课题基金 / 基金详情

Parsing the pathways of circadian dysfunction and sundowning-related behavioral aggression in dementia and Alzheimer's disease

Parsing the pathways of circadian dysfunction and sundowning-related behavioral aggression in dementia and Alzheimer's disease
解析痴呆症和阿尔茨海默病中昼夜节律功能障碍和日落相关行为攻击的途径
批准号:
10076507
负责人:
William David Todd
金额:
$14.45万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-04-01 至 2022-01-31

项目摘要

项目成果

William David Todd的其他基金

相似基金

相关文献

中文摘要
翻译
项目总结/文摘
英文摘要
Project Summary/Abstract Alzheimer's disease and related dementias are associated with progressive disruption of circadian rhythms. One particular feature of such circadian dysfunction in patients with AD and related dementias is “sundowning syndrome”, a poorly understood clinical phenomenon characterized by agitation, aggression, and delirium during the early evening hours. Such symptoms have a major impact on the quality of life for both the patient and their caregivers and often lead to the decision to seek institutionalization. The neurobiology of sundowning remains unknown, however the temporal periodicity of sundowning symptoms suggests a possible disturbance in the master circadian clock, the suprachiasmatic nucleus (SCN) of the hypothalamus, or in the pathways by which the SCN modulates particular rhythms. Rhythms of sleep-wake and LMA are known to be regulated by the SCN via a pathway through its major postsynaptic target, the subparaventricular zone (SPZ), to the dorsomedial hypothalamus (DMH). Additionally, I recently demonstrated that the propensity for behavioral aggression also follows a daily rhythm that is regulated by the SCN, via an additional pathway through the SPZ, to the ventromedial hypothalamus (VMH). Importantly, disrupting this SCNSPZVMH pathway led to increased aggression during the early resting phase (the light period for nocturnal mice), which is temporally analogous to when AD and dementia patients who experience sundowning display increased agitation and aggression. This suggests that the function of certain structures within this circuit may be compromised in AD and dementia, and that this pathway may be a promising therapeutic target for treating circadian dysfunction and aggression in patients who display sundowning. To test this novel hypothesis, I began examining circadian rhythms in the TAPP mouse model, which develops amyloid-beta (a-beta) plaques and tau neurofibrillary tangles (both hallmarks of AD neuropathology), and my preliminary results suggest that these mice exhibit increased early resting period aggression and blunted active period LMA at ages shortly after they first develop AD-related neuropathology. In this proposal, I will examine tissue from these mice for AD-related neuropathological markers in the SCN, the SPZ and its output targets the VMH and the DMH. It has been hypothesized that circadian dysfunction associated with sundowning results instead from AD-related disturbances to areas that provide input to the circadian system, such as serotoninergic and cholinergic pathways, and I will also examine neuropathology in such areas. Additionally, I will also examine activated astrocytes in all of these circadian pathways, as such glial responses have been show to be associated with neuroinflammation and neurodegeneration in AD, and normal astrocyte functioning is known to be critical to the circadian system's ability to maintain proper time-keeping. Finally, I seek to determine the effects of manipulating SPZ activity (using chemogenetic activation) on the increased daytime aggression and blunted circadian sleep-wake rhythms in TAPP mice, and on the patterns of neuropathology and astrocyte responses.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
The circuit basis of sundowning-related circadian dysfunction in Alzheimer's disease and Alzheimer's disease-related dementias
  • 批准号:
    10807621
  • 项目类别:
  • 资助金额:
    $35.18万
  • 财政年份:
    2023
  • 负责人:
    William David Todd
  • 依托单位:
Circadian behavior circuits, Alzheimer’s pathology, chemogenetic output and input
  • 批准号:
    10216281
  • 项目类别:
  • 资助金额:
    $19.74万
  • 财政年份:
    2017
  • 负责人:
    William David Todd
  • 依托单位:
Subparaventricular zone pathways to circadian synchrony
Circadian behavior circuits, Alzheimer’s pathology, chemogenetic output and input
  • 批准号:
    10214051
  • 项目类别:
  • 资助金额:
    $20.18万
  • 财政年份:
    --
  • 负责人:
    William David Todd
  • 依托单位:
国内基金
海外基金
补阳还五汤通过AGE-RAGE通路调控脓毒症免疫失衡的机制与转化研究
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
  • 批准号:
    JCZRQN202500010
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2025
  • 负责人:
  • 依托单位:
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
  • 批准号:
    2025JJ70209
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2025
  • 负责人:
    雷芬芳
  • 依托单位:
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
  • 批准号:
    --
  • 项目类别:
    面上项目
  • 资助金额:
    --
  • 批准年份:
    2024
  • 负责人:
    万荣
  • 依托单位: