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  • Oxford University Press (OUP)  (15)
  • 2020-2024  (15)
  • Linguistics  (15)
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  • Oxford University Press (OUP)  (15)
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  • 2020-2024  (15)
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  • Linguistics  (15)
Subjects(RVK)
  • 1
    Online Resource
    Online Resource
    Prediction of Alzheimer's disease using multi-variants from a Chinese genome-wide association study
    Oxford University Press (OUP) ; 2021
    In:  Brain Vol. 144, No. 3 ( 2021-04-12), p. 924-937
    Details
    In: Brain, Oxford University Press (OUP), Vol. 144, No. 3 ( 2021-04-12), p. 924-937
    Abstract: Previous genome-wide association studies have identified dozens of susceptibility loci for sporadic Alzheimer’s disease, but few of these loci have been validated in longitudinal cohorts. Establishing predictive models of Alzheimer’s disease based on these novel variants is clinically important for verifying whether they have pathological functions and provide a useful tool for screening of disease risk. In the current study, we performed a two-stage genome-wide association study of 3913 patients with Alzheimer’s disease and 7593 controls and identified four novel variants (rs3777215, rs6859823, rs234434, and rs2255835; Pcombined = 3.07 × 10−19, 2.49 × 10−23, 1.35 × 10−67, and 4.81 × 10−9, respectively) as well as nine variants in the apolipoprotein E region with genome-wide significance (P  & lt; 5.0 × 10−8). Literature mining suggested that these novel single nucleotide polymorphisms are related to amyloid precursor protein transport and metabolism, antioxidation, and neurogenesis. Based on their possible roles in the development of Alzheimer’s disease, we used different combinations of these variants and the apolipoprotein E status and successively built 11 predictive models. The predictive models include relatively few single nucleotide polymorphisms useful for clinical practice, in which the maximum number was 13 and the minimum was only four. These predictive models were all significant and their peak of area under the curve reached 0.73 both in the first and second stages. Finally, these models were validated using a separate longitudinal cohort of 5474 individuals. The results showed that individuals carrying risk variants included in the models had a shorter latency and higher incidence of Alzheimer’s disease, suggesting that our models can predict Alzheimer’s disease onset in a population with genetic susceptibility. The effectiveness of the models for predicting Alzheimer’s disease onset confirmed the contributions of these identified variants to disease pathogenesis. In conclusion, this is the first study to validate genome-wide association study-based predictive models for evaluating the risk of Alzheimer’s disease onset in a large Chinese population. The clinical application of these models will be beneficial for individuals harbouring these risk variants, and particularly for young individuals seeking genetic consultation.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awaa364
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 1474117-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    In-depth analysis reveals complex molecular aetiology in a cohort of idiopathic cerebral palsy
    Oxford University Press (OUP) ; 2022
    In:  Brain Vol. 145, No. 1 ( 2022-03-29), p. 119-141
    Details
    In: Brain, Oxford University Press (OUP), Vol. 145, No. 1 ( 2022-03-29), p. 119-141
    Abstract: Cerebral palsy is the most prevalent physical disability in children; however, its inherent molecular mechanisms remain unclear. In the present study, we performed in-depth clinical and molecular analysis on 120 idiopathic cerebral palsy families, and identified underlying detrimental genetic variants in 45% of these patients. In addition to germline variants, we found disease-related postzygotic mutations in ∼6.7% of cerebral palsy patients. We found that patients with more severe motor impairments or a comorbidity of intellectual disability had a significantly higher chance of harbouring disease-related variants. By a compilation of 114 known cerebral-palsy-related genes, we identified characteristic features in terms of inheritance and function, from which we proposed a dichotomous classification system according to the expression patterns of these genes and associated cognitive impairments. In two patients with both cerebral palsy and intellectual disability, we revealed that the defective TYW1, a tRNA hypermodification enzyme, caused primary microcephaly and problems in motion and cognition by hindering neuronal proliferation and migration. Furthermore, we developed an algorithm and demonstrated in mouse brains that this malfunctioning hypermodification specifically perturbed the translation of a subset of proteins involved in cell cycling. This finding provided a novel and interesting mechanism for congenital microcephaly. In another cerebral palsy patient with normal intelligence, we identified a mitochondrial enzyme GPAM, the hypomorphic form of which led to hypomyelination of the corticospinal tract in both human and mouse models. In addition, we confirmed that the aberrant Gpam in mice perturbed the lipid metabolism in astrocytes, resulting in suppressed astrocytic proliferation and a shortage of lipid contents supplied for oligodendrocytic myelination. Taken together, our findings elucidate novel aspects of the aetiology of cerebral palsy and provide insights for future therapeutic strategies.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awab209
