Pub Date : 2021-03-26DOI: 10.1101/2021.03.22.21253711
K. Johannesen, Yuanyuan Liu, Cathrine E Gjerulfsen, M. Koko, L. Sonnenberg, J. Schubert, C. Fenger, Ahmed Eltokhi, Maert Rannap, N. A. Koch, S. Lauxmann, J. Krüger, J. Kegele, L. Canafoglia, S. Franceschetti, T. Mayer, J. Rebstock, Pia Zacher, S. Ruf, M. Alber, K. Štěrbová, P. Laššuthová, M. Vlčková, J. Lemke, I. Krey, Constanze Heine, D. Wieczorek, Judith Kroell-Seger, C. Lund, K. Klein, P. Au, J. Rho, A. Ho, S. Masnada, P. Veggiotti, L. Giordano, P. Accorsi, C. Hoei-Hansen, P. Striano, F. Zara, H. Verhelst, Judith S.Verhoeven, B. van der Zwaag, A. V. Harder, E. Brilstra, Manuela Pendziwiat, S. Lebon, M. Vaccarezza, N. M. Le, J. Christensen, Mette U Schmidt-Petersen, S. Grønborg, S. Scherer, J. Howe, W. Fazeli, K. Howell, R. Leventer, C. Stutterd, S. Walsh, M. Gérard, B. Gérard, S. Matricardi, C. Bonardi, S. Sartori, A. Berger, D. Hoffman-Zacharska, M. Mastrangelo, F. Darra, A. Vøllo, M. Motazacker, Phillis Lakeman, M. Nizon, C. Betzler, C. Altuzarra, Roseline Caume, A. Roubertie, P. Gélisse, C. Marini,
We report detailed functional analyses and genotype-phenotype correlations in 433 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6. Five different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n=17, normal cognition, treatable seizures), 2) intermediate epilepsy (n=36, mild ID, partially pharmacoresponsive), 3) developmental and epileptic encephalopathy (DEE, n=191, severe ID, majority pharmacoresistant), 4) generalized epilepsy (n=21, mild to moderate ID, frequently with absence seizures), and 5) affected individuals without epilepsy (n=25, mild to moderate ID). Groups 1-3 presented with early-onset (median: four months) focal or multifocal seizures and epileptic discharges, whereas the onset of seizures in group 4 was later (median: 39 months) with generalized epileptic discharges. The epilepsy was not classifiable in 143 individuals. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin insensitive human NaV1.6 channels and whole-cell patch clamping. Two variants causing DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 165 individuals. All 133 individuals carrying GOF variants had either focal (76, groups 1-3), or unclassifiable epilepsy (37), whereas 32 with LOF variants had either generalized (14), no (11) or unclassifiable (5) epilepsy; only two had DEE. Computational modeling in the GOF group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. GOF variant carriers responded significantly better to sodium channel blockers (SCBs) than to other anti-seizure medications, and the same applied for all individuals of groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of LOF variant carriers and the extent of the electrophysiological dysfunction of the GOF variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that SCBs present a therapeutic treatment option in early onset SCN8A-related focal epilepsy.
{"title":"Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications","authors":"K. Johannesen, Yuanyuan Liu, Cathrine E Gjerulfsen, M. Koko, L. Sonnenberg, J. Schubert, C. Fenger, Ahmed Eltokhi, Maert Rannap, N. A. Koch, S. Lauxmann, J. Krüger, J. Kegele, L. Canafoglia, S. Franceschetti, T. Mayer, J. Rebstock, Pia Zacher, S. Ruf, M. Alber, K. Štěrbová, P. Laššuthová, M. Vlčková, J. Lemke, I. Krey, Constanze Heine, D. Wieczorek, Judith Kroell-Seger, C. Lund, K. Klein, P. Au, J. Rho, A. Ho, S. Masnada, P. Veggiotti, L. Giordano, P. Accorsi, C. Hoei-Hansen, P. Striano, F. Zara, H. Verhelst, Judith S.Verhoeven, B. van der Zwaag, A. V. Harder, E. Brilstra, Manuela Pendziwiat, S. Lebon, M. Vaccarezza, N. M. Le, J. Christensen, Mette U Schmidt-Petersen, S. Grønborg, S. Scherer, J. Howe, W. Fazeli, K. Howell, R. Leventer, C. Stutterd, S. Walsh, M. Gérard, B. Gérard, S. Matricardi, C. Bonardi, S. Sartori, A. Berger, D. Hoffman-Zacharska, M. Mastrangelo, F. Darra, A. Vøllo, M. Motazacker, Phillis Lakeman, M. Nizon, C. Betzler, C. Altuzarra, Roseline Caume, A. Roubertie, P. Gélisse, C. Marini, ","doi":"10.1101/2021.03.22.21253711","DOIUrl":"https://doi.org/10.1101/2021.03.22.21253711","url":null,"abstract":"We report detailed functional analyses and genotype-phenotype correlations in 433 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6. Five different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n=17, normal cognition, treatable seizures), 2) intermediate epilepsy (n=36, mild ID, partially pharmacoresponsive), 3) developmental and epileptic encephalopathy (DEE, n=191, severe ID, majority pharmacoresistant), 4) generalized epilepsy (n=21, mild to moderate ID, frequently with absence seizures), and 5) affected individuals without epilepsy (n=25, mild to moderate ID). Groups 1-3 presented with early-onset (median: four months) focal or multifocal seizures and epileptic discharges, whereas the onset of seizures in group 4 was later (median: 39 months) with generalized epileptic discharges. The epilepsy was not classifiable in 143 individuals. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin insensitive human NaV1.6 channels and whole-cell patch clamping. Two variants causing DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 165 individuals. All 133 individuals carrying GOF variants had either focal (76, groups 1-3), or unclassifiable epilepsy (37), whereas 32 with LOF variants had either generalized (14), no (11) or unclassifiable (5) epilepsy; only two had DEE. Computational modeling in the GOF group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. GOF variant carriers responded significantly better to sodium channel blockers (SCBs) than to other anti-seizure medications, and the same applied for all individuals of groups 1-3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of LOF variant carriers and the extent of the electrophysiological dysfunction of the GOF variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that SCBs present a therapeutic treatment option in early onset SCN8A-related focal epilepsy.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"45 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128087065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"One person, two minds.","authors":"M. Corballis","doi":"10.1093/brain/awaa308","DOIUrl":"https://doi.org/10.1093/brain/awaa308","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"143 10 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128941891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-09-15DOI: 10.1101/2020.09.14.20194217
J. Mole, S. Mead, P. Rudge, Akin Nihat, T. Mok, J. Collinge, D. Caine
The clinical effectiveness of any disease-modifying treatment for prion disease, as for other neurodegenerative disorders, will depend on early treatment before damage to neural tissue is irrevocable. Thus, there is a need to identify markers which predict disease onset in healthy at-risk individuals. Whilst imaging and neurophysiological biomarkers have shown limited use in this regard, we recently reported progressive neurophysiological changes in healthy people with the inherited prion disease mutation P102L (Rudge et al, Brain 2019). We have also previously demonstrated a signature pattern of fronto-parietal dysfunction in mild prion disease (Caine et al., 2015; 2018). Here we address whether these cognitive features anticipate the onset of symptoms in a unique sample of patients with inherited prion disease. In the cross-sectional analysis, we analysed the performance of patients at three time points in the course of disease onset: prior to symptoms (n = 27), onset of subjective symptoms without positive clinical findings (n = 8) and symptomatic with positive clinical findings (n = 24). In the longitudinal analysis, we analysed data from twenty four patients who were presymptomatic at the time of recruitment and were followed up over a period of up to seventeen years, of whom sixteen remained healthy and eight converted to become symptomatic. In the cross-sectional analysis, the key finding was that, relative to a group of 25 healthy non-gene carrier controls, patients with subjective symptoms but without positive clinical findings were impaired on a smaller but very similar set of tests (Trail Making Test part A, Stroop Test, Performance IQ, gesture repetition, figure recall) to those previously found to be impaired in mild prion disease (Caine et al., 2015; 2018). In the longitudinal analysis, Trail Making Test parts A and B, Stroop test and Performance IQ scores significantly discriminated between patients who remained presymptomatic and those who converted, even before the converters reached criteria for formal diagnosis. Notably, performance on the Stroop test significantly discriminated between presymptomatic patients and converters before the onset of clinical symptoms (AUC = .83 (95% CI, 0.62, 1.00), p =.009). Thus, we report here, for the first time, neuropsychological abnormalities in healthy patients prior to either symptom onset or clinical diagnosis of IPD. This constitutes an important component of an evolving profile of clinical and biomarker abnormalities in this crucial group for preventive medicine.
