Early Markers of Alzheimer Disease

巴尔的摩老龄化纵向研究（BLSA）成立于1958年，是美国和世界上最古老的老龄化前瞻性研究之一。BLSA的使命是了解当人们变老时会发生什么，以及如何区分由于衰老和疾病或其他原因造成的变化。 我们在巴尔的摩老龄化纵向研究（BLSA）的参与者中调查了听力损失与突发性全因痴呆和阿尔茨海默病的前瞻性关联。数据包括639人接受听力测试，并在1990年至1994年痴呆症免费。听力损失的定义是听力较好的耳朵在0.5、1、2和4 kHz时纯音听阈的平均值（正常，<25 dB n = 455;轻度损失，25-40 dB n = 125;中度损失，41-70 dB n = 53;重度损失，>70 dB n = 6）。考克斯比例风险模型用于根据听力损失的严重程度对痴呆发生的时间进行建模，并根据年龄、性别、种族、教育、糖尿病、吸烟和高血压进行调整。在中位随访11.9年期间，诊断出58例事件全因痴呆，其中37例为AD。发生全因痴呆的风险随基线听力损失的严重程度呈对数线性增加（每10 dB损失1.27; 95%置信区间，1.06-1.50）。与正常听力相比，轻度听力损失、中度听力损失和重度听力损失的全因痴呆事件的风险比（95%置信区间）分别为1.89（1.00-3.58）、3.00（1.43-6.30）和4.94（1.09-22.40）。AD事件的风险也随着基线听力损失而增加（每10 dB听力损失1.20），但置信区间更宽（0.94-1.53）。在调整性别、年龄、种族、教育、糖尿病、吸烟和高血压后，听力损失与全因痴呆事件独立相关，我们的研究结果对多项敏感性分析具有鲁棒性。全因痴呆症的风险与听力损失的严重程度呈对数线性增加，对于我们队列中60岁以上的个体来说，超过三分之一的全因痴呆症风险与听力损失有关。 使用尸检样本，我们研究了神经元基因表达的活性依赖性调节在促进神经元存活和可塑性中的作用，以及衰老和阿尔茨海默病（AD）中的神经元网络活性扰动。我们发现，大脑皮层神经元通过下调参与抑制性传递（GABA能和生长抑素）和Ca（2+）信号传导的基因及其编码蛋白的表达来响应慢性兴奋性抑制;参与脂质代谢和能量管理的途径的改变也是沉默的神经元网络的特征。一个分子指纹惊人的相似，减少网络活动发生在人类大脑在老化和AD，相反的变化发生在响应激活N-甲基-D-天冬氨酸（NMDA）和脑源性神经营养因子（BDNF）受体在培养的皮层神经元和小鼠在丰富的环境或电休克。我们的研究结果表明，在衰老和AD中抑制性神经传递的减少可能是代偿反应的结果，矛盾的是，使神经元容易受到Ca（2+）介导的变性。

The Baltimore Longitudinal Study of Aging (BLSA) was established in 1958 and is one the oldest prospective studies of aging in the USA and the world. The mission of the BLSA is to learn what happens to people as they get old and how to sort out changes due to aging and from those due to disease or other causes. We investigated the prospective association of hearing loss with incident all-cause dementia and Alzheimers disease in participants in the Baltimore Longitudinal Study of Aging (BLSA). Data included 639 individuals who underwent audiometric testing and were dementia free in 1990 to 1994. Hearing loss was defined by a pure-tone average of hearing thresholds at 0.5, 1, 2, and 4 kHz in the better-hearing ear (normal, <25 dB n = 455; mild loss, 25-40 dB n = 125; moderate loss, 41-70 dB n = 53; and severe loss, >70 dB n = 6). Cox proportional hazards models were used to model time to incident dementia according to severity of hearing loss and were adjusted for age, sex, race, education, diabetes mellitus, smoking, and hypertension. During a median follow-up of 11.9 years, 58 cases of incident all-cause dementia were diagnosed, of which 37 cases were AD. The risk of incident all-cause dementia increased log linearly with the severity of baseline hearing loss (1.27 per 10-dB loss; 95% confidence interval, 1.06-1.50). Compared with normal hearing, the hazard ratio (95% confidence interval) for incident all-cause dementia was 1.89 (1.00-3.58) for mild hearing loss, 3.00 (1.43-6.30) for moderate hearing loss, and 4.94 (1.09-22.40) for severe hearing loss. The risk of incident AD also increased with baseline hearing loss (1.20 per 10 dB of hearing loss) but with a wider confidence interval (0.94-1.53). Hearing loss was independently associated with incident all-cause dementia after adjustment for sex, age, race, education, diabetes, smoking, and hypertension, and our findings were robust to multiple sensitivity analyses. The risk of all-cause dementia increased log linearly with hearing loss severity, and for individuals older than 60 years in our cohort, more than one-third of the risk of incident all-cause dementia was associated with hearing loss. Using autopsy samples, we investigated the role of activity-dependent modulation of neuronal gene expression in promoting neuronal survival and plasticity, and neuronal network activity perturbation in aging and Alzheimer's disease (AD). We showed that cerebral cortical neurons respond to chronic suppression of excitability by downregulating the expression of genes and their encoded proteins involved in inhibitory transmission (GABAergic and somatostatin) and Ca(2+) signaling; alterations in pathways involved in lipid metabolism and energy management were also features of silenced neuronal networks. A molecular fingerprint strikingly similar to that of diminished network activity occurs in the human brain during aging and in AD, and opposite changes occur in response to activation of N-methyl-D-aspartate (NMDA) and brain-derived neurotrophic factor (BDNF) receptors in cultured cortical neurons and in mice in response to an enriched environment or electroconvulsive shock. Our findings suggest that reduced inhibitory neurotransmission during aging and in AD may be the result of compensatory responses that, paradoxically, render the neurons vulnerable to Ca(2+)-mediated degeneration.