Background

Dementia has a long prodromal stage with various pathophysiological manifestations; however, the progression of pre-diagnostic changes remains unclear. We aimed to determine the evolutional trajectories of multiple-domain clinical assessments and health conditions up to 15 years before the diagnosis of dementia.

Methods

Data was extracted from the UK-Biobank, a longitudinal cohort that recruited over 500,000 participants from March 2006 to October 2010. Each demented subject was matched with 10 healthy controls. We performed logistic regressions on 400 predictors covering a comprehensive range of clinical assessments or health conditions. Their evolutional trajectories were quantified using adjusted odds ratios (ORs) and FDR-corrected p-values under consecutive timeframes preceding the diagnosis of dementia.

Findings

During a median follow-up of 13.7 [Interquartile range, IQR 12.9–14.2] years until July 2022, 7620 subjects were diagnosed with dementia. In general, upon approaching the diagnosis, demented subjects witnessed worse functional assessments and a higher prevalence of health conditions. Associations up to 15 years preceding the diagnosis comprised declined physical strength (hand grip strength, OR 0.65 [0.63–0.67]), lung dysfunction (peak expiratory flow, OR 0.78 [0.76–0.81]) and kidney dysfunction (cystatin C, OR 1.13 [1.11–1.16]), comorbidities of coronary heart disease (OR 1.78 [1.67–1.91]), stroke (OR 2.34 [2.1–1.37]), diabetes (OR 2.03 [1.89–2.18]) and a series of mental disorders. Cognitive functions in multiple tests also demonstrate decline over a decade before the diagnosis. Inadequate activity (3–5 year, overall time of activity, OR 0.82 [0.73–0.92]), drowsiness (3–5 year, sleep duration, OR 1.13 [1.04–1.24]) and weight loss (0–5 year, weight, OR 0.9 [0.83–0.98]) only exhibited associations within five years before the diagnosis. In addition, serum biomarkers of enriched endocrine, dysregulations of ketones, deficiency of brand-chain amino acids and polyunsaturated fatty acids were found in a similar prodromal time window and can be witnessed as the last pre-symptomatic conditions before the diagnosis.

Interpretation

Our findings present a comprehensive temporal-diagnostic landscape preceding incident dementia, which could improve selection for preventive and early disease-modifying treatment trials.

中文翻译：

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诊断前 15 年痴呆发生前的临床轨迹：一项大型前瞻性队列研究

背景

痴呆症前驱期较长，病理生理表现多样；然而，诊断前变化的进展仍不清楚。我们的目标是确定痴呆症诊断前 15 年多领域临床评估和健康状况的演变轨迹。

方法

数据取自 UK-Biobank，这是一个纵向队列，从 2006 年 3 月到 2010 年 10 月招募了超过 500,000 名参与者。每个痴呆受试者都与 10 名健康对照相匹配。我们对 400 个预测变量进行了逻辑回归，涵盖了全面的临床评估或健康状况。在痴呆症诊断之前的连续时间范围内，使用调整后的比值比 (OR) 和 FDR 校正的p值对它们的进化轨迹进行量化。

发现

截至 2022 年 7 月，中位随访时间为 13.7 [四分位距，IQR 12.9–14.2] 年，7620 名受试者被诊断患有痴呆症。一般来说，在接近诊断时，痴呆症受试者的功能评估较差，健康状况患病率较高。诊断前长达 15 年的相关性包括体力下降（握力，OR 0.65 [0.63–0.67]）、肺功能障碍（呼气峰流量，OR 0.78 [0.76–0.81]）和肾功能障碍（胱抑素 C，OR 1.13） [1.11–1.16]）、冠心病（OR 1.78 [1.67–1.91]）、中风（OR 2.34 [2.1–1.37]）、糖尿病（OR 2.03 [1.89–2.18]）等合并症以及一系列精神障碍。多项测试中的认知功能也显示出诊断前十多年的衰退。活动不足（3-5 年，总活动时间，OR 0.82 [0.73-0.92]）、嗜睡（3-5 年，睡眠时间，OR 1.13 [1.04-1.24]）和体重减轻（0-5 年，体重，OR 0.9 [0.83–0.98]）仅在诊断前五年内表现出关联。此外，在相似的前驱时间窗口中发现了内分泌丰富、酮体失调、品牌链氨基酸和多不饱和脂肪酸缺乏的血清生物标志物，并且可以作为诊断前的最后一个症状前状况。

解释

我们的研究结果呈现了痴呆症发生前的全面时间诊断情况，这可以改善预防性和早期疾病缓解治疗试验的选择。