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1.
J Alzheimers Dis ; 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35491795

RESUMO

BACKGROUND: The established causative mutations in the APP, PSEN1, and PSEN2 can explain less than 1%,Alzheimer's disease (AD) patients. Of the identified variants, the PSEN2 mutations are even less common. OBJECTIVE: With the genetic study from the dementia cohort of Peking Union Medical College Hospital (PUMCH), we aim to illustrate the PSEN2 mutation spectrum and novel functionally validated mutations in Chinese AD patients. METHODS: 702 AD participants, aged 30-85, were identified in PUMCH dementia cohort. They all received history inquiry, physical examination, biochemical test, cognitive evaluation, brain CT/MRI, and next-generation DNA sequencing. Functional analysis was achieved by transfection of the HEK293 cells with plasmids harboring the wild-type PSEN2 or candidate mutations. RESULTS: Nine PSEN2 rare variants were found, including two reported (M239T, R62C) and seven novel variants (N141S, I368F, L396I, G117X, I146T, S147N, H220Y). The HEK293 cells transfected with the PSEN2 N141S, M239T, I368F plasmids showed higher Aß 42 and Aß 42/Aß 40 levels relative to the wild-type PSEN2. The PSEN2 L396I, G117X, S147N, H220Y, and R62C did not alter Aß 42, Aß 40 levels, or Aß 42/Aß 40 ratio. 1.9%,(13/702) subjects harbored rare PSEN2 variants. 0.4%,(3/702) subjects carried pathogenic/likely pathogenic PSEN2 mutations. The three subjects with the functionally validated PSEN2 mutations were all familial early-onset AD patients. The common symptoms included amnesia and mental symptom. Additionally, the M239T mutation carrier presented with dressing apraxia, visuospatial agraphia, dyscalculia and visual mislocalization. CONCLUSION: The PSEN2 N141S, M239T, and I368F are functionally validated mutations.

2.
Ecotoxicol Environ Saf ; 237: 113564, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35483139

RESUMO

Human trophoblast cell apoptosis may induce miscarriage. Trophoblast cells are sensitive to environmental BaP-7,8-dihydrodiol-9,10-epoxide (BPDE). However, how BPDE induces human trophoblast cell apoptosis is still largely elusive. In this work, we used BPDE-treated human trophoblast cells and villous tissues collected from recurrent miscarriage and health control groups to explore the underlying mechanism of BPDE-induced human trophoblast cell apoptosis. Continued with our recent work, we found that lncRNA HZ01 (lnc-HZ01) could induce human trophoblast cell apoptosis. In mechanism, lnc-HZ01 up-regulated p53 expression level by suppressing its MDM2-mediated proteasomal degradation. Meanwhile, we found that p53 acted as lnc-HZ01 transcription factor and promoted lnc-HZ01 transcription. Thus, lnc-HZ01 and p53 composed a positive feedback loop in human trophoblast cells. In normal trophoblast cells, relatively low levels of lnc-HZ01 and p53 suppressed p53/caspase-3 apoptosis pathway, giving normal pregnancy. Upon BPDE exposure, BPDE up-regulated the expression levels of lnc-HZ01 and p53, triggered this positive feedback loop, activated the p53/caspase-3 apoptosis pathway, and then induced miscarriage. Collectively, we discovered new mechanism by which lnc-HZ01 regulated BPDE-induced human trophoblast cell apoptosis, providing scientific basis for the diagnosis and treatment of unexplained recurrent miscarriage.


Assuntos
Aborto Habitual , RNA Longo não Codificante , 7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido/metabolismo , 7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido/toxicidade , Aborto Habitual/induzido quimicamente , Aborto Habitual/metabolismo , Apoptose , Caspase 3/metabolismo , Retroalimentação , Feminino , Humanos , Gravidez , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Trofoblastos/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
3.
PLoS One ; 17(3): e0264720, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35303006

RESUMO

OBJECTIVE: Sijunzi decoction (SJZD) was used to treat patients with colorectal cancer (CRC) as an adjuvant method. The aim of the study was to investigate the therapeutic targets and pathways of SJZD towards the tumor microenvironment of CRC via network pharmacology and the ESTIMATE algorithm. METHODS: The ESTIMATE algorithm was used to calculate immune and stromal scores to predict the level of infiltrating immune and stromal cells. The active targets of SJZD were searched in the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and UniProt database. The core targets were obtained by matching the differentially expressed genes in CRC tissues and the targets of SJZD. Then, GO, KEGG and validation in TCGA were carried out. RESULTS: According to the ESTIMATE algorithm and survival analysis, the median survival time of the low stromal score group was significantly higher than that of the high stromal score group (P = 0.018), while the patients showed no significant difference of OS between different immune groups (P = 0.19). A total of 929 genes were upregulated and 115 genes were downregulated between the stromal score groups (|logFC| > 2, adjusted P < 0.05); 357 genes were upregulated and 472 genes were downregulated between the immune score groups. The component-target network included 139 active components and 52 related targets. The core targets were HSPB1, SPP1, IGFBP3, and TGFB1, which were significantly associated with poor prognosis in TCGA validation. GO terms included the response to hypoxia, the extracellular space, protein binding and the TNF signaling pathway. Immunoreaction was the main enriched pathway identified by KEGG analysis. CONCLUSION: The core genes (HSPB1, SPP1, IGFBP3 and TGFB1) affected CRC development and prognosis by regulating hypoxia, protein binding and epithelial-mesenchymal transition in the extracellular matrix.


