Parkinson’s dementia is a common and devastating part of Parkinson’s disease. Whilst timing and severity vary, dementia in Parkinson’s is often preceded by visual dysfunction. White matter changes, representing axonal loss, occur early in the disease process. Clarifying which white matter connections are affected in Parkinson’s with visual dysfunction and why specific connections are vulnerable will provide important mechanistic insights. Here, we use diffusion tractography in 100 Parkinson’s patients (33 low visual performers) and 34 controls to identify patterns of connectivity loss in Parkinson’s with visual dysfunction. We examine the relationship between regional transcription and connectivity loss, using the Allen Institute for Brain Science transcriptome atlas. We show that interhemispheric connections are preferentially affected in Parkinson’s low visual performers. Interhemispheric connection loss was associated with downweighted genes related to the smoothened signalling pathway (enriched in glutamatergic neurons) and upweighted metabolic genes. Risk genes for Parkinson’s but not Alzheimer’s or Dementia with Lewy bodies were over-represented in upweighted genes associated with interhemispheric connection loss. Our findings suggest selective vulnerability in Parkinson’s patients at highest risk of dementia (those with visual dysfunction), where differences in gene expression and metabolic dysfunction, affecting longer connections with higher metabolic burden, drive connectivity loss.

帕金森痴呆是帕金森病的常见且具有破坏性的部分。虽然发生时间和严重程度各不相同，但帕金森病痴呆症通常先出现视觉功能障碍。代表轴突损失的白质变化发生在疾病过程的早期。澄清哪些白质连接受到帕金森氏症视觉功能障碍的影响，以及为什么特定的连接很脆弱，将提供重要的机制见解。在这里，我们对 100 名帕金森氏症患者（33 名视力低下者）和 34 名对照者使用弥散纤维束成像技术来识别伴有视觉功能障碍的帕金森氏症患者的连通性丧失模式。我们使用艾伦脑科学研究所转录组图谱检查区域转录和连接丢失之间的关系。我们发现，帕金森氏症低视觉表现者的半球间连接优先受到影响。半球间连接丧失与平滑信号通路（富含谷氨酸能神经元）相关基因的权重降低和代谢基因的权重增加有关。帕金森氏症的风险基因在与大脑半球间连接丧失相关的增重基因中过多，但阿尔茨海默氏症或路易体痴呆症的风险基因则不然。我们的研究结果表明，痴呆风险最高的帕金森病患者（视觉功能障碍患者）存在选择性脆弱性，其中基因表达和代谢功能障碍的差异会影响较长的连接和较高的代谢负担，从而导致连接丧失。