Application of the mild behavioral impairment checklist in Chinese patients with the behavioral variant of frontotemporal dementia.

BACKGROUND: The mild behavioral impairment checklist (MBI-C) designed to capture neuropsychiatric symptoms in the whole spectrum of elder with or without dementia, have been verified in mild behavioral impairment, mild cognitive impairment and Alzheimer's Disease, but never used in the behavioral variant of frontotemporal dementia (bvFTD). METHODS: Fifty-two patients with bvFTD (mild, n = 30; moderate-severe, n = 22) and 82 community-dwelling elderly individuals (HCs) were enrolled. All subjects were assessed with a full neuropsychological scale including the MBI-C, Neuropsychiatric Inventory Questionnaire (NPI-Q), and Frontal Behavioral Inventory (FBI). Receiver operating characteristic curves were drawn to analyze the sensitivity and specificity of the MBI-C, NPI-Q, and FBI, and cutoff points were determined using the Youden index. RESULTS: The MBI-C and domain scores in all patients with bvFTD were significantly higher than those in HCs. The most common symptoms of bvFTD were apathy (82.7%) and impulse dyscontrol (80.8%). The MBI-C score was positively correlated with the NPI-Q, FBI, and Activities of Daily Living. For differentiating patients with both bvFTD and mild bvFTD from HCs, the optimal MBI-C cutoff point was 5.5 with a sensitivity of 100% and specificity of 82%, and its sensitivity was higher than that of the NPI-Q and FBI. CONCLUSION: The MBI-C is a sensitive tool for screening behavioral and psychological symptoms in patients with bvFTD, even in the early stages of the disease.

Clinical profile of fatal familial insomnia: phenotypic variation in 129 polymorphisms and geographical regions.

OBJECTIVE: Elucidate the core clinical and genetic characteristics and identify the phenotypic variation between different regions and genotypes of fatal familial insomnia (FFI). METHODS: A worldwide large sample of FFI patients from our case series and literature review diagnosed by genetic testing were collected. The prevalence of clinical symptoms and genetic profile were obtained, and then the phenotypic comparison between Asians versus non-Asians and 129Met/Met versus 129Met/Val were conducted. RESULTS: In total, 131 cases were identified. The age of onset was 47.51±12.53 (range 17-76) years, 106 patients died and disease duration was 13.20±9.04 (range 2-48) months. Insomnia (87.0%) and rapidly progressive dementia (RPD; 83.2%) occurred with the highest frequency. Hypertension (33.6%) was considered to be an objective indicator of autonomic dysfunction. Genotype frequency at codon 129 was Met/Met (84.7%) and Met/Val (15.3%), and allele frequency was Met (92.4%) and Val (7.6%).129 Met was a risk factor (OR: 3.728, 95% CI: 2.194 to 6.333, p=0.000) for FFI in the non-Asian population. Comparison of Asians and non-Asians revealed clinical symptoms and genetic background to show some differences (p<0.05). In the comparison of 129 polymorphisms, a longer disease duration was found in the 129 MV group, with alleviation of some clinical symptoms (p<0.05). After considering survival probability, significant differences in survival time between genotypes remained (p<0.0001). CONCLUSIONS: Insomnia, RPD and hypertension are representative key clinical presentations of FFI. Phenotypic variations in genotypes and geographic regions were documented. Prion protein gene 129 Met was considered to be a risk factor for FFI in the non-Asian population, and 129 polymorphisms could modify survival duration.

Effects of the environmental endocrine disruptors di-2-ethylhexyl phthalate and mono-2-ethylhexyl phthalate on human sperm function in vitro.

Di-2-ethylhexyl phthalate (DEHP), a plastic-derived, endocrine-disrupting chemical, has been shown to exhibit male reproductive toxicity. However, its effects on human mature spermatozoa are largely unknown. In this study we investigated the invitro effects of DEHP and mono-2-ethylhexyl phthalate (MEHP; the main metabolite of DEHP) on sperm function and the mechanisms involved. Human spermatozoa were exposed to phthalates invitro at the doses that cover the concentrations detected in human semen: 20nM-8 µM DEHP, 1nM-20 µM MEHP or a mixture of 20nM-8 µM DEHP and 1nM-20 µM MEHP. DEHP and MEHP, alone or in combination, had no effect on the viability, membrane integrity, motility, homeostasis of reactive oxygen species or mitochondrial activity of human spermatozoa. Interestingly, 1nM-20 µM MEHP and combinations of 20nM-8 µM DEHP and 1nM-20 µM MEHP enhanced penetration ability, hyperactivation and the spontaneous acrosome reaction of human spermatozoa, and increased intracellular free Ca2+ concentrations ([Ca2+]i) and tyrosine phosphorylation, two key signalling pathways that regulate sperm function. The findings of this study suggest that invitro exposure to MEHP metabolised from DEHP affects human sperm function by inducing increases in sperm [Ca2+]i and tyrosine phosphorylation, which adds to our understanding of the effects of DEHP on male reproduction.