Assuntos
Neoplasias Colorretais , Medicamentos de Ervas Chinesas , Algoritmos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Hipóxia/tratamento farmacológico , Microambiente Tumoral/genética
4.
J Pers Med ; 12(1)2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-35055352

RESUMO

Background: Mini-Mental State Examination (MMSE) is the most widely used tool in cognitive screening. Some individuals with normal MMSE scores have extensive cognitive impairment. Systematic neuropsychological assessment should be performed in these patients. This study aimed to optimize the systematic neuropsychological test battery (NTB) by machine learning and develop new classification models for distinguishing mild cognitive impairment (MCI) and dementia among individuals with MMSE ≥ 26. Methods: 375 participants with MMSE ≥ 26 were assigned a diagnosis of cognitively unimpaired (CU) (n = 67), MCI (n = 174), or dementia (n = 134). We compared the performance of five machine learning algorithms, including logistic regression, decision tree, SVM, XGBoost, and random forest (RF), in identifying MCI and dementia. Results: RF performed best in identifying MCI and dementia. Six neuropsychological subtests with high-importance features were selected to form a simplified NTB, and the test time was cut in half. The AUC of the RF model was 0.89 for distinguishing MCI from CU, and 0.84 for distinguishing dementia from nondementia. Conclusions: This simplified cognitive assessment model can be useful for the diagnosis of MCI and dementia in patients with normal MMSE. It not only optimizes the content of cognitive evaluation, but also improves diagnosis and reduces missed diagnosis.

5.
Neurol Sci ; 43(5): 3255-3263, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34997422

RESUMO

OBJECTIVE: The objective of this study is to describe the typical and atypical clinical and neuroimaging features of ALD in Chinese patients, which will help early diagnosis and intervention to improve prognosis of ALD. METHODS: Forty-one patients in the Leukoencephalopathy Clinic of Neurology Department, Peking Union Medical College Hospital were enrolled. Detailed clinical manifestations and MRI features were analyzed. The relationship between phenotype and genotype as well as biochemical analysis was observed. RESULTS: The patients were classified according to phenotype and onset age, including 14 childhood cerebral ALD (CCALD), 8 adolescent cerebral ALD (adoCALD), 3 adult cerebral ALD (ACALD), 14 adrenomyeloneuropathy (AMN), and 2 ALD in women. AMN was the main presentation in adults. Visual impairment was usual onset symptom in CCALD and cognitive decline and psychiatric symptoms were found in adoCALD and ACALD. Typical MRI feature of CALD was symmetrical peri-ventricular "butterfly wings" like lesions in frontal and/or occipital lobe with peripheral DWI hyperintensities and Gd enhancement. Corpus callosum and internal capsule were always involved. Unilateral lesions were also possible. Cerebral AMN presented with centrum semiovale diffuse involvement. Spinocerebellar variant was a special subtype of AMN with obvious cerebellar and brainstem lesions. No relationships between phenotype and genotype as well as biochemical VLCFAs analysis were found. CONCLUSIONS: We emphasize that corpus callosum and internal capsule are always involved in ALD. A unilateral lesion is also possible. Neuroimaging of cerebral AMN is different from typical CALD with more centrum semiovale involvement. We support spinocerebellar variant was a rare subtype of AMN.


Assuntos
Adrenoleucodistrofia , Adolescente , Adrenoleucodistrofia/diagnóstico por imagem , Adrenoleucodistrofia/genética , Animais , Criança , China , Feminino , Genótipo , Humanos , Neuroimagem , Fenótipo
6.
J Alzheimers Dis ; 85(4): 1511-1518, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34958020

