Journal of Clinical Neuroscience 22 (2015) 1139–1143

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Clinical Study

Right temporal lobe variant of frontotemporal dementia G. González-Caballero ⇑, I. Abellán-Miralles, M.J. Sáenz-Sanjuan Unit for Behavioral Neurology and Dementia, Hospital San Vicente, 137 San Vicente del Raspeig, Alicante 03690, Spain

a r t i c l e

i n f o

Article history: Received 9 August 2014 Accepted 7 December 2014

Keywords: Frontotemporal dementia Novel GRN mutation Right temporal lobe variant Semantic variant of primary progressive aphasia Temporal lobe atrophy

a b s t r a c t We present two women with the right temporal lobe variant (RTLV) of frontotemporal dementia (FTD) and analyse the clinical features that are determined by the anatomical distribution of atrophy. Each of our patients displayed different clinical and radiological profiles which were in line with findings reported by other authors. One of two patients carries a novel mutation in the granulin gene. FTD is heterogeneous with regard to clinical manifestation, genetics, distribution of cortical atrophy and underlying disease. Its clinical manifestations are related to the distribution of the cortical atrophy. The RTLV of FTD is an uncommon entity. There is no consensus about its name despite the fact that its clinical and radiological features are well-defined and distinguish it from other types of FTD including semantic dementia. Ó 2015 Elsevier Ltd. All rights reserved.

1. Introduction Frontotemporal dementia (FTD) is a clinical syndrome characterized by the presence of behavioral disorders, altered executive functions and/or progressive language disturbance [1]. While this term is reserved for the clinical syndrome, frontotemporal lobar degeneration (FTLD) is a macro-anatomical descriptive term referring to the atrophy of the grey matter that selectively affects frontal and temporal lobes. These processes are typical in most patients with FTD [2]. There are two major clinical subtypes: behavioral-variant FTD and primary progressive aphasia (PPA). Semantic variant of PPA, also known as semantic dementia (SD), is characterized by a profound impairment in understanding concepts and word meanings leading to progressive fluent aphasia with marked anomia and vocabulary loss [3]. Even in the early stages of the disease, structural neuroimaging studies reveal signs of atrophy in the anteromedial region of the temporal lobes; atrophy is asymmetrically distributed and predominant on the left side in most patients [3,4]. Although atrophy may also be predominant in the right temporal lobe (RTL), this finding is far less common with a prevalence of three to four times lower [4,5]. The clinical manifestation differs depending on which side is most affected by atrophy [5–7]. The language disorder associated with left-sided temporal lobe atrophy has been described extensively but this is not the case when aphasia is not the dominant clinical symptom and signs of

⇑ Corresponding author. Tel.: +34 629255942. E-mail address: [email protected] (G. González-Caballero). http://dx.doi.org/10.1016/j.jocn.2014.12.022 0967-5868/Ó 2015 Elsevier Ltd. All rights reserved.

atrophy predominantly affect the RTL. Experts do not yet agree on a name for this entity. Some authors use the term ‘right temporal lobe variant (RTLV) of SD’ [4,5], others use ‘RTLV of FTD’ [8,9] and a third group clinically diagnoses patients with predominantly right-sided temporal lobe atrophy as having either SD or behavioral variant FTD [10]. Nevertheless, the clinical profile of this condition is distinctive and characterized by familiar people recognition disorder, episodic memory impairment, topographical disorientation and severe behavioral disorder [6,10,11]. Some authors have proposed that in FTD patients in whom signs of atrophy predominantly affect the RTL, certain clinical and radiological features are useful for predicting the underlying pathology [8]. In this manuscript we present two women with a diagnosis of FTD and more pronounced atrophy of the RTL as shown by structural neuroimaging studies using MRI. We analyze clinical and radiological features of both women, particularly those caused by impairment of the RTL. One woman carries a novel mutation in the granulin (GRN) gene.

2. Patients and methods The study was performed in the Unit for Behavioral Neurology and Dementia at Hospital San Vicente. Ninety-one patients diagnosed with FTD in our hospital were retrospectively examined by three neurologists. Of these patients, two showed clinical and neuroimaging features on MRI suggestive of RTLV. We reviewed both patients’ medical histories, neuropsychological studies (the short version of the Barcelona test and the frontal assessment battery) and their structural and functional neuroimaging studies. The