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

BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) is a clinically heterogeneous syndrome with high heredity. However, the frequencies of mutations associated with bvFTD have yet to be determined. The aim of the current study was to investigate the frequency of Chinese Han patients harboring genetic bvFTD variants. METHODS: A total of 49 bvFTD patients selected from our frontotemporal lobar degeneration database, including 14 familial cases belonging to eight families and 35 sporadic cases were consecutively recruited from July 2014 to December 2019 at Xuanwu Hospital (Beijing, China). Whole-exome sequencing (WES) was performed and repeat-primed PCR was used to test samples for the C9orf72 hexanucleotide repeat expansion mutation. The frequency of genetic variants and the pathogenicity of the novel variants were analyzed. RESULTS: Ten pathogenic or likely pathogenic variants were identified in 17 bvFTD patients, including C9orf72 repeat expansions, six previously reported mutations and three novel mutations (MAPT p. R5C, p. D54N, GRN p. P451L). Genetic mutations accounted for 27.9% (12/43) of total cases, 87.5% (7/8) of patients with familial bvFTD, and 14.3% (5/35) with sporadic bvFTD. Pathogenic variants mostly occurred in MAPT gene (20.9%, 9/43), followed by C9orf72 repeat expansions (2.3%, 1/43), GRN gene (2.3%, 1/43) and FUS gene (2.3%, 1/43). CONCLUSION: There was a high prevalence of genetic variants in Chinese bvFTD patients, highlighting the necessity of genetic testing for bvFTD.

Three novel mutations in Chinese patients with CSF1R-related leukoencephalopathy.

BACKGROUND: CSF1R-related encephalopathy refers to adult-onset leukodystrophy with neuroaxonal spheroids and pigmented glia (ALSP) due to CSF1R mutations, which is a rare autosomal dominant white matter disease including two pathological entities, hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD). The aim of this study was to identify additional causative mutations in the CSF1R gene and clarify their pathogenic effects. METHODS: Whole-exome sequencing was conducted for nine Chinese patients diagnosed with possible ALSP based on clinical and neuroimaging findings from March 2014 to June 2020 at Xuanwu Hospital (Beijing, China). Variant pathogenicity was assessed according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) Standards and Guidelines. RESULTS: Mean ± standard deviation (range) age of disease onset in the nine patients was 39.22±9.63 [25-54] years. Four of the nine patients were male, and four out of nine had a remarkable family history. Seven CSF1R mutations were identified in the nine patients; four (p.G17C, p.R579Q, p.I794T and c.2909_2910insATCA) have been previously reported, while three (p.V613L, p.W821R and c.2442+2_2442+3dupT) were novel. Of the latter, two (p.V613L and p.W821R) were likely pathogenic and 1 (c.2442+2_2442+3dupT) was of uncertain significance according to ACMG/AMP criteria. CONCLUSIONS: These findings expand the mutational spectrum of ALSP and provide a basis for future investigations on etiologic factors and potential management strategies for this disease.

Effects of two environmental endocrine disruptors di-n-butyl phthalate (DBP) and mono-n-butyl phthalate (MBP) on human sperm functions in vitro.

Di-n-butyl phthalate (DBP), a plastic-derived, endocrine-disrupting chemical, is regarded as a male reproductive toxicant. In this study, we investigated the in vitro actions of DBP and mono-n-butyl phthalate (MBP, the main metabolite of DBP) on human sperm functions. Human sperm were treated with DBP (2 nM-6 µM), MBP (1 nM-3 µM), and a mixture of DBP and MBP in vitro. The results showed that only DBP at 6 µM, a dose reported in semen of infertile men, MBP at 3 µM (three times of the reported maximum MBP concentration in semen), and their mixture, had obvious adverse effects on sperm motility, penetration ability and capacitation. In addition, these doses of phthalates suppressed human sperm tyrosine phosphorylation, a key signaling pathway that regulates sperm functions. Our findings indicate that DBP and MBP may compromise human sperm functions by inhibiting sperm tyrosine phosphorylation once they accumulate in semen at high levels.