RESUMO

BACKGROUND: The previous studies have identified several genes in relation to Alzheimer's disease (AD), such as ABCA7, CR1, etc. A few studies have explored the association between the common variants, mainly in the non-coding regions of these genes, and cerebrospinal fluid (CSF) biomarkers. Fewer studies target the variants in the coding regions. OBJECTIVE: To illustrate the association between the common variants within or adjacent to the coding regions of AD susceptible genes and CSF biomarkers in AD patients. METHODS: 75 sporadic probable AD patients were extracted from the dementia cohort of Peking Union Medical College Hospital. They all had history inquiry, physical examination, blood test, cognitive assessment, brain MRI, CSF testing of Aß42, 181p-tau, and t-tau, and next-generation DNA sequencing. Sixty-nine common single nucleotide polymorphisms (SNPs) (minor allele frequency > 0.01) within or near the coding region of 13 AD susceptible genes were included in the analysis. RESULTS: The rs7412-CC (APOE) genotype showed lower CSF Aß42 level and higher p-tau/Aß42 ratio than the rs7412-CT genotype. The rs3752246-C (ABCA7) allele correlated with lower CSF Aß42 level. The alternate alleles of six ABCA7 SNPs were related to lower CSF p-tau, including rs3745842, rs3764648, rs3764652, rs4147930, rs4147934 and rs881768. The rs11609582-TT (A2M) genotype showed higher CSF p-tau than the rs11609582-TA genotype. The p-tau/Aß42 ratio was higher in the rs490460-TT (BACE1) genotype relative to the rs490460-GT genotype. CONCLUSION: Some common variants within or near the coding regions of APOE, ABCA7, A2M, and BACE1 are associated with CSF Aß42, p-tau. or p-tau/Aß42.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/genética , Apolipoproteínas E/genética , Ácido Aspártico Endopeptidases/genética , Biomarcadores/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Alelos , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , alfa-Macroglobulinas/genética
7.
Clin Neurol Neurosurg ; 210: 107012, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34749022

RESUMO

OBJECTIVE: Our study aimed to identify the appropriate evaluation time point and assessment forthe CSF tap test(TT) to predict the shunting responsiveness of patients with idiopathic normal-pressure hydrocephalus (iNPH). METHODS: Eighty-eight inpatients with clinically possible iNPH who underwent CSF TT at multiple time points (baseline, 8 hours, 24 hours, and 72 hours after CSF TT) at Peking Union Medical College Hospital were recruited. The multidomain assessment included the timed up and go test(TUG), 10-meter walking tests, and a brief executive function battery. Performance in multidomain assessment at the indicated time points were compared. The positive response rate and cumulative positive rate of multidomain assessment at multiple time points were calculated. And their corresponding specificity and sensitivity of predicting shunting response were calculated according to the follow-up results after shunting. RESULTS: The multidomain assessment performance except TUG at 8 hours were significantly improved at each time point after CSF TT compared with baseline (P<0.01). Reduction more than 10% in the 10-meter walking time and number of steps at 24 hours showed the highest specificity (both 85.7%) and sensitivity (37.5% and 46.7%, respectively) for predicting shunting response. Additionally, an improvement of more than 20% in the composite z score at 72 hours showed 100% specificity and 80% sensitivity for predicting shunting response. CONCLUSION: Multiple time points and multidomain assessment were helpful to identify more shunting responders. Executive function evaluation might be a candidate tool to increase the effectiveness of CSF TT.


Assuntos
Derivações do Líquido Cefalorraquidiano/métodos , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Hidrocefalia de Pressão Normal/cirurgia , Testes de Estado Mental e Demência , Punção Espinal/métodos , Teste de Caminhada/métodos , Idoso , Função Executiva/fisiologia , Feminino , Seguimentos , Humanos , Hidrocefalia de Pressão Normal/diagnóstico , Hidrocefalia de Pressão Normal/psicologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Fatores de Tempo
8.
Ann Palliat Med ; 10(11): 11322-11332, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34551572

RESUMO

BACKGROUND: Functional recovery is an important clinical outcome for patients with stroke. Hospital-level variation occurs in functional outcome after stroke. However, the extent to which patient characteristics, hospital characteristics, process of care, and medication persistence contribute to the hospital variation in poor functional outcome after ischemic stroke is unknown in China. METHODS: We retrospectively analyzed patients enrolled in the Third China National Stroke Registry from 2015 to 2018. The outcome was poor functional outcome (modified Rankin Scale score of 3-6) at 3 months and 1 year. We used the median odds ratio to quantify the hospital-level variation in rates of poor functional outcome. A series of hierarchical logistic models were constructed to assess the extent to which patient characteristics, hospital characteristics, process of care, and medication persistence contributed to the hospital variation. RESULTS: A total of 13,218 patients with acute ischemic stroke from 159 hospitals were included. The risk-adjusted rates of the poor functional outcome at 3 months and 1 year after ischemic stroke varied across hospitals, ranging from 6.0% to 26.0% and 6.8% to 24.0%, respectively. The median odds ratio was 1.78 at 3 months and 1.67 at 1 year. Hierarchical logistic models indicated that the patient characteristics, hospital characteristics, process of care, and the medication persistence explained 27.5%, 7.0%, 6.5%, and 5.0% of the variation at 1 year. Altogether, 36.8% and 46.1% of the hospital variation in 3-month and 1-year poor functional outcome, respectively, was explained. CONCLUSIONS: There was a wide variation in rates of functional outcomes across hospitals. Approximately half of the variation at 1 year can be explained by patient characteristics, hospital characteristics, process of care, and medication persistence. Approximately 11.5% of the variation can be modified through improvements in the process of care and medication persistence. More studies are needed to explore the contribution of post-discharge care in the future.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Assistência ao Convalescente , Isquemia Encefálica/tratamento farmacológico , Hospitais , Humanos , Alta do Paciente , Sistema de Registros , Estudos Retrospectivos , Acidente Vascular Cerebral/tratamento farmacológico , Resultado do Tratamento
9.
Brain Behav ; 11(11): e2373, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34555265