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MRI and functional neuroimaging studies were also reviewed by a radiologist and a nuclear medicine specialist, respectively. We performed mutation analysis for MAPT and GRN genes in one of the two patients. Coding and intron-exon junction regions of the MAPT and GRN genes were amplified using polymerase chain reaction (PCR) and direct sequencing. 3. Results Two women were identified as presenting with FTD with predominantly right-sided atrophy. Each displayed different clinical and radiological features, as described below. One carries a novel GRN pathogenic mutation not previously described in databases (Human Gene Mutation Database, Alzheimer’s Disease & Frontotemporal Dementia Mutation Database). 3.1. Patient 1 The patient was a 57-year-old woman whose family history included a mother and maternal aunt with dementia, possibly with presenile onset, and maternal grandmother with probable dementia. She experienced multiple symptoms that had developed over approximately 3 years including a behavioral disorder with profound apathy, compulsive eating, visual, auditory, and olfactory hallucinations, disinhibition and changes in social conduct with inappropriate behavior at the table. The family reported that the woman was unable to distinguish between tones people used when speaking to her. The main cognitive concerns were short-term memory loss, attention deficit and language disturbance (limited content and difficulties with comprehension). She did not manifest any symptoms that would suggest rapid eye movement sleep behavior disorder or impaired recognition of familiar people. The neurological examination showed no signs of parkinsonism or of motor neuron disease. The palmar grasp reflex was positive on the right side. Some disorders were noted in the neuropsychological examination including deficit of selective and sustained attention, impaired temporal and spatial orientation, fluent language with limited content, echolalia, poor sentence repetition and altered comprehension of complex commands with two or more parts. Working memory showed severe impairment and episodic memory and immediate semantic recall were also mildly impaired. Her results were better for cued recall tasks. Severe impairment was also found for the executive functions (organization, planning, initiation, mental flexibility, motor sequencing). The examination also demonstrated incorrect recognition of people, impulsive and perseverant responses and difficulty curbing behavior and recognizing emotions. MRI identified signs of atrophy located mainly in the right frontotemporal area (Fig. 1). Cerebral single-photon emission CT scan showed moderate hypoperfusion of the RTL and mild hypoperfusion of the right frontal lobe (Supp. Fig. 1). Genetic analyses of MAPT were normal but the GRN sequence showed a new, previously unreported pathogenic mutation (c.147G>A; p.Trp49⁄).

Fig. 1. Cranial MRI showing predominantly right-sided frontotemporal lobar atrophy. (A) coronal, T2-weighted, (B) axial, T1-weighted.

She showed no tolerance for changes in her daily schedules and routines, no ability to improvise, emotional blunting, indifference to her husband’s illness and loss of empathy. The neurological examination showed no signs of parkinsonism or of motor neuron disease. The neuropsychological examination revealed mild deficits in attention, episodic and immediate memory and executive functions. There was also moderate impairment of delayed verbal and visual episodic memory. Language was fluent with no semantic deficits. The MRI revealed signs of atrophy with selective and profound asymmetrical impairment of the RTL (Fig. 2). The functional imaging study also showed selective hypoperfusion of the right anterior temporal lobe (Supp. Fig. 2). 4. Discussion FTD is a clinical syndrome that includes two major subtypes: behavioral-variant and PPA. Clinical manifestations are related to the distribution of the cortical atrophy. FTD patients in whom signs of atrophy predominantly affect the RTL are characterized by behavioral disorders accompanied by face recognition disorders, topographical disorientation and episodic memory deficits. Positive family history is observed in 40–50% of all FTLD patients. Molecular genetic studies have identified five genes that when mutated cause FTLD. The most frequently appearing mutations are in the MAPT gene (encoding the tau protein), the growth factor precursor gene GRN and C9orf72 [12]. Almost all cases of FTLD can be assigned to one of three categories according to the abnormal protein being deposited: tau,

3.2. Patient 2 Patient 2 was a 70-year-old woman with no family history of dementia who had developed cognitive impairment over a 4 year period. Her main concerns were short-term memory loss, topographical disorientation with difficulty navigating familiar places and inability to remember familiar routes and impaired recognition of familiar people. The woman reported having been unable to recognize her daughters who lived abroad when she went to meet them at the airport. Her behavior was rigid and inflexible.

Fig. 2. Patient 2 cranial MRI revealing clear signs of predominantly right-sided temporal atrophy. The images correspond to different stages of the disease. The image on the right (B), taken more recently, shows signs of temporal atrophy that are bilateral but noticeably asymmetrical. We observe that the MRI for Patient 1 shows more severe frontal atrophy with less pronounced hemispheric asymmetry. (A) coronal, fluid-attenuated inversion recovery (B) coronal, T1-weighted.

