disease in which atrophy of the striatum is the pre- (ALS) [8, 9]. Consequently, most tau-negative and dominant pathology. However, the striatum is also TDP-43-negative FTLD inclusions were found to be severely affected in all subtypes of FTLD. The results of FUS positive [10–12]. Accordingly, cases of FTLD a recent report found significantly greater striatal atro- with FUS-positive inclusions are now collectively phy by magnetic resonance imaging (MRI) in FTLD- called FTLD-FUS. Three rare forms of FTLD are con- FUS patients than in FTLD-TDP and FTLD-tau patients, sidered to be subtypes of FTLD-FUS: atypical FTLD- thereby distinguishing FTLD-FUS from other forms of U (aFTLD-U), basophilic inclusion body disease FTLD [16]. (BIBD), and neuronal intermediate filament inclusion Here, we identified three cases of bvFTD with chorea, disease (NIFID) [11]. Although these three subtypes which were diagnosed as FTLD-FUS and exhibit histo- mayrepresent acontinuousspectrumofFTLD-FUS pathological results indicative of the BIBD subtype. We disease, detailed histopathological investigation suggests identified the behavioral and cognitive features that dis- they are closely related but distinct entities [11–13]. tinguish this group from other FTLD-FUS cases. Fur- Several previous reports have challenged these clini- ther, we also reviewed the clinical records of 72 FTLD copathological relationships in FTLD patients. In cases to identify distinct clinical features that are pre- FTLD-FUS, which is present in a minority of FTLD dictive of FTLD-FUS, and in particular the BIBD patients, such relationships have only recently been de- subtype. scribed [12, 14–19]. These studies reveal that FTLD- FUS patients may have a relatively younger onset (often Materials and methods before the age of 40 years), absence of a family history Participants of the disease, and severe caudate atrophy on imaging Seventy-two FTLD cases were registered in the autopsy [16–18]. Recently, Snowden et al. suggested that archives of Dementia Research Project, Tokyo Metropol- aFTLD-U is associated with a cognitive and behavioral itan Institute of Medical Science, Tokyo, Japan. The mo- phenotype that is distinct from the other forms of lecular pathology observed in these cases is summarized FTLD-FUS (specifically, NIFID and BIBD). They noted in Table 1. Briefly, the archives included 29 FTLD-tau, that aFTLD-U is characterized by prominent obsessive- 32 FTLD-TDP, and 10 FTLD-FUS cases, and 1 unclassi- ness, repetitive behaviors and rituals, social withdrawal fiable case. Of these, clinical features corresponding to and lack of engagement, hyperorality with pica, and bvFTD with chorea were identified in three cases. The marked stimulus-bound behavior (e.g., utilization be- pathological diagnosis in these three cases was BIBD. havior). Furthermore, they suggested that clinical pres- Case 1 was extensively analyzed neurologically, neurora- entation of FTLD with associated FUS pathology may diologically and genetically, whereas cases 2 and 3 were not be related to mutation of the FUS gene. Addition- reviewed using their clinical records. ally, a uniform clinical phenotype of BIBD and NIFID has been reported in a few studies [12, 15]. Yokota et al. found that NIFID and BIBD share several clinical features including dysarthria, motor neuron signs, par- Neuropathological examination kinsonism, and memory impairment [15]. They also Brain and spinal cord tissue were fixed in 10 % formalin noted that it is difficult to differentiate BIBD from and embedded in paraffin. Sections (10 μm thick) were NIFID in clinical practice. While these reports indicate cut from the cerebrum, midbrain, pons, medulla oblon- variations in behavioral and cognitive features of gata, cerebellum, and spinal cord. The sections were FTLD-FUS, the features that are distinct from the other stained with hematoxylin and eosin as well as Klüver– forms of FTLD (i.e., FTLD-tau and FTLD-TDP) remain Barrera stain. Immunohistochemistry was performed for to be clarified. tau (AT8, 1:1,000; Thermo Scientific), α-synuclein Patients with FTLD often report associated motor sys- (pSyn#64, 1:1,000; Wako), TDP-43 (409/410, 1:1,000; tem impairments, such as parkinsonism and motor original antibody [22]), FUS protein (HPA008784, neuron disease [2, 20], whereas association of FTLD 1:1,000; Sigma-Aldrich; and A300-302A, 1:500–1,000; with chorea and athetosis has rarely been reported. In Bethyl Laboratories), Ewing sarcoma protein (EWS, the clinical diagnostic criteria for FTLD [2], choreoathe- 1:100; Santa Cruz Biotechnology), and TATA-binding tosis is one of the diagnostic exclusion features. Chorea protein-associated factor 15 (TAF15, 1:50; Bethyl is an abnormal involuntary movement characterized by Laboratories). Primary antibody labelling was visualized excessive, spontaneous movements that are irregularly using 0.2 % 3,3′-diaminobenzidine as the chromogen in timed, nonrepetitive, randomly distributed, and abrupt combination with an Envision Plus kit (Dako Japan, in character [21]. The classical form of chorea occurs in Tokyo), according to the manufacturer’s instructions. Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 3 of 15 Table 1 Molecular pathology of 72 FTLD cases frequency of each clinical feature. Values of P <0.05 were accepted as significant. All statistical analyses were per- Diagnosis No. of patients formed using GraphPad Prism 4 software (GraphPad Soft- FTLD-tau (29) a ware, USA). Statistical significance of the concentration of Pick’s disease 18 involuntary movement in the BIBD subtype was assessed FTDP-17tau 1 by direct calculation of probability under an assumption CBD 4 of independence in all FTLD cases. PSP 4 Unclassifiable 2, [53] Results Clinical findings FTLD-TDP (32) Case 1 Type A 4 The patient was a Japanese woman with a family history Type B 17 of schizophrenia but no dementia or movement disorders. Type C 10 She had been living outside of Japan for several years Unclassifiable 1, [54] when she developed affective incontinence at the age of FTLD-FUS (10) 32. Two years later, she was spending much of the day in bed, and displayed palilalia and hyperphagia of carbohy- BIBD 6 drates such as rice and noodles. She dressed in a provoca- NIFID 2 tive manner and was often arrested for shoplifting, but aFTLD-U 1 showed no remorse. She was initially diagnosed as having Unclassifiable 1, [55] schizophrenia or depressive disorder, and consequently Unclassifiable (1) treated with fluvoxamine and olanzapine for a short dur- CBD corticobasal degeneration, PSP progressive supranuclear palsy, FTDP-17tau ation, as well as with electroconvulsive therapy. However, frontotemporal dementia with parkinsonism linked to chromosome 17 she was unresponsive to these therapies and they were dis- associated with tau pathology, BIBD basophilic inclusion body disease, NIFID continued. At the age of 36, she returned to Japan and was neuronal intermediate filament inclusion disease; aFTLD-U atypical FTLD with ubiquitinated inclusions admitted to a psychiatric hospital. She presented with Pick’s disease refers to only FTLD-tau with Pick bodies chorea-like involuntary movements of the face, tongue, Cases with CBD and PSP were included only if the patients presented with features of FTLD, such as frontotemporal dementia, semantic dementia and neck, and four extremities. The involuntary movements progressive nonfluent aphasia included frequent jerking of the shoulders, continuous FTLD-TDP cases were classified using the system reported by Mackenzie et al. [56] movement of facial muscles (e.g., lifting the eyebrows, closing the eyes, and thrusting out the tongue), and large Immunoblot analysis amplitude movements of the lower limbs, sometimes with Fresh frozen samples for immunoblot analyses were pre- a violent, flinging or flailing quality, which was regarded as pared as previously described [23, 24]. Briefly, frozen brain ballismus. She also had athetosis-like movements in her frontal cortex tissue was obtained from one case each of right leg. When she wandered the hospital ward, she BIBD (case 1), NIFID (case 8), aFTLD-U (case 9), and a touched and tapped yellow things. Neurological examin- normal control. ation revealed reduced muscle tone, but no muscle weak- Brain tissue was homogenized in 20 volumes (w/v) of ness, atrophy, or other signs of motor neuron disease. Her homogenization buffer (10 mM Tris-HCl, pH 7.4, 0.8 M speech output was reduced, but she recognized some sim- NaCl, 1 mM EGTA, and 10 % sucrose). Homogenates ple words. Her behavior was stereotyped and ritualistic. were incubated at 37 °C for 30 min in homogenization Her blood biochemistry test results were normal, includ- buffer containing 2 % Triton X-100, and centrifuged at ing ceruloplasmin and ferritin levels and tests for syphilis. 20,000 × g for 10 min at room temperature. Supernatants Cerebrospinal fluid concentration of amyloid β-protein, were further ultracentrifuged at 100,000 × g for 20 min. total tau, and phosphorylated tau were normal. Brain MRI After ultracentrifugation, the resulting supernatants and results revealed bilateral progressive atrophy in the frontal pellets were recovered for immunoblotting analysis as and temporal cortices and the caudate nucleus (Fig. 1). Triton X-100 soluble and insoluble fractions, respectively. Hypoperfusion was apparent in these regions by cerebral For immunoblotting, primary antibodies for the FUS pro- blood flow single-photon emission computed tomography. tein were obtained from Sigma-Aldrich (HPA008784) and The results of an electromyographic investigation were Bethyl Laboratories, Inc. (A300-302A). normal. Her Mini-Mental State Examination score was 18/30. She was clinically suspected of having HD because Statistical analysis of her chorea and the severe caudate atrophy apparent on Fisher’s exact probability test was used to determine the MRI imaging. However, she had no repeat expansion in significance of differences in variables, including the the genes causing HD, spinocerebellar ataxia type 17, or Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 4 of 15 Fig. 1 Brain MRI of case 1. a and b Brain magnetic resonance (MR) images of the patient 1 at age 36. Atrophy is present in the frontal and temporal cortices and the caudate nucleus. a and b Brain MR images of the patient taken 1 year after those shown in c and d. The atrophy is more severe and the anterior horn of the lateral ventricles is markedly enlarged. Permission was obtained from the right holder [25] dentatorubral-pallidoluysian atrophy. No mutation was She showed polyphagia and subsequent rapid weight gain. found in the genes for tau, TDP-43, FUS, granulin, amyl- She was admitted to a psychiatric hospital at age 46 because oid precursor protein, presenilin-1, or presenilin-2. Based of purposeless wandering. She presented with reduced on clinical findings, she was diagnosed with bvFTD [2]. speech output, simple language with stereotypies, and per- She took milnacipran hydrochloride (100 mg) for therapy. severation. She spoke only in uncomplicated, short sen- At age 37, 5 years after symptom onset, her speech output tences, but showed no impaired verbal comprehension. was reduced and she had dysphagia. Her gross involuntary Neurological examination revealed continuous and quick movements were less severe, but slow and continuous leg chorea-like involuntary movements in the tongue, but no movements persisted. At that time, neurological examin- muscle atrophy. She was not administered any medication ation showed the presence of primitive reflexes such as before presentation of chorea. HerWechslerAdult sucking, as well as palmomental and strong grasp reflexes Intelligence Scale score was 60 (verbal IQ, 72; performance bilaterally. She was in a persistent vegetative state by the IQ, 55). Her blood biochemistry results were normal, in- age of 38. She exhibited arm contractures, but athetosis- cluding a syphilis test. Disorientation or memory impair- like movements (such as the slow, sinuous, continuous ment were not evident. She showed stereotyped behaviors, flowing external and internal rotation of her right leg) such as repeatedly throwing a lot of toilet paper into the continued until her death. She died of bronchopneumonia toilet. Chorea in her tongue diminished gradually until age at age 39. Her disease duration was 7 years. 47. She died suddenly of suffocation by food during a hos- pital stay. Her disease duration was 3 years. Case 2 The second patient was a 47-year-old Japanese woman. She Case 3 had no family history of behavioral change or dementia. The third patient was a 67-year-old Japanese woman. She presented with indifference and disinhibition at age 44. There was no relevant family history of dementia, but Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 5 of 15 her sister had died of a nonspecific psychiatric disease. athetosis in two cases and ballismus in one. The three At age 56, she began collecting elastic bands and trash, patients lacked parkinsonism signs, even at the later dis- and eating only rice and pickles. At age 58, she was ad- ease stage. In contrast, other FTLD-FUS patients, in- mitted to a psychiatric hospital because she was drinking cluding BIBD cases without chorea, always showed a lot of alcohol and committing criminal acts, such as moderate to severe parkinsonism at the same disease shoplifting. She showed severe impairment of recent stage. Gait disturbance was observed in all patients. memory and disorientation. The results of a neurological Additionally, the three patients showed neither dyspha- examination revealed no abnormalities. Her blood and sia nor upper and lower motor neuron signs, which were urine biochemistry results were normal. Behavioral and noted in some BIBD patients without chorea during the verbal stereotypy developed gradually. At age 60, she disease course. was mute and gradually became bedridden. Contractures in all four extremities were apparent. At age 65, 9 years BIBD compared with all FTLD cases after symptom onset, rapid and small chorea-like invol- The demographic data and major clinical features of all untary movements in her neck, trunk, and four extrem- our archived FTLD cases are summarized in Table 3. ities became apparent and progressively worsened. The prevalence rate of FUS pathology in the FTLD cases Athetosis-like movements were also observed in her left in our cohort was 13.9 %, which is higher than previ- upper extremity. Her chorea-like movements continued ously reported (5 %) [28]. Compared with the other sub- until her death, which was due to cardiac failure at age types of FTLD-FUS, FTLD-TDP, and FTLD-tau, the 67. We were unable to obtain drug history data for this most prominent feature in BIBD patients was chor- case. Her disease duration was 12 years. eoathetoid involuntary movements, with its occurrence converging at BIBD in all FTLD patients (0.0003 < 0.05). Clinical summary of cases No significant differences were noted for the other clin- Demographic data ical features. The clinical features of the three patients with chorea and the other FTLD-FUS cases are summarized in Table 2. Neuropathological findings More detailed clinical descriptions are provided in Japa- The atrophy and degeneration distribution has been de- nese (with English abstracts) for cases 1 [25], 2 [26], and 3 scribed previously for cases 2 and 3 [24, 29]. Here, [27]. The three patients with chorea had no family history Table 4 shows the degree and distribution of neurode- of dementia. Mean age at symptom onset (44.0 ± generation in all BIBD cases. Macroscopically, severe 12.0 years) for these patients was significantly younger frontal cortical atrophy was a consistent finding (Fig. 2 than for other FTLD patients (54.9 ± 18.8 years) obtained shows case 1). Moreover, the degree of temporal cortical from a consecutive clinical cohort in our archives. atrophy varied among cases. The caudate nucleus showed marked flattening (Fig. 3a), while pigmentation Psychiatric, behavioral, cognitive, and language disturbance in the substantia nigra and locus coeruleus was de- characteristics creased. Histopathologically, neuronal loss and gliosis The most frequent initial symptoms in the patients with were prominent in all cases in the frontal cortex and chorea were apathy and behavioral abnormalities, such caudate nucleus (Fig. 3b and c). In the striatum, both as criminal behavior and loss of manners, followed by large and small neurons were severely affected. Along polyphagia, disinhibition, and memory impairment. All the coronal (or dorsoventral) axis of the neostriatum, three patients presented with a behavioral abnormality ventral striatal regions were more affected than dorsal as the prominent feature during the disease course, and ones (Fig. 4e and f). Along the mediolateral axis, the were finally diagnosed with bvFTD. Apathy, disinhib- paraventricular region of the caudate nucleus was more ition, stereotypy, altered dietary habits, perseveration affected than the paracapsular region. The nucleus ac- and memory impairment were the most prominent clin- cumbens was severely affected (except for one case: case ical features in this group. Wandering, hypersexuality, 2). Although the degree and distribution of neurodegen- and an oral tendency were observed in two cases. Re- erative changes showed some variance among cases, al- garding language disturbances, echolalia and reduced terations in no specific region appeared related to the speech output were observed in all three patients, and presence or absence of chorea. verbal stereotypies in two. No dysarthria or semantic er- In all BIBD cases, neuronal cytoplasmic inclusions rors were recognized in this group. (NCI) were slightly basophilic (Fig. 5a and b) and immu- nopositive for FUS (Fig. 5c–f). FUS-immunopositive Neurological signs NCIs were distributed in the cerebral cortices, hippocam- The patients with chorea exhibited reduced muscle tone pus (Fig. 5c), the basal nuclei (Fig. 5f), brain stem nuclei in addition to chorea. The chorea was complicated by (Fig. 5d and e), and spinal cord (in cases where tissue Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 6 of 15 Table 2 Clinical features of FTLD-FUS BIBD NIFID aFTLD-U Unclassified 〈with chorea〉〈without chorea〉 Case No. 1 2 3 4 5 6 7 8 9 10 Sex F F F M M M F M M F Onset (age) 32 44 56 57 40 34 67 29 39 30 Duration (y) 7 3.3 12 6 7 6.3 5.7 8 13 15 Family history No No No No No No No No No No Initial symptoms Apathy, Apathy, Behavioral Obsessive Disinhibition Weakness in the Dysarthria Disinhibition Apathy, Behavioral Behavioral Polyphagia, abnormality, memory behaviors left hand, Behavioral abnormality, memory abnormality Disinhibition impairment dysarthria abnormality impairment Prominent Behavioral Behavioral Behavioral Behavioral Behavioral Motor neuron Pseudobulbar Behavioral Behavioral Behavioral features abnormality abnormality abnormality abnormality abnormality signs palsy, nonfluent abnormality abnormality abnormality aphasia Clinical bvFTD bvFTD bvFTD bvFTD bvFTD ALS with CBD bvFTD bvFTD bvFTD diagnosis dementia Psychiatric and behavioral symptoms Apathy + + + + + + + - + + Disinhibition + + + - + - + + + + Stereotypy + + + + + - + + + + Wandering + + - - - - + + + + Altered dietary++ + - - - + + +- habits, polyphagia Memory ++ + + - - - - ++ impairment Hypersexuality + + - - + - + + + - Oral tendency + + - + - - - + + - Perseverations + + + ? - ? + ? - - Language and speech Reduced speech++ + + + + + + ++ output Dysarthria - - - - - + - - - + Verbal +- + + - ? + ? +? stereotypies Semantic errors - - - ? - ? - ? - - Echolalia + + + ? ? ? + ? - - Neurological signs Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 7 of 15 Table 2 Clinical features of FTLD-FUS (Continued) Involuntary movement Onset (age) 36 46 65 - - - - - - - Chorea + + + Athetosis + - + Ballismus + - - Lack of normal++ + - - - - - - - muscular tonus Upper motor -- - - - + + + -- signs Lower motor -- - - - + + - -- signs Dysphagia - - - - + + + + + + Gait disturbance + + + + + + + + + + Parkinsonism- No No No Moderate No Moderate Mild No No Mild early Parkinsonism- No No Mild Severe Severe Severe Severe Severe Moderate Severe late Investigations CT/MRI (atrophy) FT(L = R) na na na FT(L = R) na FT(L > R) na FT(L = R) na EEG Normal Slow dominant Slow dominant na Normal na Normal na Slow dominant na rhythm rhythm rhythm EMG Normal na na na na na na na na na +, present; -, absent; na, not available Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 8 of 15 Table 3 The demographic data and major clinical features of all FTLD cases FTLD-FUS FTLD-TDP FTLD-tau Unclassified BIBD NIFID aFTLD-U Unclassified Type A Type B Type C Unclassified Pick FTDP-17 CBD PSP Unclassified (n =1) (n =6) (n =2) (n =1) (n =1) (n =4) (n = 17) (n = 10) (n =1) (n = 18) (n =1) (n =4) (n =4) (n =2) Sex [male/female(%)] 