RESUMO

INTRODUCTION: To investigate the heterogeneous effect of Apolipoprotein E (ApoE) genotype on clinical phenotypes in early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD), respectively. METHODS: 785 probable AD patients were enrolled from the dementia cohort of Peking Union Medical College Hospital (PUMCH), China. There were 386 EOAD and 399 LOAD cases. All individuals finished history inquiry, neurological examination, blood biochemical test, neuropsychological screening test, electroencephalography, brain CT/MRI, and ApoE genotyping. Some participants had neuropsychological domain assessment (n = 317), MRI morphometry (n = 130), CSF testing of Aß42, p-tau, t-tau (n = 144), or DNA sequencing (n = 690). The variables were compared mainly between ɛ4 carriers and non-carriers in EOAD and LOAD, respectively. RESULTS: In LOAD, ɛ4 carriers showed female predominance; worse performance in trail making test, delayed recall of auditory verbal learning test (AVLT) and rey complex figure; smaller hippocampal, parahippocampal, and entorhinal volume, as compared to ɛ4 non-carriers. In EOAD, ɛ4 carriers had lower scores in AVLT, episodic memory and modified Luria's tapping task; but less cortical atrophy in entorhinal, middle cingulate, inferior frontal, and parieto-occipital regions, in comparison to ɛ4 non-carriers. 6.2% (43/690) subjects harbored potential causative mutations in APP, PSEN1, and PSEN2. In both EOAD and LOAD, no differences were observed between ɛ4 carriers and non-carriers in CSF levels of Aß42, p-tau, t-tau, or mutation frequency. CONCLUSIONS: ApoE exerts a heterogeneous effect on clinical phenotypes in EOAD and LOAD, which might be related to the different genetic and pathological basis underlying them.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Feminino , Genótipo , Hospitais , Humanos , Fenótipo
10.
Curr Alzheimer Res ; 18(3): 265-272, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34102969

RESUMO

BACKGROUND: Alzheimer's disease with a causative genetic mutation (AD-CGM) is an uncommon form, characterized by a heterogeneous clinical phenotype and variations in the genotype of racial groups affected. OBJECTIVE: We aimed to systemically describe the phenotype variance and mutation spectrum in the large sample size of the Peking Union Medical College Hospital (PUMCH) cohort, Beijing, China. METHODS: Next-generation sequencing (NGS) was carried out in 1108 patients diagnosed with dementia. A total of 40 Han Chinese patients with three AD gene mutations were enrolled. A systemic review of all the patients was performed, including clinical history, neurocognitive assessment, brain magnetic resonance imaging, and cerebrospinal fluid (CSF) biomarkers. RESULTS: We studied the following gene mutation variants: 12 AßPP, 13 PSEN1, and 9 PSEN2, and 23 among them were novel. Most of them were early-onset, but PSEN1 mutation carriers had the youngest onset age. The commonest symptoms were similar to those of AD, including an amnestic syndrome, followed by psychiatric symptoms and movement disorder. On MRI, parietal and posterior temporal atrophy was prominent in PSEN1 and PSEN2 mutation carriers, while AßPP mutation carriers had more vascular changes. The CSF biomarkers profile was indistinguishable from sporadic AD. CONCLUSION: We identified a small group of AD-CGM subjects representing 3.6% among more than 1000 demented patients in the PUMCH cohort. These subjects usually presented with early-onset dementia and exhibited significant clinical and genetic heterogeneity. Identification required complete screening of genetic mutations using NGS. Although family history was usually present, we found non-familial cases of all three genetic mutations.


