一项基于尸检的研究结果表明,与17例黑质无路易体(Braak分期0期)的PD患者相比,散发性路易体病(ILBD)患者黑质总神经元密度显著降低39.8%。然而Braak1期至6期患者的神经元密度没有差异,Braak1期和2期患者在黑质纹状体系统出现路易体之前也能观察到神经元密度降低。
ILBD患者的神经元密度高于13例临床PD患者,但酪氨酸羟化酶(TH)阴性神经元的比例也较高(TH阴性表明多巴胺能细胞功能障碍)。
研究人员——美国宾夕法尼亚州费城退伍军人事务医学中心John Duda教授及其同事指出,ILBD患者的TH阴性细胞可能是在“努力生存”,但PD患者的TH阴性细胞已经死亡,这可以解释PD患者神经元总密度较低的原因(较无路易体的患者低66.7%)。
ILBD患者神经元密度的降低伴随α-突触核蛋白负荷日益加重,但TH-阴性细胞的比例与α-突触核蛋白负荷不相关,“进一步表明“路易体病理”不是黑质神经元损失的唯一原因,”该团队解释。
Schulz-Schaeffer教授说:“我们应该脱离路易体相关的细胞死亡是PD主要现象的这一概念,集中研究仍存活细胞的突触病理和轴突变性,以更好理解PD的治疗和病理生理学。”
Objective
To determine whether evidence of neuronal dysfunction or demise preceded deposition of Lewy pathology in vulnerable neurons in Parkinson disease (PD).
Methods
We examined the extent of nigral dysfunction and degeneration among 63 normal, incidental Lewy body disease (ILBD), and PD cases based on tyrosine hydroxylase (TH) immunoreactivity and neuron densities, respectively. The relationship between these markers and Lewy pathology (LP) burden in the substantia nigra (SN) and Braak PD stage was assessed.
Results
Compared with normal subjects, ILBD cases displayed a significantly higher percentage of TH-negative cells and lower neuronal densities in the SN as early as Braak PD stages 1 and 2, before LP deposition in the nigrostriatal system. ILBD nigral neuron densities were intermediate between normal subjects and PD cases, and TH-negative percentages were higher in ILBD than either normal or PD cases. Furthermore, neuron density and neuronal dysfunction levels remained relatively constant across Braak PD stages in ILBD.
Conclusions
These results suggest that significant neurodegeneration and cellular dysfunction precede LP in the SN, challenging the pathogenic role of LP in PD and the assumption that ILBD always represents preclinical PD.