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Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging


Aging has independently been associated with regional brain atrophy, reduced slow wave activity (SWA) during non–rapid eye movement (NREM) sleep and impaired long-term retention of episodic memories. However, whether the interaction of these factors represents a neuropatholgical pathway associated with cognitive decline in later life remains unknown. We found that age-related medial prefrontal cortex (mPFC) gray-matter atrophy was associated with reduced NREM SWA in older adults, the extent to which statistically mediated the impairment of overnight sleep–dependent memory retention. Moreover, this memory impairment was further associated with persistent hippocampal activation and reduced task-related hippocampal-prefrontal cortex functional connectivity, potentially representing impoverished hippocampal-neocortical memory transformation. Together, these data support a model in which age-related mPFC atrophy diminishes SWA, the functional consequence of which is impaired long-term memory. Such findings suggest that sleep disruption in the elderly, mediated by structural brain changes, represents a contributing factor to age-related cognitive decline in later life.

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Figure 1: The sleep-dependent episodic word-pair task6,9 used word-nonsense word pairs to maximize the novel episodic and associated hippocampal-dependent demands of the task33 and minimize the semantic, and therefore hippocampal-independent, demands of the task11,12,33.
Figure 2: Age differences in SWA.
Figure 3: Age differences in gray matter volume and associations with SWA and memory.
Figure 4: Age differences in memory retention.
Figure 5: SWA predicts overnight memory change in young and older adults.
Figure 6: Model schematic of mediation findings.
Figure 7: Differences in hippocampal activation and hippocampal-prefrontal task-related functional connectivity are associated with SWA and memory change.


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We thank M. Belshe, M. Bhatter, M. Binod, S. Bowditch, C. Dang, A. Hayenga, A. Horn, E. Hur, C. Markeley, E. Mormino, M. Nicholas, L. Zhang and A. Zhu for their assistance, A. Mander for his aid in task design, and M. Rubens and A. Gazzaley for use of their aging template brain. This work was supported by awards R01-AG031164 (M.P.W.), R01-AG034570 (W.J.), R01-AG08415 (S.A.-I.) and F32-AG039170 (B.A.M.) from the US National Institutes of Health.

Author information




B.A.M. designed the study, conducted the experiments, analyzed the data and wrote the manuscript. V.R. aided in data analysis and manuscript preparation. B.L. aided in study screening procedures and manuscript preparation. J.M.S. provided data analytic tools, aided in data analysis and manuscript preparation. J.R.L. aided in conducting the experiment and manuscript preparation. S.A.-I. aided in study design and manuscript preparation. W.J. provided the elderly subject pool and data analytic tools, and aided in study design and manuscript preparation. M.P.W. designed the study, aided data analysis and wrote the manuscript.

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Correspondence to Bryce A Mander or Matthew P Walker.

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The authors declare no competing financial interests.

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Mander, B., Rao, V., Lu, B. et al. Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging. Nat Neurosci 16, 357–364 (2013).

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