Divergent Associations of Slow-Wave Sleep versus Rapid Eye Movement Sleep with Plasma Amyloid-Beta.

OBJECTIVE: Recent evidence shows that during slow-wave sleep (SWS), the brain is cleared from potentially toxic metabolites, such as the amyloid-beta protein. Poor sleep or elevated cortisol levels can worsen amyloid-beta clearance, potentially leading to the formation of amyloid plaques, a neuropathological hallmark of Alzheimer disease. Here, we explored how nocturnal neural and endocrine activity affects amyloid-beta fluctuations in the peripheral blood. METHODS: We acquired simultaneous polysomnography and all-night blood sampling in 60 healthy volunteers aged 20-68 years. Nocturnal plasma concentrations of amyloid-beta-40, amyloid-beta-42, cortisol, and growth hormone were assessed every 20 minutes. Amyloid-beta fluctuations were modeled with sleep stages, (non)oscillatory power, and hormones as predictors while controlling for age and participant-specific random effects. RESULTS: Amyloid-beta-40 and amyloid-beta-42 levels correlated positively with growth hormone concentrations, SWS proportion, and slow-wave (0.3-4Hz) oscillatory and high-band (30-48Hz) nonoscillatory power, but negatively with cortisol concentrations and rapid eye movement sleep (REM) proportion measured 40-100 minutes previously (all t values > |3|, p values < 0.003). Older participants showed higher amyloid-beta-40 levels. INTERPRETATION: Slow-wave oscillations are associated with higher plasma amyloid-beta levels, whereas REM sleep is related to decreased amyloid-beta plasma levels, possibly representing changes in central amyloid-beta production or clearance. Strong associations between cortisol, growth hormone, and amyloid-beta presumably reflect the sleep-regulating role of the corresponding releasing hormones. A positive association between age and amyloid-beta-40 may indicate that peripheral clearance becomes less efficient with age. ANN NEUROL 2024;96:46-60.

Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART.

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

Cerebrospinal fluid and positron-emission tomography biomarkers for noradrenergic dysfunction in neurodegenerative diseases: a systematic review and meta-analysis.

The noradrenergic system shows pathological modifications in aging and neurodegenerative diseases and undergoes substantial neuronal loss in Alzheimer's disease and Parkinson's disease. While a coherent picture of structural decline in post-mortem and in vivo MRI measures seems to emerge, whether this translates into a consistent decline in available noradrenaline levels is unclear. We conducted a meta-analysis of noradrenergic differences in Alzheimer's disease dementia and Parkinson's disease using CSF and PET biomarkers. CSF noradrenaline and 3-methoxy-4-hydroxyphenylglycol levels as well as noradrenaline transporters availability, measured with PET, were summarized from 26 articles using a random-effects model meta-analysis. Compared to controls, individuals with Parkinson's disease showed significantly decreased levels of CSF noradrenaline and 3-methoxy-4-hydroxyphenylglycol, as well as noradrenaline transporters availability in the hypothalamus. In Alzheimer's disease dementia, 3-methoxy-4-hydroxyphenylglycol but not noradrenaline levels were increased compared to controls. Both CSF and PET biomarkers of noradrenergic dysfunction reveal significant alterations in Parkinson's disease and Alzheimer's disease dementia. However, further studies are required to understand how these biomarkers are associated to the clinical symptoms and pathology.

Women smelling men's masked body odors show enhanced harm aversion in moral dilemmas.

Among the most unnoticeable stimuli providing social information, body odors are powerful social tools that can modulate behavioral and neural processing. It has recently been shown that body odors can affect moral decision-making, by increasing the activations in neural areas processing social and emotional information during the decision process. The aim of the present study was twofold: 1) to test whether body odors selectively affect decisions to real dilemmatic moral scenario (incongruent) vs. fake (congruent) dilemmas, and 2) to characterize whether the impact of masked body odors is modulated by four conceptual factors: personal force, intentionality, benefit recipient and evitability. Women chose between utilitarian (sacrificing a person's life in order to save other lives) or deontological actions (deciding against the harmful action) in 64 moral dilemmas under the exposure of a neutral fragrance (masker) or a masked male body odor. Our results showed that the masked male body odor did not specifically affect the answers to real and fake dilemmas but instead, its effect is modulating whether the agent harms the victim in a direct or indirect manner (personal force) to save herself or only other people (benefit recipient). In particular, when exposed to the masked body odor participants gave more deontological answers when the harm was indirect and only other people were saved. These data support the hypothesis that body odors induce participants to perceive the individuals described in moral dilemmas as more real, triggering harm avoidance.

Body odors (even when masked) make you more emotional: behavioral and neural insights.

Morality evolved within specific social contexts that are argued to shape moral choices. In turn, moral choices are hypothesized to be affected by body odors as they powerfully convey socially-relevant information. We thus investigated the neural underpinnings of the possible body odors effect on the participants' decisions. In an fMRI study we presented to healthy individuals 64 moral dilemmas divided in incongruent (real) and congruent (fake) moral dilemmas, using different types of harm (intentional: instrumental dilemmas, or inadvertent: accidental dilemmas). Participants were required to choose deontological or utilitarian actions under the exposure to a neutral fragrance (masker) or body odors concealed by the same masker (masked body odor). Smelling the masked body odor while processing incongruent (not congruent) dilemmas activates the supramarginal gyrus, consistent with an increase in prosocial attitude. When processing accidental (not instrumental) dilemmas, smelling the masked body odor activates the angular gyrus, an area associated with the processing of people's presence, supporting the hypothesis that body odors enhance the saliency of the social context in moral scenarios. These results suggest that masked body odors can influence moral choices by increasing the emotional experience during the decision process, and further explain how sensory unconscious biases affect human behavior.