Abstract
In the present work, we report the case of a patient presenting signs of Lewy body dementia (DLB) and frontotemporal dementia (FTD) throughout different phases of the disease. In January 2017, a 79-year-old right-handed living man was admitted to our Memory Clinic for the presence of behavioral disturbances and progressive cognitive decline. For the previous six years, he was monitored by other Neurological Clinics for the onset of extrapyramidal features. Indeed, through the first phase of the disease (2011–2014), the patient predominantly showed: extrapyramidal features, initial cognitive decline, sleep disturbances, and visual hallucinations, together with a reduced dopamine transporter uptake in basal ganglia at the DATscan, suggesting a diagnosis of DLB. In a second phase (2015–2017), while his extrapyramidal features remained substantially stable, his cognitive profile deteriorated, with an additional development of severe behavioral and neuropsychiatric disturbances. Again, a subsequent DATscan study was positive and slightly worse than the preceding one; however, the 18F-FDG PET showed reduced metabolic activity in the frontal and temporal lobes, with the occipital regions left spared. Genetic analysis revealed a hexanucleotide expansion in C9ORF72 (6//38 repeats; ITALSGEN NV <30). In conclusion, we report the case of a patient presenting, firstly, with probable DLB and, in a second phase, with predominant bvFTD features with stable parkinsonism. Even though some clinical and neuropsychological aspects can co-exist in different neurodegenerative diseases, we find such a significant intersection of clinical features to be fairly atypical. Moreover, what is challenging to define is whether the two clinical phenotypes are somehow lying on a continuum, or if they are two individual entities.
Keywords
INTRODUCTION
Frontotemporal dementia (FTD) is a clinical term referring to a cluster of disorders that affect the frontal and temporal lobe causing a collection of diverse symptoms including: personality change (apathy, disinhibition, loss of insight and emotional control), language impairments, loss of semantics, executive dysfunction, and overall cognitive deterioration [1]. FTD consists of a spectrum of clinical syndromes: behavioral variant FTD (bvFTD) [2] and primary progressive aphasia (PPA) variants [3]. These variants are associated with different underlying neurodegenerative pathologies, all resulting in the degeneration of the frontal and temporal lobes [4]. To our knowledge, cases of FTD with atypical onset, presenting with early extrapyramidal features and hallucinations, have not been reported in the literature so far. In terms of genetic hallmarks, FTD is familial in about 30–50% of subjects, and it is associated with alterations in three main genes: Microtubule Associated Protein Tau (MAPT), Chromosome 9 Open Reading Frame 72 (C9ORF72), and Progranulin (PGRN) [5].
Dementia with Lewy bodies (DLB) presents with progressive cognitive decline together with: fluctuating cognition; recurrent and detailed visual hallucinations; REM sleep behavior; and one or more features of parkinsonism [6]. Likewise, the supportive clinical features include: sensitivity to antipsychotic agents; repeated falls; syncope or autonomic dysfunction; and systematized delusions [6]. The clinical framework is supported by an indicative biomarker (reduced dopamine transporter uptake in basal ganglia demonstrated by 123I-ioflupane SPECT) or by a supportive biomarker (reduced occipital activity with cingulate island sign on 18F-FDG PET) [6].
In the present work, we report the case of a patient showing a peculiar clinical trajectory, firstly presenting with DLB that slowly progressed toward bvFTD.
Case presentation
In January 2017, a 79-year-old right-handed man was admitted to our Memory Clinic for the presence of behavioral disturbances and progressive cognitive decline. It is important to mention that the patient had been monitored by other Neurological Clinics for the previous six years for the presence of extrapyramidal features. No family history of neurodegenerative or psychiatric diseases has been reported and other non-neurological conditions of the patient include: pleuritis, diverticulosis of the left colon, psoriasis, colon polyposis, slipped disc of L4-L5, epiaortic atherosclerosis, lumbar arthritis, reduced tolerance to carbohydrates, and arterial hypertension.
