Deepen into sleep and wake patterns across Alzheimer's disease phenotypes

Falgàs, Neus; Walsh, Christine M.; Neylan, Thomas C.; Grinberg, Lea T.

doi:10.1002/alz.12304

Cited by 15 publications

(18 citation statements)

References 24 publications

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“…Impaired PV neuronal function is considered a key abnormality in AD brains (Verret et al , 2012; Cattaud et al , 2018), which is linked to reduced gamma oscillation and impaired cognitive performance (Verret et al , 2012; Palop & Mucke, 2016). Meanwhile, disturbed sleep and circadian rhythm and impaired cholinergic function are commonly observed in AD patients, which could be initiated decades before the diagnosis and are recognized as risk factors for AD (Falgas et al , 2021). Here by showing how synaptic and neuronal properties of PV neurons are diurnally regulated, we provide new direction to investigate how AD‐associated PV's dysregulation might be triggered.…”

Section: Discussionmentioning

confidence: 99%

Circadian time‐ and sleep‐dependent modulation of cortical parvalbumin‐positive inhibitory neurons

et al. 2022

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Parvalbumin‐positive neurons (PVs) are the main class of inhibitory neurons in the mammalian central nervous system. By examining diurnal changes in synaptic and neuronal activity of PVs in the supragranular layer of the mouse primary visual cortex (V1), we found that both PV input and output are modulated in a time‐ and sleep‐dependent manner throughout the 24‐h day. We first show that PV‐evoked inhibition is stronger by the end of the light cycle (ZT12) relative to the end of the dark cycle (ZT0), which is in line with the lower inhibitory input of PV neurons at ZT12 than at ZT0. Interestingly, PV inhibitory and excitatory synaptic transmission slowly oscillate in opposite directions during the light/dark cycle. Although excitatory synapses are predominantly regulated by experience, inhibitory synapses are regulated by sleep, via acetylcholine activating M1 receptors. Consistent with synaptic regulation of PVs, we further show in vivo that spontaneous PV activity displays daily rhythm mainly determined by visual experience, which negatively correlates with the activity cycle of surrounding pyramidal neurons and the dorsal lateral geniculate nucleus‐evoked responses in V1. These findings underscore the physiological significance of PV's daily modulation.

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Section: Discussionmentioning

confidence: 99%

Circadian time‐ and sleep‐dependent modulation of cortical parvalbumin‐positive inhibitory neurons

et al. 2022

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“…LBD (synucleinopathy), particularly in the amygdala, is the most common co-pathology in EOAD, occurring even more frequently than in LOAD. It is believed that LBD co- Given that the neuropsychiatric symptoms on AD have such a negative impact on patients' and families' quality of life, and that there is a need for effective treatments, a better understanding of the underlying mechanisms within the AD spectrum is an opportunity to develop tailored treatment strategies [43].…”

Section: Discussionmentioning

confidence: 99%

“…Altogether, this reinforces the existence of different sleep profiles within AD variants, probably due to different degenerative patterns within the arousal system; it is believed that this hypothesis warrants further research. The clinical-pathological correlates already established between sleep alterations and brainstem nuclei degeneration in AD (i.e., locus coeruleus), together with the availability of objective measurements for this neuropsychiatric symptom (i.e., polysomnography, actigraphy), make sleep alterations a perfect model to investigate mechanisms of subcortical selective vulnerability in AD [43]. Another possible explanation is that with EOAD psychosocial factors such as early retirement, loss of financial independence and familial responsibilities play a role in these symptoms [44][45][46].…”

Section: Discussionmentioning

confidence: 99%

“…It would also promote research to further understand their underpinning brain changes on the subcortical structures. Given that the neuropsychiatric symptoms on AD have such a negative impact on patients’ and families’ quality of life, and that there is a need for effective treatments, a better understanding of the underlying mechanisms within the AD spectrum is an opportunity to develop tailored treatment strategies [43].…”

Section: Discussionmentioning

confidence: 99%

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The severity of neuropsychiatric symptoms is higher in early‐onset than late‐onset Alzheimer’s disease