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 1474117-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    PSAP variants in Parkinson’s disease: a large cohort study in Chinese mainland population
    Oxford University Press (OUP) ; 2021
    In:  Brain Vol. 144, No. 3 ( 2021-04-12), p. e25-e25
    Details
    In: Brain, Oxford University Press (OUP), Vol. 144, No. 3 ( 2021-04-12), p. e25-e25
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awaa391
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 1474117-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 4
    Online Resource
    Online Resource
    Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease
    Oxford University Press (OUP) ; 2022
    In:  Brain Vol. 145, No. 12 ( 2022-12-19), p. 4474-4488
    Details
    In: Brain, Oxford University Press (OUP), Vol. 145, No. 12 ( 2022-12-19), p. 4474-4488
    Abstract: Alzheimer’s disease is a neurodegenerative disorder that causes age-dependent neurological and cognitive declines. The treatments for Alzheimer’s disease pose a significant challenge, because the mechanisms of disease are not being fully understood. Malfunction of the blood–brain barrier is increasingly recognized as a major contributor to the pathophysiology of Alzheimer’s disease, especially at the early stages of the disease. However, the underlying mechanisms remain poorly characterized, while few molecules can directly target and improve blood–brain barrier function in the context of Alzheimer’s disease. Here, we showed dysfunctional blood–brain barrier in patients with Alzheimer’s disease reflected by perivascular accumulation of blood-derived fibrinogen in the hippocampus and cortex, accompanied by decreased tight junction proteins Claudin-5 and glucose transporter Glut-1 in the brain endothelial cells. In the APPswe/PS1dE9 (APP/PS1) mouse model of Alzheimer’s disease, blood–brain barrier dysfunction started at 4 months of age and became severe at 9 months of age. In the cerebral microvessels of APP/PS1 mice and amyloid-β-treated brain endothelial cells, we found suppressed Wnt/β-catenin signalling triggered by an increase of GSK3β activation, but not an inhibition of the AKT pathway or switching to the Wnt/planar cell polarity pathway. Furthermore, using our newly developed optogenetic tool for controlled regulation of LRP6 (upstream regulator of the Wnt signalling) to activate Wnt/β-catenin pathway, blood–brain barrier malfunction was restored by preventing amyloid-β-induced brain endothelial cells impairments and promoting the barrier repair. In conclusion, targeting LRP6 in the Wnt/β-catenin pathway in the brain endothelium can alleviate blood–brain barrier malfunction induced by amyloid-β, which may be a potential treatment strategy for Alzheimer’s disease.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awac236
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 1474117-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 5
    Online Resource
    Online Resource
    UQCRC1 variants in Parkinson’s disease: a large cohort study in Chinese mainland population
    Oxford University Press (OUP) ; 2021
    In:  Brain Vol. 144, No. 6 ( 2021-07-28), p. e54-e54
    Details
    In: Brain, Oxford University Press (OUP), Vol. 144, No. 6 ( 2021-07-28), p. e54-e54
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awab137
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 1474117-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 6
    Online Resource
    Online Resource
    Expansion of GGC repeat in the human-specific NOTCH2NLC gene is associated with essential tremor
    Oxford University Press (OUP) ; 2020
    In:  Brain Vol. 143, No. 1 ( 2020-01-01), p. 222-233
    Details
    In: Brain, Oxford University Press (OUP), Vol. 143, No. 1 ( 2020-01-01), p. 222-233
    Abstract: Essential tremor is one of the most common movement disorders. Despite its high prevalence and heritability, the genetic aetiology of essential tremor remains elusive. Up to now, only a few genes/loci have been identified, but these genes have not been replicated in other essential tremor families or cohorts. Here we report a genetic study in a cohort of 197 Chinese pedigrees clinically diagnosed with essential tremor. Using a comprehensive strategy combining linkage analysis, whole-exome sequencing, long-read whole-genome sequencing, repeat-primed polymerase chain reaction and GC-rich polymerase chain reaction, we identified an abnormal GGC repeat expansion in the 5′ region of the NOTCH2NLC gene that co-segregated with disease in 11 essential tremor families (5.58%) from our cohort. Clinically, probands that had an abnormal GGC repeat expansion were found to have more severe tremor phenotypes, lower activities of daily living ability. Obvious genetic anticipation was also detected in these 11 essential tremor-positive families. These results indicate that abnormal GGC repeat expansion in the 5′ region of NOTCH2NLC gene is associated with essential tremor, and provide strong evidence that essential tremor is a family of diseases with high clinical and genetic heterogeneities.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awz372