3/3 (50.0) 1/1 1/0 0/1 (0) 2/2 7/10 6/4 1/0 (100.0) 10/8 1/0 1/3 3/1 (0.75) 0/2 (0) 1/0 (50.0) (100.0) (50.0) (41.2) (60.0) (55.6) (100.0) (0.25) onset (y) 49.5 ± 48 ± 26.9 39 30 53 ± 16.4 58.9 ± 55.6 ± 75 56.5 ± 51 61 ± 3.4 52.5 ± 53 ± 5.7 46 12.1 11.0 3.5 10.9 10.6 duration (y) 8 ± 4.6 6.9 ± 1.6 13 15 9.5 ± 7.9 2.6 ± 1.4 12.5 ± 5.1 8.3 ± 4.5 8 5.5 ± 2.6 13 ± 7.1 6.5 ± 2.1 3.1 4.8 clinical diagnosis as 5(83.3) 1(50.0) 1(100.0) 1(100.0) 3(75.0) 2(11.8) 5(50.0) 0(0) 12(66.7) 1(100.0) 3(75.0) 1(25.0) 1(50.0) 1(100.0) bvFTD[n(%)] involuntary movements[n(%)] 3(50.0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) mortor signs[n(%)] 1(16.7) 2(100.0) 0(0) 0(0) 3(75.0) 7(41.2) 7(70.0) 0(0) 2(11.1) 0(0) 0(0) 0(0) 1(50.0) 0(0) Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 9 of 15 Table 4 Distribution and severity of neurodegenerative changes in patients with BIBD Cases with chorea Cases without chorea 1 2 345 6 Brain weight (g) 800 1190 880 1140 940 1230 Cortical atrophy F, T(base) F(tip) F&T(base) F&T(base) F,T(base) T(tip) Frontal cortex +++ +++ ++ +++ +++ +++ Cingulate gyrus +++ +++ +++ +++ +++ +++ Temporal cortex ++ + ++ ++ +++ +++ Hippocampus +++ + +++ +++ na +++ Amygdala +++ + na +++ +++ +++ Caudate nucleus +++ +++ +++ +++ +++ +++ Putamen +++ + +++ ++ +++ +++ Globus pallidus +++ ± ++ ++ ++ ++ Thalamus +++ ± ± ++ +++ + Subthalamic nucleus ± ± ± ± ± ± Nucleus basalis of Meynert + - ± ± ± + Cerebellar dentate nucleus ± - ± ± ± + Red nucleus ± ± ± na na ± Substantia nigra +++ + +++ ++ +++ +++ Locus coeruleus +++ - ± ± ++ ++ Pontine nucleus ± ± ± ± ± ± Dorsal vagal nucleus ± ± ± na ± ± Hypoglossal nucleus ± - ± ± ± ± Inferior olivary nucleus ± ± ± ± + + Spinal cord - - na na na ± Data for cases 2 through 6 were assembled from previously published materials [15, 29]. F, frontal lobe; T, temporal lobe; F(tip), frontal tip; F(base), frontal base, T(tip), temporal tip; T(base), temporal base. Rating for the severity of degeneration: -, no degeneration; ±, no neuronal loss but gliosis; +, slight neuronal loss and gliosis; ++, moderate neuronal loss and gliosis; +++, severe neuronal loss and gliosis. Degeneration in the corticospinal tract: +, present; -, absent. na, tissue not available was available). Morphology of the NCIs was variable, and either round, crescent, or annular. Furthermore, NCIs were also immunopositive for EWS (Fig. 5h) and TAF15 (Fig. 5g), but immunonegative for tau, α- synuclein, and TDP-43. The morphology and distribu- tion of NCIs were consistent with those previously de- scribed for BIBD [12, 13, 30]. BIBD cases had numerous basophilic inclusions compared with other types of FTLD-FUS. No BIBD (except for case 1) aFTLD-U, or unclassifiable cases had intermediate filament- immunoreactive NCIs. The occurrence of NCIs did not distinguish between the presence or absence of chorea. Biochemical findings Triton X-100 soluble and insoluble brain fractions ex- tracted from patients diagnosed as BIBD with chorea, aFTLD-U, or NIFID, as well as from a control patient Fig. 2 Macroscopic photograph of patient 1. The right hemisphere were separated by 7.5 % sodium dodecyl sulfate poly- of the patient is shown. Severe atrophy is present in the frontal acrylamide gel electrophoresis (SDS-PAGE) and immu- cortex and temporal tip. White arrows indicate the precentral gyrus. noblotted with an anti-FUS antibody (Fig. 6). All cases Scale bar, 2 cm showed a strong 73-kDa band in both the soluble and Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 10 of 15 Fig. 3 Neuropathological findings of case 1. a Semi-macro photograph of the right hemisphere showing severe atrophy of the frontal cortex and caudate nucleus (Klüver–Barrera stain). b Severe neuronal loss and astrocytosis in the supragranular layer of the frontal cortex (hematoxylin and eosin stain). c Marked neuronal loss and astrocytosis with tissue rarefarction in the caudate head (hematoxylin and eosin stain). a–c are from case 1. Scale bars, 1 cm (a); 200 μm(b and c) insoluble fractions. A strong band at approximately been described, and were considered atypical, as in Pick’s 33 kDa was detected in the sample from the patient di- disease [33–36]. One clinical report suggested that cho- agnosed as having BIBD with chorea, but this band was rea is present in FTD patients [37], reporting that two less prominent in the samples from the other patients. bvFTD cases could be associated with chorea but lack an HTT mutation. They further mentioned the potential Discussion of a clinical phenotype presenting chorea in FTD, but In the present study, we found that chorea in FTLD pa- unfortunately these cases lacked autopsy confirmation of tients is related to FUS pathology. Chorea involves con- the diagnosis. tinuous movements that are irregular and nonrepetitive, To our knowledge, chorea is rarely described in which differ from the repetitive stereotypic behaviors FTLD-tau cases. In patients with TDP-43 mutations, [31] that are present in FTLD patients. These patients chorea may be present [38, 39]. A patient with a K263E lacked muscle tone but show no muscle atrophy. In clin- TARDBP mutation developed FTD, supranuclear palsy, ical practice, a combination of various movements is and chorea, but not ALS, which was associated with often encountered in a single patient [31, 32]. Determi- TDP-43 accumulation predominantly in subcortical nu- nig the dominant movement type is important in such clei and the brainstem [40]. More recently, C9ORF72 re- cases. In our series, chorea was identified as the domin- peat expansions were reported to be the most common ant movement disorder syndrome by each attending genetic cause of non-HD syndromes [41]. Only two doctor during the disease course. Indeed, most HD pa- cases of FTLD-FUS with chorea have been previously re- tients not only exhibit the characteristic chorea, but also ported. Lee et al. described one patient with late onset display bradykinesia and akinesia [31]. We suggest that BIBD who was clinically diagnosed with ALS-plus syn- clinicians should be aware of the various involuntary drome, and showed diffuse chorea and cognitive dys- movements (including chorea) in treatment of FTLD- function but no parkinsonism [42]. The second case was FUS patients. described by Yokota et al. [15], and was case 3 in our Historically, there has been a general agreement that current study. In our study, we did not detect any chorea-like involuntary movements are rare in FTLD FTLD-tau or FTLD-TDP cases with chorea-like involun- [2]. Until recently, few cases of FTLD with chorea have tary movements. Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 11 of 15 Fig. 4 Neostriatum of FTLD-FUS cases. a and b Semi-macro photograph of the rostal neostriatum including the caudate nucleus head (rectangle), nucleus accumbens (asterisk), and putamen. Severe gliosis (Holzer stain) (a) and atrophy (hematoxylin and eosin stain) (b). c Marked neuronal loss and astrocytosis in the magnified area of the nucleus accumbens (shown by asterisk in b). d Severe neuronal loss with astrocytosis in the magnified area of the caudate nucleus (shown by the rectangle in b). In FTLD-FUS cases, the ventral putamen (e) is more involved than the dorsal region (f) Chorea is the most common clinical feature in HD, the responsible regions. Differences in the region initially with patients showing severe striatal atrophy. Although affected or the speed and direction of degeneration may the striatum is also severely affected in FTLD-FUS, cho- influence the clinical symptoms (including chorea) in rea is considered to be a relatively rare clinical feature in FTLD-FUS cases, although more detailed studies are FTLD-FUS, especially compared with HD. In FTLD- needed to clarify this issue. FUS, the topographic distribution pattern of the caudate As in the pathophysiology of HD, striatal projection nucleus, nucleus accumbens, and putamen is different neurons of the indirect pathway are vulnerable, while from HD. In our series, the head and body of the caud- those of the direct pathway are relatively preserved [46]. ate nucleus is more degenerated than the body and tail, Severe involvement of striatal projection neurons in both whereas the tail is more degenerated than the body and the indirect and direct pathways may explain the rarity head in HD [43]. Moreover, the nucleus accumbens is of chorea in FTLD-FUS. Alternatively, lesions outside severely degenerated in FTLD-FUS, in contrast to being the striatum may cause such a phenotypic difference. remarkably preserved in the advanced stage (stage 4) of The striatum regulates movement through interactions HD [43, 44]. With the evolution of FTLD-FUS, degener- with the cerebral cortex as well as with multiple subcor- ation in the neostriatum appears to move in a rostro- tical nuclei including the globus pallidus, subthalamic caudal, ventro-dorsal, and medio-lateral direction. nucleus, and some brainstem nuclei. The presence or Chorea is associated with the striatum (caudate nu- absence of chorea and related involuntary movements cleus and putamen), globus pallidus, substantia nigra, may depend on a delicate functional balance between subthalamic nucleus, and cerebral cortex [43, 45]. Unfor- these structures that form the striatal motor circuits. tunately, it is difficult to specify the correlation between Among the FTLD cases in our brain archives, only chorea and our neuropathological findings, since we did three patients displayed chorea, and all three patients not find any significantly different neurodegenerative were diagnosed as having FTLD-FUS with the BIBD changes between cases with and without chorea, even in subtype. None of the FTLD-tau or FTLD-TDP cases Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 12 of 15 Fig. 5 Inclusions detected in patients. Inclusions observed in cases 1 (a, e, f, g, h), 2 (c, d), and 3 (b). a A basophilic inclusion in the pontine nucleus (hematoxylin and eosin stain). b A basophilic inclusion in the inferior olivary nucleus (Klüver–Barrera stain). c, d, e and f FUS-immunopositive labelling of neuronal cytoplasmic inclusions (NCI) in the hippocampal dentate gyrus (c), inferior olivary nucleus (d, e) and caudate nucleus (f).g and h NCI in the thoracic spinal cord are immunopositive for TATA-binding protein-associated factor 15 (g) and Ewing sarcoma protein (h). Scale bars: 10 μm(a, b, d, f, and h); 30 μm(c); 15 μm(e) Fig. 6 Biochemical analysis of FUS. Proteins were sequentially extracted