Assuntos
Doença de Alzheimer/genética , Mutação/genética , Fenótipo , Adulto , Precursor de Proteína beta-Amiloide/genética , China , Estudos de Coortes , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Presenilina-1/genética , Presenilina-2/genética
11.
J Alzheimers Dis ; 82(1): 205-214, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34024840

RESUMO

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers are widely accepted as manifestations of Alzheimer's disease (AD) pathogenesis and incorporated into biological definition of AD. However, the correlations between CSF and other biomarkers such as neuroimaging and neuropsychiatric evaluation are complicated and inconsistent. OBJECTIVE: We aimed to better interpreting CSF biomarkers results accompanying with other indexes in improving accurate diagnosis of AD. METHODS: 112 AD patients and 30 cognitive normal controls were selected. Commercial accessible ELISA kits were introduced for measurement of CSF t-tau, p-tau181, Aß1-42, and NfL based on standard protocol. MRI examinations were performed using a 3-T MRI scanner and visual rating scales including medial temporal atrophy score and Koedam's scale were used to evaluate medial temporal atrophy and posterior region atrophy. RESULTS: CSF biomarkers' profile including decreased concentration of Aß1-42, increased concentration of t-tau, p-tau181, t-tau/Aß 1-42, and NfL were diagnostic between AD and control. CSF biomarkers profile was not influenced by the APOE genotype. Increased concentration of t-tau and NfL, as well as ratio of t-tau/Aß 1-42 were related to decrease of Mini-Mental State Examination (MMSE) score while concentration of Aß1-42 not. Visual assessed cortical atrophy was related to MMSE score, but most of the CSF biomarkers were not related to atrophy, except that increased concentration of p-tau181 was significantly associated with atrophy of posterior cortical region. CONCLUSION: Our results supported CSF biomarkers were helpful in diagnosis of AD. However, CSF biomarkers were cross-sectional reflection of pathogenesis, which did not correlate well with clinical progression. CSF biomarkers should be interpreted in combination with MRI and cognitive evaluation in clinical use.


Assuntos
Doença de Alzheimer/diagnóstico , Atrofia/patologia , Biomarcadores/líquido cefalorraquidiano , Cognição/fisiologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , China , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Proteínas tau/líquido cefalorraquidiano
12.
Clin Neurol Neurosurg ; 205: 106604, 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33887505

RESUMO

INTRODUCTION: Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are the leading causes of dementia. To better understand the disease development of cognitive function and anatomical structure in AD and FTLD, we analyzed the changes in brain volume by MRI and the psychological test results. Here, we report a dynamic observation of brain structure. METHODS: Thirteen patients diagnosed with probable AD by the 2011 NIA-AA criteria and eight FTLD patients diagnosed by the FTLD criteria underwent MRI at baseline. All subjects were rescanned after 5 months to 3 years of follow-up. The anatomic changes on T1-weighted imaging of each subject were measured, and the separate changes in the two groups and the differences in the changes between AD and FTLD were analyzed. RESULTS: In AD patients, the anterior and posterior horns of the lateral ventricle and lateral fissure enlarged progressively (p < 0.001). The volume of the regions, including the medial and lateral temporal lobe, especially the parahippocampal gyrus, and the frontal lobe decreased significantly as the disease progressed (p < 0.001). Additionally, the volume of white matter in the frontal, parietal, temporal lobe and cerebellum decreased in a relatively symmetric pattern (p < 0.001). In FTLD patients, the anterior horn of the lateral ventricle, lateral fissure, cerebral longitudinal fissure, external space of the orbitofrontal cortex, and mesencephalon surrounding the cisterna were enlarged (p < 0.005), while regions including the left frontal lobe, anterior cingulate cortex, basal ganglia (especially the left basal ganglia), left lateral temporal lobe and inferior cerebellar vermis decreased as the disease progressed (p < 0.005). Regarding the differences between AD and FTLD, atrophy of the frontal lobe and bilateral basal ganglia was more significant in FTLD than in AD (p < 0.01). In addition, enlargements of the anterior horn of the lateral ventricle, left lateral fissure and interpeduncular cistern were more significant in FTLD patients than in AD patients (p < 0.01). CONCLUSIONS: These findings suggest that AD and FTLD have distinctly different atrophy patterns: AD patients show diffuse atrophy while FTLD patients show an asymmetrical focal atrophy pattern, which might explain the relatively better and longer preservation of daily living function in FTLD patients.

13.
Adv Exp Med Biol ; 1300: 151-160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33523433

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) are widely spread persistent environmental toxicants. Its typical representative benzo[a]pyrene (BaP) is a human carcinogen. BaP can pass through the placental barrier and is finally metabolized into benzo[a]pyren-7, 8-dihydrodiol-9, 10-epoxide (BPDE). BPDE can form DNA adducts, which directly affect the female reproductive health. Based on the special physiological functions of trophoblast cells and its important effect on normal pregnancy, this chapter describes the toxicity and molecular mechanism of BPDE-induced dysfunctions of trophoblast cells. By affecting the invasion, migration, apoptosis, proliferation, inflammation, and hormone secretion of trophoblast cells, BPDE causes diseases such as choriocarcinoma, intrauterine growth restriction, eclampsia, and abortion. In the end, it is expected to provide a scientific basis and prevention approach for women's reproductive health and decision-making basis for the formulation of environmental health standards.