与其他神经退行性疾病一样，朊病毒疾病的任何疾病改善治疗的临床效果将取决于神经组织损伤不可挽回之前的早期治疗。因此，有必要确定在健康的高危人群中预测疾病发病的标志物。虽然成像和神经生理生物标志物在这方面的应用有限，但我们最近报道了患有遗传性朊病毒疾病突变P102L的健康人的进行性神经生理变化(Rudge等人，Brain 2019)。我们之前也证明了轻度朊病毒疾病的额顶叶功能障碍的特征模式(Caine等人，2015;2018)。在这里，我们讨论这些认知特征是否预测了遗传性朊病毒疾病患者的独特样本中症状的发作。在横断面分析中，我们分析了患者在发病过程中三个时间点的表现:出现症状前(n = 27)，出现主观症状但无阳性临床表现(n = 8)和出现症状但有阳性临床表现(n = 24)。在纵向分析中，我们分析了24名在招募时出现症状前的患者的数据，并对其进行了长达17年的随访，其中16人保持健康，8人转为出现症状。在横断面分析中，关键的发现是，相对于一组25名健康的非基因携带者对照，有主观症状但没有阳性临床结果的患者在一组较小但非常相似的测试(Trail Making Test part a, Stroop Test, Performance IQ，手势重复，图形回忆)中受损的患者与先前发现的轻度朊病毒疾病受损的患者(Caine et al.， 2015;2018)。在纵向分析中，Trail Making Test A和B部分、Stroop Test和Performance IQ得分显著区分了症状前患者和转化者，甚至在转化者达到正式诊断标准之前。值得注意的是，在症状前患者和临床症状出现之前的转换者之间，Stroop测试的表现显著区分(AUC = 0.83 (95% CI, 0.62, 1.00)， p = 0.009)。因此，我们在此首次报道了健康患者在IPD症状发作或临床诊断之前的神经心理异常。这构成了预防医学中这一关键群体的临床和生物标志物异常不断发展的重要组成部分。
{"title":"Cognitive decline heralds onset of symptomatic inherited prion disease","authors":"J. Mole, S. Mead, P. Rudge, Akin Nihat, T. Mok, J. Collinge, D. Caine","doi":"10.1101/2020.09.14.20194217","DOIUrl":"https://doi.org/10.1101/2020.09.14.20194217","url":null,"abstract":"The clinical effectiveness of any disease-modifying treatment for prion disease, as for other neurodegenerative disorders, will depend on early treatment before damage to neural tissue is irrevocable. Thus, there is a need to identify markers which predict disease onset in healthy at-risk individuals. Whilst imaging and neurophysiological biomarkers have shown limited use in this regard, we recently reported progressive neurophysiological changes in healthy people with the inherited prion disease mutation P102L (Rudge et al, Brain 2019). We have also previously demonstrated a signature pattern of fronto-parietal dysfunction in mild prion disease (Caine et al., 2015; 2018). Here we address whether these cognitive features anticipate the onset of symptoms in a unique sample of patients with inherited prion disease. In the cross-sectional analysis, we analysed the performance of patients at three time points in the course of disease onset: prior to symptoms (n = 27), onset of subjective symptoms without positive clinical findings (n = 8) and symptomatic with positive clinical findings (n = 24). In the longitudinal analysis, we analysed data from twenty four patients who were presymptomatic at the time of recruitment and were followed up over a period of up to seventeen years, of whom sixteen remained healthy and eight converted to become symptomatic. In the cross-sectional analysis, the key finding was that, relative to a group of 25 healthy non-gene carrier controls, patients with subjective symptoms but without positive clinical findings were impaired on a smaller but very similar set of tests (Trail Making Test part A, Stroop Test, Performance IQ, gesture repetition, figure recall) to those previously found to be impaired in mild prion disease (Caine et al., 2015; 2018). In the longitudinal analysis, Trail Making Test parts A and B, Stroop test and Performance IQ scores significantly discriminated between patients who remained presymptomatic and those who converted, even before the converters reached criteria for formal diagnosis. Notably, performance on the Stroop test significantly discriminated between presymptomatic patients and converters before the onset of clinical symptoms (AUC = .83 (95% CI, 0.62, 1.00), p =.009). Thus, we report here, for the first time, neuropsychological abnormalities in healthy patients prior to either symptom onset or clinical diagnosis of IPD. This constitutes an important component of an evolving profile of clinical and biomarker abnormalities in this crucial group for preventive medicine.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"18 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2020-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115312866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"La Folie des Grandeurs.","authors":"A. Lees","doi":"10.1093/brain/awaa172","DOIUrl":"https://doi.org/10.1093/brain/awaa172","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"275 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115885803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-06-01DOI: 10.1101/2020.05.31.20061010
Y. Sosero, S. Bandres-Ciga, S. Hassin-Baer, R. Alcalay, Z. Gan-Or
The PSAP gene encodes prosaposin, which is later cleaved into four active saposins: saposin A, B, C and D. Mutations in these enzymes have been linked to specific lysosomal storage disorders. Recently, a genetic association between mutations in saposin D and Parkinson disease (PD) has been reported. To further examine whether variants in saposin D or the other saposins could be associated with Parkinson s disease, we performed Optimized Sequence Kernel Association Test (SKAT-O) in 4,132 Parkinson s disease patients and 4,470 controls. Furthermore, we analyzed data from a PD Genome Wide Association Study (GWAS) to examine the association of common variants in the PSAP locus with Parkinson s disease risk (analysis on 56,308 patients) and age at onset (analysis on 28,568 patients). We did not find any statistically significant associations between neither rare nor common variants in saposin D, nor any of the other saposins, and PD risk or onset. These results suggest that PSAP variants play either a very minor role, or more likely, no role, in PD.