from brains of patients with BIBD, aFTLD-U, NIFID, and from a control subject. Fractions from patients diagnosed as BIBD with chorea (case 1, lane 1), aFTLD-U (case 9, lane 2), or NIFID (case 8, lane 3) and the control patient (lane 4) were separated by 7.5 % SDS-PAGE and immunoblotted with anti-FUS antibodies (a A300-302A; b HPA008784). All cases, including the control, show a strong 73-kDa band (white arrow) in both soluble and insoluble high-salt fractions. Additionally, the BIBD with chorea patient has a strong band at approximately 33 kDa (black arrow; b TX-ppt, lane 1), which is less prominent in the other samples Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 13 of 15 were associated with chorea. Because FTLD-tau and intensity in both soluble and insoluble fractions in all FTLD-TDP comprise the majority of FTLD cases, the cases. This result is inconsistent with a previous report, paucity of cases with chorea in these groups is remark- which showed that the 73-kDa band intensity in the in- able. BIBD is considered to be a generalized variant of soluble fraction was stronger in FTLD-FUS cases than Pick’s disease because of its relatively broad distribution normal controls [10]. In the present study, we identified of degenerative changes that extend to subcortical struc- a new FUS fragment of approximately 33 kDa in the in- tures [47]. The involvement of multiple subcortical nu- soluble fraction, which was derived from a patient diag- clei may increase the chances of some BIBD patients nosed as having BIBD with chorea. Because we could developing chorea. It may be noteworthy that BIBD pa- not biochemically analyze the BIBD case without chorea, tients without chorea show moderate to severe parkin- it is unclear whether this fragment is associated with the sonism symptoms in the later stage of disease, whereas pathogenic mechanism of BIBD with chorea. However, those with chorea lack parkinsonism throughout the dis- previous reports show a clear relationship between the ease course. Chorea in HD is treated with anti- band pattern of low molecular weight fragments of in- dopaminergic agents [48]. In BIBD, both the striatum soluble proteins and clinicopathological phenotypes in and substantia nigra undergo degenerative changes. FTLD-tau [52] and FTLD-TDP [22], suggesting that fur- Cases with relatively depleted nigral dopaminergic regu- ther biochemical study of insoluble FUS fragments may lation of the striatal motor circuits may be associated shed light on FTLD-FUS. with parkinsonism, while those with relatively less severe nigral dysfunction may develop chorea in the absence of Conclusions parkinsonism. Accordingly, postmortem histopatho- Our results suggest that choreoathetosis observed in pa- logical analysis of terminal stage lesions may not be sen- tients with bvFTD could be a clinical marker of the sitive enough to detect such a premortem functional underlying pathology of BIBD. In these cases, severe at- imbalance. rophy of the caudate nucleus and relatively preserved ni- The choreoathetoid movements identified in our series gral dopaminergic regulation might be associated with might be influenced by antipsychotic drugs as a risk factor chorea in the absence of parkinsonism in BIBD. Further for severe caudate atrophy. Previous studies have stated studies are needed to elucidate the exact mechanism by that chorea in HD is difficult to distinguish from tardive which chorea occurs, which in turn may develop new dyskinesia [49]. However, in general, the movements ob- therapeutic approaches for this incurable condition in served in our cases is unlikely to be diagnosed as tardive FTLD patients. dyskinesia because of the following points. Tardive dyskin- esia is defined in diagnostic criteria as developing due to Ethics approval and consent to participate the use of medications such as antipsychotic drugs (dopa- All patients, or in one case in which the patient had mine receptor blocking agents) for more than 3 months, died, the next of kin, provided written consent for aut- and specifically, dystonia must be present either during on- opsy and postmortem analyses for research purposes. going antipsychotic treatment or within 3 months of its dis- This study was approved by the ethics committee at the continuation [50]. In addition, second generation Tokyo Metropolitan Institute of Medical Science, and antipsychotics (e.g., olanzapine) rarely cause acute dystonic was performed in accordance with the ethical standards reactions [51], and tardive dyskinesia might only present outlined in the 1964 Declaration of Helsinki and its later when the patients take high-doses [49]. In HD, choreic amendments. movements are random, flowing from one part of the body to the other, and frequently superimposed by semi- Consent for publication purposeful movements in an attempt to mask involuntary Details that might disclose the identity of the partici- movements. In contrast, movement in tardive dyskinesia is pants in this study were omitted. slow, stereotypic, and repetitive. In cases 1 and 3, we were able to reconfirm such movement features in HD from the Competing interests clinical records. From our own experience, patients at the The authors declare that they have no competing interests. onset of tardive dyskinesia predominantly show akathisia and tremor, although choreiform movements may occur. Authors’ contributions IK performed microscopy, immunoblot, and statistical analyses, and also However, this point might reflect a limitation of our study, drafted the manuscript. ZK, TA, and OY participated in study design and and further efforts are needed to unveil the association be- coordination. ZK and TA helped with the microscopy analysis. OY, NA, OK, tween drug-induced choreoathetoid movements and KN, and KO organized the brain archives (including clinical information and selection of appropriate cases), and neuropathologically analyzed all cases. FTLD-FUS accumulation in diseased conditions. TN contributed to sample preparation and immunoblot analysis. SH In our biochemical analyses, a 73-kDa band corre- conceived the study and participated in its initial design. MHo contributed to sponding to full-length FUS was found at the same reagents, materials, and analysis tools. MHa participated in the study design Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 14 of 15 and initial manuscript draft. HA supervised the study design and its 8. Kwiatkowski Jr TJ, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ coordination. All authors read and approved the final manuscript. C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers Acknowledgments JE, Brown RH Jr. Mutations in the FUS/TLS gene on chromosome 16 cause We thank Ms. Hiromi Kondo, Yoko Shimomura, and Chie Haga (Tokyo familial amyotrophic lateral sclerosis. Science. 2009;323(5918):1205–8. Metropolitan Institute of Medical Science) for their excellent technical 9. Vance C, Rogelj B, Hortobágyi T, De Vos KJ, Nishimura AL, Sreedharan J, assistance. Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Funding Brown RH Jr. Mutations in FUS, an RNA processing protein, cause familial This research was supported by Grants-in-Aid from the Ministry of Health, amyotrophic lateral sclerosis type 6. Science. 2009;323(5918):1208–11. Labour and Welfare (13800916), and the Japan Society for the Promotion of doi:10.1126/science.1166066. Science (JSPS KAKENHI) (Grant No. 24500429). 10. Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie Author details IR. A new subtype of frontotemporal lobar degeneration with FUS Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, pathology. Brain. 2009;132:2922–31. doi:10.1093/brain/awp214. 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. Department of 11. Neumann M, Roeber S, Kretzschmar HA, Rademakers R, Baker M, Mackenzie Psychiatry, Tokyo Metropolitan Matsuzawa Hospital (TMMH), Tokyo, Japan. IR. Abundant FUS-immunoreactive pathology in neuronal intermediate 3 4 Department of Neurology, JA Toride Medical Center, Ibaraki, Japan. Division filament inclusion disease. Acta Neuropathol. 2009;118:605–16. of Clinical Medicine, Department of Neuropsychiatry, Faculty of Medicine, doi:10.1007/s00401-009-0581-5. University of Tsukuba, Ibaraki, Japan. Department of Neuropsychiatry, 12. Munoz DG, Neumann M, Kusaka H, Yokota O, Ishihara K, Terada S, Kuroda S, Okayama University Graduate School of Medicine, Dentistry and Mackenzie IR. FUS pathology in basophilic inclusion body disease. Acta Pharmaceutical Sciences, Okayama, Japan. Department of Psychiatry, Neuropathol. 2009;118:617–27. doi:10.1007/s00401-009-0598-9. 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C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies. Neurology. 2014;82(4):292–9. Submit your next manuscript to BioMed Central doi:10.1212/WNL.0000000000000061. 42. Lee EB, Russ J, Jung H, Elman LB, Chahine LM, Kremens D, Miller BL, Branch and we will help you at every step: Coslett H, Trojanowski JQ, Van Deerlin VM, McCluskey LF. Topography of • We accept pre-submission inquiries FUS pathology distinguishes late-onset BIBD from aFTLD-U. Acta Neuropathol Commun. 2013;1(9):1–11. � Our selector tool helps you to find the most relevant journal 43. Vonsattel JP. Huntington disease models and human neuropathology: � We provide round the clock customer support similarities and differences. Acta Neuropathol. 2008;115(1):55–69. � Convenient online submission 44. Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson Jr EP. Neuropathological classification of Huntington’s disease. J Neuropathol Exp � Thorough peer review Neurol. 1985;44(6):559–77. � Inclusion in PubMed and all major indexing services 45. Sanger TD, Chen D, Fehlings DL, Hallett M, Lang AE, Mink JW, Singer HS, � Maximum visibility for your research Alter K, Ben-Pazi H, Butler EE, Chen R, Collins A, Dayanidhi S, Forssberg H, Fowler E, Gilbert DL, Gorman SL, Gormley ME Jr, Jinnah HA, Kornblau B, Submit your manuscript at Krosschell KJ, Lehman RK, MacKinnon C, Malanga CJ, Mesterman R, Michaels www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Neuropathologica Communications Springer Journals

Chorea as a clinical feature of the basophilic inclusion body disease subtype of fused-in-sarcoma-associated frontotemporal lobar degeneration

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Springer Journals
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Copyright © 2016 by Kawakami et al.