Assuntos
7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido , Trofoblastos , 7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido/farmacologia , Benzo(a)pireno/farmacologia , Carcinógenos/farmacologia , Adutos de DNA , Feminino , Humanos , Gravidez
14.
Clin Neurol Neurosurg ; 203: 106552, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33601235

RESUMO

OBJECTIVE: White matter hyperintensities could be found in many degenerative dementias including Alzheimer's disease (AD). Pathogenesis of white matter hyperintensities in AD is complicated. We aim to identify the features of white matter hyperintensities and the atrophy pattern in early onset Alzheimer's disease with causative gene mutations. METHODS: 7 AD dementia patients with causative mutations were included and the clinical history, neuropsychology, neuroimaging,APOE genotype and whole-genome sequencing (WGS) were analyzed. Axial T1-weighted images and Fluid attenuated inversion recovery (FLAIR) were analyzed with visual rating scale to examine cortical atrophy and white matter hyperintensities. RESULTS: 5 female and 2 male patients with 4PSEN1, 2PSEN2 and 1APP mutation were included. The average age of onset was 46.7y/o (44-52) and the duration of disease was 28.6 months (8-60). Clinical phenotype included memory loss (100 %), visual/spatial disorder (100 %), executive dysfunction (100 %), calculation disorder (85.7 %), disorientation (85.7 %), language problem (57.1 %), personality change (28.6 %) and movement disorder (14.3 %). The grading of posterior cortex atrophy was higher than medial temporal lobe atrophy. Periventricular hyperintensities surrounding occipital and frontal horn of ventricle and sub-ventricular bands were most common, while small foci of lesions were also detected in deep white matter, sub-cortical and juxta-cortical area. Mutations carriers in the APP gene or PSEN1 gene postcodon 200 had more severe white matter hyperintensities than other mutations. CONCLUSION: White matter hyperintensities were found in early onset AD with causative mutations. The severity was related to genotypes and spatial distributions. Axon degeneration following neuronal loss and ischemic injury might be the pathogenesis of white matter damage. Severer atrophy in the posterior cortex than medial temporal lobe can present in early onset AD.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Mutação/genética , Substância Branca/patologia , Adulto , Idade de Início , Precursor de Proteína beta-Amiloide/genética , Atrofia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Presenilina-1/genética , Presenilina-2/genética
15.
Stroke Vasc Neurol ; 6(2): 291-297, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33443231

RESUMO

BACKGROUND AND PURPOSE: Stroke is the second leading cause of death worldwide and the leading cause of mortality and long-term disability in China, but its underlying risk genes and pathways are far from being comprehensively understood. We here describe the design and methods of whole genome sequencing (WGS) for 10 914 patients with acute ischaemic stroke or transient ischaemic attack from the Third China National Stroke Registry (CNSR-III). METHODS: Baseline clinical characteristics of the included patients in this study were reported. DNA was extracted from white blood cells of participants. Libraries are constructed using qualified DNA, and WGS is conducted on BGISEQ-500 platform. The average depth is intended to be greater than 30× for each subject. Afterwards, Sentieon software is applied to process the sequencing data under the Genome Analysis Toolkit best practice guidance to call genotypes of single nucleotide variants (SNVs) and insertion-deletions. For each included subject, 21 fingerprint SNVs are genotyped by MassARRAY assays to verify that DNA sample and sequencing data originate from the same individual. The copy number variations and structural variations are also called for each patient. All of the genetic variants are annotated and predicted by bioinformatics software or by reviewing public databases. RESULTS: The average age of the included 10 914 patients was 62.2±11.3 years, and 31.4% patients were women. Most of the baseline clinical characteristics of the 10 914 and the excluded patients were balanced. CONCLUSIONS: The WGS data together with abundant clinical and imaging data of CNSR-III could provide opportunity to elucidate the molecular mechanisms and discover novel therapeutic targets for stroke.