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G. González-Caballero et al. / Journal of Clinical Neuroscience 22 (2015) 1139–1143 Table 1 Frontotemporal dementia. Clinical syndromes, brain atrophy patterns, proteinopathies and genetic associations [3,10,14,18] Clinical syndrome

Earliest symptoms

Atrophy pattern

Proteinopathy

Genetic associations

PNFA

Nonfluent speech, apraxia of speech

Dominant perisylvian atrophy

bvFTD

Apathy disinhibition, loss of empathy, alterations in social conduct

Anterior cingulate frontoinsular, symmetric to moderately right predominant

SD left variant SD right variant

Anomia, loss of word meaning

Left anterior temporal

GRN MAPT GRN MAPT C9orf72 FUS NA

Personality changes, impaired recognition of familiar people

Right anterior temporal

TDP-43 Type A Tau Tau TDP-43 Type A, B, D FUS TDP-43 Type C Tau (rare) TDP-43 Type C Tau (rare)

NA

bvFTD = behavioral variant FTD, C9orf72 = chromosome 9 open reading frame 72, FUS = fusion in sarcoma protein, GRN = granulin gene, MAPT = microtubule associated protein tau gene, NA = not applicable, PNFA = progressive non-fluent aphasia, SD = semantic dementia, TDP-43 = transactive response DNA binding protein 43.

TDP-43 or FUS. Additionally, FTLD associated with TDP-43 pathology can be classified in four subgroups from A to D according to Mackenzie’s new system [13]. There is an excellent clinicopathological correlation between SD and Mackenzie’s C subgroup given that the disease in most C subgroup patients manifests similarly to SD and, conversely, almost all patients with SD present the TDP-43 type C subgroup of FTLD [14–17]. Moreover, patients with TDP-43 subgroup C pathology display a profoundly asymmetric pattern of atrophy that affects the anterior temporal lobe mostly on the left side which is consistent with a diagnosis of SD. This finding of asymmetrical temporal lobe atrophy is practically specific to this disease with the one exception being patients with mutations in the MAPT gene. However, these patients generally display a lack of marked asymmetry and a greater degree of frontal atrophy than that seen in patients with TDP-43 subgroup C pathology [18]. Therefore, despite the clinical, pathological and neuroimaging heterogeneity that characterizes FTD (Table 1) it is possible to distinguish a homogeneous group of patients with SD, asymmetrical signs of atrophy with temporal predominance and TDP-43 subgroup C pathology. The profoundly asymmetrical distribution of the atrophy results in more prominent, prevalent and early language disorders or face/object recognition disorders depending on whether impairment is left or right-sided [5,6,9,11]. 4.1. Clinical aspects Personality changes and impaired recognition of familiar people are frequently among the first symptoms in patients exhibiting a marked atrophy of the RTL [6,8]. Behavioral alterations in RTLV of FTD are more significant than in SD [4,11] particularly regarding changes in social behavior and loss of insight [5,11]. Several authors have associated difficulty perceiving and interpreting facial expressions, most of all negative emotions and emotion comprehension deficits with lesions in the right hemisphere, especially in the anterior half [19,20]. Our patients exhibited difficulty recognizing emotions and this was more marked in Patient 2 who showed indifference to her husband’s illness even at times when manifestations were severe. Numerous authors have suggested that the RTL (especially the anterior temporal region and the fusiform gyrus) plays a key role in the recognition of familiar faces [21–23]. Gainotti has described the familiar people recognition disorders observed in patients with right anterior temporal lobe lesions. In most patients, impaired recognition of familiar people is multimodal preventing identification of both voices and faces [21]. In Patient 2, profound impairment of the RTL gave rise to difficulty recognizing very familiar people even in the early stages of the disease. Topographical disorientation and episodic memory deficit are usually present during the course of RTLV of FTD. Impairment of

