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Home , Frontotemporal dementia

and Related Disorders 20 (2014) 957e964

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Parkinsonism and Related Disorders

journal homepage: www.elsevier.com/locate/parkreldis

Editor's comment: Familial frontotemporal with parkinsonism is one of those disorders that occurs frequently enough that movement disorders specialists know they should be familiar with it, but infrequently enough that it is difficult to remember it, particu- larly in light of its complexities. Therefore, this review by Siuda and colleagues is an especially informative refresher that provides a cogent, succinct exposition of the clinical presentation of the various mutations, not just on the more familiar chromosome 17, but also on chro- mosomes 1, 3, 9 and 16, that produce the disorder. In addition to detailing the clinical presentation of the various mutations, the authors describe the characteristics, delineate the pathologic findings and discuss the differential diagnosis and treatment of this important disorder. Ronald F. Pfeiffer, Editor-in-Chief Department of , University of Tennessee HSC, 855 Monroe Avenue, Memphis, TN 38163, USA

Review Parkinsonian syndrome in familial

* Joanna Siuda a, b, Shinsuke Fujioka c, Zbigniew K. Wszolek c, a Department of Neurology, Silesian Medical University, Katowice, Poland b Department of Neuroscience, Mayo Clinic Jacksonville, FL, USA c Department of Neurology, Mayo Clinic Jacksonville, FL, USA article info abstract

Article history: Parkinsonism in frontotemporal dementia (FTD) was first described in families with mutations in the Received 26 March 2014 microtubule-associated protein tau (MAPT) and progranulin (PRGN) genes. Since then, mutations in several Received in revised form other genes have been identified for FTD with parkinsonism, including chromosome 9 open reading frame 27 May 2014 72 (), chromatin modifying protein 2B (CHMP2B), valosin-containing protein (VCP), fused in sar- Accepted 6 June 2014 coma (FUS) and transactive DNA-binding protein (TARDBP). The clinical presentation of patients with fa- milial forms of FTD with parkinsonism is highly variable. The parkinsonism seen in FTD patients is usually Keywords: characterized by akinetic-rigid syndrome and is mostly associated with the behavioral variant of FTD Parkinsonism ' Familial (bvFTD); however, some cases may present with classical Parkinson s disease. In other cases, atypical Frontotemporal dementia parkinsonism resembling progressive supranuclear palsy (PSP) or (CBS) has also Genetics been described. Although rare, parkinsonism in FTD may coexist with motor disease. Structural Autosomal dominant neuroimaging, which is crucial for the diagnosis of FTD, shows characteristic patterns of brain atrophy Mutation associated with specific mutations. Structural neuroimaging is not helpful in distinguishing among patients with parkinsonian features. Furthermore, dopaminergic imaging that shows nigrostriatal neuro- degeneration in FTD with parkinsonism cannot discriminate parkinsonian syndromes that arise from different mutations. Generally, parkinsonism in FTD is levodopa unresponsive, but there have been cases where a temporary benefit has been reported, so dopaminergic treatment is worth trying, especially, when motor and non-motor manifestations can cause significant problems with daily functioning. In this review, we present an update on the clinical and genetic correlations of FTD with parkinsonism. © 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

1. Introduction

In 1996, an international consensus conference was held in Ann Arbor, MI, USA, to discuss the association of parkinsonism with frontotemporal dementia (FTD), and the term Frontotemporal De- * Corresponding author. Department of Neurology, Mayo Clinic Jacksonville, 4500 mentia and Parkinsonism linked to chromosome 17 (FTDP-17) was San Pablo Road, Jacksonville, FL 32224, USA. Tel.: þ1 904 953 7229; fax: þ1 904 953 0760. introduced [1]. At that time, 13 families were described as having E-mail address: [email protected] (Z.K. Wszolek). FTDP-17 with an autosomal dominant pattern of inheritance. The http://dx.doi.org/10.1016/j.parkreldis.2014.06.004 1353-8020/© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). 958 J. Siuda et al. / Parkinsonism and Related Disorders 20 (2014) 957e964 clinical features of patients in these families were characterized as parkinsonian features and other motor and non-motor manifesta- behavioral changes, dementia, parkinsonism, amyotrophy, dysto- tions that could be present in patients with FTD. nia, and supranuclear gaze palsy. FTD is clinically characterized by early behavioral changes and/or 2.1. FTDP-17 (MAPT) language impairment, which is followed by cognitive decline and dementia. Parkinsonism is usually present in the behavioral variant Mutations in the MAPT account for up to approximately 50% of of FTD (bvFTD), but it is rarely seen in primary progressive FTD cases and the majority of FTDP-17 cases. Over 50 pathogenic (PPA), which is a language variant of FTD [2e4]. Parkinsonism in FTD MAPT mutations have been described (www.molgen.ua.ac.be/ may present before, during, or after the development of behavioral FTDMutations) [16]. The mode of inheritance is autosomal domi- or language disturbances. The clinical manifestations of parkin- nant. The mean age at onset is 49 years, but this can range from 25 sonism seen in FTD patients are varied. Parkinsonian syndrome in to 76 years. The mean disease duration is approximately 7 years, FTD ranges from an apparent classical presentation of Parkinson's but the disease duration could be longer; for example, tau p.R406W disease (PD) to atypical parkinsonism that resembles progressive mutation carriers can survive into the eighth decade of life supranuclear palsy (PSP) and corticobasal syndrome (CBS) [2]. [12,17e19]. A positive family history is almost always present in Up to 40% of FTD patients have a positive family history, which MAPT mutation carriers, and their penetrance is nearly 100% [20]. suggests a strong genetic component to these disorders. It is esti- No gender predilection has been identified [21]. The clinical pre- mated that autosomal dominant cases account for over 13% of the sentation of FTDP-17 (MAPT) is variable, but cardinal signs include total number of FTD cases [5,6]. Currently, the best understood personality and behavioral changes, dementia, and parkinsonism. forms of autosomal dominant FTD associated with parkinsonism At the onset of the disease, only one of these signs is typically are those linked to chromosome 17 and related to mutations in the exhibited, but in advanced disease stages, all of the signs could be microtubule-associated protein tau (MAPT) and progranulin (PGRN) present. Based on the type of MAPT mutation, the initial FTDP-17 genes [7e9]. Besides MAPT and PGRN, the chromosome 9 open phenotype can be divided into frontotemporal dementia- reading frame 72 (C9ORF72) gene, which was identified in 2011, predominant or parkinsonism-predominant [22]. However, the is known to be the major causative gene for familial FTD most common clinical presentation of FTDP-17 (MAPT) is bvFTD. that is also associated with parkinsonism [10,11]. Mutations in FTDP-17 (MAPT) patients experience slowly progressive dementia four other genes: chromatin modifying protein 2B (CHMP2B), with gradual functional decline. Motor neuron deficits such as valosin-containing protein (VCP), transactive DNA-binding protein amyotrophy and fasciculation are rarely seen [23e25]. (TARDBP), and fused-in-sarcoma (FUS) are identified in a minority of FTD cases accompanied by the parkinsonian phenotype [12e15]. 2.1.1. Parkinsonism in FTDP-17 (MAPT) In this review we describe the clinical features in familial FTD with Parkinsonism can be the first manifestation of FTDP-17 caused parkinsonism with known genetic defect. by mutations in MAPT (FTDP-17 (MAPT)), and it can initially have a good response to levodopa therapy. Because of this, some patients 2. Clinical genetics, general characteristic, and parkinsonian could be misdiagnosed as having PD at the early stage of the dis- features in familial FTD with parkinsonism ease. When parkinsonism is the first symptom of FTDP-17, it is usually caused by mutations in exon 10 of the MAPT gene (p.N279K, Molecular genetic studies in patients with FTD associated with p.delN296, p.S305S, p.N296N, and p.G303V) [17,25]. However in parkinsonism have identified mutations in several genes: MAPT, some FTDP-17 (MAPT) mutations, parkinsonism occurs late in the PGRN, C9ORF72, CHMP2B, and VCP. Mutations found in common ALS disease course (p.P301S and p.N296H), or is rare and minimal genes, TARDBP and FUS, may also contribute to FTD associated with (p.P301L, p.S305N and p.G272V). Parkinsonism seen in FTDP-17 parkinsonism (Table 1). Parkinsonism seen in FTD patients carrying (MAPT) patients includes severe limb bradykinesia, axial and limb different autosomal dominant gene mutations can have a diverse rigidity, and postural instability. These signs are often symmetric, clinical manifestation. In Table 2 we provide a summary of and there is usually no resting . Postural or action tremor

Table 1 The profile of genes associated with parkinsonism in FTD.