{"title":"Lack of evidence for genetic association of saposins A, B, C and D with Parkinson disease","authors":"Y. Sosero, S. Bandres-Ciga, S. Hassin-Baer, R. Alcalay, Z. Gan-Or","doi":"10.1101/2020.05.31.20061010","DOIUrl":"https://doi.org/10.1101/2020.05.31.20061010","url":null,"abstract":"The PSAP gene encodes prosaposin, which is later cleaved into four active saposins: saposin A, B, C and D. Mutations in these enzymes have been linked to specific lysosomal storage disorders. Recently, a genetic association between mutations in saposin D and Parkinson disease (PD) has been reported. To further examine whether variants in saposin D or the other saposins could be associated with Parkinson s disease, we performed Optimized Sequence Kernel Association Test (SKAT-O) in 4,132 Parkinson s disease patients and 4,470 controls. Furthermore, we analyzed data from a PD Genome Wide Association Study (GWAS) to examine the association of common variants in the PSAP locus with Parkinson s disease risk (analysis on 56,308 patients) and age at onset (analysis on 28,568 patients). We did not find any statistically significant associations between neither rare nor common variants in saposin D, nor any of the other saposins, and PD risk or onset. These results suggest that PSAP variants play either a very minor role, or more likely, no role, in PD.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"8 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2020-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128891332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-05-30DOI: 10.1101/2020.05.29.20116111
Uladzislau Rudakou, E. Yu, L. Krohn, J. Ruskey, F. Asayesh, Y. Dauvilliers, D. Spiegelman, L. Greenbaum, S. Fahn, C. Waters, N. Dupré, G. Rouleau, S. Hassin-Baer, E. Fon, R. Alcalay, Z. Gan-Or
Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson's disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson's disease in 2,657 patients and 3,647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests (SKAT-O). The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson's disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that the SYT11 GWAS association is driven by variants in the nearby GBA gene. However, the association of SYT11 was mainly driven by a rare 3' UTR variant (rs945006601) and was independent of GBA variants (p=5.23E-05 after exclusion of all GBA variant carriers). The association of FGF20 was driven by a rare 5' UTR variant (rs1034608171) located in the promoter region. The previously reported association of GCH1 with Parkinson's Disease is driven by rare nonsynonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in ten and eight controls, respectively, but not in patients. We ideniified common variants associated with Parkinson's disease in MAPT, TMEM175, BST1, SNCA and GPNMB which are all in strong linkage disequilibrium (LD) with known GWAS hits in their respective loci. A common coding PM20D1 variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson's disease (OR 0.73, 95% CI 0.60-0.89, p=1.161E-03). This variant is not in LD with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson's disease-related genes.
