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

Abstract

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.

Figure 1

The sleep-dependent episodic word-pair task^, utilized word-nonsense word pairs to 1) maximize the novel episodic and associated hippocampal-dependent demands of the task, and 2) minimize the semantic, and thus hippocampal-independent, demands of the task^,,. Words were 3–8 letters in length and drawn from a normative set of English words. Nonsense words were 6–14 letters in length, derived from groups of common phonemes. The word pair task began with an encoding phase composed of 120 word-nonsense word trials. (a) During each encoding trial, a word-nonsense word pair was shown for 5 s. Criterion training occurred immediately after encoding. (b) During each self-paced criterion trial, a previously studied probe word was presented with its original nonsense word associate from encoding (outlined in the grey box) and two new nonsense words not previously shown. Upon responding, the participant was given feedback for 1 s, with incorrect responses resulting in trial repetition at random intervals. (c) During recognition trials, either a previously studied probe word or a new (foil) probe word was shown for 5 s with four response options presented below. When a previously studied probe word was presented, the following response options were presented below: (1) the nonsense word originally paired with that probe word at encoding (‘Hit’), (2) a previously studied nonsense word, but one presented with a different previously studied probe word (‘Lure’), (3) a new nonsense word never seen during encoding, and (4) an option designating the shown probe word as “new”. New nonsense words were only presented once during the entire experiment, while previously studied nonsense words were presented twice during recognition testing, always in the same session, as a lure on one trial and the correct paired associate on another. When a foil probe word was presented, the four responses options consisted of three new nonsense words never presented during learning (which if chosen, would designate a ‘False alarm’), and an option designating this foil probe word as “new” (which if chosen, would designate a ‘Correct rejection’). Forty-five null events, consisting of a fixation display (1.5 s – 10 s), were interspersed throughout long delay recognition testing during fMRI acquisition, jittering trial onsets.

Figure 2

EEG topographic plots of relative (a) slow wave activity (SWA: 0.8Hz–4.6Hz) during slow wave sleep in Young and Older adults, and the relative (b) SWA difference between Young and Older adults both averaged across all electrode sites for a metric of global SWA (left) and averaged across prefrontal electrode sites (right), outlined in the box in (a: Fp1 and Fp2) exhibiting peak relative SWA in both groups. (c) EEG topographic plots of absolute slow wave activity (SWA: 0.8Hz–4.6Hz) during slow wave sleep in all adults collapsed and Young (top plot) and Older (bottom plot) adults separately, and (d) the SWA difference between Young and Older adults both averaged across all electrode sites for a metric of global SWA (left) and averaged across prefrontal electrode sites (right), outlined in the box in (a: Fp1 and Fp2) exhibiting prefrontal derivations where absolute SWA was averaged and then compared between groups. Error bars indicate s.e.m. *denotes significance at P<0.001. %PTOT denotes percentage of total spectral power (0.4–50Hz)

Figure 3

(a) Age effects (Older<Young adults) in grey matter volume, with mean medial prefrontal grey matter volume in young (red) and older (blue) adults plotted to the right. Regression between mean prefrontal grey matter volume and global slow wave activity (SWA) (b), defined as the average relative SWA across all electrode sites, and (c) associative episodic memory change. Activations are displayed and considered significant at the voxel level of P<0.05 family-wise error (FWE) corrected for multiple comparisons across the whole brain volume. Cool colors represent the extent of reduced grey matter volume in Older relative to Young adults. Error bars indicate s.e.m. *denotes significance at P<0.05 FWE whole brain corrected. au denotes arbitrary units. %PTOT denotes percentage of total spectral power (0.4–50Hz)

Figure 4

(a) Recognition performance (HR–LR–FAR: [hit rate to originally studied word pairs – false alarm rate to originally studied word pairs – false alarm rate to new, unstudied words]) in Young (red) and Older (blue) adults both at pre (short delay) and post-sleep (long delay) testing, and (b) the change in recognition performance (long delay – short delay), reflecting a measure of associative episodic memory change. Age differences in recognition performance were driven by changes in hit rate (P<0.001) and not Lure rate (P=0.16) or False alarm rate (P=0.17), suggesting that age differences in recognition performance were driven by changes in memory and not response bias. Error bars indicate s.e.m. *denotes significance at P<0.05, **P<0.01, ***P<0.001.

Figure 5

Topographic plots of the association between relative slow wave activity (SWA: 0.8Hz–4.6Hz) during slow wave sleep and associative episodic memory change in (a) all participants collapsed and (b) in Young (top plots) and Older (bottom plots) adults, with corresponding regressions for Young (red) and Older (blue) adults plotted for global relative SWA (c), defined as the average relative SWA across all electrode sites, and prefrontal SWA (d), defined as the average at prefrontal electrodes outlined in the box in (a & b: Fp1 and Fp2) exhibiting peak relative SWA in both groups. Associations were specific to SWA, as measures of subjective sleepiness and alertness, objective alertness, circadian preference, neurocognitive status, fast spindle density during stage 2 sleep (Fig. S1), total sleep time, wake after sleep onset time, and sleep efficiency did not correlate with episodic memory change in either young or older adults separately (Table S3). Similar to relative slow wave activity, both global absolute SWA (r=0.57, P=0.001) and prefrontal absolute SWA (Fp1 & Fp2 mean; r=0.60, P<0.001) predicted episodic memory change across all participants. While not significant in all cases, a similar association was detected within each group separately for both global (young adults: r=0.49 P=0.045, older adults: r=0.36 P=0.21) and prefrontal (young adults: r=0.56 P=0.019, older adults: r=0.24 P=0.41) absolute SWA. *denotes significance at P<0.05 corrected. %PTOT denotes percentage of total spectral power (0.4–50Hz)

Figure 6

Model schematic of mediation findings. Aging is associated with grey matter atrophy, which mediates the degree of slow wave activity disruption, with slow wave activity, in turn, mediating the degree of impaired memory retention.

Figure 7

(a) Age effects (Older>Young adults) in left hippocampal activation greater during successful associative episodic retrieval than correct rejection of novel words (Hits-Correct Rejections; 6mm-sphere ROI: [x=−33, y=−32, z=−7]). No age differences in activation were detected outside the Hippocampus when employing FWE correction across the whole brain. Regressions between global slow wave activity (SWA) (b), defined as the average relative SWA across all electrode sites, and prefrontal SWA (c), defined as the average at prefrontal electrodes exhibiting peak relative SWA in both groups and left hippocampal activation (Hits-Correct Rejections; 6mm-sphere ROI: [x=−33, y=−32, z=−7]). Regression between associative episodic memory change (d) and left hippocampal activation (Hits-Correct Rejections) at peak of both SWA correlations. Activations are displayed and considered significant at the voxel level of P<0.05 family-wise error (FWE) corrected for multiple comparisons within the a priori hippocampal regions of interest. Hot colors represent the extent of increased activation in Older relative to Young adults, and cold colors represent the extent of the negative correlation between hippocampal activation and SWA. While the 6mm-sphere ROIs used to correct for multiple comparisons did extend outside the hippocampus, no effects were detected or presented outside the hippocampus in the current report. Error bars indicate s.e.m. *denotes significance at P<0.05 FWE corrected. au denotes arbitrary units. %PTOT denotes percentage of total spectral power (0.4–50Hz)