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 1474117-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 7
    Online Resource
    Online Resource
    ARSA gene variants and Parkinson’s disease
    Oxford University Press (OUP) ; 2020
    In:  Brain Vol. 143, No. 6 ( 2020-06-01), p. e47-e47
    Details
    In: Brain, Oxford University Press (OUP), Vol. 143, No. 6 ( 2020-06-01), p. e47-e47
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awaa134
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 1474117-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 8
    Online Resource
    Online Resource
    Bi-allelic loss of function variants in COX20 gene cause autosomal recessive sensory neuronopathy
    Oxford University Press (OUP) ; 2021
    In:  Brain Vol. 144, No. 8 ( 2021-09-04), p. 2457-2470
    Details
    In: Brain, Oxford University Press (OUP), Vol. 144, No. 8 ( 2021-09-04), p. 2457-2470
    Abstract: Sensory neuronopathies are a rare and distinct subgroup of peripheral neuropathies, characterized by degeneration of the dorsal root ganglia neurons. About 50% of sensory neuronopathies are idiopathic and genetic causes remain to be clarified. Through a combination of homozygosity mapping and whole exome sequencing, we linked an autosomal recessive sensory neuronopathy to pathogenic variants in the COX20 gene. We identified eight unrelated families from the eastern Chinese population carrying a founder variant c.41A & gt;G (p.Lys14Arg) within COX20 in either a homozygous or compound heterozygous state. All patients displayed sensory ataxia with a decrease in non-length-dependent sensory potentials. COX20 encodes a key transmembrane protein implicated in the assembly of mitochondrial complex IV. We showed that COX20 variants lead to reduction of COX20 protein in patient’s fibroblasts and transfected cell lines, consistent with a loss-of-function mechanism. Knockdown of COX20 expression in ND7/23 sensory neuron cells resulted in complex IV deficiency and perturbed assembly of complex IV, which subsequently compromised cell spare respiratory capacity and reduced cell proliferation under metabolic stress. Consistent with mitochondrial dysfunction in knockdown cells, reduced complex IV assembly, enzyme activity and oxygen consumption rate were also found in patients’ fibroblasts. We speculated that the mechanism of COX20 was similar to other causative genes (e.g. SURF1, COX6A1, COA3 and SCO2) for peripheral neuropathies, all of which are functionally important in the structure and assembly of complex IV. Our study identifies a novel causative gene for the autosomal recessive sensory neuronopathy, whose vital function in complex IV and high expression in the proprioceptive sensory neuron further underlines loss of COX20 contributing to mitochondrial bioenergetic dysfunction as a mechanism in peripheral sensory neuron disease.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awab135
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 1474117-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 9
    Online Resource
    Online Resource
    The efficacy and deficiency of contemporary treatment for spinal cord arteriovenous shunts
    Oxford University Press (OUP) ; 2021
    In:  Brain Vol. 144, No. 11 ( 2021-12-16), p. 3381-3391
    Details
    In: Brain, Oxford University Press (OUP), Vol. 144, No. 11 ( 2021-12-16), p. 3381-3391
    Abstract: Contemporary treatments for spinal cord arteriovenous shunts are only based on clinicians’ treatment experiences and expertise due to its rarity. We reviewed the clinical course of the largest multicentred cohort to evaluate the efficacy and deficiency of contemporary interventional treatments for spinal cord arteriovenous shunts. The clinical features, treatment results and clinical outcomes of 463 patients with spinal cord arteriovenous shunts were retrospectively assessed. The main outcome was the neurological deterioration that was evaluated based on the modified Aminoff and Logue scale. According to post-treatment digital subtraction angiography, complete obliteration was defined as disappearance of the intradural lesion, whereas partial obliteration was defined as any residual intradural lesion remaining visible and was further categorized as shunt-reduction obliteration (the nidus or shunt points were reduced) or palliative obliteration (only obliterated aneurysms or feeders). Cure rate was 40.6% for the whole cohort, 58.5% after microsurgery, and 26.4% after embolization. The curative resection was associated with non-metameric lesions, lesions with a maximum diameter & lt;3 cm and lesions without anterior sulcal artery supply. The curative embolization was associated with fistula-type lesions, non-metameric lesions, and main drainage diameter & lt;1.5 mm. The permanent treatment-related neurological deficits rate was 11.2% for the whole cohort, 