{"title":"Targeted sequencing of Parkinson's disease loci genes highlights SYT11, FGF20 and other associations","authors":"Uladzislau Rudakou, E. Yu, L. Krohn, J. Ruskey, F. Asayesh, Y. Dauvilliers, D. Spiegelman, L. Greenbaum, S. Fahn, C. Waters, N. Dupré, G. Rouleau, S. Hassin-Baer, E. Fon, R. Alcalay, Z. Gan-Or","doi":"10.1101/2020.05.29.20116111","DOIUrl":"https://doi.org/10.1101/2020.05.29.20116111","url":null,"abstract":"Genome-wide association studies (GWAS) have identified numerous loci associated with Parkinson's disease. The specific genes and variants that drive the associations within the vast majority of these loci are unknown. We aimed to perform a comprehensive analysis of selected genes to determine the potential role of rare and common genetic variants within these loci. We fully sequenced 32 genes from 25 loci previously associated with Parkinson's disease in 2,657 patients and 3,647 controls from three cohorts. Capture was done using molecular inversion probes targeting the exons, exon-intron boundaries and untranslated regions (UTRs) of the genes of interest, followed by sequencing. Quality control was performed to include only high-quality variants. We examined the role of rare variants (minor allele frequency < 0.01) using optimized sequence Kernel association tests (SKAT-O). The association of common variants was estimated using regression models adjusted for age, sex and ethnicity as required in each cohort, followed by a meta-analysis. After Bonferroni correction, we identified a burden of rare variants in SYT11, FGF20 and GCH1 associated with Parkinson's disease. Nominal associations were identified in 21 additional genes. Previous reports suggested that the SYT11 GWAS association is driven by variants in the nearby GBA gene. However, the association of SYT11 was mainly driven by a rare 3' UTR variant (rs945006601) and was independent of GBA variants (p=5.23E-05 after exclusion of all GBA variant carriers). The association of FGF20 was driven by a rare 5' UTR variant (rs1034608171) located in the promoter region. The previously reported association of GCH1 with Parkinson's Disease is driven by rare nonsynonymous variants, some of which are known to cause dopamine-responsive dystonia. We also identified two LRRK2 variants, p.Arg793Met and p.Gln1353Lys, in ten and eight controls, respectively, but not in patients. We ideniified common variants associated with Parkinson's disease in MAPT, TMEM175, BST1, SNCA and GPNMB which are all in strong linkage disequilibrium (LD) with known GWAS hits in their respective loci. A common coding PM20D1 variant, p.Ile149Val, was nominally associated with reduced risk of Parkinson's disease (OR 0.73, 95% CI 0.60-0.89, p=1.161E-03). This variant is not in LD with the top GWAS hits within this locus and may represent a novel association. These results further demonstrate the importance of fine mapping of GWAS loci, and suggest that SYT11, FGF20, and potentially PM20D1, BST1 and GPNMB should be considered for future studies as possible Parkinson's disease-related genes.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2020-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116312978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Neurology and what?","authors":"N. Scolding","doi":"10.1093/brain/awaa132","DOIUrl":"https://doi.org/10.1093/brain/awaa132","url":null,"abstract":"","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"16 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2020-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125897264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tomoyuki Taguchi, M. Ikuno, M. Hondo, L. Parajuli, K. Taguchi, Jun Ueda, M. Sawamura, S. Okuda, E. Nakanishi, J. Hara, N. Uemura, Yusuke Hatanaka, T. Ayaki, S. Matsuzawa, Masaki Tanaka, O. El‐Agnaf, M. Koike, M. Yanagisawa, Maiko T Uemura, H. Yamakado, R. Takahashi
Parkinson's disease is one of the most common movement disorders and is characterized by dopaminergic cell loss and the accumulation of pathological α-synuclein, but its precise pathogenetic mechanisms remain elusive. To develop disease-modifying therapies for Parkinson's disease, an animal model that recapitulates the pathology and symptoms of the disease, especially in the prodromal stage, is indispensable. As subjects with α-synuclein gene (SNCA) multiplication as well as point mutations develop familial Parkinson's disease and a genome-wide association study in Parkinson's disease has identified SNCA as a risk gene for Parkinson's disease, the increased expression of α-synuclein is closely associated with the aetiology of Parkinson's disease. In this study we generated bacterial artificial chromosome transgenic mice harbouring SNCA and its gene expression regulatory regions in order to maintain the native expression pattern of α-synuclein. Furthermore, to enhance the pathological properties of α-synuclein, we inserted into SNCA an A53T mutation, two single-nucleotide polymorphisms identified in a genome-wide association study in Parkinson's disease and a Rep1 polymorphism, all of which are causal of familial Parkinson's disease or increase the risk of sporadic Parkinson's disease. These A53T SNCA bacterial artificial chromosome transgenic mice showed an expression pattern of human α-synuclein very similar to that of endogenous mouse α-synuclein. They expressed truncated, oligomeric and proteinase K-resistant phosphorylated forms of α-synuclein in the regions that are specifically affected in Parkinson's disease and/or dementia with Lewy bodies, including the olfactory bulb, cerebral cortex, striatum and substantia nigra. Surprisingly, these mice exhibited rapid eye movement (REM) sleep without atonia, which is a key feature of REM sleep behaviour disorder, at as early as 5 months of age. Consistent with this observation, the REM sleep-regulating neuronal populations in the lower brainstem, including the sublaterodorsal tegmental nucleus, nuclei in the ventromedial medullary reticular formation and the pedunculopontine nuclei, expressed phosphorylated α-synuclein. In addition, they also showed hyposmia at 9 months of age, which is consistent with the significant accumulation of phosphorylated α-synuclein in the olfactory bulb. The dopaminergic neurons in the substantia nigra pars compacta degenerated, and their number was decreased in an age-dependent manner by up to 17.1% at 18 months of age compared to wild-type, although the mice did not show any related locomotor dysfunction. In conclusion, we created a novel mouse model of prodromal Parkinson's disease that showed RBD-like behaviour and hyposmia without motor symptoms.
