The Frequency of Genetic Mutations Associated With Behavioral Variant Frontotemporal Dementia in Chinese Han Patients

Liu, Li; Cui, Bo; Chu, Min Kyung; Cui, Yue; Jing, Donglai; Li, Dan; Xie, Kexin; Kong, Yu; Xia, Tian; Wang, Chaodong; Wu, Liyong

doi:10.3389/fnagi.2021.699836

Cited by 14 publications

(21 citation statements)

References 36 publications

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“…Genomic DNA was extracted from fresh peripheral blood leukocytes, and whole-exome sequencing (WES) libraries were generated using the Agilent SureSelect Human All Exon V6 Kit (Agilent Technologies, Santa Clara, CA, USA). The detailed procedure has been described in our previous study [ 27 ].…”

Section: Methodsmentioning

confidence: 99%

Genetic prion diseases presenting as frontotemporal dementia: clinical features and diagnostic challenge

et al. 2022

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Background To elucidate the clinical and ancillary features of genetic prion diseases (gPrDs) presenting with frontotemporal dementia (FTD) to aid early identification. Methods Global data of gPrDs presenting with FTD caused by prion protein gene mutations were collected from literature review and our records. Fifty-one cases of typical FTD and 136 cases of prion diseases admitted to our institution were included as controls. Clinical and ancillary data of the different groups were compared. Results Forty-nine cases of gPrDs presenting with FTD were identified. Compared to FTD or prion diseases, gPrDs presenting with FTD were characterized by earlier onset age (median 45 vs. 61/60 years, P < 0.001, P < 0.001) and higher incidence of positive family history (81.6% vs. 27.5/13.2%, P < 0.001, P < 0.001). Furthermore, GPrDs presenting with FTD exhibited shorter duration (median 5 vs. 8 years) and a higher rate of parkinsonism (63.7% vs. 9.8%, P < 0.001), pyramidal signs (39.1% vs. 7.8%, P = 0.001), mutism (35.9% vs. 0%, P < 0.001), seizures (25.8% vs. 0%, P < 0.001), myoclonus (22.5% vs. 0%, P < 0.001), and hyperintensity on MRI (25.0% vs. 0, P < 0.001) compared to FTD. Compared to prion diseases, gPrDs presenting with FTD had a longer duration of symptoms (median 5 vs. 1.1 years, P < 0.001), higher rates of frontotemporal atrophy (89.7% vs. 3.3%, P < 0.001), lower rates of periodic short-wave complexes on EEG (0% vs. 30.3%, P = 0.001), and hyperintensity on MRI (25.0% vs. 83.0%, P < 0.001). The frequency of codon 129 Val allele in gPrDs presenting with FTD was significantly higher than that reported in the literature for gPrDs in the Caucasian and East Asian populations (33.3% vs. 19.2%/8.0%, P = 0.005, P < 0.001). Conclusions GPrDs presenting with FTD are characterized by early-onset, high incidence of positive family history, high frequency of the Val allele at codon 129, overlapping symptoms with prion disease and FTD, and ancillary features closer to FTD. PRNP mutations may be a rare cause in the FTD spectrum, and PRNP genotyping should be considered in patients with these features.

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Section: Methodsmentioning

confidence: 99%

Genetic prion diseases presenting as frontotemporal dementia: clinical features and diagnostic challenge

et al. 2022

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“…The prepared libraries were sequenced using the HiSeq-2000 platform (Illumina, San Diego, CA, USA). DNA sequencing and genetic analysis were performed as previously described 5 . Repeat primed PCR was performed as previously described to obtain a qualitative estimation of the presence of C9orf72-expanded repeats 28 .…”

Section: Genetic Analysesmentioning

confidence: 99%

“…The chromosome 9 open reading frame 72 (C9orf72) hexanucleotide repeat expansion was first discovered in 2011, which is mainly associated with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD), and is characteristic of involvement in the extramotor neocortex, hippocampus, and lower motor neurons [1][2][3] . Recent studies have also revealed C9ofr72 as a causative gene of frontotemporal dementia with parkinsonism (FTDP) 4,5 . However, the underlying pathogenesis of parkinsonism in FTDP with C9orf72 repeat expansion remains unclear.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, striatal subregions associated with movement can be analyzed by an atlas based on their distinct cortical connectivity profiles, which functionally defined striatal subregions 15 . In our previous study, we described the first Chinese FTDP family with C9orf72 repeat expansions, however, it is currently unclear whether C9ORF721 mutation carriers develop parkinsonism because of C9ORF721 causing involvement of the striatal motor regions 5 .…”

Section: Introductionmentioning

confidence: 99%

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Involvement of striatal motoric subregions in familial frontotemporal dementia with parkinsonism harboring the C9orf72 repeat expansions

Liu

Chu

et al. 2022

npj Parkinsons Dis.