16.1% after microsurgery, and 5.6% after embolization. The pretreatment clinical deterioration rate was 32.5%/year, which decreased to 9.3%/year after clinical interventions. Following partial treatment, the long-term acute and gradual deterioration rates were 5.3%/year and 3.6%/year, respectively. The acute deteriorations were associated with metameric lesions, craniocervical lesions, lesions with a maximum diameter ≥2 cm and residual aneurysm. Residual aneurysm was the only predictor of acute deterioration for non-metameric spinal cord arteriovenous shunts. The gradual deteriorations were associated with palliative obliteration, absence of pretreatment acute deterioration and intact main drainage. Although clinical risks of spinal cord arteriovenous shunts were reduced following clinical interventions, contemporary treatments for spinal cord arteriovenous shunt remains associated with considerable risks and incomplete efficacy. Individualized treatment plans should be adopted according to the angio-architectural features and major clinical risks of specific lesions. There is a higher opportunity for complete obliteration for lesions with simple angio-architecture. However, for most of spinal cord arteriovenous shunts with complex vascular anatomy, partial treatment is the only choice. For these patients, palliative obliteration targeting the aneurysms is recommended for reducing haemorrhagic risk, whereas shunt-reduction obliteration is necessary for non-haemorrhagic myelopathy. Contemporary treatment is ineffective in reducing haemorrhagic risk of incurable metameric spinal cord arteriovenous shunts.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awab237
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 1474117-9
    SSG: 12
    Location Call Number Limitation Availability
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  • 10
    Online Resource
    Online Resource
    Characteristics, surgical outcomes, and influential factors of epilepsy in Sturge-Weber syndrome
    Oxford University Press (OUP) ; 2022
    In:  Brain Vol. 145, No. 10 ( 2022-10-21), p. 3431-3443
    Details
    In: Brain, Oxford University Press (OUP), Vol. 145, No. 10 ( 2022-10-21), p. 3431-3443
    Abstract: Few studies have reported the clinical presentation, surgical treatment, outcomes and influential factors for patients with epilepsy and Sturge-Weber syndrome. This large-scale retrospective study continuously enrolled 132 patients with Sturge-Weber syndrome and epilepsy from January 2008 to December 2018 at our hospital to analyse their characteristics. Among these patients, 90 underwent epilepsy surgery, and their postoperative 2-year follow-up seizure, cognitive and motor functional outcomes were assessed and analysed. Univariable and multivariable logistic analyses were conducted to explore the influential factors. Among the patients with Sturge-Weber syndrome for whom characteristics were analysed (n = 132), 76.52% of patients had their first epileptic seizures within their first year of life. The risk factors for cognitive decline were seizure history ≥ 2 years [adjusted odds ratio (aOR) = 3.829, 95% confidence interval (CI): 1.810–9.021, P = 0.008)], bilateral leptomeningeal angiomas (aOR = 3.173, 95% CI: 1.970–48.194, P = 0.013), age at onset & lt;1 year (aOR = 2.903, 95% CI: 1.230–6.514, P = 0.013), brain calcification (aOR = 2.375, 95% CI: 1.396–5.201, P = 0.021) and left leptomeningeal angiomas (aOR = 2.228, 95% CI: 1.351–32.571, P = 0.030). Of the patients who underwent epilepsy surgery (n = 90), 44 were subject to focal resection, and 46 underwent hemisphere surgery (19 anatomical hemispherectomies and 27 modified hemispherotomies). A postoperative seizure-free status, favourable cognitive outcomes, and favourable motor outcomes were achieved in 83.33%, 44.44% and 43.33% of surgical patients, respectively. The modified hemispherotomy group had similar surgical outcomes, less intraoperative blood loss and shorter postoperative hospital stays than the anatomical hemispherectomy group. Regarding seizure outcomes, full resection (aOR = 11.115, 95% CI: 1.260–98.067, P = 0.020) and age at surgery & lt; 2 years (aOR = 6.040, 95% CI: 1.444–73.367, P = 0.031) were positive influential factors for focal resection. Age at surgery & lt; 2 years (aOR = 15.053, 95% CI: 1.050–215.899, P = 0.036) and infrequent seizures (aOR = 8.426, 95% CI: 1.086–87.442, P = 0.042; monthly versus weekly) were positive influential factors for hemisphere surgery. In conclusion, epilepsy surgery resulted in a good postoperative seizure-free rate and favourable cognitive and motor functional outcomes and showed acceptable safety for patients with epilepsy and Sturge-Weber syndrome. Modified hemispherotomy is a less invasive and safer type of hemisphere surgery than traditional anatomic hemispherectomy with similar surgical outcomes. Early surgery may be helpful to achieve better seizure outcomes and cognitive protection, while the risk of surgery for young children should also be considered.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awab470
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 1474117-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
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