{"title":"α-Synuclein BAC transgenic mice exhibited RBD-like behaviour and hyposmia: a prodromal Parkinson's disease model.","authors":"Tomoyuki Taguchi, M. Ikuno, M. Hondo, L. Parajuli, K. Taguchi, Jun Ueda, M. Sawamura, S. Okuda, E. Nakanishi, J. Hara, N. Uemura, Yusuke Hatanaka, T. Ayaki, S. Matsuzawa, Masaki Tanaka, O. El‐Agnaf, M. Koike, M. Yanagisawa, Maiko T Uemura, H. Yamakado, R. Takahashi","doi":"10.1093/brain/awz380","DOIUrl":"https://doi.org/10.1093/brain/awz380","url":null,"abstract":"Parkinson's disease is one of the most common movement disorders and is characterized by dopaminergic cell loss and the accumulation of pathological α-synuclein, but its precise pathogenetic mechanisms remain elusive. To develop disease-modifying therapies for Parkinson's disease, an animal model that recapitulates the pathology and symptoms of the disease, especially in the prodromal stage, is indispensable. As subjects with α-synuclein gene (SNCA) multiplication as well as point mutations develop familial Parkinson's disease and a genome-wide association study in Parkinson's disease has identified SNCA as a risk gene for Parkinson's disease, the increased expression of α-synuclein is closely associated with the aetiology of Parkinson's disease. In this study we generated bacterial artificial chromosome transgenic mice harbouring SNCA and its gene expression regulatory regions in order to maintain the native expression pattern of α-synuclein. Furthermore, to enhance the pathological properties of α-synuclein, we inserted into SNCA an A53T mutation, two single-nucleotide polymorphisms identified in a genome-wide association study in Parkinson's disease and a Rep1 polymorphism, all of which are causal of familial Parkinson's disease or increase the risk of sporadic Parkinson's disease. These A53T SNCA bacterial artificial chromosome transgenic mice showed an expression pattern of human α-synuclein very similar to that of endogenous mouse α-synuclein. They expressed truncated, oligomeric and proteinase K-resistant phosphorylated forms of α-synuclein in the regions that are specifically affected in Parkinson's disease and/or dementia with Lewy bodies, including the olfactory bulb, cerebral cortex, striatum and substantia nigra. Surprisingly, these mice exhibited rapid eye movement (REM) sleep without atonia, which is a key feature of REM sleep behaviour disorder, at as early as 5 months of age. Consistent with this observation, the REM sleep-regulating neuronal populations in the lower brainstem, including the sublaterodorsal tegmental nucleus, nuclei in the ventromedial medullary reticular formation and the pedunculopontine nuclei, expressed phosphorylated α-synuclein. In addition, they also showed hyposmia at 9 months of age, which is consistent with the significant accumulation of phosphorylated α-synuclein in the olfactory bulb. The dopaminergic neurons in the substantia nigra pars compacta degenerated, and their number was decreased in an age-dependent manner by up to 17.1% at 18 months of age compared to wild-type, although the mice did not show any related locomotor dysfunction. In conclusion, we created a novel mouse model of prodromal Parkinson's disease that showed RBD-like behaviour and hyposmia without motor symptoms.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"297 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126728026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qi-ying Sun, Qian Xu, Yun Tian, Zhengmao Hu, Lixia Qin, Jinxia Yang, Wen Huang, Jin Xue, Jin-chen Li, Sheng Zeng, Ying Wang, Hao-Xuan Min, Xiaoyu Chen, Jun-Pu Wang, B. Xie, Fan Liang, Hai-nan Zhang, Chun-Yu Wang, L. Lei, Xinxiang Yan, Hongwei Xu, R. Duan, K. Xia, Jing-Yu Liu, Hong Jiang, Lu Shen, Ji-feng Guo, B. Tang
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.
