Cognitive Decline Alzheimer’s

Cognitive Decline and Alzheimer’s Linked to Low Systemic REST Levels and Deficient Stress Protection of the Aging Brain

Cognitive Decline Alzheimer’s Linked – Low REST Levels

A study published in Translational Psychiatry indicates that low systemic (plasma) levels of the repressor element 1-silencing transcription (REST) factor represent a candidate biomarker of cognitive decline and Alzheimer’s disease (AD).

The study also suggests that low systemic REST levels may be associated with a poor brain stress protection during aging.

The repressor element 1-silencing transcription (REST) factor, alternatively named neuron-restrictive silencing factor (NRSF), is a protein that modulates neuronal differentiation and gene expression, and has recently been found to play an important role in Alzheimer’s disease neuropathology.

Recent research suggests that the REST factor is a major regulator of the aging brain’s stress response. It is reduced in conditions of stress and Alzheimer’s disease, which suggests that increasing REST may be neuroprotective.

Importantly, it appears that REST protects mature hippocampal neurons from toxic insults, for example, hyperexcitation, and to play a key role in regulating the aging brain’s response to stress. Furthermore, preclinical and clinical evidence demonstrate that reduced brain REST levels are associated with reductions in hippocampal volume and increased cognitive impairment.

It appears that during aging REST may act as a neuronal protective factor by suppressing genes that drive neurotoxic processes resulting in cognitive decline and neuronal death. REST is almost absent from the nucleus of cortical and hippocampal neurons in AD, frontotemporal dementia and dementia with Lewy bodies.

It is known that psychological distress and female sex are risk factors for Alzheimer’s degeneration. Stress also increases the risk of developing amnestic cognitive impairment and dementia. Of note, REST is dysregulated in depression, a ‘stress’-related disorder with increased risk for AD. Moreover, anxiety is a predictor for cognitive decline and dementia, while anxiety and vulnerability to stress contribute to the development of dementia.

In the Translational Psychiatry study, NJ Ashton and colleagues from the Institute of Psychiatry, Psychology and Neuroscience, King’s College London, UK report that the blood plasma REST levels are reduced in AD compared to healthy elderly controls (HECs).

The researchers found that patients with mild cognitive impairment (MCI) who later converted to AD had low plasma REST levels, whereas nonconverters or participants with stable MCI had a REST levels comparable to healthy control individuals.

Of note, and as discussed by the authors it remains unclear whether the peripheral blood REST measured in their study reflects levels in the central nervous system.

The authors also used mindfulness-based stress reduction (MBSR) intervention, demonstrating that REST levels can be modulated through this relatively brief intervention, and that changes in REST are associated with clinical improvements. Importantly, they report that in older adults at risk of developing dementia, a significant increase in REST levels was induced by a stress reduction intervention after 8 weeks.

The authors conclude that “determining REST in blood provides a prognostic marker that can help stratify patients for inclusion in trials, identify those at high risk of ‘stress-induced’ cognitive decline and determine the efficacy of therapeutic interventions”.

Source: Transl Psychiatry, 2017; 7(6):e1148. doi: 10.1038/tp.2017.113.
Read more: Translational Psychiatry

Image Credit: A model developed at MIT predicts the cognitive decline of patients at risk for Alzheimer’s disease by forecasting their cognition test scores up to two years in the future, which could help zero in on the right patients to select for clinical trials. Credits, Image: Christine Daniloff, MIT,

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