MAPT PGRN C9ORF72 CHMP2B VCP TARDBP FUS

Chromosomal localization 17q21.32 17q.21.31 9p21.2 3p11.2 9p13.3 1p36.22 16p11.2 Inheritance AD AD AD AD AD AD AD Penetrance Almost 100% 90% by 70 years Probably high UKN Incomplete UKN UKN Anticipation 0 þþþUKN UKN UKN UKN Estimated mutation frequency in FTD 0e50% 3e26% 14-48% <1% <1% <1% <1% Mean AAO (range) 49 years (25e76) 59 years (44e83) 55 years (33e75) 58 years 55 years 54 years 43 years (46e71) (37e79) (35e74) (30e60) Mean DD (range) 7 years (2e30) 7 years (1e14) 4.5 years (3e10) 10 years (5e21) 6 years (1e21) 3 years (1e6) 3 years (3e7) Most frequent initial Dx. bvFTD ± P bvFTD ± P FTD/ALS ALS, FTD IBMPFD ALS, bvFTD FTD, ALS Clinical Dx. during the Most FTD FTD FTD FTD FTD MNDa FTD disease course frequent Dx. Parkinsonism CBS MNDa Dementia MNDa MNDa Relatively Pyramidal signs Parkinsonism Parkinsonism Parkinsonism Dementia FTD Dementia common Dx. PSP Pyramidal signs Parkinsonism Rare Dx. CBS MDSa CBS MNDa Language Dementia Parkinsonism MDSa Hallucinations impairment Parkinsonism Prominent neuropathology Tau TDP-43 TDP-43, U U TDP-43 TDP-43 FUS

AAO ¼ age at onset; AD ¼ autosomal dominant; ALS ¼ amyotrophic lateral sclerosis; bvFTD ¼ behavioral variant frontotemporal dementia; DD ¼ disease duration; Dx. ¼ diagnosis; FTD ¼ frontotemporal dementia; FUS ¼ fused in sarcoma; IBMPFD ¼ inclusion body myopathy and Paget's disease of the bone and frontotemporal dementia; P ¼ Parkinsonism; TDP-43 ¼ transactive DNA-binding protein; U ¼ ; UKN ¼ unknown; 0 ¼ not present; (þ) ¼ present in some cases; (þþ) ¼ frequent. a Includes upper and deficits. J. Siuda et al. / Parkinsonism and Related Disorders 20 (2014) 957e964 959

Table 2 Summary of characteristics of parkinsonism and motor and non-motor manifestations seen in patients carrying autosomal dominant genes mutations for FTD associated with parkinsonism.

MAPT PGRN C9ORF72 CHMP2B VCP TARDBP FUS

Parkinsonism Bradykinesia þþþ þþþ þþ þ þþ þþ þþ Rigidity þþþ þþþ þþ þþ þ þþ þ Postural instability þþ þþ þ Resting tremor ±± ± þ Gait impairment þþþþ PSP phenotype Supranuclear gaze palsy þþ þ þ þ þ Difficulty initiating saccades þþ þ þ þ þ CBS phenotype Apraxia þ þþ þ þþ þþ þ Cortical sensory loss þþ Alien limb phenomenon þþþ Other movement disorders Tremor (except resting tremor) ± þ þþ þþþþþþ þþþþ ± Tics þ RBD ± þ Asymmetry þþþþ Levodopa responsiveness Might be temporarily Usually not Might be temporarily UKN Might be Effective UKN effective effective effective effective

CBS ¼ corticobasal syndrome; PSP ¼ progressive supranuclear palsy; RBD ¼ REM behavioral ; UKN ¼ unknown; () ¼ not present/not assessed; (±) ¼ infrequent; (þ) ¼ present in some cases; (þþ) ¼ moderate frequency; (þþþ) ¼ very frequent. may be observed, but this is rare. Atypical parkinsonian syndromes is rarely present; however, p.K317M, are also described in association with MAPT mutations; these are p.N296N, and p.P301L mutations could be associated with amyo- more likely associated with PSP syndrome than CBS. Parkinsonism trophy, fasciculation, and denervation. The most common MAPT accompanied by oculomotor abnormalities is usually present in mutations associated with parkinsonian features and their clinical patients with p.delN296, p.S305S, and p.N279K mutations; these presentations are summarized in Table 3. include slowed saccades, supranuclear gaze palsy resembling PSP syndrome. Rarely, CBS with eyelid apraxia may be present in MAPT 2.2. FTDP-17 (PGRN) mutations (p.P301S). Parkinsonism in FTDP-17 (MAPT) may also be accompanied by bulbar symptoms, including dysarthria and Mutations in the PGRN account for up to approximately 26% of dysphagia, or corticospinal tract involvement, which may present FTD cases. More than 70 pathogenic PGRN mutations have been fl as hyperre exia, clonus, extensor plantar responses, and dystonia described so far (www.molgen.ua.ac.be/FTDMutations). The mode or myoclonus. Patients may occasionally respond to levodopa of inheritance is autosomal dominant. The mean age at onset is therapy at the initial stage of their illness; however, that is rarely around 59 years, almost a decade later than that of FTDP-17 (MAPT) sustained during the disease course [4,21,23,26]. There is no clear cases, but it can range from 44 to 83 years [3]. The disease duration association between cognitive decline and the presence, severity, or is variable and ranges from 1 to 14 years and is usually shorter on onset of parkinsonism in FTDP-17 (MAPT). In most MAPT mutations, average than that of MAPT mutation carriers. PGRN mutations show

