Neuroimaging and Functional Senscence in Aging

恒河猴是研究正常衰老的一个很好的模型，因为它的大脑组织和认知能力与人类非常相似，而且猴子不会患上阿尔茨海默氏症。此外，猴子可以在受控条件下进行研究，行为评估可以在死亡前进行，大脑可以在没有死后延迟的情况下得到最佳保存。这类研究表明，与年龄相关的认知能力下降，神经元和突触得到保留，但在标准MRI扫描中，脑白质丢失和损伤以及脑白质体积丢失。但是，目前尚不清楚髓鞘的丢失或损伤是弥漫性的还是局限于特定的途径。由于髓鞘的破坏与认知能力下降有关，可能是皮质纤维束的破坏导致了与年龄相关的认知障碍。一种新的神经成像方法-扩散张量成像(DT-MRI)已被用于活体识别和测量人脑中的长白束，但由于死后延迟和浸泡固定，在人类中解释DT-MRI的一个主要限制是很难通过白质束的死后检查进行验证。这项拟议的先导性研究将适用于猴子的大脑，这种新的DT-MRI方法可以识别和量化幼猴和老年猴子的白质束。这些猴子可以从美国国立卫生研究院资助的项目拨款中获得，该项目收集认知表现的行为测量，传导速度的神经生理学测量，然后准备整个半球的连续大脑切片。这些数据和备用系列切片将用于与特定纤维束的CT-MRI数据进行比较。为了确定它们的“功能”意义，将识别、量化和测定与年龄相关的体积变化，然后将其与DT-MRI观察到的行为和神经生理学数据相关联。此外，将使用备用的组织切片系列来验证DT-MRI观察到的实际白质，并提供必要的试点数据，为猴子和人类的正常衰老的额外DT-MRI研究寻求资金。

The rhesus monkey is an excellent model for studies of normal aging since brain organization and cognitive capacity are quite similar to humans and the monkey does not get Alzheimer's disease. Additionally monkeys can be studied under controlled conditions, behavioral assessment can be done prior to death and the brain can be optimally preserved without post-mortem delay. Such studies demonstrate age- related cognitive decline with preservation of neurons and synapses but loss and damage to white matter and volumetric loss of white matter in standard MRI scans. But, it is not clear whether loss or damage to myelin is diffuse or localized to specific pathways. Since breakdown in myelin correlates with cognitive decline, it is probably that disruption of corticocortical fiber tracts my contribute to age-related cognitive impairments. A new neuroimaging method, Diffusion Tensor MRI (DT- MRI) has been used for in vivo identification and measurement of long white tracts in the human brain but a major limitation on interpretation of the DT-MRI in humans is the difficulty of validation by post-mortem examination of white matter tracts because of post-mortem delay and immersion fixation. This proposed pilot investigation will adapt to the monkey brain this new DT-MRI method to identify and quantify white matter tracts in young and old monkeys. These monkeys are available to us from an NIH funded Program Project grant which collects behavioral measures of cognitive performance, neurophysiological measures of conduction velocity and then prepares whole hemisphere serial brain sections. These data and spare series of sections will be available for comparisons with the CT-MRI data on specific fiber tracts. To determine their "functional" significance the long corticocortical association pathways will be identified, quantified and age-related changes in volume determined and then correlated with the behavioral and neurophysiological data of the DT-MRI observations. In addition spare series of histological sections will be used to validate the DT-MRI observations with actual white matter and provide the pilot data necessary to seek funding for additional DT-MRI studies of normal aging in both monkeys and humans.