Mitochondrial genomic variation in dementia with Lewy bodies: association with disease risk and neuropathological measures.
Mitochondrial genomic variation in dementia with Lewy bodies: association with disease risk and neuropathological measures.
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DOI：
10.1186/s40478-022-01399-4
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发表时间：
2022-07-14
影响因子：
7.1
通讯作者：
中科院分区：
文献类型：
--
作者：
路易体痴呆症（DLB）是临床诊断时，患者发展痴呆症不到一年后帕金森病发作。年龄是DLB的主要风险因素，线粒体健康通过有效的氧化磷酸化（OXPHOS）影响衰老。线粒体基因组（mtDNA）中的稳定多态性模式改变OXPHOS效率，并将个体定义为特定的mtDNA单倍型群。本研究调查mtDNA单倍型组背景是否影响临床DLB风险和神经病理学疾病严重程度。360例临床DLB病例，446例神经病理学证实的路易体病（LBD）病例（LBD-hDLB）和910例神经学正常对照具有欧洲mtDNA单倍型群，使用Escherina Biosciences MassARRAY iPlex技术定义。对39个独特的mtDNA变异体进行了基因分型，并将mtDNA单倍型群分配给线粒体单倍型。还在LBD-hDLB病例的不同脑区域中评估了纹状体多巴胺能变性、神经元损失和路易体计数。在病例对照分析中，使用经年龄和性别调整的Logistic回归模型评估mtDNA单倍型群与DLB或LBD-hDLB风险之间的关联。其他适当的回归模型，调整死亡年龄和性别，评估单倍型组与每个不同的神经病理学结果的措施。经Bonferroni校正后，未发现mtDNA单倍群与DLB或LBD-hDLB风险显著相关，单倍群H提示DLB风险名义上显著降低（OR=0.61，P=0.006），但与LBD-hDLB风险无关（OR=0.87，P=0.34）。在额外校正APOE ε4等位基因数量后，DLB单倍群H观察结果一致（OR=0.59，P=0.004）。单倍型组H也显示与腹外侧黑质神经元丢失减少相关（OR=0.44，P=0.033）。线粒体单倍群H可能对LBD-hDLB病例中的DLB风险和黑质区域的神经元损失具有保护作用，但需要进一步验证。在线版本包含补充材料，可通过10.1186/s40478-022-01399-4获得。
Dementia with Lewy bodies (DLB) is clinically diagnosed when patients develop dementia less than a year after parkinsonism onset. Age is the primary risk factor for DLB and mitochondrial health influences ageing through effective oxidative phosphorylation (OXPHOS). Patterns of stable polymorphisms in the mitochondrial genome (mtDNA) alter OXPHOS efficiency and define individuals to specific mtDNA haplogroups. This study investigates if mtDNA haplogroup background affects clinical DLB risk and neuropathological disease severity. 360 clinical DLB cases, 446 neuropathologically confirmed Lewy body disease (LBD) cases with a high likelihood of having DLB (LBD-hDLB), and 910 neurologically normal controls had European mtDNA haplogroups defined using Agena Biosciences MassARRAY iPlex technology. 39 unique mtDNA variants were genotyped and mtDNA haplogroups were assigned to mitochondrial phylogeny. Striatal dopaminergic degeneration, neuronal loss, and Lewy body counts were also assessed in different brain regions in LBD-hDLB cases. Logistic regression models adjusted for age and sex were used to assess associations between mtDNA haplogroups and risk of DLB or LBD-hDLB versus controls in a case-control analysis. Additional appropriate regression models, adjusted for age at death and sex, assessed associations of haplogroups with each different neuropathological outcome measure. No mtDNA haplogroups were significantly associated with DLB or LBD-hDLB risk after Bonferroni correction.Haplogroup H suggests a nominally significant reduced risk of DLB (OR=0.61, P=0.006) but no association of LBD-hDLB (OR=0.87, P=0.34). The haplogroup H observation in DLB was consistent after additionally adjusting for the number of APOE ε4 alleles (OR=0.59, P=0.004). Haplogroup H also showed a suggestive association with reduced ventrolateral substantia nigra neuronal loss (OR=0.44, P=0.033). Mitochondrial haplogroup H may be protective against DLB risk and neuronal loss in substantia nigra regions in LBD-hDLB cases but further validation is warranted. The online version contains supplementary material available at 10.1186/s40478-022-01399-4.