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Biomedicine; Neurosciences; Pathology; Neurology
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2051-5960
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10.1186/s40478-016-0304-9
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27044537
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Abstract

Choreoathetoid involuntary movements are rarely reported in patients with frontotemporal lobar degeneration (FTLD), suggesting their exclusion as a supportive feature in clinical diagnostic criteria for FTLD. Here, we identified three cases of the behavioral variant of frontotemporal dementia (bvFTD) that display chorea with fused in sarcoma (FUS)-positive inclusions (FTLD-FUS) and the basophilic inclusion body disease (BIBD) subtype. We determined the behavioral and cognitive features in this group that were distinct from other FTLD-FUS cases. We also reviewed the clinical records of 72 FTLD cases, and clarified additional clinical features that are predictive of the BIBD pathology. Symptom onset in the three patients with chorea was at 44.0 years of age (±12.0 years), and occurred in the absence of a family history of dementia. The cases were consistent with a clinical form of FTD known as bvFTD, as well as reduced neurological muscle tone in addition to chorea. The three patients showed no or mild parkinsonism, which by contrast, increased substantially in the other FTLD cases until a later stage of disease. The three patients exhibited severe caudate atrophy, which has previously been reported as a histological feature distinguishing FTLD-FUS from FTLD-tau or FTLD-TAR DNA-binding protein 43. Thus, our findings suggest that the clinical feature of choreoathetosis in bvFTD might be associated with FTLD-FUS, and in particular, with the BIBD subtype. Keywords: FTLD-FUS, BIBD, bvFTD, Chorea, Involuntary movement, Parkinsonism Introduction picture in the early disease stage are currently referred Frontotemporal lobar degeneration (FTLD) is a neurode- to as having a behavioral variant of FTD (bvFTD) [3]. generative disease that commonly causes dementia [1]. The neuropathology of FTLD is as complex as the In clinical practice, FTLD is considered a syndrome and clinical syndrome. Virtually all patients with FTLD have is presently classified by the consensus criteria of Neary abnormal intracellular accumulations of disease-specific and colleagues [2] into three subtypes: frontotemporal molecules. These molecules include tau, TAR DNA- dementia (FTD), progressive nonfluent aphasia, and se- binding protein 43 (TDP-43), and fused in sarcoma mantic dementia. Most patients with progressive nonflu- (FUS) [4, 5]. FTLD cases are now assigned to one of ent aphasia and semantic dementia show some features three major molecular subgroups based on histopatho- of FTD (e.g., behavioral symptoms), later on in their dis- logical findings: FTLD-tau, FTLD-TDP, or FTLD-FUS ease course. Those with FTD as the dominant clinical [5]. Before the discovery of TDP-43 in 2006 [6, 7], most cases of tau-negative FTLD were collectively termed FTLD-U because their inclusions were ubiquitin- * Correspondence: kawakami-it@igakuken.or.jp 1 positive. Subsequently, it became apparent that the ma- Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan jority of FTLD-U cases were in fact FTLD-TDP, (i.e., Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital (TMMH), FTLD with TDP-43 inclusions), with 10 to 20 % of Tokyo, Japan FTLD-U cases remaining as tau-negative and TDP-43- Full list of author information is available at the end of the article © 2016 Kawakami et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 2 of 15 negative FTLD. In 2009, FUS was identified as one of Huntington’s disease (HD), an inherited neurodegenera- the genes for familial amyotrophic lateral sclerosis tive disease in which atrophy of the striatum is the pre- (ALS) [8, 9]. Consequently, most tau-negative and dominant pathology. However, the striatum is also TDP-43-negative FTLD inclusions were found to be severely affected in all subtypes of FTLD. The results of FUS positive [10–12]. Accordingly, cases of FTLD a recent report found significantly greater striatal atro- with FUS-positive inclusions are now collectively phy by magnetic resonance imaging (MRI) in FTLD- called FTLD-FUS. Three rare forms of FTLD are con- FUS patients than in FTLD-TDP and FTLD-tau patients, sidered to be subtypes of FTLD-FUS: atypical FTLD- thereby distinguishing FTLD-FUS from other forms of U (aFTLD-U), basophilic inclusion body disease FTLD [16]. (BIBD), and neuronal intermediate filament inclusion Here, we identified three cases of bvFTD with chorea, disease (NIFID) [11]. Although these three subtypes which were diagnosed as FTLD-FUS and exhibit histo- mayrepresent acontinuousspectrumofFTLD-FUS pathological results indicative of the BIBD subtype. We disease, detailed histopathological investigation suggests identified the behavioral and cognitive features that dis- they are closely related but distinct entities [11–13]. tinguish this group from other FTLD-FUS cases. Fur- Several previous reports have challenged these clini- ther, we also reviewed the clinical records of 72 FTLD copathological relationships in FTLD patients. In cases to identify distinct clinical features that are pre- FTLD-FUS, which is present in a minority of FTLD dictive of FTLD-FUS, and in particular the BIBD patients, such relationships have only recently been de- subtype. scribed [12, 14–19]. These studies reveal that FTLD- FUS patients may have a relatively younger onset (often Materials and methods before the age of 40 years), absence of a family history Participants of the disease, and severe caudate atrophy on imaging Seventy-two FTLD cases were registered in the autopsy [16–18]. Recently, Snowden et al. suggested that archives of Dementia Research Project, Tokyo Metropol- aFTLD-U is associated with a cognitive and behavioral itan Institute of Medical Science, Tokyo, Japan. The mo- phenotype that is distinct from the other forms of lecular pathology observed in these cases is summarized FTLD-FUS (specifically, NIFID and BIBD). They noted in Table 1. Briefly, the archives included 29 FTLD-tau, that aFTLD-U is characterized by prominent obsessive- 32 FTLD-TDP, and 10 FTLD-FUS cases, and 1 unclassi- ness, repetitive behaviors and rituals, social withdrawal fiable case. Of these, clinical features corresponding to and lack of engagement, hyperorality with pica, and bvFTD with chorea were identified in three cases. The marked stimulus-bound behavior (e.g., utilization be- pathological diagnosis in these three cases was BIBD. havior). Furthermore, they suggested that clinical pres- Case 1 was extensively analyzed neurologically, neurora- entation of FTLD with associated FUS pathology may diologically and genetically, whereas cases 2 and 3 were not be related to mutation of the FUS gene. Addition- reviewed using their clinical records. ally, a uniform clinical phenotype of BIBD and NIFID has been reported in a few studies [12, 15]. Yokota et al. found that NIFID and BIBD share several clinical features including dysarthria, motor neuron signs, par- Neuropathological examination kinsonism, and memory impairment [15]. They also Brain and spinal cord tissue were fixed in 10 % formalin noted that it is difficult to differentiate BIBD from and embedded in paraffin. Sections (10 μm thick) were NIFID in clinical practice. While these reports indicate cut from the cerebrum, midbrain, pons, medulla oblon- variations in behavioral and cognitive features of gata, cerebellum, and spinal cord. The sections were FTLD-FUS, the features that are distinct from the other stained with hematoxylin and eosin as well as Klüver– forms of FTLD (i.e., FTLD-tau and FTLD-TDP) remain Barrera stain. Immunohistochemistry was performed for to be clarified. tau (AT8, 1:1,000; Thermo Scientific), α-synuclein Patients with FTLD often report associated motor sys- (pSyn#64, 1:1,000; Wako), TDP-43 (409/410, 1:1,000; tem impairments, such as parkinsonism and motor original antibody [22]), FUS protein (HPA008784, neuron disease [2, 20], whereas association of FTLD 1:1,000; Sigma-Aldrich; and A300-302A, 1:500–1,000; with chorea and athetosis has rarely been reported. In Bethyl Laboratories), Ewing sarcoma protein (EWS, the clinical diagnostic criteria for FTLD [2], choreoathe- 1:100; Santa Cruz Biotechnology), and TATA-binding tosis is one of the diagnostic exclusion features. Chorea protein-associated factor 15 (TAF15, 1:50; Bethyl is an abnormal involuntary movement characterized by Laboratories). Primary antibody labelling was visualized excessive, spontaneous movements that are irregularly using 0.2 % 3,3′-diaminobenzidine as the chromogen in timed, nonrepetitive, randomly distributed, and abrupt combination with an Envision Plus kit (Dako Japan, in character [21]. The classical form of chorea occurs in Tokyo), according to the manufacturer’s instructions. Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 3 of 15 Table 1 Molecular pathology of 72 FTLD cases frequency of each clinical feature. Values of P <0.05 were accepted as significant. All statistical analyses were per- Diagnosis No. of patients formed using GraphPad Prism 4 software (GraphPad Soft- FTLD-tau (29) a ware, USA). Statistical significance of the concentration of Pick’s disease 18 involuntary movement in the BIBD subtype was assessed FTDP-17tau 1 by direct calculation of probability under an assumption CBD 4 of independence in all FTLD cases. PSP 4 Unclassifiable 2, [53] Results Clinical findings FTLD-TDP (32) Case 1 Type A 4 The patient was a Japanese woman with a family history Type B 17 of schizophrenia but no dementia or movement disorders. Type C 10 She had been living outside of Japan for several years Unclassifiable 1, [54] when she developed affective incontinence at the age of FTLD-FUS (10) 32. Two years later, she was spending much of the day in bed, and displayed palilalia and hyperphagia of carbohy- BIBD 6 drates such as rice and noodles. She dressed in a provoca- NIFID 2 tive manner and was often arrested for shoplifting, but aFTLD-U 1 showed no remorse. She was initially diagnosed as having Unclassifiable 1, [55] schizophrenia or depressive disorder, and consequently Unclassifiable (1) treated with fluvoxamine and olanzapine for a short dur- CBD corticobasal degeneration, PSP progressive supranuclear palsy, FTDP-17tau ation, as well as with electroconvulsive therapy. However, frontotemporal dementia with parkinsonism linked to chromosome 17 she was unresponsive to these therapies and they were dis- associated with tau pathology, BIBD basophilic inclusion body disease, NIFID continued. At the age of 36, she returned to Japan and was neuronal intermediate filament inclusion disease; aFTLD-U atypical FTLD with ubiquitinated inclusions admitted to a psychiatric hospital. She presented with Pick’s disease refers to only