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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.
Stem Cell Res ; 61: 102769, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35421846

RESUMO

Alzheimer's disease (AD) is a common neurodegenerative disease characterized by cognitive decline even leading to incapacity, which prevalence estimates that about 5% of AD cases are caused by mutations in genes such as Presenilin-1 (PSEN1). Here we report the generation and characterization of an iPSC line derived from a patient carrying an E363Q mutation in PSEN1 gene. The iPSC line we generated presented a typical morphology, normal karyotype, free from Sendai viral vectors and exogenous factors, expressed endogenous pluripotency marker genes and proteins, which could form embryoid bodies in vitro and form teratoma in vivo as well, demonstrating its pluripotency.


Assuntos
Doença de Alzheimer , Células-Tronco Pluripotentes Induzidas , Doenças Neurodegenerativas , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Diferenciação Celular , Fibroblastos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Mutação/genética , Doenças Neurodegenerativas/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo
3.
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.

4.
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
5.
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
6.
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
7.
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
8.
Front Neurosci ; 15: 687053, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421518

RESUMO

BACKGROUND: Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two main types of dementia. We investigated the electroencephalogram (EEG) difference and clinical correlation in early-onset Alzheimer's disease (EOAD), and FTD using multimodal EEG analyses. EOAD had more severe EEG abnormalities than late-onset AD (LOAD). Group comparisons between EOAD and LOAD were also performed. METHODS: Thirty patients diagnosed with EOAD, nine patients with LOAD, and 14 patients with FTD (≤65 y) were recruited (2008.1-2020.2), along with 24 healthy controls (≤65 y, n = 18; >65 y, n = 6). Clinical data were reviewed. Visual EEG, EEG microstate, and spectral analyses were performed. RESULTS: Compared to controls, markedly increased mean microstate duration, reduced mean occurrence, and reduced global field power (GFP) peaks per second were observed in EOAD and FTD. We found increased durations of class B in EOAD and class A in FTD. EOAD had reduced occurrences in classes A, B, and C, while only class C occurrence was reduced in FTD. The visual EEG results did not differ between AD and FTD. Microstate B showed correlations with activities of daily living score (r = 0.780, p = 0.008) and cerebrospinal fluid (CSF) Aß42 (r = -0.833, p = 0.010) in EOAD. Microstate D occurrence was correlated with the CSF Aß42 level in FTD (r = 0.786, p = 0.021). Spectral analysis revealed a general slowing EEG, which may contribute to microstate dynamic loss. Power in delta was significantly higher in EOAD than in FTD all over the head. In addition, EOAD had a marked increased duration and decreased occurrence than late-onset AD (LOAD), with no group differences in visual EEG results. CONCLUSION: The current study found that EOAD and FTD had different EEG changes, and microstate had an association with clinical severity and CSF biomarkers. EEG microstate is more sensitive than visual EEG and may be useful for the differentiation between AD and FTD. The observations support that EEG can be a potential biomarker for the diagnosis and assessment of early-onset dementias.

9.
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
10.
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
11.
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.

12.
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
13.
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
14.
Chin Med J (Engl) ; 134(2): 178-184, 2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33109952

RESUMO

BACKGROUND: Homozygous or compound heterozygous mutations in high temperature requirement serine peptidase A1 (HTRA1) gene are responsible for cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Recently, increasing evidence has shown that heterozygous HTRA1 mutations are also associated with cerebral small vessel disease (CSVD) with an autosomal dominant pattern of inheritance. This study was aimed to analyze the genetic and clinical characteristics of HTRA1-related autosomal dominant CSVD. METHODS: We presented three new Chinese cases of familial CSVD with heterozygous HTRA1 mutations and reviewed all clinical case reports and articles on HTRA1-related autosomal dominant CSVD included in PUBMED by the end of March 1, 2020. CARASIL probands with genetic diagnosis reported to date were also reviewed. The genetic and clinical characteristics of HTRA1-related autosomal dominant CSVD were summarized and analyzed by comparing with CARASIL. RESULTS: Forty-four HTRA1-related autosomal dominant CSVD probands and 22 CARASIL probands were included. Compared with typical CARASIL, HTRA1-related autosomal dominant probands has a higher proportion of vascular risk factors (P < 0.001), a later onset age (P < 0.001), and a relatively slower clinical progression. Alopecia and spondylosis can be observed, but less than those in the typical CARASIL. Thirty-five heterozygous mutations in HTRA1 were reported, most of which were missense mutations. Amino acids located close to amino acids 250-300 were most frequently affected, followed by these located near 150∼200. While amino acids 250∼300 were also the most frequently affected region in CARASIL patients, fewer mutations precede the 200th amino acids were detected, especially in the Kazal-type serine protease domain. CONCLUSIONS: HTRA1-related autosomal dominant CSVD is present as a mild phenotype of CARASIL. The trend of regional concentration of mutation sites may be related to the concentration of key sites in these regions which are responsible for pathogenesis of HTRA1-related autosomal dominant CSVD.


