Sparse Asymmetry in Locus Coeruleus Pathology in Alzheimer's Disease.

peer reviewed Tau accumulation in and neurodegeneration of locus coeruleus (LC) neurons is observed in Alzheimer's disease (AD). We investigated whether tangle and neuronal density in the rostral and caudal LC is characterized by an asymmetric pattern in 77 autopsy cases of the Rush Memory and Aging Project. We found left-right equivalence for tangle density across individuals with and without AD pathology. However, neuronal density, particularly in the caudal-rostral axis of the LC, is asymmetric among individuals with AD pathology. Asymmetry in LC neuronal density may signal advanced disease progression and should be considered in AD neuroimaging studies of LC neurodegeneration

Heterogeneity in the links between sleep arousals, amyloid-beta and cognition

peer reviewedBACKGROUND. Tight relationships between sleep quality, cognition and amyloid-beta (Aβ) accumulation, a hallmark of Alzheimer’s disease (AD) neuropathology, emerge in the literature. Sleep arousals become more prevalent with ageing and are considered to reflect poorer sleep quality. Yet, heterogeneity in arousals has been suggested while their associations with Aβ and cognition are not established. METHODS. We recorded undisturbed night-time sleep with EEG in 101 healthy individuals in late midlife (50-70y), devoid of cognitive and sleep disorders. We classified spontaneous arousals according to their association with muscular tone increase (M+/M-) and sleep stage transition (T+/T-). We assessed cortical Aβ burden over earliest affected regions via PET imaging, and cognition via extensive neuropsychological testing. RESULTS. Arousal types differed in their oscillatory composition in theta and beta EEG bands. Furthermore, T+M- arousals, which interrupt sleep continuity, were positively linked to Aβ burden (p=.0053, R²β*=0.08). By contrast, more prevalent T-M+ arousals, upholding sleep continuity, were associated with lower Aβ burden (p=.0003, R²β*=0.13), and better cognition, particularly over the attentional domain (p<.05, R²β*≥0.04). CONCLUSION. Contrasting with what is commonly accepted, we provide empirical evidence that arousals are diverse and differently associated with early AD-related neuropathology and cognition. This suggests that sleep arousals, and their coalescence with other brain oscillations during sleep, may actively contribute to the beneficial functions of sleep. This warrants re-evaluation of age-related sleep changes and suggests that spontaneous arousals could constitute a marker of favourable brain and cognitive health trajectories

Positive Effect of Cognitive Reserve on Episodic Memory, Executive and Attentional Functions Taking Into Account Amyloid-Beta, Tau, and Apolipoprotein E Status

peer reviewedStudies exploring the simultaneous influence of several physiological and environmental factors on domain-specific cognition in late middle-age remain scarce. Therefore, our objective was to determine the respective contribution of modifiable risk/protective factors (cognitive reserve and allostatic load) on specific cognitive domains (episodic memory, executive functions, and attention), taking into account non-modifiable factors [sex, age, and genetic risk for Alzheimer’s disease (AD)] and AD-related biomarker amount (amyloid-beta and tau/neuroinflammation) in a healthy late-middle-aged population. One hundred and one healthy participants (59.4 ± 5 years; 68 women) were evaluated for episodic memory, executive and attentional functioning via neuropsychological test battery. Cognitive reserve was determined by the National Adult Reading Test. The allostatic load consisted of measures of lipid metabolism and sympathetic nervous system functioning. The amyloid-beta level was assessed using positron emission tomography in all participants, whereas tau/neuroinflammation positron emission tomography scans and apolipoprotein E genotype were available for 58 participants. Higher cognitive reserve was the main correlate of better cognitive performance across all domains. Moreover, age was negatively associated with attentional functioning, whereas sex was a significant predictor for episodic memory, with women having better performance than men. Finally, our results did not show clear significant associations between performance over any cognitive domain and apolipoprotein E genotype and AD biomarkers. This suggests that domain-specific cognition in late healthy midlife is mainly determined by a combination of modifiable (cognitive reserve) and non-modifiable factors (sex and age) rather than by AD biomarkers and genetic risk for AD.Cognitive Fitness in Aging stud

Cognitive efficiency in late midlife is linked to lifestyle characteristics and allostatic load

We investigated whether cognitive fitness in late midlife is associated with physiological and psychological factors linked to increased risk of age-related cognitive decline. Eighty-one healthy late middle-aged participants (mean age: 59.4 y; range: 50-69 y) were included. Cognitive fitness consisted of a composite score known to be sensitive to early subtle cognitive change. Lifestyle factors (referenced below as cognitive reserve factors; CRF) and affective state were determined through questionnaires, and sleep-wake quality was also assessed through actimetry. Allostatic load (AL) was determined through a large range of objective health measures. Generalized linear mixed models, controlling for sex and age, revealed that higher cognitive reserve and lower allostatic load are related to better cognitive efficiency. Crystallized intelligence, sympathetic nervous system functioning and lipid metabolism were the only sub-fields of CRF and AL to be significantly associated with cognition. These results show that previous lifestyle characteristics and current physiological status are simultaneously explaining variability in cognitive abilities in late midlife. Results further encourage early multimodal prevention programs acting on both of these modifiable factors to preserve cognition during the aging process

