Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease that commonly causes dementia [1]. In clinical practice, FTLD is considered a syndrome and is presently classified by the consensus criteria of Neary and colleagues [2] into three subtypes: frontotemporal dementia (FTD), progressive nonfluent aphasia, and semantic dementia. Most patients with progressive nonfluent aphasia and semantic dementia show some features of FTD (e.g., behavioral symptoms), later on in their disease course. Those with FTD as the dominant clinical picture in the early disease stage are currently referred to as having a behavioral variant of FTD (bvFTD) [3].

The neuropathology of FTLD is as complex as the clinical syndrome. Virtually all patients with FTLD have abnormal intracellular accumulations of disease-specific molecules. These molecules include tau, TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS) [4, 5]. FTLD cases are now assigned to one of three major molecular subgroups based on histopathological findings: FTLD-tau, FTLD-TDP, or FTLD-FUS [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-positive. Subsequently, it became apparent that the majority of FTLD-U cases were in fact FTLD-TDP, (i.e., FTLD with TDP-43 inclusions), with 10 to 20 % of FTLD-U cases remaining as tau-negative and TDP-43-negative FTLD. In 2009, FUS was identified as one of the genes for familial amyotrophic lateral sclerosis (ALS) [8, 9]. Consequently, most tau-negative and TDP-43-negative FTLD inclusions were found to be FUS positive [10–12]. Accordingly, cases of FTLD with FUS-positive inclusions are now collectively called FTLD-FUS. Three rare forms of FTLD are considered to be subtypes of FTLD-FUS: atypical FTLD-U (aFTLD-U), basophilic inclusion body disease (BIBD), and neuronal intermediate filament inclusion disease (NIFID) [11]. Although these three subtypes may represent a continuous spectrum of FTLD-FUS disease, detailed histopathological investigation suggests they are closely related but distinct entities [11–13].

Several previous reports have challenged these clinicopathological relationships in FTLD patients. In FTLD-FUS, which is present in a minority of FTLD patients, such relationships have only recently been described [12, 14–19]. These studies reveal that FTLD-FUS patients may have a relatively younger onset (often before the age of 40 years), absence of a family history of the disease, and severe caudate atrophy on imaging [16–18]. Recently, Snowden et al. suggested that aFTLD-U is associated with a cognitive and behavioral phenotype that is distinct from the other forms of FTLD-FUS (specifically, NIFID and BIBD). They noted that aFTLD-U is characterized by prominent obsessiveness, repetitive behaviors and rituals, social withdrawal and lack of engagement, hyperorality with pica, and marked stimulus-bound behavior (e.g., utilization behavior). Furthermore, they suggested that clinical presentation of FTLD with associated FUS pathology may not be related to mutation of the FUS gene. Additionally, 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, parkinsonism, and memory impairment [15]. They also noted that it is difficult to differentiate BIBD from NIFID in clinical practice. While these reports indicate variations in behavioral and cognitive features of FTLD-FUS, the features that are distinct from the other forms of FTLD (i.e., FTLD-tau and FTLD-TDP) remain to be clarified.

Patients with FTLD often report associated motor system impairments, such as parkinsonism and motor neuron disease [2, 20], whereas association of FTLD with chorea and athetosis has rarely been reported. In the clinical diagnostic criteria for FTLD [2], choreoathetosis is one of the diagnostic exclusion features. Chorea is an abnormal involuntary movement characterized by excessive, spontaneous movements that are irregularly timed, nonrepetitive, randomly distributed, and abrupt in character [21]. The classical form of chorea occurs in Huntington’s disease (HD), an inherited neurodegenerative disease in which atrophy of the striatum is the predominant pathology. However, the striatum is also severely affected in all subtypes of FTLD. The results of a recent report found significantly greater striatal atrophy by magnetic resonance imaging (MRI) in FTLD-FUS patients than in FTLD-TDP and FTLD-tau patients, thereby distinguishing FTLD-FUS from other forms of FTLD [16].