{"title":"Expansion of GGC repeat in the human-specific NOTCH2NLC gene is associated with essential tremor.","authors":"Qi-ying Sun, Qian Xu, Yun Tian, Zhengmao Hu, Lixia Qin, Jinxia Yang, Wen Huang, Jin Xue, Jin-chen Li, Sheng Zeng, Ying Wang, Hao-Xuan Min, Xiaoyu Chen, Jun-Pu Wang, B. Xie, Fan Liang, Hai-nan Zhang, Chun-Yu Wang, L. Lei, Xinxiang Yan, Hongwei Xu, R. Duan, K. Xia, Jing-Yu Liu, Hong Jiang, Lu Shen, Ji-feng Guo, B. Tang","doi":"10.1093/brain/awz372","DOIUrl":"https://doi.org/10.1093/brain/awz372","url":null,"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.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"23 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121361537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cameron P. Casey, H. Lindroth, R. Mohanty, Zahra Farahbakhsh, Tyler Ballweg, Sara Twadell, Samantha Miller, Bryan M. Krause, V. Prabhakaran, K. Blennow, H. Zetterberg, R. Sanders
While delirium is associated with cognitive decline and dementia, there is limited evidence to support causality for this relationship. Clarification of how delirium may cause cognitive decline, perhaps through evidence of contemporaneous neuronal injury, would enhance plausibility for a causal relationship. Dose-dependence of neuronal injury with delirium severity would further enhance the biological plausibility for this relationship. We tested whether delirium is associated with neuronal injury in 114 surgical patients recruited to a prospective biomarker cohort study. Patients underwent perioperative testing for changes in neurofilament light, a neuronal injury biomarker, as well as a panel of 10 cytokines, with contemporaneous assessment of delirium severity and incidence. A subset of patients underwent preoperative MRI. Initially we confirmed prior reports that neurofilament light levels correlated with markers of neurodegeneration [hippocampal volume (ΔR2 = 0.129, P = 0.015)] and white matter changes including fractional anisotropy of white matter (ΔR2 = 0.417, P < 0.001) with similar effects on mean, axial and radial diffusivity) in our cohort and that surgery was associated with increasing neurofilament light from preoperative levels [mean difference (95% confidence interval, CI) = 0.240 (0.178, 0.301) log10 (pg/ml), P < 0.001], suggesting putative neuronal injury. Next, we tested the relationship with delirium. Neurofilament light rose more sharply in participants with delirium compared to non-sufferers [mean difference (95% CI) = 0.251 (0.136, 0.367) log10 (pg/ml), P < 0.001]. This relationship showed dose-dependence, such that neurofilament light rose proportionately to delirium severity (ΔR2 = 0.199, P < 0.001). Given that inflammation is considered an important driver of postoperative delirium, next we tested whether neurofilament light, as a potential marker of neurotoxicity, may contribute to the pathogenesis of delirium independent of inflammation. From a panel of 10 cytokines, the pro-inflammatory cytokine IL-8 exhibited a strong correlation with delirium severity (ΔR2 = 0.208, P < 0.001). Therefore, we tested whether the change in neurofilament light contributed to delirium severity independent of IL-8. Neurofilament light was independently associated with delirium severity after adjusting for the change in inflammation (ΔR2 = 0.040, P = 0.038). These data suggest delirium is associated with exaggerated increases in neurofilament light and that this putative neurotoxicity may contribute to the pathogenesis of delirium itself, independent of changes in inflammation.