The onset of neurological symptoms started in 2011, at the age of 72, when he presented with resting tremors of the right hand, initial cognitive decline, episodes of confusion, and topographical disorientation. In 2012, the patient underwent a 123I-ioflupane SPECT scan (DATscan) that showed bilateral nigro-striatal denervation with more hypoactivity of the putamen (more enhanced on the right side) and normal uptake in the caudate nucleus (Fig. 3a). He was, therefore, diagnosed with Parkinson’s disease and accordingly treated with selegiline. Consequently, in 2013 he developed depressive symptoms for which he was treated with unspecified antidepressants for a short period of time. In 2014, he had no insight of his deficits, which were increasingly getting worse overtime. The same year, he was admitted to the emergency room for a severe episode of delusions, topographical disorientation, and visual hallucinations, for which he was prescribed with quetiapine 25 mg daily and he had to suspend the therapy with selegiline. In the same year, he was evaluated by another neurologist, who diagnosed him with DLB and monitored him for two years (until 2016), maintaining the therapy with quetiapine 25 mg daily. Also, in 2014, he was started on rivastigmine 1.5 mg twice a day, which was suspended after a few weeks following the occurrence of several side effects. Subsequently, in 2015, the neurologist reported episodes of aggressive behavior, persistent visual hallucinations (he talked to his deceased brother), aberrant motor behavior, and thought fixations. In 2016, the neurologist reported the onset of sleep behavior disorder (RBD) characterized by severe insomnia and nocturnal agitation and the intensification of both diurnal and nocturnal visual hallucinations. Hyperphagia and weight gain were also reported.
The patient was referred to our Memory Clinic in January of 2017, following aggravating cognitive symptoms. During the neurological examination, the patient was alert and showed: tendency to motor akathisia; hypomimia with reduced blinking; and asymmetric resting pill rolling tremor of the right hand. Additionally, he showed normal gait with reduced arm swing on the right side.
The clinical investigation at first admission included: a CT scan, a 18F-FDG PET scan, and a full neuropsychological evaluation. Subsequently, 4 months later, the patient came back for a control. The caregiver referred a worsening of hyperorality and compulsive food disturbances with further weight gain. Also, aberrant and repetitive motor behavior was referred and it was also noticed during the neurological examination. Considering the clinical picture, we recommended another DATscan for comparison. Also, to complete the investigation, Progranulin plasma levels and C9ORF72 gene were analyzed. We oriented toward a diagnosis of bvFTD with parkinsonism [7].
We continued the treatment with quetiapine for behavioral disorders. To avoid psychopathological imbalance and considering the stability of extrapyramidal signs, we did not prescribe a dopaminergic therapy.
The overall clinical history, neuropsychological, metabolic and genetic evidence suggested a peculiar clinical trajectory characterized, in the first stage, by DLB-like symptoms that remained stable overtime and, at the second stage, by predominant and aggravating bvFTD-like characteristics.
MATERIALS AND METHODS
Neuropsychological evaluation
A neuropsychological evaluation was carried out at admission in 2017. Representative psychometric test results are included in Table 1 (raw scores, corrected scores, and cut-offs). The evaluation included the following tests: Clinical Dementia Rating (CDR) [8], Mini-Mental State Examination (MMSE) [9], Digit Span [10], Visuospatial Span [10], Short-Story Memory Test [10], Rey Auditory Verbal Learning Test (RAVLT) [11], Attentive Matrices [12], Phonemic and Semantic Verbal Fluencies [10, 12], Token Test [10], Design Copy Test [12], Clock Drawing Test [13], Cognitive Estimation Test [13], and the Neuropsychiatric Inventory (NPI) [14].
Neuropsychological evaluations. The table shows the performances on tests for memory, attention, language, constructional praxia, executive functions and the comprehensive neuropsychiatric profile (raw, corrected scores and cut-off values are reported)
RI, immediate recall; RD, delayed recall; N.A., not applicable; scores outside the normal range are shown in bold. The neuropsychological assessment showed a deficit in memory (RAVLT, Short Story Memory Test), attention and executive functions (Attentive Matrices, Clock Drawing Test, Cognitive Estimation Test and Token Test). The Neuropsychiatric Inventory (NPI) revealed behavioral symptoms.