Assuntos
Doenças de Pequenos Vasos Cerebrais , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Leucoencefalopatias , Infarto Cerebral , Doenças de Pequenos Vasos Cerebrais/genética , Heterozigoto , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Humanos , Leucoencefalopatias/genética , Mutação/genética
15.
Front Neurol ; 11: 621, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32714273

RESUMO

Actinomycosis is a slowly progressing infection caused by Actinomyces species, which consists of filamentous gram-positive bacteria. Intraspinal actinomycosis is very rare and most of the previous cases presented with epidural lesions. Only two cases of intrathecal actinomycosis have been described. We reported a case of intrathecal actinomycosis in a 46-year-old woman. Our patient presented with multisegmental root failure, which was different from previous intrathecal cases mainly involving the spinal cord. The manifestations, cervical MR imaging results, biopsy and histopathological features, and treatment history of the patient were reviewed. Clinical features of this disease resemble intraspinal neoplasms, other infectious processes, and granulomatous diseases, thus being difficult to diagnose preoperatively. Histopathological evidence from the biopsy is important for timely diagnosis. Early diagnosis and treatment may greatly improve the prognosis.

16.
Neurol Res ; 42(2): 164-169, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31939712

RESUMO

Objectives: To compare the efficacy and safety of anterior temporal lobotomy (ATLo) and anterior temporal lobectomy (ATLe) in drug-resistant temporal lobe epilepsy.Methods: Patients diagnosed with pharmacoresistant temporal lobe epilepsy who underwent anterior temporal lobotomy (ATLo) or anterior temporal lobectomy (ATLe) performed by a single surgeon were retrospectively included. Every patient was followed up annually after surgery. The postoperative seizure outcome evaluation was based on the Engel and ILAE classifications. We compared postoperative complications and 2-year follow-up seizure outcomes between the ATLo group and the ATL group.Results: A total of 42 individuals (21 ATLo and 20 ATLe) were included. At the two-year follow-up, more patients in the ATLo group than the ATLe group had reached Engel class I (20 versus 14) and ILAE I (19 versus 13). However, these differences were not significant. One patient in the ATLo group had intraparenchymal hematoma and fully recovered. The two groups had similar incidences of other short-term complications, and no patients died or had any permanent complications.Discussion: ATLo is not inferior to ATLe for patients with drug-resistant temporal epilepsy. There was no significant difference in seizure outcomes or the rate of postoperative complications between the two groups. A large sample randomized control study is needed.


Assuntos
Lobectomia Temporal Anterior/efeitos adversos , Epilepsia do Lobo Temporal/cirurgia , Complicações Pós-Operatórias/epidemiologia , Psicocirurgia/efeitos adversos , Convulsões/epidemiologia , Adulto , China/epidemiologia , Epilepsia Resistente a Medicamentos/cirurgia , Feminino , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
17.
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
18.
Neurodegener Dis ; 20(5-6): 165-172, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-34077945

RESUMO

INTRODUCTION: Idiopathic normal pressure hydrocephalus (iNPH) is one of the potentially reversible dementias. Early and accurate diagnosis is important for patients' prognosis. Emerging evidence shows fluid biomarkers are useful in diagnosis and pathophysiological research of iNPH. METHODS: Probable iNPH and Alzheimer's disease (AD) patients were recruited. Clinical diagnosis was performed according to international guidelines. CSF collection complied with a standard protocol. Commercial accessible ELISA kits were introduced for measurement of CSF t-tau, p-tau181, Aß42, and NfL. RESULTS: Twenty-seven iNPH, 27 AD, and 18 controls were included. The profiles of CSF t-tau, p-tau181, and t-tau/Aß42 in the iNPH and AD were significantly different (p < 0.0001). The profiles of CSF t-tau, p-tau181, and t-tau/Aß42 in the iNPH and control were not different (p > 0.05). Level of CSF Aß42 in iNPH was significantly lower than control (p < 0.0001) and also significantly higher than AD (p < 0.05). NfL level in iNPH and AD was increased, but its level in iNPH was significantly lower than that in AD (p = 0.005). NfL and t-tau level in the iNPH group was significantly correlated (coefficient = 0.649, p = 0.005), but not in AD (coefficient = 0.298, p = 0.157). CONCLUSION: Alzheimer's CSF biomarker profile of iNPH subjects showed moderately decreased Aß42 and normal t-tau, p-tau181, and t-tau/Aß42, which was distinguishable from AD. The different profiles and correlation of t-tau and NfL suggested different pathophysiology of AD and iNPH. t-tau was relatively an AD-specific neurodegenerative biomarker compared to NfL.