Here, we identified three cases of bvFTD with chorea, which were diagnosed as FTLD-FUS and exhibit histopathological results indicative of the BIBD subtype. We identified the behavioral and cognitive features that distinguish this group from other FTLD-FUS cases. Further, we also reviewed the clinical records of 72 FTLD cases to identify distinct clinical features that are predictive of FTLD-FUS, and in particular the BIBD subtype.

In the present study, we found that chorea in FTLD patients is related to FUS pathology. Chorea involves continuous movements that are irregular and nonrepetitive, which differ from the repetitive stereotypic behaviors [31] that are present in FTLD patients. These patients lacked muscle tone but show no muscle atrophy. In clinical practice, a combination of various movements is often encountered in a single patient [31, 32]. Determinig the dominant movement type is important in such cases. In our series, chorea was identified as the dominant movement disorder syndrome by each attending doctor during the disease course. Indeed, most HD patients not only exhibit the characteristic chorea, but also display bradykinesia and akinesia [31]. We suggest that clinicians should be aware of the various involuntary movements (including chorea) in treatment of FTLD-FUS patients.

Historically, there has been a general agreement that chorea-like involuntary movements are rare in FTLD [2]. Until recently, few cases of FTLD with chorea have been described, and were considered atypical, as in Pick’s disease [33–36]. One clinical report suggested that chorea is present in FTD patients [37], reporting that two bvFTD cases could be associated with chorea but lack an HTT mutation. They further mentioned the potential of a clinical phenotype presenting chorea in FTD, but unfortunately these cases lacked autopsy confirmation of the diagnosis.

To our knowledge, chorea is rarely described in FTLD-tau cases. In patients with TDP-43 mutations, chorea may be present [38, 39]. A patient with a K263E TARDBP mutation developed FTD, supranuclear palsy, and chorea, but not ALS, which was associated with TDP-43 accumulation predominantly in subcortical nuclei and the brainstem [40]. More recently, C9ORF72 repeat expansions were reported to be the most common genetic cause of non-HD syndromes [41]. Only two cases of FTLD-FUS with chorea have been previously reported. Lee et al. described one patient with late onset BIBD who was clinically diagnosed with ALS-plus syndrome, and showed diffuse chorea and cognitive dysfunction but no parkinsonism [42]. The second case was described by Yokota et al. [15], and was case 3 in our current study. In our study, we did not detect any FTLD-tau or FTLD-TDP cases with chorea-like involuntary movements.

Chorea is the most common clinical feature in HD, with patients showing severe striatal atrophy. Although the striatum is also severely affected in FTLD-FUS, chorea is considered to be a relatively rare clinical feature in FTLD-FUS, especially compared with HD. In FTLD-FUS, the topographic distribution pattern of the caudate nucleus, nucleus accumbens, and putamen is different from HD. In our series, the head and body of the caudate nucleus is more degenerated than the body and tail, whereas the tail is more degenerated than the body and head in HD [43]. Moreover, the nucleus accumbens is severely degenerated in FTLD-FUS, in contrast to being remarkably preserved in the advanced stage (stage 4) of HD [43, 44]. With the evolution of FTLD-FUS, degeneration in the neostriatum appears to move in a rostro-caudal, ventro-dorsal, and medio-lateral direction.

Chorea is associated with the striatum (caudate nucleus and putamen), globus pallidus, substantia nigra, subthalamic nucleus, and cerebral cortex [43, 45]. Unfortunately, it is difficult to specify the correlation between chorea and our neuropathological findings, since we did not find any significantly different neurodegenerative changes between cases with and without chorea, even in the responsible regions. Differences in the region initially affected or the speed and direction of degeneration may influence the clinical symptoms (including chorea) in FTLD-FUS cases, although more detailed studies are needed to clarify this issue.

As in the pathophysiology of HD, striatal projection neurons of the indirect pathway are vulnerable, while those of the direct pathway are relatively preserved [46]. Severe involvement of striatal projection neurons in both the indirect and direct pathways may explain the rarity of chorea in FTLD-FUS. Alternatively, lesions outside the striatum may cause such a phenotypic difference. The striatum regulates movement through interactions with the cerebral cortex as well as with multiple subcortical nuclei including the globus pallidus, subthalamic nucleus, and some brainstem nuclei. The presence or absence of chorea and related involuntary movements may depend on a delicate functional balance between these structures that form the striatal motor circuits.