Structural and nuclear medicine imaging
The CT scans were acquired with the volumetric scanner EMOTION 6 Siemens. Section orientation was parallel to the orbitomeatal plane. Sections on the same plane (time of 2 s, 120 kV, 130 mA, section thickness of 5 mm, no intersection gap) covered the remaining brain from the inferior aspect of the cerebellum to the vertex of the cranium.
The patient underwent a 18F-FDG PET brain scan using a PET tomograph Discovery 710 (General Electric Healthcare). The CT scan was used for attenuation and scatter correction with set voltage tuned to 120 kV. The FDG scan was obtained over 15 min starting 60 min after i.v. of 227 MBq. The images of the two scans were only visually assessed.
Moreover, for obtaining the DATscan images, the patient was administered two capsules of 200 mg of potassium perchlorate orally, approximately 1 h before the injection of 123I-ioflupane. The patient was administered 5 mCi of 123I-ioflupane intravenously, and SPECT imaging was started between 3 and 5 h post-injection.
Genetic analysis
Considering that mutations in GRN and C9ORF72 are often associated with symptoms exhibited by the patient and mutations have an incomplete penetrance, on a candidate-based approach, we evaluated progranulin plasma levels and analyzed the C9ORF72 gene. Progranulin plasma levels were determined by using commercial ELISA kit according to the procedure of the manufacturer (AdipoGen, Korea). PCR reagents were optimized for the amplification of the C9ORF72 hexanucleotide repeats (AmplideX®PCR/CE C9ORF72 Kit, Asuragen, Inc.). Amplicons were sized using capillary electrophoresis (CE) on a 3100 Genetic Analyzer (Thermo Fisher).
RESULTS
Neuropsychological evaluation
During the neuropsychological evaluation, the patient seemed alert but not entirely aware of his deficits. The patient appeared relatively motivated but he was not able to maintain adequate attention throughout the whole testing session. He presented a non-fluent speech characterized by echolalia and auditory comprehension was reduced. The neuropsychological assessment showed a deficit in: memory (RAVLT [11], Short Story Memory Test [10]), attention and executive functions (Attentive Matrices [12], Clock Drawing Test [13], Cognitive Estimation Test [13], and Token Test [10]). The NPI revealed his behavioral symptoms [14]. The caregiver specified that the patient was experiencing: delusions, visual and auditory hallucinations (usually related to his deceased brother), agitation, anxiety, apathy, disinhibited behavior, irritability, aberrant motor behavior, dietary disturbances, and sleep disturbances (insomnia with night hallucinations and agitation with aberrant motor behavior in bed).
Structural and nuclear medicine imaging
The CT scan showed moderate-to-severe frontal cortical atrophy, more prominent on the right hemisphere. In particular, the regions more involved were the mesial prefrontal cortex and anterior cingulate (Fig. 1a, b, d). Also, the atrophy involved subcortical areas, with enlargement of the lateral ventricles (Fig. 1a). Furthermore, a discrete vascular burden with white matter hypodensity was evident more on the frontal right hemisphere (Fig. 1a–d). Medial temporal regions (including hippocampal formation) appeared relatively spared (Fig. 1c, d), when compared to cortical frontal atrophy.
CT scan showing moderate-to-severe frontal cortical atrophy, more prominent on the right hemisphere. In particular, the regions more involved are the mesial prefrontal cortex and anterior cingulate (1a, b, d). Also, the atrophy involved subcortical areas, with enlargement of the lateral ventricles (1a). Furthermore, a discrete vascular burden, with white matter hypodensities, was evident more on the frontal right hemisphere (1a–d). Medial temporal regions (including hippocampal formation) appeared relatively spared (1c, d), when compared to cortical frontal atrophy.
