Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Parkinson's Foundation Centre of Excellence, King's College Hospital, London, United Kingdom.
Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Parkinson's Foundation Centre of Excellence, King's College Hospital, London, United Kingdom; Center for Neurodegenerative Diseases and the Aging Brain, Department of Clinical Research in Neurology, University of Bari 'Aldo Moro', "Pia Fondazione Cardinale G. Panico", Tricase, Lecce, Italy.
Neurobiol Dis. 2023 Jul;183:106182. doi: 10.1016/j.nbd.2023.106182. Epub 2023 Jun 5.
It has been recently suggested that LRRK2 mutations are associated with a more benign clinical phenotype and a potentially more preserved cholinergic function in Parkinson's disease (PD). However, to our knowledge, no studies have tested whether the better clinical progression observed in LRRK2-PD patients is associated with more preserved volumes of a cholinergic brain area, the basal forebrain (BF). To address this hypothesis, here we compared BF volumes in LRRK2 carriers with and without PD with respect to idiopathic PD (iPD) patients and controls, and assessed whether they are associated with better clinical progression observed in LRRK2-PD compared to iPD.
Thirty-one symptomatic LRRK2-PD patients and 13 asymptomatic LRRK2 individuals were included from the Parkinson's Progression Markers Initiative. In addition, 31 patients with iPD and 13 healthy controls matched to the previous groups were also included. BF volumes were automatically extracted from baseline T1-weighted MRI scans using a stereotactic atlas of cholinergic nuclei. These volumes were then compared between groups and their relationship with longitudinal cognitive changes was evaluated using linear mixed effects models. Mediation analyses assessed whether BF volumes mediated differences in cognitive trajectories between groups.
LRRK2-PD patients showed significantly higher BF volumes compared to iPD (P = 0.019) as did asymptomatic LRRK2 subjects compared to controls (P = 0.008). There were no other significant differences in cortical regions or subcortical volumes between these groups. BF volumes predicted longitudinal decline in several cognitive functions in iPD patients but not in LRRK2-PD, who did not show cognitive changes over a 4-year follow-up period. BF volumes were a significant mediator of the different cognitive trajectories between iPD and LRRK2-PD patients (95% CI 0.056-2.955).
Our findings suggest that mutations in LRRK2 are associated with increased BF volumes, potentially reflecting a compensatory hypercholinergic state that could prevent cognitive decline in LRRK2-PD patients.
最近有研究表明 LRRK2 突变与帕金森病（PD）更良性的临床表型和潜在更完好的胆碱能功能相关。然而，据我们所知，尚无研究检测 LRRK2-PD 患者中观察到的更好的临床进展是否与更完好的胆碱能脑区基底前脑（BF）体积相关。为了验证这一假说，我们比较了 LRRK2 携带者中有无 PD 的 BF 体积与特发性 PD（iPD）患者和对照组之间的差异，并评估了它们与 LRRK2-PD 患者相比 iPD 患者中观察到的更好的临床进展是否相关。
纳入帕金森进展标志物倡议中的 31 名有症状的 LRRK2-PD 患者和 13 名无症状的 LRRK2 个体。此外，还纳入了 31 名 iPD 患者和 13 名与前两组相匹配的健康对照者。使用胆碱能核立体定向图谱从基线 T1 加权 MRI 扫描中自动提取 BF 体积。然后在组间进行比较，并使用线性混合效应模型评估它们与纵向认知变化的关系。中介分析评估了 BF 体积是否在组间认知轨迹的差异中起中介作用。
与 iPD 相比，LRRK2-PD 患者的 BF 体积明显更高（P=0.019），无症状的 LRRK2 个体与对照组相比也是如此（P=0.008）。这些组之间在皮质区域或皮质下体积方面没有其他显著差异。BF 体积预测了 iPD 患者的几项认知功能的纵向下降，但在 4 年随访期间，LRRK2-PD 患者没有认知变化。BF 体积是 iPD 和 LRRK2-PD 患者之间不同认知轨迹的重要中介（95%CI 0.056-2.955）。
我们的研究结果表明，LRRK2 突变与 BF 体积增加相关，这可能反映了一种代偿性的高胆碱能状态，可以防止 LRRK2-PD 患者的认知下降。