FTLD-tau with Pick bodies chorea-like involuntary movements of the face, tongue, Cases with CBD and PSP were included only if the patients presented with features of FTLD, such as frontotemporal dementia, semantic dementia and neck, and four extremities. The involuntary movements progressive nonfluent aphasia included frequent jerking of the shoulders, continuous FTLD-TDP cases were classified using the system reported by Mackenzie et al. [56] movement of facial muscles (e.g., lifting the eyebrows, closing the eyes, and thrusting out the tongue), and large Immunoblot analysis amplitude movements of the lower limbs, sometimes with Fresh frozen samples for immunoblot analyses were pre- a violent, flinging or flailing quality, which was regarded as pared as previously described [23, 24]. Briefly, frozen brain ballismus. She also had athetosis-like movements in her frontal cortex tissue was obtained from one case each of right leg. When she wandered the hospital ward, she BIBD (case 1), NIFID (case 8), aFTLD-U (case 9), and a touched and tapped yellow things. Neurological examin- normal control. ation revealed reduced muscle tone, but no muscle weak- Brain tissue was homogenized in 20 volumes (w/v) of ness, atrophy, or other signs of motor neuron disease. Her homogenization buffer (10 mM Tris-HCl, pH 7.4, 0.8 M speech output was reduced, but she recognized some sim- NaCl, 1 mM EGTA, and 10 % sucrose). Homogenates ple words. Her behavior was stereotyped and ritualistic. were incubated at 37 °C for 30 min in homogenization Her blood biochemistry test results were normal, includ- buffer containing 2 % Triton X-100, and centrifuged at ing ceruloplasmin and ferritin levels and tests for syphilis. 20,000 × g for 10 min at room temperature. Supernatants Cerebrospinal fluid concentration of amyloid β-protein, were further ultracentrifuged at 100,000 × g for 20 min. total tau, and phosphorylated tau were normal. Brain MRI After ultracentrifugation, the resulting supernatants and results revealed bilateral progressive atrophy in the frontal pellets were recovered for immunoblotting analysis as and temporal cortices and the caudate nucleus (Fig. 1). Triton X-100 soluble and insoluble fractions, respectively. Hypoperfusion was apparent in these regions by cerebral For immunoblotting, primary antibodies for the FUS pro- blood flow single-photon emission computed tomography. tein were obtained from Sigma-Aldrich (HPA008784) and The results of an electromyographic investigation were Bethyl Laboratories, Inc. (A300-302A). normal. Her Mini-Mental State Examination score was 18/30. She was clinically suspected of having HD because Statistical analysis of her chorea and the severe caudate atrophy apparent on Fisher’s exact probability test was used to determine the MRI imaging. However, she had no repeat expansion in significance of differences in variables, including the the genes causing HD, spinocerebellar ataxia type 17, or Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 4 of 15 Fig. 1 Brain MRI of case 1. a and b Brain magnetic resonance (MR) images of the patient 1 at age 36. Atrophy is present in the frontal and temporal cortices and the caudate nucleus. a and b Brain MR images of the patient taken 1 year after those shown in c and d. The atrophy is more severe and the anterior horn of the lateral ventricles is markedly enlarged. Permission was obtained from the right holder [25] dentatorubral-pallidoluysian atrophy. No mutation was She showed polyphagia and subsequent rapid weight gain. found in the genes for tau, TDP-43, FUS, granulin, amyl- She was admitted to a psychiatric hospital at age 46 because oid precursor protein, presenilin-1, or presenilin-2. Based of purposeless wandering. She presented with reduced on clinical findings, she was diagnosed with bvFTD [2]. speech output, simple language with stereotypies, and per- She took milnacipran hydrochloride (100 mg) for therapy. severation. She spoke only in uncomplicated, short sen- At age 37, 5 years after symptom onset, her speech output tences, but showed no impaired verbal comprehension. was reduced and she had dysphagia. Her gross involuntary Neurological examination revealed continuous and quick movements were less severe, but slow and continuous leg chorea-like involuntary movements in the tongue, but no movements persisted. At that time, neurological examin- muscle atrophy. She was not administered any medication ation showed the presence of primitive reflexes such as before presentation of chorea. HerWechslerAdult sucking, as well as palmomental and strong grasp reflexes Intelligence Scale score was 60 (verbal IQ, 72; performance bilaterally. She was in a persistent vegetative state by the IQ, 55). Her blood biochemistry results were normal, in- age of 38. She exhibited arm contractures, but athetosis- cluding a syphilis test. Disorientation or memory impair- like movements (such as the slow, sinuous, continuous ment were not evident. She showed stereotyped behaviors, flowing external and internal rotation of her right leg) such as repeatedly throwing a lot of toilet paper into the continued until her death. She died of bronchopneumonia toilet. Chorea in her tongue diminished gradually until age at age 39. Her disease duration was 7 years. 47. She died suddenly of suffocation by food during a hos- pital stay. Her disease duration was 3 years. Case 2 The second patient was a 47-year-old Japanese woman. She Case 3 had no family history of behavioral change or dementia. The third patient was a 67-year-old Japanese woman. She presented with indifference and disinhibition at age 44. There was no relevant family history of dementia, but Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 5 of 15 her sister had died of a nonspecific psychiatric disease. athetosis in two cases and ballismus in one. The three At age 56, she began collecting elastic bands and trash, patients lacked parkinsonism signs, even at the later dis- and eating only rice and pickles. At age 58, she was ad- ease stage. In contrast, other FTLD-FUS patients, in- mitted to a psychiatric hospital because she was drinking cluding BIBD cases without chorea, always showed a lot of alcohol and committing criminal acts, such as moderate to severe parkinsonism at the same disease shoplifting. She showed severe impairment of recent stage. Gait disturbance was observed in all patients. memory and disorientation. The results of a neurological Additionally, the three patients showed neither dyspha- examination revealed no abnormalities. Her blood and sia nor upper and lower motor neuron signs, which were urine biochemistry results were normal. Behavioral and noted in some BIBD patients without chorea during the verbal stereotypy developed gradually. At age 60, she disease course. was mute and gradually became bedridden. Contractures in all four extremities were apparent. At age 65, 9 years BIBD compared with all FTLD cases after symptom onset, rapid and small chorea-like invol- The demographic data and major clinical features of all untary movements in her neck, trunk, and four extrem- our archived FTLD cases are summarized in Table 3. ities became apparent and progressively worsened. The prevalence rate of FUS pathology in the FTLD cases Athetosis-like movements were also observed in her left in our cohort was 13.9 %, which is higher than previ- upper extremity. Her chorea-like movements continued ously reported (5 %) [28]. Compared with the other sub- until her death, which was due to cardiac failure at age types of FTLD-FUS, FTLD-TDP, and FTLD-tau, the 67. We were unable to obtain drug history data for this most prominent feature in BIBD patients was chor- case. Her disease duration was 12 years. eoathetoid involuntary movements, with its occurrence converging at BIBD in all FTLD patients (0.0003 < 0.05). Clinical summary of cases No significant differences were noted for the other clin- Demographic data ical features. The clinical features of the three patients with chorea and the other FTLD-FUS cases are summarized in Table 2. Neuropathological findings More detailed clinical descriptions are provided in Japa- The atrophy and degeneration distribution has been de- nese (with English abstracts) for cases 1 [25], 2 [26], and 3 scribed previously for cases 2 and 3 [24, 29]. Here, [27]. The three patients with chorea had no family history Table 4 shows the degree and distribution of neurode- of dementia. Mean age at symptom onset (44.0 ± generation in all BIBD cases. Macroscopically, severe 12.0 years) for these patients was significantly younger frontal cortical atrophy was a consistent finding (Fig. 2 than for other FTLD patients (54.9 ± 18.8 years) obtained shows case 1). Moreover, the degree of temporal cortical from a consecutive clinical cohort in our archives. atrophy varied among cases. The caudate nucleus showed marked flattening (Fig. 3a), while pigmentation Psychiatric, behavioral, cognitive, and language disturbance in the substantia nigra and locus coeruleus was de- characteristics creased. Histopathologically, neuronal loss and gliosis The most frequent initial symptoms in the patients with were prominent in all cases in the frontal cortex and chorea were apathy and behavioral abnormalities, such caudate nucleus (Fig. 3b and c). In the striatum, both as criminal behavior and loss of manners, followed by large and small neurons were severely affected. Along polyphagia, disinhibition, and memory impairment. All the coronal (or dorsoventral) axis of the neostriatum, three patients presented with a behavioral abnormality ventral striatal regions were more affected than dorsal as the prominent feature during the disease course, and ones (Fig. 4e and f). Along the mediolateral axis, the were finally diagnosed with bvFTD. Apathy, disinhib- paraventricular region of the caudate nucleus was more ition, stereotypy, altered dietary habits, perseveration affected than the paracapsular region. The nucleus ac- and memory impairment were the most prominent clin- cumbens was severely affected (except for one case: case ical features in this group. Wandering, hypersexuality, 2). Although the degree and distribution of neurodegen- and an oral tendency were observed in two cases. Re- erative changes showed some variance among cases, al- garding language disturbances, echolalia and reduced terations in no specific region appeared related to the speech output were observed in all three patients, and presence or absence of chorea. verbal stereotypies in two. No dysarthria or semantic er- In all BIBD cases, neuronal cytoplasmic inclusions rors were recognized in this group. (NCI) were slightly basophilic (Fig. 5a and b) and immu- nopositive for FUS (Fig. 5c–f). FUS-immunopositive Neurological signs NCIs were distributed in the cerebral cortices, hippocam- The patients with chorea exhibited reduced muscle tone pus (Fig. 5c), the basal nuclei (Fig. 5f), brain stem nuclei in addition to chorea. The chorea was complicated