Assuntos
Isquemia Encefálica , Ataque Isquêmico Transitório , AVC Isquêmico , Acidente Vascular Cerebral , Idoso , Variações do Número de Cópias de DNA , Feminino , Humanos , Ataque Isquêmico Transitório/diagnóstico , Ataque Isquêmico Transitório/genética , AVC Isquêmico/diagnóstico , AVC Isquêmico/genética , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/genética , Sequenciamento Completo do Genoma/métodos
16.
J Mol Neurosci ; 71(5): 1015-1022, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33006106

RESUMO

Frontotemporal dementia (FTD) is a heterogeneous disease both clinically and pathologically. Genetic mutation in microtubule-associated protein tau (MAPT) is the most common cause of FTD, and the phenotype is related to the mutation location. However, the phenotype and genotype correlation varies somewhat among different cohorts and ethnicities. Whole-genome next-generation sequencing (NGS) was carried out for 1351 patients with dementia at Peking Union Medical College Hospital. MAPT variations classified as pathogenic and of uncertain significance were identified. Demographic information, clinical presentations, and neuroimaging were collected, and the phenotype-genotype correlation was analyzed with a concurrent literature review. Twenty-four patients were enrolled; 8 patients carrying the D177V mutation are discussed separately. The average onset age was young, and most of them had a positive family history. Cognitive dysfunction, behavior, and personality changes as well as aphasia were the most common presentations. Most structural MRIs showed asymmetrical atrophy of the temporal lobe, with/without similar changes in the frontal lobe. L266V carriers presented with youngest onset typical behavior variant FTD or aphasia; P301L carriers presented with behavior variant FTD or aphasia. Functional MRI and molecular imaging also showed that the involved areas were similar to those with structural atrophy. D296N carriers presented atypical parkinsonism and cognitive dysfunction at older ages. Eight D177V carriers had extraordinarily different manifestations. The clinical phenotype of most of them was not FTD, though cerebral vascular lesions were obvious in some of them. MAPT mutation is rare in Chinese dementia patients. The phenotype and genotype correlation is specific and overlaps. The D177V mutation is possibly not directly pathogenic in our cohort. Some of the variants might increase the genetic risk of neurodegenerative diseases.


Assuntos
Demência Frontotemporal/genética , Mutação de Sentido Incorreto , Fenótipo , Proteínas tau/genética , Adulto , Idoso , Feminino , Demência Frontotemporal/patologia , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade
17.
Front Mol Neurosci ; 14: 810919, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35282655

RESUMO

Neuromuscular junctions (NMJs) are the key interface between terminal nerves and targeted muscle, which undergo degeneration during denervation periods. Denervation-related NMJs changes limits the recovery level of nerve repair strategies. Insights into mechanisms behind neuromuscular junction degeneration and regeneration, following denervation and reinnervation, are of clinical value. Developing some therapies to maintain or protect structures and functions of NMJs may contribute to a better prognosis. Here, we reviewed previous studies of NMJs focusing on the morphological, functional, and molecular changes after denervation, and if those changes can be reversed after reinnervation. Also, we reviewed about the present probable strategies that have been applied clinically or could still be studied in targeting the neuromuscular junction protection or regeneration improvement.

18.
Arq Neuropsiquiatr ; 78(2): 76-80, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32022122

RESUMO

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia. Despite numerous studies on the subject, the pathologies for AD are still unclear and there is still no ideal biomarker for diagnosis. The present study aimed to investigate clinical significance of human complement factor H (CFH) in patients with late-onset AD. METHODS: The present prospective study included 187 late-onset AD patients who went to our hospital from January 2015 to December 2017. One hundred patients with mild cognitive impairment (MCI) and 80 healthy individuals who were age and gender matched to AD patients were enrolled as controls. Demographic data such as age, gender, and education duration were recorded. Blood samples were collected and serum levels of C-reactive protein (CRP), CFH, and brain-derived neurotrophic factor (BDNF) were determined by Enzyme-linked immunosorbent assay (ELISA). The mini-mental state examination (MMSE) score was measured for all patients. RESULTS: No significant difference was found in age, gender, and education duration for all participants. The MMSE scores showed AD patients had lower MMES scores than the other two groups. All factors of CFH, CRP, and BDNF were dramatically decreased in AD patients compared with the MCI and the ealthy control. Levels of CFH were found to be positively correlated with levels of CRP; however, no significant correlation was found between CFH and BDNF, nor CFH and MMSE. CONCLUSION: CFH was decreased in late-onset AD patients, and serum levels of CFH was correlated with serum levels of CRP, but not MMSE and BDNF. These results may provide more clinical evidences for the role of CFH in AD patients.


