11 C-CFT-PET in Presymptomatic FTDP-17: A Potential Biomarker Predicting Onset

INTRODUCTION

Frontotemporal dementia (FTD) is an umbrella for a group of neurodegenerative disorders with heterogeneous clinical, genetic, and pathological features [1, 2]. It has been estimated that about 30–50% of FTD is familial [3]. Frontotemporal dementia with parkinsonism-linked to chromosome 17 (FTDP-17) is a rare autosomal dominant neurodegenerative disorder with mutations in two genes, microtubule associated protein tau (MAPT) and progranulin (PGRN) [4].

Most FTDP-17 cases are caused by mutations in MAPT. In fact, MAPT mutations account for up to 50% of FTD cases. More than 50 pathogenic MAPT mutations have been reported so far (see http://www.molgen.ua.ac.be/ADMutations). In the past, FTDP-17 was only ever recognized as pallido-ponto-nigraldegeneration according to the findings of neuropathology until the genetic era [5–7]. Neuropathology is featured by neuronal and glial tau-rich inclusions in the globus pallidus and substantialnigra, as well as neocortical and subcortical regions, which is formed by aggregated filaments and hyper-phosphorylated tau proteins [8]. Worldwide, seven FTDP-17 families with MAPT mutations have been reported (see http://www.molgen.ua.ac.be/ADMutations). However, information on FTDP-17 pedigrees in the Chinese Han is limited and only focused on symptomatic patients [9].

Biomarkers for FTDP-17 have been investigated in symptomatic patients and presymptomaticmutation carriers [10–13]. Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed asymmetric temporal lobe hypometabolism in symptomatic patients of N279K mutation in MAPT [10]. Magnetic resonance imaging (MRI) suggested hippocampal atrophy [11]. For presymptomatic mutation carriers, both FDG-PET and MRI findings were normal [10, 11]. Parkinsonism is a prominent manifestation in FTDP-17; however, studies on dopamine transporter are rare. Presynaptic dopaminergic dysfunction has been found in striatum of symptomatic patients and presymptomatic mutation carriers [12, 13]. In this study, we aimed to determine if 2b-carbomethoxy-3b-(4-trimethylstannylphenyl) tropane (¹¹C-CFT)-PET can be used as a potential biomarker in the presymptomatic stage of FTDP-17.

PATIENTS AND METHODS

This study was approved by the Ethics Committee, Xuanwu Hospital, Capital Medical University, China. Informed consent was acquired from all the participants and the next of kin. A pedigree in Chinese Han nationality suffering frontotemporal dementia with parkinsonism was found, in which there were 15 patients (six alive) in four generations (Fig. 1). Genetic analysis was carried out with the finding of N279K mutation in MAPT at chromosome 17q21.3 [14], while no other dementia-related mutations were found. In this study, five family members with two symptomatic patients (cases 1 & 2) and three presymptomatic mutation carriers (cases 3–5) from this pedigree were enrolled from October to November 2014. The proband was case 1.Thereafter, we collected the clinical information including clinical history, physical examination, lumbar puncture, biosample test, and MRI, as well as neuropsychological test in memory, executive function, speech, naming, and other dimensions via the scales such as the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR), World Health Organization-University of California-Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT), Boston Naming Test (BNT), Digit Span, and Trial making test.

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Fig.1

FTDP-17 pedigree with MAPT N279K mutation. There were 15 symptomatic patients in four generations of this pedigree. The age of onset was in the fourth to fifth decades with genetic anticipation. Clinical symptoms mainly included dizziness, bradykinesia, rigidity, mask face, and cognitive decline. The disease duration was 3–7 years. Case 1 (proband): IV-1, Case 2: IV-4; Case 3: IV-6; Case 4: IV-20; Case 5: IV-21.

RESULTS

In our study, five participants were included and analyzed (two symptomatic patients and three presymptomatic mutation carriers) from the FTDP-17 pedigree with N279K mutation in MAPT. Clinical, neuropsychological, and neuroimaging findings were summarized in Table 1. In summary, parkinsonism was the initial symptom of onset for symptomatic patients (case 1&2), which could be partly released by levodopa or dopamine agonists. Case 1 (proband) developed agitation and cataphasia. In neurological examinations, slow saccades, hypermyotonia, and tendon hyperreflexia more severe on the left, as well as bilateral Babinski signs were found. Dementia was observed in case 1 at one and a half years after parkinsonism onset (MMSE 15; MoCA 6), while case 2 did not suffer obvious cognitive impairment seven months after disease onset (MMSE 24; MoCA 24). Brain MRI was normal in case 2, however, mild cortical atrophy and white matter lesions were detected in case 1. Three presymptomatic mutation carriers (case 3–5) were free of any symptoms at baseline. No abnormal results were found in five participants in blood, urine, stool routine, blood coagulation, thyroid function, tumor markers, rheumatoid factor, erythrocyte sedimentation rate, folic acid, vitamin B12, anti-neutrophil cytoplasmic antibody, and anti-nuclear antibody profile. Intracranial pressure was in the normal range. Cerebrospinal fluid (CSF) routine, biochemistry, immunity, toxoplasma, rubella virus, cytomegalovirus, and herpes virus were negative in all five participants. CSF total-tau, phosphorylated-tau, and alpha-synuclein were not assayed.