Table 3 The MAPT mutations in FTDP-17 and their characteristic clinical phenotype.

Gene MAPT

Amino acid change N279K delN296 S305S N296N G303V K317M P301S N296H P301L S305N G272V Mutation type Point Deletion Silent Silent Point Point Point Point Point Point Point Genomic region Exon 10 Exon 10 Exon 10 Exon 10 Exon 10 Exon 11 Exon 10 Exon 10 Exon 10 Exon 10 Exon 9 AAO (years) 41e50 31e40 >50 >50 31e40 41e50 30 >50 41e50 31e40 41e50 DD (years) 6e10 56e10 6e10 56e10 6e10 56e10 56e10 Early parkinsonism þþþ þþþ þþþ þþþ þþþ þþþ Late parkinsonism þþþþþþ Rare parkinsonism þþþ Personality changes þþ þþþ þþþ þþ þþþ þþþ þþþ Dementia þþ þþþ þþþ þ þ þþþ þþþ þþþ þþþ Language difficulties þþþþþþþþþþþþ Supranuclear gaze palsy þþþþþþþþþþ Apraxia þ þþþþ Pyramidal signs þþþþþþþ Amyotrophy þþþ

AAO ¼ age at onset; DD ¼ disease duration; () ¼ not present/not assessed; (þ) ¼ rare; (þþ) ¼ present in some cases; (þþþ) ¼ frequent. 960 J. Siuda et al. / Parkinsonism and Related Disorders 20 (2014) 957e964 age-dependent penetrance. The penetrance reaches 90% at age 70 from cases with FTD and ALS revealed an association with years [27e30]. A wide spectrum of cognitive, behavioral, and motor age at onset in the frontal cortex and disease duration in the cer- features in FTDP-17 is associated with PGRN mutations, but the ebellum, but a similar association was not detected in blood [39].It particular type of mutation does not predict the clinical syndrome is not yet known whether the C9ORF72 expansion length contrib- [27e29,31,32]. PGRN mutations are usually associated with bvFTD, utes to the different phenotypes associated with the disease thus but unlike MAPT mutation carriers, an isolated language dysfunc- further studies are needed. The mode of inheritance is autosomal tion and primary progressive aphasia syndrome (PPA) can be also dominant. Anticipation was observed in some families. The age at observed [3]. A careful language evaluation may help to predict onset and disease duration is highly variable. The mean age at onset PGRN mutations in FTDP patients [33]. Measurement of serum is around 55 years (range 33e75 years). The mean disease duration progranulin levels, which are extremely low in PGRN mutation is approximately 4.5 years, and typically ranges from 3 to 10 years carriers, may help achieve a correct diagnosis in FTDP-17 inde- [40,41]. The clinical phenotype of C9ORF72 expansion carriers pendently of the phenotypic presentation when genetic testing is mainly consists of bvFTD, ALS, or FTD with motor neuron disease. unavailable. It has been suggested that this approach could be used as a cost-effective prediction of PGRN mutations among FTDP-17 2.3.1. Parkinsonism in C9ORF72 expansion patients [33,34]. Parkinsonism is reported in about one-third of patients with C9ORF72 expansions [41,42]. Parkinsonism in FTD due to C9ORF72 2.2.1. Parkinsonism in FTDP-17 (PGRN) repeat expansions is usually characterized by a relatively sym- Mild parkinsonism characterized by akinetic-rigid syndrome metric akinetic-rigid syndrome and gait disturbances. Postural and occurs relatively frequently (40e60%) in patients with PGRN mu- action can occasionally be observed, but resting tremor is tations, but this is usually late in the disease course and occurs after rarely seen [40,43]. Parkinsonism is usually associated with pre- the development of FTD phenotype [9]. In minority of the cases dominant bvFTD or FTD/ALS, but this was not described in patients carrying PGRN mutations (p.Leu271LeufsX10), parkinsonism has with pure ALS [44,45]. Parkinsonism in C9ORF72 FTD patients may been described as a predominant clinical manifestation [4,31]. remain pure, without associated