Among the FTLD cases in our brain archives, only three patients displayed chorea, and all three patients were diagnosed as having FTLD-FUS with the BIBD subtype. None of the FTLD-tau or FTLD-TDP cases were associated with chorea. Because FTLD-tau and FTLD-TDP comprise the majority of FTLD cases, the paucity of cases with chorea in these groups is remarkable. BIBD is considered to be a generalized variant of Pick’s disease because of its relatively broad distribution of degenerative changes that extend to subcortical structures [47]. The involvement of multiple subcortical nuclei may increase the chances of some BIBD patients developing chorea. It may be noteworthy that BIBD patients without chorea show moderate to severe parkinsonism symptoms in the later stage of disease, whereas those with chorea lack parkinsonism throughout the disease course. Chorea in HD is treated with anti-dopaminergic agents [48]. In BIBD, both the striatum and substantia nigra undergo degenerative changes. Cases with relatively depleted nigral dopaminergic regulation of the striatal motor circuits may be associated with parkinsonism, while those with relatively less severe nigral dysfunction may develop chorea in the absence of parkinsonism. Accordingly, postmortem histopathological analysis of terminal stage lesions may not be sensitive enough to detect such a premortem functional imbalance.

The choreoathetoid movements identified in our series might be influenced by antipsychotic drugs as a risk factor for severe caudate atrophy. Previous studies have stated that chorea in HD is difficult to distinguish from tardive dyskinesia [49]. However, in general, the movements observed in our cases is unlikely to be diagnosed as tardive dyskinesia because of the following points. Tardive dyskinesia is defined in diagnostic criteria as developing due to the use of medications such as antipsychotic drugs (dopamine receptor blocking agents) for more than 3 months, and specifically, dystonia must be present either during ongoing antipsychotic treatment or within 3 months of its discontinuation [50]. In addition, second generation antipsychotics (e.g., olanzapine) rarely cause acute dystonic reactions [51], and tardive dyskinesia might only present when the patients take high-doses [49]. In HD, choreic movements are random, flowing from one part of the body to the other, and frequently superimposed by semi-purposeful movements in an attempt to mask involuntary movements. In contrast, movement in tardive dyskinesia is slow, stereotypic, and repetitive. In cases 1 and 3, we were able to reconfirm such movement features in HD from the clinical records. From our own experience, patients at the onset of tardive dyskinesia predominantly show akathisia and tremor, although choreiform movements may occur. However, this point might reflect a limitation of our study, and further efforts are needed to unveil the association between drug-induced choreoathetoid movements and FTLD-FUS accumulation in diseased conditions.

In our biochemical analyses, a 73-kDa band corresponding to full-length FUS was found at the same intensity in both soluble and insoluble fractions in all cases. This result is inconsistent with a previous report, which showed that the 73-kDa band intensity in the insoluble fraction was stronger in FTLD-FUS cases than normal controls [10]. In the present study, we identified a new FUS fragment of approximately 33 kDa in the insoluble fraction, which was derived from a patient diagnosed as having BIBD with chorea. Because we could not biochemically analyze the BIBD case without chorea, it is unclear whether this fragment is associated with the pathogenic mechanism of BIBD with chorea. However, previous reports show a clear relationship between the band pattern of low molecular weight fragments of insoluble proteins and clinicopathological phenotypes in FTLD-tau [52] and FTLD-TDP [22], suggesting that further biochemical study of insoluble FUS fragments may shed light on FTLD-FUS.

Our results suggest that choreoathetosis observed in patients with bvFTD could be a clinical marker of the underlying pathology of BIBD. In these cases, severe atrophy of the caudate nucleus and relatively preserved nigral dopaminergic regulation might be associated with chorea in the absence of parkinsonism in BIBD. Further studies are needed to elucidate the exact mechanism by which chorea occurs, which in turn may develop new therapeutic approaches for this incurable condition in FTLD patients.