During follow-up, case 1 died two and a half years after onset. She was bedridden six weeks before death with fever and reduced appetite. Three years after disease onset in the follow-up visit, case 2 could not speak or walk with dysphagia, severe dementia, and psychiatric symptoms. Meanwhile, two presymptomatic mutation carriers (case 4 & 5) gradually developed symptoms two years after baseline examination. Case 4 presented as ptosis, mask face, and hypokinesia with tremor in the left limbs. Case 5 suffered bradykinesia with festinating gait. Case 3 was still free of any symptoms.

Four participants (one symptomatic patient and three presymptomatic mutation carriers) from the FTDP-17 pedigree were evaluated by ¹¹C-CFT-PET, in comparison to six normal controls (4 females and 2 males) with the same equipment and method. The axial striatum image was segmented into six parts (left/right caudate head, body, and putamen). Demographic information and ¹¹C-CFT uptake were listed in the Table 2. Both axial and coronal striatum images illustrated severe low ¹¹C-CFT uptake in symptomatic patient (case 2) and mild low ¹¹C-CFT uptake in presymptomatic mutation carriers (case 3, Fig. 2).

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Fig.2

Axial and coronal positron emission tomographic images of ¹¹C-CFT-PET. A-C: axial images; D-F: coronal images. A & D: case 2 images (symptomatic patient); B & E: case 3 images (presymptomatic mutation carrier); C & F: control 1 images (normal control). Color scale: from the coldest (black) to the hottest (white).

SUVR analysis suggested that normal ¹¹C-CFT uptake was only detected in left caudate head in symptomatic patient (case 2). For presymptomatic mutation carriers, asymmetric significant low ¹¹C-CFT uptake was in case 3 in most parts, but was normal in right putamen. Bilateral putamen was affected with significant low ¹¹C-CFT uptake in case 4 & 5, while caudate was relatively spared.

DISCUSSION

To the best of our knowledge, reports on FTDP-17 pedigree in Chinese Han are very few. Furthermore, this is the first study with the utilization of ¹¹C-CFT-PET and involving both symptomatic patients and presymptomatic mutation carriers. Two patients and two presymptomatic mutation carriers with onset during follow-up, initiated with parkinsonism. Thus, striatum and dopaminergic dysfunction were predominantly and early affected in FTDP-17. Previous ¹¹C-CFT-PET study on a Chinese pedigree did not focus on presymptomatic mutation carriers [9]. A Japanese study referred to presymptomatic mutation carriers via ¹¹C-dopa-PET [13]; however, it was only cross-sectional without follow-up.

The pattern of presynaptic dopaminergic dysfunction in presymptomatic mutation carriers was more affected in putamen than caudate reported by previous study [11], while putamen plays a vital role in the development of parkinsonism [15]. Our study confirmed dopaminergic dysfunction in presymptomatic MAPT mutation carriers of FTDP-17 via ¹¹C-CFT-PET. Dopaminergic dysfunction is prior to symptom onset, and more severe in symptomatic patients. ¹¹C-CFT uptake was obviously affected in putamen in presymptomatic mutation carriers, which suggested putamen dopamine synthesis might be early impaired. On the other hand, asymmetric striatal ¹¹C-CFT uptake was demonstrated in symptomatic patients and presymptomatic mutation carriers. Thus, lateralization of pathologic change is a probable feature of FTLD-17. During follow-up, only case 3 was still free of parkinsonism. Considering the ages of three presymptomatic mutation carriers are comparable, normal ¹¹C-CFT uptake in putamen reflects compensated dopaminergic level and potentially predict late onset.

It is necessary to differentiate FTDP-17 from other tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The characteristics of PSP including parkinsonism and slow saccades. Dopaminergic deficits can be seen in FTDP-17 [16]. However, asymmetric dopaminergic dysfunction in FTDP-17 is different from PSP [17]. CBD is featured by asymmetric extrapyramidal signs in accordance with neuroimagic asymmetric dopaminergic dysfunction [18]. Alien hand syndrome, apraxia, and aphasia are the typical symptoms in CBD, which are uncommon in FTDP-17. Moreover, most PSP and CBD are sporadic, but FTDP-17 is autosomal dominantly inherited.

In this study, we conclude that ¹¹C-CFT-PET could be the potential biomarkers for the presymptomatic stage of FTDP-17 to predict the onset of disease. However, some limitations need to be considered, such as small sample size and unstrict statistical method. The sensitivity and specificity of the biomarkers are still need to be further confirmed by well-designed rigorous studies.