cognitive deficits or dementia for Some FTDP-17 cases with PGRN mutations present both visual over 10 years, but this is rare [45,46]. Cases that present with CBS or hallucinations and parkinsonism, which is suggestive of PSP syndromes have also been described [47]. Parkinsonian fea- disease [21,35]. Some cases may have atypical parkinsonian fea- tures in patients with C9ORF72 expansion typically evolve within tures characterized by progressive asymmetric rigidity and apraxia, the first years of the disease course and can temporarily be levo- which is reminiscent of CBS (p.V200GfsX18, p.A9D and dopa responsive, but most patients do not benefit from anti- p.E498DfsX12) [36]. Asymmetric apraxia that is consistent with parkinsonian treatment [40]. parietal lobe dysfunction and is associated with parkinsonian signs that present early in the disease course may help distinguish PGRN 2.4. FTD-3 (CHMP2B) mutation carriers from other FTD patients with parkinsonian syn- dromes. PGRN mutations are suggested to be one of the most In 2005, the CHMP2B gene, located on chromosome 3p11.2, was common causes of familial CBS [29]. Parkinsonism seen in FTDP-17 associated with FTD linked to chromosome 3 (FTD-3) in large (PGRN) cases may initially respond to levodopa; however, in most kindred from Denmark and one unrelated Belgian familial FTLD cases, it is not levodopa-sensitive [37,38]. The specific PGRN mu- patient [29]. The CHMP2B gene mutations are currently understood tations in which parkinsonism are most likely to be observed are to be a rare genetic cause of familial FTD; only four pathogenic summarized in Table 4. mutations have been described (www.molgen.ua.ac.be/ FTDMutations). The mode of inheritance is autosomal dominant. 2.3. C9ORF72 expansion Since the disease has a subtle onset and often slow progression, the exact age at onset can be difficult to determine. The mean age at The C9ORF72 expansion accounts for up to approximately 48% of onset has been reported to be around 58 years, and the mean FTD cases. The C9ORF72 gene located on chromosome 9 encodes disease duration is approximately 10 years with great variability the chromosome 9 open reading frame 72 protein. Abnormal ex- [48,49]. CHMP2B mutation carriers typically present with bvFTD at pansions of a noncoding GGGGCC hexanucleotide repeat an early stage of their disease, but patients can develop more global (700e1600 repeats) cause a variable combination of clinical phe- loss of cognition [50]. Infrequently, bvFTD can be accompanied by notypes. The C9ORF72 expansion length in specific brain regions motor symptoms, including parkinsonian features, dystonia,

Table 4 The PGRN mutations in FTDP-17 and their characteristic clinical phenotype.

Gene PGRN

Amino acid change R493X T304LfsX58 C253X A9D T7A G401X E498DfsX12 L271LfsX10 V200GfsX18 Mutation type Point Insertion Deletion Point Point Point Deletion Deletion Point Genomic region Exon 12 Exon 9 Exon 8 Exon 2 Exon 2 Exon 11 Exon 12 Exon 7 Intron 7 AAO (years) 44e62 57 60 46e59 50 55e69 NA 66 62 DD (years) 3e9 5 NA 4e7NANANA1e89 Parkinsonism þþ þ þ þ þ þ þ þþþ þ Personality changes þ þ þþ þ þ þþ þ þþ þ Dementia þþ þ þþþþ þ þ Language difficulties þþ þ þ þ þ þ Supranuclear gaze palsy þþ Apraxia þþ þþþþþþþþþþ Pyramidal signs þ Amyotrophy þ

AAO ¼ age at onset; DD ¼ disease duration; NA ¼ not present/not assessed; () ¼ absent; (þ) ¼ rare; (þþ) ¼ present in some cases; (þþþ) ¼ frequent. J. Siuda et al. / Parkinsonism and Related Disorders 20 (2014) 957e964 961 pyramidal signs, and myoclonus; this is especially true in the later with parkinsonian features. Responsiveness to levodopa therapy is stages of the disease [51]. typically good.