虽然谵妄与认知能力下降和痴呆有关，但支持这种关系的因果关系的证据有限。澄清谵妄是如何导致认知能力下降的，或许可以通过同时发生的神经元损伤的证据来证明，这将增强因果关系的合理性。神经损伤与谵妄严重程度的剂量依赖性将进一步增强这种关系的生物学合理性。我们在一项前瞻性生物标志物队列研究中招募了114名外科患者，测试了谵妄是否与神经元损伤有关。患者接受围手术期神经丝光变化检测，神经损伤生物标志物，以及10种细胞因子，同时评估谵妄严重程度和发生率。一部分患者术前接受MRI检查。首先，我们证实了先前的报道，即神经丝光水平与我们队列中神经退行性标志物[海马体积(ΔR2 = 0.129, P = 0.015)]和白质变化相关，包括白质的分数各向异性(ΔR2 = 0.417, P < 0.001)，对平均、轴向和径向扩散率有相似的影响)，手术与术前水平增加的神经丝光相关[平均差异(95%置信区间，CI) = 0.240 (0.178, P = 0.015)，0.301) log10 (pg/ml, P < 0.001)，提示可能存在神经元损伤。接下来，我们测试了与谵妄的关系。与非谵妄患者相比，谵妄患者的神经丝光上升更明显[95% CI = 0.251 (0.136, 0.367) log10 (pg/ml)， P < 0.001]。这种关系表现出剂量依赖性，神经丝光与谵妄严重程度成正比(ΔR2 = 0.199, P < 0.001)。鉴于炎症被认为是术后谵妄的重要驱动因素，接下来我们测试神经丝光，作为神经毒性的潜在标志，是否可能独立于炎症导致谵妄的发病机制。在一组10种细胞因子中，促炎细胞因子IL-8与谵妄严重程度有很强的相关性(ΔR2 = 0.208, P < 0.001)。因此，我们测试了神经丝光的改变是否独立于IL-8对谵妄严重程度的影响。调整炎症变化后，神经丝光与谵妄严重程度独立相关(ΔR2 = 0.040, P = 0.038)。这些数据表明，谵妄与神经丝光的过度增加有关，这种假定的神经毒性可能与谵妄本身的发病机制有关，而与炎症的变化无关。
{"title":"Postoperative delirium is associated with increased plasma neurofilament light.","authors":"Cameron P. Casey, H. Lindroth, R. Mohanty, Zahra Farahbakhsh, Tyler Ballweg, Sara Twadell, Samantha Miller, Bryan M. Krause, V. Prabhakaran, K. Blennow, H. Zetterberg, R. Sanders","doi":"10.1093/brain/awz354","DOIUrl":"https://doi.org/10.1093/brain/awz354","url":null,"abstract":"While delirium is associated with cognitive decline and dementia, there is limited evidence to support causality for this relationship. Clarification of how delirium may cause cognitive decline, perhaps through evidence of contemporaneous neuronal injury, would enhance plausibility for a causal relationship. Dose-dependence of neuronal injury with delirium severity would further enhance the biological plausibility for this relationship. We tested whether delirium is associated with neuronal injury in 114 surgical patients recruited to a prospective biomarker cohort study. Patients underwent perioperative testing for changes in neurofilament light, a neuronal injury biomarker, as well as a panel of 10 cytokines, with contemporaneous assessment of delirium severity and incidence. A subset of patients underwent preoperative MRI. Initially we confirmed prior reports that neurofilament light levels correlated with markers of neurodegeneration [hippocampal volume (ΔR2 = 0.129, P = 0.015)] and white matter changes including fractional anisotropy of white matter (ΔR2 = 0.417, P < 0.001) with similar effects on mean, axial and radial diffusivity) in our cohort and that surgery was associated with increasing neurofilament light from preoperative levels [mean difference (95% confidence interval, CI) = 0.240 (0.178, 0.301) log10 (pg/ml), P < 0.001], suggesting putative neuronal injury. Next, we tested the relationship with delirium. Neurofilament light rose more sharply in participants with delirium compared to non-sufferers [mean difference (95% CI) = 0.251 (0.136, 0.367) log10 (pg/ml), P < 0.001]. This relationship showed dose-dependence, such that neurofilament light rose proportionately to delirium severity (ΔR2 = 0.199, P < 0.001). Given that inflammation is considered an important driver of postoperative delirium, next we tested whether neurofilament light, as a potential marker of neurotoxicity, may contribute to the pathogenesis of delirium independent of inflammation. From a panel of 10 cytokines, the pro-inflammatory cytokine IL-8 exhibited a strong correlation with delirium severity (ΔR2 = 0.208, P < 0.001). Therefore, we tested whether the change in neurofilament light contributed to delirium severity independent of IL-8. Neurofilament light was independently associated with delirium severity after adjusting for the change in inflammation (ΔR2 = 0.040, P = 0.038). These data suggest delirium is associated with exaggerated increases in neurofilament light and that this putative neurotoxicity may contribute to the pathogenesis of delirium itself, independent of changes in inflammation.","PeriodicalId":121505,"journal":{"name":"Brain : a journal of neurology","volume":"240 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116134054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：