Falgàs¹,

Allen

Spina³

et al. 2021

Euro J of Neurology

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Background and purpose The faster rates of cognitive decline and predominance of atypical forms in early‐onset Alzheimer's disease (EOAD) suggest that neuropsychiatric symptoms could be different in EOAD compared to late‐onset AD (LOAD); however, prior studies based on non‐biomarker‐diagnosed cohorts show discordant results. Our goal was to determine the profile of neuropsychiatric symptoms in EOAD and LOAD, in a cohort with biomarker/postmortem‐confirmed diagnoses. Additionally, the contribution of co‐pathologies was explored. Methods In all, 219 participants (135 EOAD, 84 LOAD) meeting National Institute on Aging and Alzheimer's Association criteria for AD (115 amyloid positron emission tomography/cerebrospinal fluid biomarkers, 104 postmortem diagnosis) at the University of California San Francisco were evaluated. The Neuropsychiatric Inventory—Questionnaire (NPI‐Q) was assessed at baseline and during follow‐up. The NPI‐Q mean comparisons and regression models adjusted by cognitive (Mini‐Mental State Examination) and functional status (Clinical Dementia Rating Sum of Boxes) were performed to determine the effect of EOAD/LOAD and amnestic/non‐amnestic diagnosis on NPI‐Q. Regression models assessing the effect of co‐pathologies on NPI‐Q were performed. Results At baseline, the NPI‐Q scores were higher in EOAD compared to LOAD (p < 0.05). Longitudinally, regression models showed a significant effect of diagnosis, where EOAD had higher NPI‐Q total, anxiety, motor disturbances and night‐time behavior scores (p < 0.05). No differences between amnestics/non‐amnestics were found. Argyrophilic grain disease co‐pathology predicted a higher severity of NPI‐Q scores in LOAD. Conclusions Anxiety, night‐time behaviors and motor disturbances are more severe in EOAD than LOAD across the disease course. The differential patterns of neuropsychiatric symptoms observed between EOAD/LOAD could suggest a pattern of selective vulnerability extending to the brain's subcortical structures. Further, co‐pathologies such as argyrophilic grain disease in LOAD may also play a role in increasing neuropsychiatric symptoms.

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“…sedation, falls). The use of polysomnography provides the potential to target treatment for those patients with LC dysfunction that may be affecting the sleep–wake cycle 118 . New technologies have enabled higher quality home assessment of sleep physiology, and these are likely to lead to better diagnosis of sleep abnormalities 119 and targeted treatment approaches.…”

Section: Using Biomarkers To Guide Therapeutic Approachesmentioning

confidence: 99%

New approaches for the quantification and targeting of noradrenergic dysfunction in Alzheimer's disease

David

Malhotra

2022

Ann Clin Transl Neurol

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There is clear, early noradrenergic dysfunction in Alzheimer's disease. This is likely secondary to pathological tau deposition in the locus coeruleus, the pontine nucleus that produces and releases noradrenaline, prior to involvement of cortical brain regions. Disruption of noradrenergic pathways affects cognition, especially attention, impacting memory and broader functioning. Additionally, it leads to autonomic and neuropsychiatric symptoms. Despite the strong evidence of noradrenergic involvement in Alzheimer's, there are no clear trial data supporting the clinical use of any noradrenergic treatments. Several approaches have been tried, including proof‐of‐principle studies and (mostly small scale) randomised controlled trials. Treatments have included pharmacotherapies as well as stimulation. The lack of clear positive findings is likely secondary to limitations in gauging locus coeruleus integrity and dysfunction at an individual level. However, the recent development of several novel biomarkers holds potential and should allow quantification of dysfunction. This may then inform inclusion criteria and stratification for future trials. Imaging approaches have improved greatly following the development of neuromelanin‐sensitive sequences, enabling the use of structural MRI to estimate locus coeruleus integrity. Additionally, functional MRI scanning has the potential to quantify network dysfunction. As well as neuroimaging, EEG, fluid biomarkers and pupillometry techniques may prove useful in assessing noradrenergic tone. Here, we review the development of these biomarkers and how they might augment clinical studies, particularly randomised trials, through identification of patients most likely to benefit from treatment. We outline the biomarkers with most potential, and how they may transform symptomatic therapy for people living with Alzheimer's disease.

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Deepen into sleep and wake patterns across Alzheimer's disease phenotypes

Cited by 15 publications

References 24 publications

Circadian time‐ and sleep‐dependent modulation of cortical parvalbumin‐positive inhibitory neurons

Circadian time‐ and sleep‐dependent modulation of cortical parvalbumin‐positive inhibitory neurons

The severity of neuropsychiatric symptoms is higher in early‐onset than late‐onset Alzheimer’s disease

New approaches for the quantification and targeting of noradrenergic dysfunction in Alzheimer's disease

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