Isonaka Risa, Sullivan Patti, Holmes Courtney, Goldstein David S
Autonomic Medicine Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
Res Sq. 2024 Mar 1:rs.3.rs-3988235. doi: 10.21203/rs.3.rs-3988235/v1.
Neurogenic orthostatic hypotension (nOH) results from deficient reflexive delivery of norepinephrine to cardiovascular receptors in response to decreased cardiac venous return. Lewy body (LB) forms of nOH entail low F-dopamine-derived radioactivity (a measure of cardiac noradrenergic deficiency), olfactory dysfunction by the University of Pennsylvania Smell Identification Test (UPSIT), and increased deposition of alpha-synuclein (ɑ-syn) in dermal sympathetic noradrenergic nerves by the ɑ-syn-tyrosine hydroxylase (TH) colocalization index. This observational, cross-sectional study explored whether combinations of these biomarkers specifically identify LB forms of nOH.
Clinical laboratory data were reviewed from patients referred for evaluation at the National Institutes of Health for chronic autonomic failure between 2011 and 2023. The cutoff value for low myocardial F-dopamine-derived radioactivity was 6,000 nCi-kg/cc-mCi, for olfactory dysfunction an UPSIT score ≤ 28, and for an increased ɑ-syn-TH colocalization index ≥ 1.57.
A total of 44 patients (31 LB, 13 non-LB nOH) had data for all 3 biomarkers. Compared to the non-LB group, the LB nOH group had low myocardial F-dopamine-derived radioactivity, low UPSIT scores, and high ɑ-syn-TH colocalization indexes (p<0.0001 each). Combining the 3 biomarkers completely separated the groups. Cluster analysis identified 2 distinct groups (p<0.0001) independently of the clinical diagnosis, 1 cluster corresponding exactly to LB nOH.
LB forms of nOH feature cardiac noradrenergic deficiency, olfactory dysfunction, and increased ɑ-syn-TH colocalization in skin biopsies. Combining the data for these variables efficiently separates LB from non-LB nOH. Independently of the clinical diagnosis, this biomarker triad identifies a pathophysiologically distinct cluster of nOH patients.
神经源性直立性低血压（nOH）是由于心脏静脉回流减少时，去甲肾上腺素向心血管受体的反射性传递不足所致。路易体（LB）型nOH表现为低F - 多巴胺衍生放射性（一种衡量心脏去甲肾上腺素能缺乏的指标）、宾夕法尼亚大学嗅觉识别测试（UPSIT）显示的嗅觉功能障碍，以及通过α-突触核蛋白（ɑ-syn）-酪氨酸羟化酶（TH）共定位指数衡量的真皮交感去甲肾上腺素能神经中α-突触核蛋白（ɑ-syn）沉积增加。这项观察性横断面研究探讨了这些生物标志物的组合是否能特异性识别LB型nOH。
回顾了2011年至2023年间在美国国立卫生研究院因慢性自主神经功能衰竭接受评估的患者的临床实验室数据。低心肌F - 多巴胺衍生放射性的临界值为6,000 nCi-kg/cc-mCi，嗅觉功能障碍的临界值为UPSIT评分≤28，ɑ-syn-TH共定位指数增加的临界值≥1.57。
共有44例患者（31例LB型，13例非LB型nOH）有所有3种生物标志物的数据。与非LB组相比，LB型nOH组心肌F - 多巴胺衍生放射性低、UPSIT评分低且ɑ-syn-TH共定位指数高（每项p<0.0001）。这3种生物标志物的组合完全区分了两组。聚类分析独立于临床诊断确定了2个不同的组（p<0.0001），其中1个聚类与LB型nOH完全对应。
LB型nOH的特征是心脏去甲肾上腺素能缺乏、嗅觉功能障碍以及皮肤活检中ɑ-syn-TH共定位增加。综合这些变量的数据可有效区分LB型与非LB型nOH。独立于临床诊断，这个生物标志物三联体识别出了nOH患者中一个病理生理上不同的聚类。