2.4.1. Parkinsonism in FTD-3 (CHMP2B) 2.7. FUS mutations bvFTD in FTD-3 can be accompanied by motor symptoms, which include parkinsonian features, dystonia, pyramidal signs and In 2009, mutations in the FUS gene were originally described in myoclonus, but this finding is infrequent or is found late in the familial ALS. Mutations in the FUS account for up to 4% of familial disease course [51]. Classical parkinsonism is seen in a minority of ALS cases [63]. The FUS gene, located on chromosome 16p11.2., patients carrying CHMP2B mutations, and it is usually characterized encodes fused in sarcoma protein [64,65]. A number of specific by asymmetrical akinetic-rigid syndrome [50,52]. Parkinsonism in mutations in FUS have been suggested to cause FTD and essential FTD-3 typically occurs a few years after the symptomatic disease tremor [66,67]. In a cohort of 476 familial ALS and 41 sporadic ALS onset. Rarely, an atypical parkinsonian phenotype that is accom- cases, a family with the FUS p.R521C mutation was identified in the panied by supranuclear gaze palsy or apraxia could be observed in proband, who developed ALS with parkinsonism and dementia. FTD-3. Responsiveness to levodopa therapy has not been reported. 2.7.1. Parkinsonism in FUS mutations 2.5. VCP mutations A single case of a patient with a p.M254V mutation that was associated with bvFTD and parkinsonian signs that developed The VCP gene is located on chromosome 9p13.3 and encodes further in the disease course has been reported [15]. The parkin- valosin-containing protein. In 2004, a mutation in VCP was found in sonism in this case was characterized by rigidity; however, infor- a rare autosomal dominant multisystem degenerative disorder, mation about other motor and non-motor manifestations and inclusion body myopathy and Paget's disease of the bone and responsiveness to levodopa was not provided. So far, very little is frontotemporal dementia (IBMPFD) [53]. Over 15 potentially known about FTD with parkinsonism due to FUS mutations. pathogenic mutations in VCP have been described to date. The Clinical characteristic of C9ORF72, CHMP2B, VCP, TARDBP, and phenotypic presentations within families with VCP mutations are FUS genes mutations associated with parkinsonism in FTD are highly variable; about 35% of patients present with personality and summarized in Table 5. cognitive changes. VCP mutation phenotypes may also include motor neuron degeneration in the form of familial ALS [54]. Several 3. Neuroimaging in FTD with parkinsonism affected individuals from families with IBMPFD and VCP mutations have been reported to manifest with parkinsonism, especially in Structural neuroimaging (MRI) is essential to the evaluation of the late disease stages [54e58]. patients with FTD, and characteristic patterns of brain atrophy are associated with specific genetic mutations (Table 6). FTDP-17 2.5.1. Parkinsonism in VCP mutations (MAPT) typically shows symmetrical fronto- atro- Several affected individuals from families with IBMPFD and VCP phy, with the most severe abnormalities observed in the temporal mutations (p.R159C, p.R191Q, p.T262A, p.P137L, p.R191G, and lobes, whereas highly asymmetrical fronto-parieto-temporal atro- p.R159C) have been reported to manifest with akinetic-rigid parkin- phy is seen in FTDP-17 (PGRN) [68e70]. If symmetrical fronto- sonism that usually presents in the late disease stages [54,55,57,58]. temporal atrophy is associated