19.
Epilepsy Res ; 157: 106189, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31472401

RESUMO

PURPOSE: Type IIB focal cortical dysplasia (FCD) is an important cause of drug-resistant epilepsy. However, balloon cells located in the medial temporal lobe have been seldom reported. We aimed to discuss the clinical and pathological features of Type IIB FCD with balloon cells in the medial temporal lobe (MTLE-FCDIIB) and the differential diagnosis with other types of mesial temporal lobe epilepsy. METHODS: Three MTLE-FCDIIB cases were enrolled from Peking Union Medical College Hospital. Clinical and neuroimaging data were analyzed and histology features observed on hematoxylin-eosin (H&E) staining and immunochemical staining, including vimentin, nestin, S-100, CD34, neuronal nuclei antigen (Neun), glial fibrillary acidic protein (GFAP), neurofilament heavy chain (SMI32), were discussed. RESULTS: All cases involved drug-resistant epilepsy patients with childhood onset. The semiology of the epileptic seizure was a highly frequent partial seizure with or without generalized tonic-clonic seizures. Magnetic resonance imaging showed hyper-intensity in the medial temporal lobe without atrophy, different from mesial temporal sclerosis. Histological examination indicated the presence of balloon cells in the white matter of the para-hippocampal gyrus, subiculum, and cornu ammonis with cortical disorganization, and SMI32 positive dysmorphic neurons in the gray matter. Balloon cells were immunohistochemically stained with vimentin and nestin. Granular cell dispersion and pyramidal cell loss were not found. CONCLUSIONS: The presence of balloon cells in the medial temporal lobe is observed in a rare subgroup of FCD, named MTLE-FCDIIB. It has distinct clinical manifestations, neuroimaging features, pathological changes, and prognosis, which should be differentiated from mesial temporal lobe sclerosis and mesial temporal lobe tumors. Our findings enable more accurate diagnosis of mesial temporal lobe epilepsy.


Assuntos
Epilepsia do Lobo Temporal/patologia , Epilepsia/patologia , Hipocampo/patologia , Malformações do Desenvolvimento Cortical do Grupo I/patologia , Giro Para-Hipocampal/patologia , Adolescente , Adulto , Antígenos Nucleares/metabolismo , Epilepsia/diagnóstico por imagem , Epilepsia/metabolismo , Epilepsia do Lobo Temporal/diagnóstico por imagem , Epilepsia do Lobo Temporal/metabolismo , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Humanos , Imageamento por Ressonância Magnética , Malformações do Desenvolvimento Cortical do Grupo I/diagnóstico por imagem , Malformações do Desenvolvimento Cortical do Grupo I/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Nestina/metabolismo , Neuroimagem , Neurônios/metabolismo , Neurônios/patologia , Giro Para-Hipocampal/diagnóstico por imagem , Giro Para-Hipocampal/metabolismo , Tomografia Computadorizada por Raios X , Vimentina/metabolismo
20.
Front Neurol ; 9: 471, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29971042

RESUMO

Background: Neurocysticercosis (NCC) is the most common helminthic infection of the central nervous system (CNS). The diagnosis of NCC is sometimes challenging due to its heterogenous clinical manifestations and the variable sensitivity and specificity of neuroimaging and serological tests. Methods: Next-generation sequencing (NGS) of cerebrospinal fluid (CSF) was used to detect pathogens in patients with clinically suspected CNS infections. A series of patients diagnosed with NCC is reviewed here. Results: Using NGS of CSF, four patients were diagnosed with NCC. The reads corresponding to Taenia solium ranged from 478 to 117,362, with genomic coverage of 0.0564-11.15%. Reads corresponding to T. solium were not found in non-template controls and far exceeded those of the background microorganisms in patients with NCC, facilitating the interpretation of the NGS results. Conclusions: This case series demonstrates that NGS of CSF is promising in the diagnosis of NCC in difficult to diagnose cases. Larger studies are needed in the future.

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