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

Steady-State Pupil Size Varies with Circadian Phase and Sleep Homeostasis in Healthy Young Men

peer reviewe

Importance of the locus coeruleus-norepinephrine system in sleep-wake regulation:Implications for aging and Alzheimer's disease

peer reviewedFive decades ago, seminal studies positioned the brainstem locus coeruleus (LC) norepinephrine (NE) system as a key substrate for the regulation of wakefulness and sleep, and this picture has recently been elaborated thanks to methodological advances in the precise investigation and experimental modulation of LC structure and functions. This review presents and discusses findings that support the major role of the LC-NE system at different levels of sleep-wake organization, ranging from its involvement in the overall architecture of the sleep-wake cycle to its associations with sleep microstructure, while accounting for the intricate neuroanatomy surrounding the LC. Given the particular position held by the LC-NE system by being at the intersection of sleep-wake dysregulation and initial pathophysiological processes of Alzheimer's disease (AD), we conclude by examining emerging opportunities to investigate LC-NE mediated relationships between sleep-wake alteration and AD in human aging. We further propose several research perspectives that could support the LC-NE system as a promising target for the identification of at-risk individuals in the preclinical stages of AD, and for the development of novel preventive interventions

Importance of the locus coeruleus-norepinephrine system in sleep-wake regulation: Implications for aging and Alzheimer's disease.

peer reviewedFive decades ago, seminal studies positioned the brainstem locus coeruleus (LC) norepinephrine (NE) system as a key substrate for the regulation of wakefulness and sleep, and this picture has recently been elaborated thanks to methodological advances in the precise investigation and experimental modulation of LC structure and functions. This review presents and discusses findings that support the major role of the LC-NE system at different levels of sleep-wake organization, ranging from its involvement in the overall architecture of the sleep-wake cycle to its associations with sleep microstructure, while accounting for the intricate neuroanatomy surrounding the LC. Given the particular position held by the LC-NE system by being at the intersection of sleep-wake dysregulation and initial pathophysiological processes of Alzheimer's disease (AD), we conclude by examining emerging opportunities to investigate LC-NE mediated relationships between sleep-wake alteration and AD in human aging. We further propose several research perspectives that could support the LC-NE system as a promising target for the identification of at-risk individuals in the preclinical stages of AD, and for the development of novel preventive interventions

Increased cortical excitability and reduced brain response propagation during attentional lapses

Modern lifestyle curtails sleep and increases nighttime work and leisure activities. This has a deleterious impact on vigilance and attention, exacerbating chances of committing attentional lapses, with potential dramatic outcomes. A full characterization of the brain mechanisms associated with lapses is still lacking. Here, we investigated the brain signature of attentional lapses and assessed whether cortical excitability and brain response propagation were modified during lapses and whether these modifications changed with aging. We compared electroencephalogram (EEG) responses to transcranial magnetic stimulation (TMS) during lapse and no-lapse periods while performing a continuous attentional/vigilance task at night, after usual bedtime. Data were collected in healthy younger (N=12; 18-30 y) and older individuals (N=12; 50- 70 y) of both sexes. Amplitude and slope of the first component of the TMS-Evoked Potential (TEP) and Response Scattering (ReSc) were used to assess cortical excitability and brain response propagation, respectively. In line with our predictions, TEP during lapses was characterized by larger amplitude and slope. We further found that ReSc over the cortical surface was lower during lapses. Importantly, cortical excitability increase and response propagation decrease during lapse did not significantly differ between age groups. These results demonstrate that attentional lapses are associated with transient increase of excitability, and decrease in response propagation and effective connectivity. This pattern is similar to what is observed during sleep, suggesting that lapses reflect a sleep-like phenomenon. These findings could contribute to develop models aimed to predicting and preventing lapses in real life situations

Increased cortical excitability but stable effective connectivity index during attentional lapses.

Modern lifestyle curtails sleep and increases night-time work and leisure activities. This has a deleterious impact on vigilance and attention, exacerbating chances of committing attentional lapses, with potential dramatic outcomes. Here, we investigated the brain signature of attentional lapses and assessed whether cortical excitability and brain response propagation were modified during lapses and whether these modifications changed with aging. We compared electroencephalogram (EEG) responses to transcranial magnetic stimulation (TMS) during lapse and no-lapse periods while performing a continuous attentional/vigilance task at night, after usual bedtime. Data were collected in healthy younger (N=12; 18-30 y) and older individuals (N=12; 50-70 y) of both sexes. The amplitude and slope of the first component of the TMS-Evoked Potential (TEP) were larger during lapses. In contrast, TMS response scattering over the cortical surface, as well as EEG response complexity, did not significantly vary between lapse and no-lapse periods. Importantly, despite qualitative differences, age did not significantly affect any of the TMS-EEG measures. These results demonstrate that attentional lapses are associated with a transient increase of cortical excitability. This initial change is not associated with detectable changes in subsequent effective connectivity - as indexed by response propagation - and are not markedly different between younger and older adults. These findings could contribute to develop models aimed to predicting and preventing lapses in real life situations