with midbrain atrophy, usually Single cases with an p.R159C mutation in the VCP have been reported similar extrapyramidal features to those seen in PSP syndrome are with typical PD features including resting tremor, REM sleep behav- observed. The presence of early parietal lobe atrophy in patients ioral disorder (RBD), and lasting levodopa responsiveness [53,54,59]. with PGRN mutations may help to distinguish such cases from other However, VCP is rarely associated with parkinsonism [53]. patients with parkinsonian features in FTD. PGRN mutations are also associated with faster rates of whole brain atrophy compared 2.6. TARDBP mutations to MAPT mutations [70]. It has been demonstrated that apart from fronto-temporal pathology, atrophy in the occipital lobes and cer- In 2008, the TARDBP gene mutation was identified as a causative ebellum can help differentiate subjects with C9ORF72 mutations gene for ALS. The TARDBP gene, located on chromosome 1p36.22, from those with MAPT or PGRN mutations or sporadic disease encodes a 43-kDa ubiquitously expressed nuclear DNA- and RNA- [10,11,42]. Structural neuroimaging studies of patients with binding protein (TDP-43) [60]. To date, more than 30 TARDBP mu- CHMP2B, VCP, TARDBP, and FUS mutations do not show specific tations have been reported, which explains approximately 4% of patterns of brain atrophy, but atrophy that is usually spread familial ALS cases and a smaller proportion of FTD cases [61]. The throughout the frontal, temporal, and parietal lobes [12,71e74]. mode of inheritance is autosomal dominant. The most common Structural neuroimaging cannot help distinguish between FTD clinical phenotype associated with TARDBP mutations is ALS. cases with and without parkinsonian features. Furthermore, in pa- Several patients carrying TARDBP mutations have been reported to tients showing clear brain atrophy on MRI, little additional diag- develop parkinsonism [60e62]. nostic benefit is gained by doing single photon emission computed tomography (SPECT) or positron emission tomography (PET) scans 2.6.1. Parkinsonism in TARDBP mutations because hypoperfusion and hypometabolism are usually present in Several patients carrying TARDBP mutations have been reported the same regions where MRI shows atrophy [75]. However, in pa- to develop parkinsonism in addition to the FTD phenotype [60e62]. tients with parkinsonism in FTD, perfusion SPECT with 99Technet- An A382T mutation was described to be associated with a typical ethylene cystine dimer (99Tc-ECD-SPECT) or 18F-fluorodeoxyglucose PD phenotype or FTD with levodopa-responsive parkinsonism in PET (FDG-PET) may confirm the dysfunction the absence of cognitive or motor neuron disturbances [60]. Other by showing reduced cerebral blood flow (99Tc-ECD-SPECT) and mutation carriers (p.K263E, p.N267S, and p.A315E) presented with hypometabolism (FDG-PET) in the [75e78]. a combination of parkinsonism and ALS and/or FTD. Parkinsonism Functional imaging with specific dopamine-related tracers (e.g. due to TARDBP mutations is characterized as a mixed type with 99mTc-TRODAT-1, 123I-b-CIT, and 123I-FP-CIT for SPECT, and 18F- predominant akinetic-rigid syndrome and may be accompanied by DOPA, 11C-DOPA, and 11C-raclopride for PET) may assist in con- dystonia or tics. RBD was also reported in TARDBP mutation carriers firming the nigrostriatal seen in various 962 J. Siuda et al. / Parkinsonism and Related Disorders 20 (2014) 957e964

