Șerban Matei, Toader Corneliu, Covache-Busuioc Răzvan-Adrian
Puls Med Association, 051885 Bucharest, Romania.
Department of Neurosurgery, "Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania.
Int J Mol Sci. 2025 Aug 22;26(17):8114. doi: 10.3390/ijms26178114.
Brain tumors elicit complex neuropsychiatric disturbances that frequently occur prior to radiological detection and hinder differentiation from major psychiatric disorders. These syndromes stem from tumor-dependent metabolic reprogramming, neuroimmune activation, neurotransmitter dysregulation, and large-scale circuit disruption. Dinucleotide hypermethylation (e.g., IDH-mutant gliomas), through the accumulation of 2-hydroxyglutarate (2-HG), execute broad DNA and histone hypermethylation, hypermethylating serotonergic and glutamatergic pathways, and contributing to a treatment-resistant cognitive-affective syndrome. High-grade gliomas promote glutamate excitotoxicity via system Xc transporter upregulation that contributes to cognitive and affective instability. Cytokine cascades induced by tumors (e.g., IL-6, TNF-α, IFN-γ) lead to the breakdown of the blood-brain barrier (BBB), which is thought to amplify neuroinflammatory processes similar to those seen in schizophrenia spectrum disorders and autoimmune encephalopathies. Frontal gliomas present with apathy and disinhibition, and temporal tumors lead to hallucinations, emotional lability, and episodic memory dysfunction. Tumor-associated neuropsychiatric dysfunction, despite increasing recognition, is underdiagnosed and commonly misdiagnosed. This paper seeks to consolidate the mechanistic understanding of these syndromes, drawing on perspectives from neuroimaging, molecular oncology, neuroimmunology, and computational psychiatry. Novel approaches, including lesion-network mapping, exosomal biomarkers or AI-based predictive modeling, have projected early detection and precision-targeted interventions. In the context of the limitations of conventional psychotropic treatments, mechanistically informed therapies, including neuromodulation, neuroimmune-based interventions, and metabolic reprogramming, are essential to improving psychiatric and oncological outcomes. Paraneoplastic neuropsychiatric syndromes are not due to a secondary effect, rather, they are manifestations integral to the biology of a tumor, so they require a new paradigm in both diagnosis and treatment. And defining their molecular and circuit-level underpinnings will propel the next frontier of precision psychiatry in neuro-oncology, cementing the understanding that psychiatric dysfunction is a core influencer of survival, resilience, and quality of life.
脑肿瘤引发复杂的神经精神障碍，这些障碍常在影像学检测之前出现，并阻碍与主要精神疾病的鉴别。这些综合征源于肿瘤相关的代谢重编程、神经免疫激活、神经递质失调和大规模神经回路破坏。二核苷酸高甲基化（如异柠檬酸脱氢酶（IDH）突变型胶质瘤）通过2-羟基戊二酸（2-HG）的积累，导致广泛的DNA和组蛋白高甲基化，使血清素能和谷氨酸能通路发生高甲基化，从而导致一种难治性认知-情感综合征。高级别胶质瘤通过上调系统Xc转运体促进谷氨酸兴奋性毒性，这导致认知和情感不稳定。肿瘤诱导的细胞因子级联反应（如白细胞介素-6、肿瘤坏死因子-α、干扰素-γ）导致血脑屏障（BBB）破坏，这被认为会放大神经炎症过程，类似于精神分裂症谱系障碍和自身免疫性脑病中所见的情况。额叶胶质瘤表现为淡漠和去抑制，颞叶肿瘤导致幻觉、情绪不稳定和情景记忆功能障碍。尽管肿瘤相关的神经精神功能障碍越来越受到重视，但仍存在诊断不足和普遍误诊的情况。本文旨在整合对这些综合征的机制理解，借鉴神经影像学、分子肿瘤学、神经免疫学和计算精神病学的观点。包括病变-网络映射、外泌体生物标志物或基于人工智能的预测模型在内的新方法，有望实现早期检测和精准靶向干预。在传统精神药物治疗存在局限性的背景下，基于机制的治疗方法，包括神经调节、基于神经免疫的干预和代谢重编程，对于改善精神和肿瘤治疗结果至关重要。副肿瘤性神经精神综合征并非继发效应，相反，它们是肿瘤生物学的固有表现，因此在诊断和治疗方面都需要新的范式。确定其分子和回路水平的基础将推动神经肿瘤学中精准精神病学的下一个前沿领域，强化精神功能障碍是生存、恢复力和生活质量的核心影响因素这一认识。
