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前瞻性老龄化研究之一。BLSA的使命是了解人们变老后会发生什么，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全因痴呆症和阿尔茨海默病的前瞻性关联。数据包括1990至1994年间接受听力测试并未患痴呆症的639人。听力损失的定义是听力较好的耳朵在0.5、1、2和4 kHz的纯音平均听力阈值(正常，25dBn=455；轻度损失，25-40dBn=125；中度损失，41-70dBn=53；和严重损失，&gt；70dBn=6)。COX比例风险模型被用来根据听力损失的严重程度来模拟痴呆发生的时间，并根据年龄、性别、种族、教育程度、糖尿病、吸烟和高血压进行了调整。在中位数11.9年的随访中，共诊断出58例偶发性全因痴呆，其中37例为阿尔茨海默病。发生全因痴呆的风险与基线听力损失的严重程度呈对数线性增加(每10分贝听力损失1.27；95%可信区间，1.06-1.50)。与听力正常相比，全因痴呆的危险比(95%可信区间)为1.89(1.00~3.58)，中度听力损失为3.00(1.43~6.30)，重度听力损失为4.94(1.09~22.40)。基线听力损失(每10分贝听力损失1.20)，但可信区间(0.94-1.53)越大，发生AD的风险也越高。在对性别、年龄、种族、教育程度、糖尿病、吸烟和高血压进行调整后，听力损失与全因痴呆症的发生独立相关，我们的发现经多重敏感性分析是可靠的。全因痴呆症的风险与听力损失的严重程度成对数线性增加，对于我们队列中60岁以上的人，超过三分之一的事件全因痴呆的风险与听力损失有关。 利用尸检标本，我们研究了神经元基因表达的活性依赖调节在促进神经元存活和可塑性中的作用，以及神经元网络活动在衰老和阿尔茨海默病(AD)中的扰动。我们发现，大脑皮层神经元对兴奋性的慢性抑制是通过下调参与抑制性传递的基因及其编码蛋白(GABA能和生长抑素)以及钙(2+)信号的表达来做出反应的；参与脂质代谢和能量管理的通路的改变也是沉默神经元网络的特征。在衰老和AD期间，人类大脑中会出现与网络活性降低非常相似的分子指纹，而在培养的皮质神经元和小鼠对丰富的环境或电惊厥的反应中，N-甲基-D-天冬氨酸(NMDA)和脑源性神经营养因子(BDNF)受体的激活会发生相反的变化。我们的发现表明，衰老和AD期间抑制性神经传递的减少可能是代偿反应的结果，矛盾的是，这种反应使神经元容易受到钙(2+)介导的变性的影响。

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.