The 18F-FDG PET scan showed reduced metabolic activity of the frontal lobes (more enhanced on the right side) (Fig. 2b–e) and temporal lobes (Fig. 2a–d). It also revealed a relatively reduced concentration in the right inferior parietal region (Fig. 2d) and decreased activity in the right grey nuclei of the caudate-putamen-thalamic region (Fig. 2a). In addition, reduced uptake in the right cerebellum was also reported. A few months later, another DATscan was requested, and it confirmed the previously found bilateral nigro-striatal denervation with more hypoactivity of the putamen (Fig. 3b). In addition, there was a further reduction of the right caudate nucleus and of the central structures of the left putamen (Fig. 3b).
18F-FDG PET scan showing reduced metabolic activity of the frontal lobes (more enhanced on the right side) (2a-d) and temporal lobes (2a-c). It also revealed a relatively reduced concentration in the right inferior parietal region (2d) and decreased activity in the right grey nuclei of the caudate-putamen-thalamic region (2b).
First DATscan (2012) showed bilateral nigro-striatal denervation with more hypoactivity of the putamen (more enhanced on the right side) and normal uptake in the caudate nucleus (3a). Second DATscan (2017) showed abnormal reuptake in the caudate-putamen complex. Compared to the previous DATscan. there was a further reduction of the right caudate nucleus and of the central structures of the left putamen (3b).
Genetics analysis
Progranulin plasma levels were found to be within normal range (147 pg/mL; NV >61 pg/mL). Thus, no further GRN sequencing was carried out. C9ORF72 analysis disclosed the presence of an expanded allele (genotype: 6//38 repeats).
DISCUSSION
Here we describe a patient presenting a peculiar clinical trajectory, ranging from DLB to bvFTD symptoms. In the initial phase (2011–2014), he mainly presented with extrapyramidal features and cognitive decline, with subsequent RBD and visual hallucinations. These symptoms, together with the positive DATscan, suggested DLB [6]. However, in a second phase (2015–2017), his extrapyramidal features remained substantially stable, while his cognitive profile deteriorated. Indeed, there was an additional development of severe behavioral disturbances. Also, he presented with frontal hypometabolism at 18F-FDG PET and frontal lobe atrophy at CT scan, all of these suggesting a bvFTD-like disorder. However, we are aware that the bvFTD-like symptoms occurred years later from the onset of his initial symptoms and that the current criteria for bvFTD impose that the behavioral/cognitive symptoms must appear early (within the first three years) [2]. Thus, a diagnosis of pure bvFTD would not be appropriate in our case.
Furthermore, in the literature, it has been established that patients with pathologically definite diagnosis of FTD can later acquire parkinsonism [7]. Also, patients with DLB normally have executive dysfunctions in association with visuo-spatial deficits [15]. Additionally, a research paper reported that DLB patients endorsed FTD-like symptoms (disinhibition, apathy, hyperphagia and delusions) and memory impairments [16]. This indicates that the two neurodegenerative diseases share clinical and neuropsychological features. Likewise, at least in some cases, patients may have mixed features of both diseases [15]. Indeed, a study identified 6 patients that met consensus criteria for a diagnosis of both FTD and DLB and, yet, they seemed to be different from both typical FTD and typical DLB. At initial evaluation, these patients presented with parkinsonism, hallucinations, and FTD symptoms, supporting the concept that features of the two pathologies can be present throughout the course of the same disease [15].
Regarding the clinical presentation, the patient showed: executive dysfunctions, behavioral and neuropsychiatric disturbances (delusions, hallucinations, agitation, anxiety, apathy, disinhibited behavior, irritability, aberrant motor behavior, sleep disturbances, and dietary disturbances), memory decline, and constructional apraxia. The patient’s neuropsychological profile is majorly characterized by bvFTD-like symptoms. Still, similar neuropsychiatric symptoms have been reported in DLB patients (41,7%) [16]. Nonetheless, it is important to point out that we only have the neuropsychological evaluation from the second phase of the disease and not from the onset. For this reason, the patient’s cognitive profile might have been already very compromised, presenting extended impairments.