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The chromosome 9 open reading frame 72 (C9ORF72) has been proposed as the causative gene of frontotemporal dementia with parkinsonism (FTDP), but its pathophysiological mechanism of parkinsonism is poorly understood. To explore the roles of striatal motor subdivisions in the pathogenesis of parkinsonism resulting from C9ORF72 repeat expansions in the FTDP, two patients with FTDP from one pedigree and seventeen healthy controls were enrolled. The participants received clinical interviews, physical examinations, genetic testing, [18F]-fluorodeoxyglucose PET/MRI, and [18F]-dihydrotetrabenazine PET/CT. Voxel-wise and region of interest analysis were conducted with respect to gray matter volume, metabolism, and dopamine transport function between patients and controls, focusing on the motor part of the striatum according to the Oxford-GSK-Imanova Striatal Connectivity Atlas. Patient 1 presented with parkinsonism as the initial symptom, while patient 2 exhibited behavior disturbance as the first symptom, followed by parkinsonism within one year. Both patients had the hexanucleotide expansion detected in C9ORF72(>52 repeats). Gray matter volume atrophy, hypometabolism and dopamine dysfunction were observed in the motor areas of the striatum. Of the two patients, marked glucose hypometabolism within the striatal motor subregion was observed in patient 1, with corresponding gray matter atrophy. In addition, presynaptic dopaminergic integrity of patient 2 was deteriorated in the motor subregions which was consistent with gray matter atrophy. These findings imply that parkinsonism in FTDP may be associated with the degeneration and dopaminergic dysfunction of the striatal motor subregion, which might be attributed to C9orf72 repeat expansions.

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“…Up to 40% of FTD cases are genetic, with the most common cause being mutations of the microtubule-associated protein tau (MAPT) gene, especially in China. FTD is characterized by extensive tau pathology, and the most prevalent clinical phenotype is the behavioral variant of FTD (bvFTD) [ 2 , 3 ]. Increasing evidence has confirmed the presence of pathophysiological changes during the presymptomatic stage of genetic FTD [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Reconfigured metabolism brain network in asymptomatic microtubule-associated protein tau mutation carriers: a graph theoretical analysis

et al. 2022

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Background Studies exploring topological properties of the metabolic network during the presymptomatic stage of genetic frontotemporal dementia (FTD) are scarce. However, such knowledge is important for understanding brain function and disease pathogenesis. Therefore, we aimed to explore FTD-specific patterns of metabolism topology reconfiguration in microtubule-associated protein tau (MAPT) mutation carriers before the onset of symptoms. Methods Six asymptomatic carriers of the MAPT P301L mutation were compared with 12 non-carriers who all belonged to the same family of FTD. For comparison, we included 32 behavioral variant FTD (bvFTD) patients and 33 unrelated healthy controls. Each participant underwent neuropsychological assessments, genetic testing, and a hybrid positron emission tomography (PET)/magnetic resonance imaging (MRI) scan. Voxel-wise gray matter volumes and standardized uptake value ratios were calculated and compared for structural MRI and fluorodeoxyglucose (FDG)-PET, separately. The sparse inverse covariance estimation method (SICE) was applied to topological properties and metabolic connectomes of brain functional networks derived from 18F-FDG PET/MRI data. Independent component analysis was used to explore the metabolic connectivity of the salience (SN) and default mode networks (DMN). Results The asymptomatic MAPT carriers performed normal global parameters of the metabolism network, whereas bvFTD patients did not. However, we revealed lost hubs in the ventromedial prefrontal, orbitofrontal, and anterior cingulate cortices and reconfigured hubs in the anterior insula, precuneus, and posterior cingulate cortex in asymptomatic carriers compared with non-carriers, which overlapped with the comparisons between bvFTD patients and controls. Similarly, significant differences in local parameters of these nodes were present between asymptomatic carriers and non-carriers. The reduction in the connectivity of lost hub regions and the enhancement of connectivity between reconfigured hubs and components of the frontal cortex were marked during the asymptomatic stage. Metabolic connectivity within the SN and DMN was enhanced in asymptomatic carriers compared with non-mutation carriers but reduced in bvFTD patients relative to controls. Conclusions Our findings showed that metabolism topology reconfiguration, characterized by the earliest involvement of medial prefrontal areas and active compensation in task-related regions, was present in the presymptomatic phase of genetic FTD with MAPT mutation, which may be used as an imaging biomarker of increased risk of FTD.

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The Frequency of Genetic Mutations Associated With Behavioral Variant Frontotemporal Dementia in Chinese Han Patients

Cited by 14 publications

References 36 publications

Genetic prion diseases presenting as frontotemporal dementia: clinical features and diagnostic challenge

Genetic prion diseases presenting as frontotemporal dementia: clinical features and diagnostic challenge

Involvement of striatal motoric subregions in familial frontotemporal dementia with parkinsonism harboring the C9orf72 repeat expansions

Reconfigured metabolism brain network in asymptomatic microtubule-associated protein tau mutation carriers: a graph theoretical analysis

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