Table 5 Specific mutations associated with parkinsonism in FTD and their characteristic clinical phenotype.

Gene C9ORF72 CHMP2B TARDBP VCP FUS

Amino acid change NA N143Sa A382T K263E N267S A315E R159C R191Q T262A P137L R191G M254Va R521C

Mutation type G4C2 hexanucleotide Point Point Point Point Point Point Point Point Point Point Point Point repeat expansion Genomic region NA Exon 5 Exon 6 Exon 6 Exon 6 Exon 6 Exon 5 Exon 5 Exon 5 Exon 4 Exon 5 Exon 6 Exon 15 AAO (years) 33e75 71 53 35 69e74 57e63 50e73 37e63 51e56 38e50 42e45 52 NA DD (years) 3e10 9 42NA4e61e51e74e15 10e21 9 NA NA Parkinsonism þþ þ þþþþþþþþþþþþþþ Personality changes þþþ þ þþþþþþþþþ Dementia þ þ þþþþþþþþ þ Language difficulties þ þþþþþ Supranuclear gaze palsy þ Apraxia þ Pyramidal signs þ þ þþ þþþ þ þþþ þþ Amyotrophy þþ þ þ þþþ þþþ þþ þþ þþþ þþþ

AAO ¼ age at onset; DD ¼ disease duration; NA ¼ not present/not assessed; Sub ¼ substitution; () ¼ absent; (þ) ¼ rare; (þþ) ¼ present in some cases; (þþþ) ¼ frequent. a Not proven to be pathogenic; only one mutations carrier has been identified for each mutation written in italics. parkinsonian syndromes including FTD with parkinsonism and subcortical [65]. However, more than 50% of FTLD may be used to discriminate between neurodegenerative parkin- patients present with tau-negative, TDP-43-positive ubiquitinated sonism and its mimics e.g. drug-induced parkinsonism [75]. In FTD neuronal and glial cytoplasmic inclusions (FTLD-TDP). TDP-43- patients, where neuroleptics are widely used to assist with behavior positive inclusions are the pathological hallmark in FTD with disorders, it is important to differentiate between parkinsonism with parkinsonism caused by PGRN, C9ORF72, VCP and TARDBP muta- underlying neurodegenerative pathology and a drug-induced syn- tions. FUS mutation carriers have FUS-positive, and TDP-43- drome. The uptake of tracer is normal in drug-induced parkinsonism, negative inclusions and are thus referred to as FTLD-FUS. In and an abnormal image supports the diagnosis of dopaminergic CHMP2B mutation carriers the inclusion protein remains unknown; system neurodegeneration [79]. Unfortunately, neuroimaging of the they exhibit ubiquitin-positive but tau negative inclusions and TDP- dopaminergic system has cannot differentiate between PD and 43-negative and FUS-negative cytoplasmic inclusions, which are atypical parkinsonism well [75]. Furthermore, dopaminergic imag- referred to as FTLD-ubiquitin system (FTLD-UPS), ing is not helpful in discrimination between different atypical previously known as FTLD-ubiquitin (FTLD-U) [81]. parkinsonian syndromes, including FTD with parkinsonism [80]. 5. Differential diagnosis of parkinsonism in FTD 4. Pathologic findings in FTD with parkinsonism The main considerations in the differential diagnosis of Neuropathologically, FTD is defined as Frontotemporal Lobar parkinsonism in FTD are other neurodegenerative diseases. Degeneration (FTLD), a proteinopathy characterized by the pres- Parkinsonism in FTD is present in addition to behavioral and per- ence of abnormal protein inclusions in the cytoplasm or nuclei of sonality changes and usually occurs a few years after the cardinal neuronal and glial cells. Parkinsonian features in FTD are most FTD symptoms are present. likely associated with tau pathology (FTLD-tau). MAPT mutation Atypical parkinsonism with oculomotor disturbances and se- carriers with parkinsonism in FTD exhibit a combination of tau- vere postural instability causing frequent falls are characteristic for immunoreactive aggregates in , astrocytes, and oligoden- PSP and can occur in the disease course of FTD with parkinsonism droglial cells that are localized in the cortex, basal ganglia, and the caused by dominant gene mutations. The same is true for the

Table 6 Pattern of changes of neuroimaging in genetic forms of FTD associated with parkinsonism (findings from structural and functional studies).

MAPT PGRN C9ORF72 CHMP2Ba VCPa TARDBPa FUSa

Asymmetry ± þþþ ± þþ þ þ Atrophy seen in structural neuroimaging studies (CT/MRI) þþþ þþ þþþ þ þ þþ þ Temporal lobe þþþ þþ þþ þ þ þ Parietal lobe þ þþþ þ þ þ þ Other regions Basal ganglia Occipital lobe, Midbrain Thalamus Cerebellum Hypometabolism seen in 18FDG-PET Frontal lobe þþþþþþþþþþþþ Temporal lobe þþ þþ þþ þ þþ þ þ Parietal lobe ± þþþ þ þþ þ þ Other regions Putamen, Caudate nucleus Hypoperfusion seen in 99Tc-ECD-SPECT Frontal lobe þþ þþ þþ NA þþ þþ NA Temporal lobe þþ þ þþ NA þþ þ NA Parietal lobe þþþþ NA þ NA Other regions Hippocampus, Cerebellum Caudate nucleus, Cingulate cortex Putamen

CT ¼ computed tomography; MRI ¼ magnetic resonance imaging; 18FDG-PET ¼ 18F-fluorodeoxyglucose positron emission tomography; 99Tc-ECD-SPECT ¼ 99Technet- ethylene cystine dimer single photon emission tomography; () ¼ not present; (±) ¼ infrequent; (þ) ¼ present in some cases; (þþ) ¼ moderate frequency; (þþþ) ¼ very frequent; NA ¼ not assessed. a Limited information. J. Siuda et al. / Parkinsonism and Related Disorders 20 (2014) 957e964 963 asymmetrical parkinsonian syndrome with additional motor and Acknowledgments non-motor manifestations such as myoclonus and dystonia fol- lowed by focal cortical deficits, which are characteristic for CBS. Kelly E. Viola, ELS, is thankfully acknowledged for language Conversely to sporadic disease, the PSP and CBS phenotypes editing the manuscript. associated with FTD with parkinsonism usually develop after the behavioral and personality changes that are characteristic for References bvFTD. 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