Sex differences for clinical correlates of substantia nigra neuron loss in people with Lewy body pathology

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Biology of Sex Differences Pub Date : 2024-01-19 DOI:10.1186/s13293-024-00583-6
Ece Bayram, David G. Coughlin, Ravi Rajmohan, Irene Litvan
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Abstract

Lewy body dementia (LBD) phenotype is associated with the presence and degree of Lewy body, Alzheimer’s pathologies, and substantia nigra neuron loss. Nigral neuron loss is associated with parkinsonism in LBD, and females with LBD are less likely than males to have parkinsonism. As sex differences were reported for clinical correlates of Lewy body and Alzheimer’s pathologies, we aimed to investigate whether there are also sex differences for correlates of nigral neuron loss. Data were obtained from the National Alzheimer’s Coordinating Center for females (n = 159) and males (n = 263) with brainstem, limbic, and neocortical Lewy body pathology. Sex differences for the nigral neuron loss’ association with Lewy body pathology staging and core clinical LBD features (cognitive fluctuations, visual hallucinations, rapid eye movement sleep behavior disorder, parkinsonism) during follow-up were analyzed with generalized linear models adjusting for age and Alzheimer’s pathology staging. Whether any of the core clinical features at the time of dementia onset can predict underlying nigral neuron loss for females and males were also analyzed with generalized linear models. Compared to males, females died older and had higher levels of Braak tau staging, but had similar levels of Lewy body pathology staging and nigral neuron loss. Females were less likely than males to have a clinical Lewy body disease diagnosis during follow-up. More advanced Lewy body pathology staging was associated with more nigral neuron loss, more so for males than females. More nigral neuron loss was associated with parkinsonism and clinical LBD diagnosis during follow-up, more so for males than females. Across the subgroup with dementia (40 females, 58 males), core LBD features at first visit with dementia were not associated with nigral neuron loss. Nigral neuron loss’ association with Lewy body pathology staging and core LBD features can differ by sex. Compared to males, females with Lewy body pathology have a higher risk of underdiagnosis. There is a need to elucidate the mechanisms underlying sex differences for pathology and clinicopathological correlations to advance diagnostic and therapeutic efforts in LBD. Lewy body dementia (LBD) is the third most common dementia associated with Lewy body pathology, Alzheimer’s pathology, and substantia nigra loss. It is often less recognized in females compared to males, because the typical symptoms are less evident in females. In this study, we investigated whether substantia nigra neuron loss plays a role in the atypical presentation of LBD in females, contributing to the underdiagnosis compared to males. We analyzed data from 159 females and 263 males with pathological Lewy body disease obtained from the National Alzheimer's Coordinating Center. Females tended to be older at the time of death and had more tau buildup, but similar levels of Lewy body pathology and substantia nigra neuron loss compared to males. When we compared males and females of similar age with similar levels of Alzheimer's pathology, we observed that females had less substantia nigra neuron loss at less advanced Lewy body pathology stages. Greater nigral neuron loss was associated with parkinsonism and the typical LBD symptoms in males, but not as strongly in females. The extent of nigral loss could not be predicted based on the clinical features at the time of dementia diagnosis. Thus, the relationship between nigral neuron loss and the LBD symptoms seems to vary by sex. Females with underlying Lewy body disease are more likely to be underdiagnosed compared to males. We need further work to understand why these sex differences exist and how we can better identify and treat LBD.
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路易体病变患者黑质神经元缺失临床相关性的性别差异
路易体痴呆(LBD)的表型与路易体、阿尔茨海默氏症病变和黑质神经元缺失的存在和程度有关。黑质神经元缺失与路易氏痴呆的帕金森氏症有关,而女性路易氏痴呆患者出现帕金森氏症的可能性低于男性。由于路易体和阿尔茨海默病的临床相关性存在性别差异,我们旨在研究黑质神经元缺失的相关性是否也存在性别差异。我们从国家阿尔茨海默氏症协调中心获得了患有脑干、边缘和新皮质路易体病变的女性(n = 159)和男性(n = 263)的数据。通过调整年龄和阿尔茨海默病分期的广义线性模型,分析了黑质神经元缺失与路易体病理分期和随访期间核心临床特征(认知波动、视幻觉、快速眼动睡眠行为障碍、帕金森病)之间的性别差异。此外,还利用广义线性模型分析了女性和男性痴呆症发病时的核心临床特征是否可以预测潜在的黑质神经元缺失。与男性相比,女性的死亡年龄更大,Braak tau分期水平更高,但路易体病理学分期和黑质神经元缺失水平相似。与男性相比,女性在随访期间被诊断为临床路易体疾病的可能性较低。路易体病理分期越晚,黑质神经元丢失越多,男性比女性更明显。更多的黑质神经元缺失与帕金森症和随访期间的临床路易体疾病诊断有关,男性比女性更为明显。在痴呆症亚组(40 名女性,58 名男性)中,痴呆症患者首次就诊时的枸杞多糖核心特征与黑质神经元缺失无关。黑质神经元缺失与路易体病理学分期和核心枸杞多糖特征的关系可能因性别而异。与男性相比,女性路易体病理患者被漏诊的风险更高。有必要阐明路易体病理学和临床病理学相关性的性别差异机制,以推进路易体痴呆的诊断和治疗工作。路易体痴呆症(LBD)是与路易体病理学、阿尔茨海默氏症病理学和黑质丧失相关的第三大常见痴呆症。与男性相比,女性对这种疾病的认识往往较少,因为女性的典型症状并不明显。在这项研究中,我们探讨了黑质神经元缺失是否是女性枸杞多糖症表现不典型的原因之一,从而导致女性枸杞多糖症的诊断率低于男性。我们分析了从美国国家阿尔茨海默病协调中心(National Alzheimer's Coordinating Center)获得的159名女性和263名男性病理路易体病患者的数据。与男性相比,女性在死亡时往往年龄较大,tau堆积较多,但路易体病理和黑质神经元丢失的程度相似。当我们比较年龄相仿、阿尔茨海默病病理程度相似的男性和女性时,我们发现女性在路易体病理阶段较晚时,黑质神经元丢失较少。在男性中,黑质神经元丢失较多与帕金森氏症和典型的路易体病症状有关,但在女性中则不尽相同。根据痴呆症诊断时的临床特征无法预测黑质神经元缺失的程度。因此,黑质神经元缺失与路易体痴呆症状之间的关系似乎因性别而异。与男性相比,患有潜在路易体疾病的女性更容易被漏诊。我们需要进一步研究,以了解这些性别差异存在的原因,以及如何更好地识别和治疗路易体痴呆症。
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来源期刊
Biology of Sex Differences
Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY
CiteScore
12.10
自引率
1.30%
发文量
69
审稿时长
14 weeks
期刊介绍: Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.
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