various regions of the brain such as the lingual gyrus and the posterior parietal, cingulate and parahippocampal cortices can produce topographical disorientation including topographical agnosia and anterograde disorientation. In topographical disorientation the patient experiences difficulty recognizing the structures, buildings and monuments that are used as orientation references. This condition is associated with bilateral or right-sided lesions in occipitotemporal regions [24]. The symptoms reported by Patient 2 are compatible with topographical agnosia. Anterograde disorientation refers to the selective disorder for acquiring novel information and it has been linked to lesions to the right parahippocampal gyrus that are located immediately anterior to the region affected in topographical agnosia. For this reason, both types of disorientation often appear in the same patients [24]. Episodic memory deficit has historically been considered an exclusion criterion for a clinical diagnosis of FTD. However, recent clinical and experimental findings describe distinct profiles of episodic memory deficit for the different variants of FTD [25]. The involvement of autobiographical episodic memory in SD shows a characteristic pattern in which remote memories are more affected than recent ones in contrast to the hippocampal episodic memory impairment seen in patients with Alzheimer’s disease (AD) [4,25]. This pattern may be explained by the gradient of rostrocaudal hippocampal atrophy exhibited by patients with SD who show more marked impairment of the anterior hippocampal region, whereas AD patients show overall atrophy of that structure. Furthermore, other brain regions are affected in AD including the posterior cingulum and precuneus which are relevant in autobiographical memory processes [25]. Anterograde episodic memory performance will vary depending on which hemisphere has sustained the most damage. Patients with predominantly left-sided atrophy score lower on verbal tasks than on non-verbal ones whereas the opposite is true of patients with predominantly right-sided atrophy. Patients with progressive non-fluent aphasia do not exhibit deficits in episodic memory whether anterograde or retrograde, whereas episodic memory impairment in patients with behavioral variant FTD is related to executive dysfunction [25]. Patients with behavioral variant FTD produced by mutation in the MAPT gene may present deficits in episodic and semantic memory that are related to the severe pattern of temporal atrophy [18]. In the neuropsychological examination, both of our patients showed poor performance on episodic memory tasks especially Patient 2 who showed moderately impaired delayed episodic memory. 4.2. Clinicopathological features Several terms have been used to describe this clinical and radiological entity since 1990 when Tyrell published the case study of a patient with symptoms of slowly progressive prosopagnosia

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followed by dysnomia and whose structural and functional neuroimaging studies revealed right-sided temporal lobe atrophy [26]. Some authors include these patients within the SD group although their clinical features differ from the patients in whom temporal atrophy is predominantly left-sided [3,5]. Aphasia plays only a small role in the early stages of this disease and a new classification system for PPA includes the semantic variant of PPA (also known as SD or as PPA-semantic) as one of the three variants of PPA [3]. Based on the above, we feel that the term RTLV of FTD used by numerous authors is an appropriate term for clinical symptoms characterized not by language disorder but rather by behavioral and familiar people recognition disorders, topographical disorientation and episodic memory deficits accompanied by neuroimaging studies revealing signs of asymmetrical, predominantly right-sided temporal atrophy [6,8,9,11]. A predominantly anterior pattern in temporal atrophy is not exclusive to TDP-43 subgroup C pathology. Patients with MAPT gene mutations can present similar neuroimaging profiles. Nevertheless, atrophy in these patients also affects the orbitofrontal cortex and insula and its distribution is more symmetrical [2,18]. On this basis, several authors have differentiated two patient subgroups in the RTLV [8]: 1) Consisting of patients who meet clinical criteria for behavioral variant FTD and who present behavioral disorder as the predominant symptom, generally having a family history of neurodegenerative diseases; MRI will show more extensive frontal atrophy and more symmetrical hemispheres; the predominant pathological substrate is tauopathy; 2) Characterized by early and prominent symptoms of familiar people recognition disorder, topographical disorientation and language disturbance, usually with no family history of neurodegenerative diseases; MRI shows signs of atrophy affecting the temporal lobe almost exclusively with very pronounced hemispheric asymmetry; pathological substrate tends to be TDP-43 type C proteinopathy. Taking into account clinical and radiological features, Patient 1 is suggestive of tauopathy but genetic analyses of MAPT were normal and the patient carries a novel GRN mutation (c.147G>A; p.Trp49⁄). This is slightly surprising because RTL atrophy is not a feature of GRN mutations [27]. Furthermore, GRN mutations have not been associated with the RTLV in previously published case studies and case series. The profile of Patient 2 is suggestive of TDP-43 pathology but unfortunately we have not yet received confirmation from the pathology study. 5. Conclusion Although the RTLV of FTD shares common features with the semantic variant of PPA and behavioral variant FTD, it also shows clinical characteristics that are determined by the anatomical distribution of the atrophy affecting the right anterior temporal region. On this basis, it can be defined as a clinical and radiological entity that is well-differentiated from other types of FTD. Symptoms are characterized by behavioral disorder, defect of familiar people recognition, topographical disorientation and deficits in episodic memory. Neuroimaging findings reveal signs of predominantly right-sided temporal atrophy. The RLTV of FTD is an uncommon entity that is probably underdiagnosed. We present two patients, both diagnosed with RLTV of FTD, who display different clinical and radiological profiles, one who carries a novel GRN mutation. Although several authors have described two clinicopathological profiles in RTLV which are associated with taupathy and TDP-43 subgroup C pathology, progranulin mutations should be considered as a cause of RTLV. Identifying patients with RTLV and describing their clinical features is useful for predicting the pathological substrate. This will

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