by (Fig. 5d and e), and spinal cord (in cases where tissue Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 6 of 15 Table 2 Clinical features of FTLD-FUS BIBD NIFID aFTLD-U Unclassified 〈with chorea〉〈without chorea〉 Case No. 1 2 3 4 5 6 7 8 9 10 Sex F F F M M M F M M F Onset (age) 32 44 56 57 40 34 67 29 39 30 Duration (y) 7 3.3 12 6 7 6.3 5.7 8 13 15 Family history No No No No No No No No No No Initial symptoms Apathy, Apathy, Behavioral Obsessive Disinhibition Weakness in the Dysarthria Disinhibition Apathy, Behavioral Behavioral Polyphagia, abnormality, memory behaviors left hand, Behavioral abnormality, memory abnormality Disinhibition impairment dysarthria abnormality impairment Prominent Behavioral Behavioral Behavioral Behavioral Behavioral Motor neuron Pseudobulbar Behavioral Behavioral Behavioral features abnormality abnormality abnormality abnormality abnormality signs palsy, nonfluent abnormality abnormality abnormality aphasia Clinical bvFTD bvFTD bvFTD bvFTD bvFTD ALS with CBD bvFTD bvFTD bvFTD diagnosis dementia Psychiatric and behavioral symptoms Apathy + + + + + + + - + + Disinhibition + + + - + - + + + + Stereotypy + + + + + - + + + + Wandering + + - - - - + + + + Altered dietary++ + - - - + + +- habits, polyphagia Memory ++ + + - - - - ++ impairment Hypersexuality + + - - + - + + + - Oral tendency + + - + - - - + + - Perseverations + + + ? - ? + ? - - Language and speech Reduced speech++ + + + + + + ++ output Dysarthria - - - - - + - - - + Verbal +- + + - ? + ? +? stereotypies Semantic errors - - - ? - ? - ? - - Echolalia + + + ? ? ? + ? - - Neurological signs Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 7 of 15 Table 2 Clinical features of FTLD-FUS (Continued) Involuntary movement Onset (age) 36 46 65 - - - - - - - Chorea + + + Athetosis + - + Ballismus + - - Lack of normal++ + - - - - - - - muscular tonus Upper motor -- - - - + + + -- signs Lower motor -- - - - + + - -- signs Dysphagia - - - - + + + + + + Gait disturbance + + + + + + + + + + Parkinsonism- No No No Moderate No Moderate Mild No No Mild early Parkinsonism- No No Mild Severe Severe Severe Severe Severe Moderate Severe late Investigations CT/MRI (atrophy) FT(L = R) na na na FT(L = R) na FT(L > R) na FT(L = R) na EEG Normal Slow dominant Slow dominant na Normal na Normal na Slow dominant na rhythm rhythm rhythm EMG Normal na na na na na na na na na +, present; -, absent; na, not available Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 8 of 15 Table 3 The demographic data and major clinical features of all FTLD cases FTLD-FUS FTLD-TDP FTLD-tau Unclassified BIBD NIFID aFTLD-U Unclassified Type A Type B Type C Unclassified Pick FTDP-17 CBD PSP Unclassified (n =1) (n =6) (n =2) (n =1) (n =1) (n =4) (n = 17) (n = 10) (n =1) (n = 18) (n =1) (n =4) (n =4) (n =2) Sex [male/female(%)] 3/3 (50.0) 1/1 1/0 0/1 (0) 2/2 7/10 6/4 1/0 (100.0) 10/8 1/0 1/3 3/1 (0.75) 0/2 (0) 1/0 (50.0) (100.0) (50.0) (41.2) (60.0) (55.6) (100.0) (0.25) onset (y) 49.5 ± 48 ± 26.9 39 30 53 ± 16.4 58.9 ± 55.6 ± 75 56.5 ± 51 61 ± 3.4 52.5 ± 53 ± 5.7 46 12.1 11.0 3.5 10.9 10.6 duration (y) 8 ± 4.6 6.9 ± 1.6 13 15 9.5 ± 7.9 2.6 ± 1.4 12.5 ± 5.1 8.3 ± 4.5 8 5.5 ± 2.6 13 ± 7.1 6.5 ± 2.1 3.1 4.8 clinical diagnosis as 5(83.3) 1(50.0) 1(100.0) 1(100.0) 3(75.0) 2(11.8) 5(50.0) 0(0) 12(66.7) 1(100.0) 3(75.0) 1(25.0) 1(50.0) 1(100.0) bvFTD[n(%)] involuntary movements[n(%)] 3(50.0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) mortor signs[n(%)] 1(16.7) 2(100.0) 0(0) 0(0) 3(75.0) 7(41.2) 7(70.0) 0(0) 2(11.1) 0(0) 0(0) 0(0) 1(50.0) 0(0) Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 9 of 15 Table 4 Distribution and severity of neurodegenerative changes in patients with BIBD Cases with chorea Cases without chorea 1 2 345 6 Brain weight (g) 800 1190 880 1140 940 1230 Cortical atrophy F, T(base) F(tip) F&T(base) F&T(base) F,T(base) T(tip) Frontal cortex +++ +++ ++ +++ +++ +++ Cingulate gyrus +++ +++ +++ +++ +++ +++ Temporal cortex ++ + ++ ++ +++ +++ Hippocampus +++ + +++ +++ na +++ Amygdala +++ + na +++ +++ +++ Caudate nucleus +++ +++ +++ +++ +++ +++ Putamen +++ + +++ ++ +++ +++ Globus pallidus +++ ± ++ ++ ++ ++ Thalamus +++ ± ± ++ +++ + Subthalamic nucleus ± ± ± ± ± ± Nucleus basalis of Meynert + - ± ± ± + Cerebellar dentate nucleus ± - ± ± ± + Red nucleus ± ± ± na na ± Substantia nigra +++ + +++ ++ +++ +++ Locus coeruleus +++ - ± ± ++ ++ Pontine nucleus ± ± ± ± ± ± Dorsal vagal nucleus ± ± ± na ± ± Hypoglossal nucleus ± - ± ± ± ± Inferior olivary nucleus ± ± ± ± + + Spinal cord - - na na na ± Data for cases 2 through 6 were assembled from previously published materials [15, 29]. F, frontal lobe; T, temporal lobe; F(tip), frontal tip; F(base), frontal base, T(tip), temporal tip; T(base), temporal base. Rating for the severity of degeneration: -, no degeneration; ±, no neuronal loss but gliosis; +, slight neuronal loss and gliosis; ++, moderate neuronal loss and gliosis; +++, severe neuronal loss and gliosis. Degeneration in the corticospinal tract: +, present; -, absent. na, tissue not available was available). Morphology of the NCIs was variable, and either round, crescent, or annular. Furthermore, NCIs were also immunopositive for EWS (Fig. 5h) and TAF15 (Fig. 5g), but immunonegative for tau, α- synuclein, and TDP-43. The morphology and distribu- tion of NCIs were consistent with those previously de- scribed for BIBD [12, 13, 30]. BIBD cases had numerous basophilic inclusions compared with other types of FTLD-FUS. No BIBD (except for case 1) aFTLD-U, or unclassifiable cases had intermediate filament- immunoreactive NCIs. The occurrence of NCIs did not distinguish between the presence or absence of chorea. Biochemical findings Triton X-100 soluble and insoluble brain fractions ex- tracted from patients diagnosed as BIBD with chorea, aFTLD-U, or NIFID, as well as from a control patient Fig. 2 Macroscopic photograph of patient 1. The right hemisphere were separated by 7.5 % sodium dodecyl sulfate poly- of the patient is shown. Severe atrophy is present in the frontal acrylamide gel electrophoresis (SDS-PAGE) and immu- cortex and temporal tip. White arrows indicate the precentral gyrus. noblotted with an anti-FUS antibody (Fig. 6). All cases Scale bar, 2 cm showed a strong 73-kDa band in both the soluble and Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 10 of 15 Fig. 3 Neuropathological findings of case 1. a Semi-macro photograph of the right hemisphere showing severe atrophy of the frontal cortex and caudate nucleus (Klüver–Barrera stain). b Severe neuronal loss and astrocytosis in the supragranular layer of the frontal cortex (hematoxylin and eosin stain). c Marked neuronal loss and astrocytosis with tissue rarefarction in the caudate head (hematoxylin and eosin stain). a–c are from case 1. Scale bars, 1 cm (a); 200 μm(b and c) insoluble fractions. A strong band at approximately been described, and were considered atypical, as in Pick’s 33 kDa was detected in the sample from the patient di- disease [33–36]. One clinical report suggested that cho- agnosed as having BIBD with chorea, but this band was rea is present in FTD patients [37], reporting that two less prominent in the samples from the other patients. bvFTD cases could be associated with chorea but lack an HTT mutation. They further mentioned the potential Discussion of a clinical phenotype presenting chorea in FTD, but In the present study, we found that chorea in FTLD pa- unfortunately these cases lacked autopsy confirmation of tients is related to FUS pathology. Chorea involves con- the diagnosis. tinuous movements that are irregular and nonrepetitive, To our knowledge, chorea is rarely described in which differ from the repetitive stereotypic behaviors FTLD-tau cases. In patients with TDP-43 mutations, [31] that are present in FTLD patients. These patients chorea may be present [38, 39]. A patient with a K263E lacked muscle tone but show no muscle atrophy. In clin- TARDBP mutation developed FTD, supranuclear palsy, ical practice, a combination of various movements is and chorea, but not ALS, which was associated with often encountered in a single patient [31, 32]. Determi- TDP-43 accumulation predominantly in subcortical nu- nig the dominant movement type is important in such clei and the brainstem [40]. More recently, C9ORF72 re- cases. In our series, chorea was identified as the domin- peat expansions were reported to be the most common ant movement disorder syndrome by each attending genetic cause of non-HD syndromes [41]. Only two doctor during the disease course. Indeed, most HD pa- cases of FTLD-FUS with chorea have been previously re- tients not only exhibit the characteristic chorea, but also ported. Lee et al. described one patient with late onset display bradykinesia and akinesia [31]. We suggest that BIBD who was clinically diagnosed with ALS-plus syn- clinicians should be aware of the various involuntary drome, and showed diffuse chorea and cognitive dys- movements (including chorea) in treatment of FTLD- function but no parkinsonism [42]. The second case was FUS patients. described by Yokota et al. [15], and was case 3 in our Historically, there has been a general agreement that current study. In our study, we did not detect any chorea-like involuntary movements are rare in FTLD FTLD-tau or FTLD-TDP cases with chorea-like involun- [2]. Until recently, few cases of FTLD with chorea have tary movements. Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 11 of 15 Fig. 4 Neostriatum of FTLD-FUS cases. a and b Semi-macro photograph of the rostal neostriatum including the caudate nucleus head (rectangle), nucleus accumbens (asterisk), and putamen. Severe gliosis (Holzer stain) (a) and atrophy (hematoxylin and eosin stain) (b). c Marked neuronal loss and astrocytosis in the magnified area of the nucleus accumbens (shown by asterisk in b). d Severe neuronal loss with astrocytosis in the magnified area of the caudate nucleus (shown by the rectangle in b). In FTLD-FUS cases, the ventral putamen (e) is more involved than the dorsal region (f) Chorea is the most common clinical feature in HD, the responsible regions. Differences in the region initially with patients showing severe striatal atrophy. Although affected or the speed and direction of degeneration may the striatum is also severely affected in FTLD-FUS, cho- influence the clinical symptoms (including chorea) in rea is considered to be a relatively rare clinical feature in FTLD-FUS cases, although more detailed studies are FTLD-FUS, especially compared with HD. In FTLD- needed to clarify this issue. FUS, the topographic distribution pattern of the caudate As in the pathophysiology of HD, striatal projection nucleus, nucleus accumbens, and putamen is different neurons of the indirect pathway are vulnerable, while from HD. In our series, the head and body of the caud- those of the direct pathway are relatively preserved [46]. ate nucleus is more degenerated than the body and tail, Severe involvement of striatal projection neurons in both whereas the tail is more degenerated than the body and the indirect and direct pathways may explain the rarity head in HD [43]. Moreover, the nucleus accumbens is of chorea in FTLD-FUS. Alternatively, lesions outside severely degenerated in FTLD-FUS, in contrast to being the striatum may cause such a phenotypic difference. remarkably preserved in the advanced stage (stage 4) of The striatum regulates movement through interactions HD [43, 44]. With the evolution of FTLD-FUS, degener- with the cerebral cortex as well as with multiple subcor- ation in the neostriatum appears to move in a rostro- tical nuclei including the globus pallidus, subthalamic caudal, ventro-dorsal, and medio-lateral direction. nucleus, and some brainstem nuclei. The presence or Chorea is associated with the striatum (caudate nu- absence of chorea and related involuntary movements cleus and putamen), globus pallidus, substantia nigra, may depend on a delicate functional balance between subthalamic nucleus, and cerebral cortex [43, 45]. Unfor- these structures that form the striatal motor circuits. tunately, it is difficult to specify the correlation between Among the FTLD cases in our brain archives, only chorea and our neuropathological findings, since we did three patients displayed chorea, and all three patients not find any significantly different neurodegenerative were diagnosed as having FTLD-FUS with the BIBD changes between cases with and without chorea, even in subtype. None of the FTLD-tau or FTLD-TDP cases Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 12 of 15 Fig. 5 Inclusions detected in patients. Inclusions observed in cases 1 (a, e, f, g, h), 2 (c, d), and 3 (b). a A basophilic inclusion in the pontine nucleus (hematoxylin and eosin stain). b A basophilic inclusion in the inferior olivary nucleus (Klüver–Barrera stain). c, d, e and f FUS-immunopositive labelling of neuronal cytoplasmic inclusions (NCI) in the hippocampal dentate gyrus (c), inferior olivary nucleus (d, e) and caudate nucleus (f).g and h NCI in the thoracic spinal cord are immunopositive for TATA-binding protein-associated factor 15 (g) and Ewing sarcoma protein (h). Scale bars: 10 μm(a, b, d, f, and h); 30 μm(c); 15 μm(e) Fig. 6 Biochemical analysis of FUS. Proteins were sequentially extracted from brains of patients with BIBD, aFTLD-U, NIFID, and from a control subject. Fractions from patients diagnosed as BIBD with chorea (case 1, lane 1), aFTLD-U (case 9, lane 2), or NIFID (case 8, lane 3) and the control patient (lane 4) were separated by 7.5 % SDS-PAGE and immunoblotted with anti-FUS antibodies (a A300-302A; b HPA008784). All cases, including the control, show a strong 73-kDa band (white arrow) in both soluble and insoluble high-salt fractions. Additionally, the BIBD with chorea patient has a strong band at approximately 33 kDa (black arrow; b TX-ppt, lane 1), which is less prominent in the other samples Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 13 of 15 were associated with chorea. Because FTLD-tau and intensity in both soluble and insoluble fractions in all FTLD-TDP comprise the majority of FTLD cases, the cases. This result is inconsistent with a previous report, paucity of cases with chorea in these groups is remark- which showed that the 73-kDa band intensity in the in- able. BIBD is considered to be a generalized variant of soluble fraction was stronger in FTLD-FUS cases than Pick’s disease because of its relatively broad distribution normal controls [10]. In the present study, we identified of degenerative changes that extend to subcortical struc- a new FUS fragment of approximately 33 kDa in the in- tures [47]. The involvement of multiple subcortical nu- soluble fraction, which was derived from a patient diag- clei may increase the chances of some BIBD patients nosed as having BIBD with chorea. Because we could developing chorea. It may be noteworthy that BIBD pa- not biochemically analyze the BIBD case without chorea, tients without chorea show moderate to severe parkin- it is unclear whether this fragment is associated with the sonism symptoms in the later stage of disease, whereas pathogenic mechanism of BIBD with chorea. However, those with chorea lack parkinsonism throughout the dis- previous reports show a clear relationship between the ease course. Chorea in HD is treated with anti- band pattern of low molecular weight fragments of in- dopaminergic agents [48]. In BIBD, both the striatum soluble proteins and clinicopathological phenotypes in and substantia nigra undergo degenerative changes. FTLD-tau [52] and FTLD-TDP [22], suggesting that fur- Cases with relatively depleted nigral dopaminergic regu- ther biochemical study of insoluble FUS fragments may lation of the striatal motor circuits may be associated shed light on FTLD-FUS. with parkinsonism, while those with relatively less severe nigral dysfunction may develop chorea in the absence of Conclusions parkinsonism. Accordingly, postmortem histopatho- Our results suggest that choreoathetosis observed in pa- logical analysis of terminal stage lesions may not be sen- tients with bvFTD could be a clinical marker of the sitive enough to detect such a premortem functional underlying pathology of BIBD. In these cases, severe at- imbalance. rophy of the caudate nucleus and relatively preserved ni- The choreoathetoid movements identified in our series gral dopaminergic regulation might be associated with might be influenced by antipsychotic drugs as a risk factor chorea in the absence of parkinsonism in BIBD. Further for severe caudate atrophy. Previous studies have stated studies are needed to elucidate the exact mechanism by that chorea in HD is difficult to distinguish from tardive which chorea occurs, which in turn may develop new dyskinesia [49]. However, in general, the movements ob- therapeutic approaches for this incurable condition in served in our cases is unlikely to be diagnosed as tardive FTLD patients. dyskinesia because of the following points. Tardive dyskin- esia is defined in diagnostic criteria as developing due to Ethics approval and consent to participate the use of medications such as antipsychotic drugs (dopa- All patients, or in one case in which the patient had mine receptor blocking agents) for more than 3 months, died, the next of kin, provided written consent for aut- and specifically, dystonia must be present either during on- opsy and postmortem analyses for research purposes. going antipsychotic treatment or within 3 months of its dis- This study was approved by the ethics committee at the continuation [50]. In addition, second generation Tokyo Metropolitan Institute of Medical Science, and antipsychotics (e.g., olanzapine) rarely cause acute dystonic was performed in accordance with the ethical standards reactions [51], and tardive dyskinesia might only present outlined in the 1964 Declaration of Helsinki and its later when the patients take high-doses [49]. In HD, choreic amendments. movements are random, flowing from one part of the body to the other, and frequently superimposed by semi- Consent for publication purposeful movements in an attempt to mask involuntary Details that might disclose the identity of the partici- movements. In contrast, movement in tardive dyskinesia is pants in this study were omitted. slow, stereotypic, and repetitive. In cases 1 and 3, we were able to reconfirm such movement features in HD from the Competing interests clinical records. From our own experience, patients at the The authors declare that they have no competing interests. onset of tardive dyskinesia predominantly show akathisia and tremor, although choreiform movements may occur. Authors’ contributions IK performed microscopy, immunoblot, and statistical analyses, and also However, this point might reflect a limitation of our study, drafted the manuscript. ZK, TA, and OY participated in study design and and further efforts are needed to unveil the association be- coordination. ZK and TA helped with the microscopy analysis. OY, NA, OK, tween drug-induced choreoathetoid movements and KN, and KO organized the brain archives (including clinical information and selection of appropriate cases), and neuropathologically analyzed all cases. FTLD-FUS accumulation in diseased conditions. TN contributed to sample preparation and immunoblot analysis. SH In our biochemical analyses, a 73-kDa band corre- conceived the study and participated in its initial design. MHo contributed to sponding to full-length FUS was found at the same reagents, materials, and analysis tools. MHa participated in the study design Kawakami et al. Acta Neuropathologica Communications (2016) 4:36 Page 14 of 15 and initial manuscript draft. HA supervised the study design and its 8. Kwiatkowski Jr TJ, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ coordination. All authors read and approved the final manuscript. C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers Acknowledgments JE, Brown RH Jr. Mutations in the FUS/TLS gene on chromosome 16 cause We thank Ms. Hiromi Kondo, Yoko Shimomura, and Chie Haga (Tokyo familial amyotrophic lateral sclerosis. Science. 2009;323(5918):1205–8. Metropolitan Institute of Medical Science) for their excellent technical 9. Vance C, Rogelj B, Hortobágyi T, De Vos KJ, Nishimura AL, Sreedharan J, assistance. Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Funding Brown RH Jr. Mutations in FUS, an RNA processing protein, cause familial This research was supported by Grants-in-Aid from the Ministry of Health, amyotrophic lateral sclerosis type 6. Science. 2009;323(5918):1208–11. Labour and Welfare (13800916), and the Japan Society for the Promotion of doi:10.1126/science.1166066. Science (JSPS KAKENHI) (Grant No. 24500429). 10. Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie Author details IR. A new subtype of frontotemporal lobar degeneration with FUS Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, pathology. Brain. 2009;132:2922–31. doi:10.1093/brain/awp214. 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. Department of 11. Neumann M, Roeber S, Kretzschmar HA, Rademakers R, Baker M, Mackenzie Psychiatry, Tokyo Metropolitan Matsuzawa Hospital (TMMH), Tokyo, Japan. IR. Abundant FUS-immunoreactive pathology in neuronal intermediate 3 4 Department of Neurology, JA Toride Medical Center, Ibaraki, Japan. Division filament inclusion disease. Acta Neuropathol. 2009;118:605–16. of Clinical Medicine, Department of Neuropsychiatry, Faculty of Medicine, doi:10.1007/s00401-009-0581-5. University of Tsukuba, Ibaraki, Japan. Department of Neuropsychiatry, 12. Munoz DG, Neumann M, Kusaka H, Yokota O, Ishihara K, Terada S, Kuroda S, Okayama University Graduate School of Medicine, Dentistry and Mackenzie IR. FUS pathology in basophilic inclusion body disease. Acta Pharmaceutical Sciences, Okayama, Japan. Department of Psychiatry, Neuropathol. 2009;118:617–27. doi:10.1007/s00401-009-0598-9. 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