Assuntos
Doença de Alzheimer , Proteína C-Reativa/análise , Fator H do Complemento/análise , Humanos , Estudos Prospectivos
19.
Arq. neuropsiquiatr ; 78(2): 76-80, Feb. 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1088993

RESUMO

Abstract Alzheimer's disease (AD) is the most common cause of dementia. Despite numerous studies on the subject, the pathologies for AD are still unclear and there is still no ideal biomarker for diagnosis. The present study aimed to investigate clinical significance of human complement factor H (CFH) in patients with late-onset AD. Methods: The present prospective study included 187 late-onset AD patients who went to our hospital from January 2015 to December 2017. One hundred patients with mild cognitive impairment (MCI) and 80 healthy individuals who were age and gender matched to AD patients were enrolled as controls. Demographic data such as age, gender, and education duration were recorded. Blood samples were collected and serum levels of C-reactive protein (CRP), CFH, and brain-derived neurotrophic factor (BDNF) were determined by Enzyme-linked immunosorbent assay (ELISA). The mini-mental state examination (MMSE) score was measured for all patients. Results: No significant difference was found in age, gender, and education duration for all participants. The MMSE scores showed AD patients had lower MMES scores than the other two groups. All factors of CFH, CRP, and BDNF were dramatically decreased in AD patients compared with the MCI and the ealthy control. Levels of CFH were found to be positively correlated with levels of CRP; however, no significant correlation was found between CFH and BDNF, nor CFH and MMSE. Conclusion: CFH was decreased in late-onset AD patients, and serum levels of CFH was correlated with serum levels of CRP, but not MMSE and BDNF. These results may provide more clinical evidences for the role of CFH in AD patients.


Resumo A doença de Alzheimer (DA) é a causa mais comum de demência. Apesar de inúmeros estudos sobre DA, suas patologias ainda não são claras e ainda não existe um biomarcador ideal para o diagnóstico da condição. O presente estudo teve como objetivo investigar a significância clínica do fator H do complemento humano (CFH) em pacientes com DA de início tardio. Métodos: O presente estudo prospectivo incluiu um total de 187 pacientes com DA de início tardio que foram ao nosso hospital entre janeiro de 2015 e dezembro de 2017. Cem pacientes com comprometimento cognitivo leve (CCL) e 80 indivíduos saudáveis com idade e sexo pareados com pacientes com DA foram incluídos como controle. Dados demográficos como idade, sexo e duração da educação foram registrados. As amostras de sangue foram coletadas e os níveis séricos de proteína C-reativa (PCR), CFH e fator neurotrófico derivado do cérebro (BDNF) foram determinados pelo ensaio imunoabsorvente ligado à enzima (ELISA). O escore do miniexame do estado mental (MEEM) foi medido para todos os pacientes. Resultados: Não foram encontradas diferenças significativas em idade, sexo e duração da educação para todos os participantes. Pacientes com DA tinham os menores escores de MEEM em relação aos outros dois grupos. Todos os fatores de CFH, PCR e BDNF diminuíram drasticamente em pacientes com DA em comparação com o CCL e o controle saudável. Os níveis de CFH mostraram correlação positiva com os níveis de PCR; no entanto, não foi encontrada correlação significativa entre CFH e BDNF, nem CFH e MEEM. Conclusão: A CFH diminuiu nos pacientes com DA de início tardio e os níveis séricos de CFH foram correlacionados com os níveis séricos de PCR, mas não o MEEM e o BDNF. Esses resultados podem fornecer mais evidências clínicas do papel da CFH em pacientes com DA.


Assuntos
Humanos , Proteína C-Reativa/análise , Fator H do Complemento/análise , Doença de Alzheimer , Estudos Prospectivos
20.
Neurol Sci ; 41(2): 403-409, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31705326

RESUMO

AIM: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an inherited rare disease affecting young adults. We present the clinical, imaging, and neuropathological results of our case series, emphasizing biopsy histology combined with clinical information will increase the accuracy of early diagnosis. METHODS: In total, 4 females and 2 male ALSP patients with onset at ages 24-45 years were enrolled. Clinical manifestations, neuroimaging, and histopathology as well as gene mutation were analyzed and compared with literature. RESULTS: Clinical manifestations include cognitive decline with/without psycho-behavior problems and movement disorders including paralysis, hemiplegia, parkinsonism, and pyramidal tract injury, as well as dysarthria, dysphagia, and sensory disturbances. MRI showed multiple periventricular and subcortical white matter lesions, involving the corpus callosum, with no enhancement, but with persistent hyperintensity on diffuse-weighted imaging. Histology showed widespread white matter damage and pale stain, especially destroyed axons with spheroids and funicular axons which were stained with neurofilament and ubiquitin. Foamy and pigmented macrophages were another typical change. CSF1R mutation was found in 4 of them. All of the patients were misdiagnosed and treated for a long time for multiple sclerosis, cerebral infarction, normal pressure hydrocephalus, etc. CONCLUSION: ALSP will cause rapidly progressing dementia with/without movement disorders in young adults. The definite diagnosis should be based on a comprehensive analysis of clinical manifestations, and neuroimaging, histology, and genetic results. Early biopsy will add to the accuracy of the diagnosis.


Assuntos
Axônios/patologia , Neuroglia/patologia , Tratos Piramidais/patologia , Substância Branca/patologia , Adulto , Biópsia/métodos , Feminino , Humanos , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/patologia , Neuroimagem/métodos
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