Linking Sleep Dysfunction to Tau-related Degeneration across AD Progression

将睡眠功能障碍与 AD 进展过程中 Tau 蛋白相关的退化联系起来

基本信息

项目摘要

PROJECT SUMMARY / ABSTRACT Wake, sleep and circadian disturbances are common occurrences in Alzheimer' disease (AD), often times preceding amnestic symptoms. Such disturbances affect the quality of life of patients and caregivers alike and boost institutionalization. A bidirectional correlation between amyloid-beta (Aβ) deposition and disturbed sleep contributes to slow wave sleep (SWS) deficits and sleep fragmentation. We discovered converging evidence in human sleep and neuropathological studies suggesting that individuals with progressive supranuclear palsy (PSP), a primary tauopathy, show an extreme sleep phenotype featuring a much shorter sleep duration. This point for a role of tau-related degeneration as an underlying cause of sleep disfunction, independent of Aβ deposition. Interestingly, brainstem, hypothalamic and basal forebrain nuclei involved in circandian-sleep-wake regulation develop AD- tau-based neurofibrillary tangles preceding tangles in cortical areas and often, before Aβ plaques appear. Our working hypothesis is that tau-induced degeneration of key brainstem, hypothalamic and basal forebrain nuclei controlling 1) SWS; 2) waking-arousal; and 3) circadian timing underlie sleep-wake behavior in AD, preceding both cognitive decline and later emergence of the feedforward cycle of sleep disturbance and accelerated Aβ deposition. We will test our hypothesis contrasting sleep-wake behavior in progressive AD stages versus healthy controls by analyzing differences in objective sleep measurements, clinical and molecular imaging profiles and quantitative pathoanatomical measures in nuclei involved in wake, NREM sleep regulation and circadian rhythm. Moreover, we will add a PSP as a positive control group. We are uniquely poised to succeed due to our group expertise, track record of working together and our access to uniquely well characterized clinicopathological cohort. This combination of factors creates a unique opportunity to exploit novel human findings that will inform and complement mechanistic hypotheses and testing in model systems. This is critical because animals' sleep-wake patterns and AD-like models diverge from those of humans and experimental models rather mimic non-AD tauopathies than tau-related AD patterns. We anticipate our findings will inform critical information on the temporal sequence of disrupted sleep and/or circadian rhythms and the accumulation and spreading of protein aggregates such as phospho-tau and Aβ in AD. Beyond this, results from this study will inform rational therapies for treating disturbed sleep in AD.
项目摘要/摘要

项目成果

期刊论文数量(0)
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Lea Tenenholz Grinberg其他文献

Hypertension may associate with cerebral small vessel disease and infarcts through the pathway of intracranial atherosclerosis
  • DOI:
    10.1016/j.neurobiolaging.2024.11.001
  • 发表时间:
    2025-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Marcelo Kenzo Naya Takahashi;Regina Silva Paradela;Lea Tenenholz Grinberg;Renata Elaine Paraizo Leite;Daniela Souza Farias-Itao;Vitor Ribeiro Paes;Maria Eduarda Braga;Michel Satya Naslavsky;Mayana Zatz;Wilson Jacob-Filho;Ricardo Nitrini;Carlos Augusto Pasqualucci;Claudia Kimie Suemoto
  • 通讯作者:
    Claudia Kimie Suemoto
Cause of Death Determined by Full-body Autopsy in Neuropathologically Diagnosed Dementias
通过全身尸检确定神经病理学诊断的痴呆症的死因
  • DOI:
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    2.1
  • 作者:
    Beatriz Astolfi Neves;Paula Villela Nunes;Roberta Diehl Rodriguez;Atmis Medeiros Haidar;Renata Elaine Paraizo Leite;C. Nascimento;Carlos Augusto Pasqualucci;R. Nitrini;W. Jacob;B. Lafer;Lea Tenenholz Grinberg;Claudia Kimie Suemoto
  • 通讯作者:
    Claudia Kimie Suemoto

Lea Tenenholz Grinberg的其他文献

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{{ truncateString('Lea Tenenholz Grinberg', 18)}}的其他基金

Imaging brain iron and protein aggregation with MRI for assessing Alzheimer's disease pathology and progression
使用 MRI 对脑铁和蛋白质聚集进行成像,以评估阿尔茨海默病的病理学和进展
  • 批准号:
    10563181
  • 财政年份:
    2021
  • 资助金额:
    $ 78.27万
  • 项目类别:
Imaging brain iron and protein aggregation with MRI for assessing Alzheimer's disease pathology and progression
使用 MRI 对脑铁和蛋白质聚集进行成像,以评估阿尔茨海默病的病理学和进展
  • 批准号:
    10331335
  • 财政年份:
    2021
  • 资助金额:
    $ 78.27万
  • 项目类别:
Core C: Human Tissue Validation
核心 C:人体组织验证
  • 批准号:
    10295515
  • 财政年份:
    2021
  • 资助金额:
    $ 78.27万
  • 项目类别:
Better memory with literacy acquisition later in life: a randomized controlled trial
晚年读写能力提高记忆力:一项随机对照试验
  • 批准号:
    10054007
  • 财政年份:
    2020
  • 资助金额:
    $ 78.27万
  • 项目类别:
Better memory with literacy acquisition later in life: a randomized controlled trial
晚年读写能力提高记忆力:一项随机对照试验
  • 批准号:
    10263225
  • 财政年份:
    2020
  • 资助金额:
    $ 78.27万
  • 项目类别:
Clinical Features and Neuropathological Basis of Sleep Wake Behavior in Alzheimer's and PSP
阿尔茨海默病和 PSP 睡眠觉醒行为的临床特征和神经病理学基础
  • 批准号:
    10112791
  • 财政年份:
    2019
  • 资助金额:
    $ 78.27万
  • 项目类别:
Linking Sleep Dysfunction to Tau-related Degeneration across AD Progression
将睡眠功能障碍与 AD 进展过程中 Tau 蛋白相关的退化联系起来
  • 批准号:
    10636812
  • 财政年份:
    2019
  • 资助金额:
    $ 78.27万
  • 项目类别:
Linking Sleep Dysfunction to Tau-related Degeneration across AD Progression
将睡眠功能障碍与 AD 进展过程中 Tau 蛋白相关的退化联系起来
  • 批准号:
    10328419
  • 财政年份:
    2019
  • 资助金额:
    $ 78.27万
  • 项目类别:
Linking Sleep Dysfunction to Tau-related Degeneration across AD Progression
将睡眠功能障碍与 AD 进展过程中 Tau 蛋白相关的退化联系起来
  • 批准号:
    9803439
  • 财政年份:
    2019
  • 资助金额:
    $ 78.27万
  • 项目类别:
Clinical Features and Neuropathological Basis of Sleep Wake Behavior in Alzheimer's and PSP
阿尔茨海默病和 PSP 睡眠觉醒行为的临床特征和神经病理学基础
  • 批准号:
    10589765
  • 财政年份:
    2019
  • 资助金额:
    $ 78.27万
  • 项目类别:

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