Table_1_Severe and Regionally Widespread Increases in Tissue Urea in the Human Brain Represent a Novel Finding of Pathogenic Potential in Parkinson’s Disease Dementia.DOCX

Widespread elevations in brain urea have, in recent years, been reported in certain types of age-related dementia, notably Alzheimer’s disease (AD) and Huntington’s disease (HD). Urea increases in these diseases are substantive, and approximate in magnitude to levels present in uraemic encephalopathy. In AD and HD, elevated urea levels are widespread, and not only in regions heavily affected by neurodegeneration. However, measurements of brain urea have not hitherto been reported in Parkinson’s disease dementia (PDD), a condition which shares neuropathological and symptomatic overlap with both AD and HD. Here we report measurements of tissue urea from nine neuropathologically confirmed regions of the brain in PDD and post-mortem delay (PMD)-matched controls, in regions including the cerebellum, motor cortex (MCX), sensory cortex, hippocampus (HP), substantia nigra (SN), middle temporal gyrus (MTG), medulla oblongata (MED), cingulate gyrus, and pons, by applying ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Urea concentrations were found to be substantively elevated in all nine regions, with average increases of 3–4-fold. Urea concentrations were remarkably consistent across regions in both cases and controls, with no clear distinction between regions heavily affected or less severely affected by neuronal loss in PDD. These urea elevations mirror those found in uraemic encephalopathy, where equivalent levels are generally considered to be pathogenic, and those previously reported in AD and HD. Increased urea is a widespread metabolic perturbation in brain metabolism common to PDD, AD, and HD, at levels equal to those seen in uremic encephalopathy. This presents a novel pathogenic mechanism in PDD, which is shared with two other neurodegenerative diseases.

近年来，多项研究证实部分年龄相关性痴呆患者存在广泛的脑尿素水平升高现象，其中以阿尔茨海默病（Alzheimer’s disease, AD）与亨廷顿病（Huntington’s disease, HD）最为突出。此类疾病中的尿素升高幅度显著，浓度水平接近尿毒症性脑病（uraemic encephalopathy）中的浓度。在AD与HD患者中，尿素水平升高的分布范围广泛，且并非仅局限于神经退行性病变严重累及的脑区。然而，迄今为止尚未见关于帕金森病痴呆（Parkinson’s disease dementia, PDD）患者脑尿素水平的检测报道；该疾病与AD及HD均存在神经病理与临床症状的重叠。本研究采用超高效液相色谱-串联质谱法（ultra-high-performance liquid chromatography-tandem mass spectrometry, UHPLC-MS/MS），对PDD患者及死后延迟时间（post-mortem delay, PMD）匹配的对照个体的9个经神经病理确认的脑区组织尿素水平进行了检测，所涉脑区包括小脑（cerebellum）、运动皮层（motor cortex, MCX）、感觉皮层（sensory cortex）、海马体（hippocampus, HP）、黑质（substantia nigra, SN）、颞中回（middle temporal gyrus, MTG）、延髓（medulla oblongata, MED）、扣带回（cingulate gyrus）及脑桥（pons）。检测结果显示，全部9个脑区的尿素浓度均显著升高，平均增幅达3~4倍。无论病例组还是对照组，尿素浓度在各脑区间均表现出显著的一致性；在PDD患者中，神经元丢失严重程度不同的脑区间并未呈现出明显的尿素水平差异。此类尿素水平升高现象与尿毒症性脑病中的情况一致，该病症中达到此类水平的尿素通常被认为具有致病性，同时也与此前在AD及HD中报道的结果相符。尿素水平升高是PDD、AD及HD共有的广泛脑代谢紊乱现象，其升高幅度与尿毒症性脑病中所见的水平相当。这一发现为PDD提出了一种全新的致病机制，且该机制同样存在于另外两种神经退行性疾病中。