Imaging analyses were helpful but they were not conclusive for excluding one of the two neurodegenerative diseases. The use of DATscan for both neurodegenerative diseases has been well described [17]. Indeed, in some FTD cases, a DATscan showed the same dopaminergic pattern as seen in DLB, making it difficult to use it as a unique tool for formulating a differential diagnosis [18]. With respect to the 18F-FDG PET, FTD patients show a marked hypometabolism of the frontal lobes [1], whereas DLB patients mainly show occipital hypometabolism [15, 17]. Thus, our imaging data is slightly contradictive and would orient toward FTD.
We studied GRN and C9ORF72 genes on a candidate-based hypothesis, as they are associated with a wide phenotypic expression, including the variety of symptoms observed in the patients.
First, we analyzed Progranulin plasma levels as it is known that it predicts the presence of mutation with an accuracy >97% [19], but levels were normal. Next, we considered the gene C9ORF72, which is often associated with psychotic symptoms [20] and found that the patient carries a C9ORF72 expanded allele with 38 (6//38 repeats). We cannot rule out whether the presence of intermediate alleles is causative or not since the threshold has not yet been fully established [21]: on one hand, the cut-off suggested by the ITALSGEN consortium is >30 repeats [22], but on the other, pathogenic mechanisms such as methylation, have been shown in carriers of more than 50 repeats only [23]. In this scenario, a recent meta-analysis [24] identified 49 studies with adequate available data on normal or intermediate C9ORF72 repeat length, but concluded that the ‘critical’ repeat size required for initiation of neurodegeneration remains unknown and requires further study.
We did not have the possibility to investigate a wider panel, i.e., through next generation sequencing. Therefore, we cannot exclude the presence of any other causative gene for dementia, although this would be quite unlike given the complete penetrance in young age of such mutations.
It is worth to consider that FTD with C9ORF72 HREs often presents with late-onset psychosis and memory impairment [20]. While C9ORF72 HREs has been widely documented in FTD, there is little evidence regarding its involvement in patients with parkinsonism [25, 26]. Yet, on the basis of a clinic-pathological study, it has been demonstrated that C9ORF72 expansions are not a major cause of idiopathic Parkinson’s disease [25]. Nevertheless, C9ORF72 HREs might contribute to the expression of parkinsonism in ALS C9ORF72+ patients due to the degeneration of substantia nigra [26]. More recently, by studying a large sample (N = 1238) of pathologically confirmed DLB, a group of researchers did not detect any repeat expansions of C9ORF72, suggesting that it is not a common cause of DLB [27]. Hence, to our knowledge, our case is the first “mixed” phenotype in a patient with C9ORF72 partial HREs to be reported. Still, we are not implying any causative relationship between the presence of C9ORF72 HRE and the peculiar clinical presentation of the patient, but we believe that it is a relevant data to report.
Nevertheless, we have collected enough evidence to claim that our patient crossed two clinical phenotypes (DLB and FTD) at different phases of the disease. Even though some clinical and neuropsychological aspects can co-exist in different neurodegenerative diseases, we find such a significant intersection of clinical features to be fairly atypical. Moreover, what is challenging to define is, whether the two clinical phenotypes are somehow lying on a continuum, or if they are two distinct entities that co-exists.
The classical method used by clinicians to classify and diagnose neurodegenerative diseases is based on the combination of clinical and pathological features. ‘Consensus’ criteria have been established and constantly updated to identify the main features that outline different diagnosis [15]. Still, as the consensus criteria are fairly restrictive and there is a continuous variation among disorders, there are cases that present clinical and pathological features of more diagnostic frameworks, where more than one neurodegenerative process takes place in the same individual (also labelled as “complex syndromes”). According to the overlap model [28], separate neurodegenerative diseases might lay on a continuum, where patients can meet criteria for more disorders. Moreover, clinical trials and researches are usually designed to study single diseases, without considering the possibility of intersections among them. In a large retrospective study on 9,953 patients, it was found that 24.8% of them had an overlap between at least two neurodegenerative diseases [29].
Although treatment for both diseases is not offered yet, understanding the neuropathological profile of these conditions could be essential in the future when different classes of proteins will be the target of forthcoming therapies [15].
DISCLOSURE STATEMENT
Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/18-1298r2).