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影响因子：
30.8
作者：
Chia R;Sabir MS;Bandres-Ciga S;Saez-Atienzar S;Reynolds RH;Gustavsson E;Walton RL;Ahmed S;Viollet C;Ding J;Makarious MB;Diez-Fairen M;Portley MK;Shah Z;Abramzon Y;Hernandez DG;Blauwendraat C;Stone DJ;Eicher J;Parkkinen L;Ansorge O;Clark L;Honig LS;Marder K;Lemstra A;St George-Hyslop P;Londos E;Morgan K;Lashley T;Warner TT;Jaunmuktane Z;Galasko D;Santana I;Tienari PJ;Myllykangas L;Oinas M;Cairns NJ;Morris JC;Halliday GM;Van Deerlin VM;Trojanowski JQ;Grassano M;Calvo A;Mora G;Canosa A;Floris G;Bohannan RC;Brett F;Gan-Or Z;Geiger JT;Moore A;May P;Krüger R;Goldstein DS;Lopez G;Tayebi N;Sidransky E;American Genome Center;Norcliffe-Kaufmann L;Palma JA;Kaufmann H;Shakkottai VG;Perkins M;Newell KL;Gasser T;Schulte C;Landi F;Salvi E;Cusi D;Masliah E;Kim RC;Caraway CA;Monuki ES;Brunetti M;Dawson TM;Rosenthal LS;Albert MS;Pletnikova O;Troncoso JC;Flanagan ME;Mao Q;Bigio EH;Rodríguez-Rodríguez E;Infante J;Lage C;González-Aramburu I;Sanchez-Juan P;Ghetti B;Keith J;Black SE;Masellis M;Rogaeva E;Duyckaerts C;Brice A;Lesage S;Xiromerisiou G;Barrett MJ;Tilley BS;Gentleman S;Logroscino G;Serrano GE;Beach TG;McKeith IG;Thomas AJ;Attems J;Morris CM;Palmer L;Love S;Troakes C;Al-Sarraj S;Hodges AK;Aarsland D;Klein G;Kaiser SM;Woltjer R;Pastor P;Bekris LM;Leverenz JB;Besser LM;Kuzma A;Renton AE;Goate A;Bennett DA;Scherzer CR;Morris HR;Ferrari R;Albani D;Pickering-Brown S;Faber K;Kukull WA;Morenas-Rodriguez E;Lleó A;Fortea J;Alcolea D;Clarimon J;Nalls MA;Ferrucci L;Resnick SM;Tanaka T;Foroud TM;Graff-Radford NR;Wszolek ZK;Ferman T;Boeve BF;Hardy JA;Topol EJ;Torkamani A;Singleton AB;Ryten M;Dickson DW;Chiò A;Ross OA;Gibbs JR;Dalgard CL;Traynor BJ;Scholz SW
通讯作者：
Scholz SW
影响因子：
3.3
作者：
Gaweda-Walerych, Katarzyna;Maruszak, Aleksandra;Zekanowski, Cezary
通讯作者：
Zekanowski, Cezary
DOI：
10.1016/j.jalz.2017.09.014
发表时间：
2018-03
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Ferman TJ;Aoki N;Crook JE;Murray ME;Graff-Radford NR;van Gerpen JA;Uitti RJ;Wszolek ZK;Graff-Radford J;Pedraza O;Kantarci K;Boeve BF;Dickson DW
通讯作者：
Dickson DW
影响因子：
9.9
作者：
Chinnery, PF;Taylor, GA;Turnbull, DM
通讯作者：
Turnbull, DM
影响因子：
6
作者：
Hsu, LJ;Sagara, Y;Masliah, E
通讯作者：
Masliah, E