Disturbances In Alzheimer's Disease Research Articles

Predicting Alzheimer's disease CSF core biomarkers: a multimodal Machine Learning approach.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Current core cerebrospinal fluid (CSF) AD biomarkers, widely employed for diagnosis, require a lumbar puncture to be performed, making them impractical as screening tools. Considering the role of sleep disturbances in AD, recent research suggests quantitative sleep electroencephalography features as potential non-invasive biomarkers of AD pathology. However, quantitative analysis of comprehensive polysomnography (PSG) signals remains relatively understudied. PSG is a non-invasive test enabling qualitative and quantitative analysis of a wide range of parameters, offering additional insights alongside other biomarkers. Machine Learning (ML) gained interest for its ability to discern intricate patterns within complex datasets, offering promise in AD neuropathology detection. Therefore, this study aims to evaluate the effectiveness of a multimodal ML approach in predicting core AD CSF biomarkers. Mild-moderate AD patients were prospectively recruited for PSG, followed by testing of CSF and blood samples for biomarkers. PSG signals underwent preprocessing to extract non-linear, time domain and frequency domain statistics quantitative features. Multiple ML algorithms were trained using four subsets of input features: clinical variables (CLINVAR), conventional PSG parameters (SLEEPVAR), quantitative PSG signal features (PSGVAR) and a combination of all subsets (ALL). Cross-validation techniques were employed to evaluate model performance and ensure generalizability. Regression models were developed to determine the most effective variable combinations for explaining variance in the biomarkers. On 49 subjects, Gradient Boosting Regressors achieved the best results in estimating biomarkers levels, using different loss functions for each biomarker: least absolute deviation (LAD) for the Aβ42, least squares (LS) for p-tau and Huber for t-tau. The ALL subset demonstrated the lowest training errors for all three biomarkers, albeit with varying test performance. Specifically, the SLEEPVAR subset yielded the best test performance in predicting Aβ42, while the ALL subset most accurately predicted p-tau and t-tau due to the lowest test errors. Multimodal ML can help predict the outcome of CSF biomarkers in early AD by utilizing non-invasive and economically feasible variables. The integration of computational models into medical practice offers a promising tool for the screening of patients at risk of AD, potentially guiding clinical decisions.

Linking activity dyshomeostasis and sleep disturbances in Alzheimer disease.

The presymptomatic phase of Alzheimer disease (AD) starts with the deposition of amyloid-β in the cortex and begins a decade or more before the emergence of cognitive decline. The trajectory towards dementia and neurodegeneration is shaped by the pathological load and the resilience of neural circuits to the effects of this pathology. In this Perspective, I focus on recent advances that have uncovered the vulnerability of neural circuits at early stages of AD to hyperexcitability, particularly when the brain is in a low-arousal states (such as sleep and anaesthesia). Notably, this hyperexcitability manifests before overt symptoms such as sleep and memory deficits. Using the principles of control theory, I analyse the bidirectional relationship between homeostasis of neuronal activity and sleep and propose that impaired activity homeostasis during sleep leads to hyperexcitability and subsequent sleep disturbances, whereas sleep disturbances mitigate hyperexcitability via negative feedback. Understanding the interplay among activity homeostasis, neuronal excitability and sleep is crucial for elucidating the mechanisms of vulnerability to and resilience against AD pathology and for identifying new therapeutic avenues.

Hypoexcitation and connectome disintegration via whole‐brain semi‐empirical modeling in neurodegeneration

AbstractBackgroundNeuroimaging biomarkers are intensively investigated in Alzheimer disease (AD) and the behavioral variant frontotemporal dementia (bvFTD). However, advanced ND biomarkers (i.e., PET and plasma) are expensive or not widely available/validated in underrepresented regions. EEG emerges as a promising alternative, due to its low‐cost, non‐invasiveness, portability, and wide availability in clinical research, although they lack mechanistic explications and robust modeling approaches. The aim of our work was to characterize the functional alterations in AD and bvFTD by combining EEG source‐level metaconnectivity (that captures high‐order interactions), anatomical priors, whole‐brain modeling, and a perturbational approach.MethodDemographic‐matched data were collected via the Dementia Latin American Consortium (ReDLat; AD = 31, bvFTD = 18, Control = 46). From EEG source level recordings and using machine learning classifiers, we compared the pairwise functional connectivity with high‐order correlations captured by metaconnectivity. Then, neural mass modeling was used to propose biophysical mechanisms specifically ascribed to AD and bvFTD. Finally, a perturbational approach was employed to characterize the brain trajectories involved in the healthy and pathological states.ResultsUsing metaconnectivity, we found specific subnetworks of brain regions compromised in AD and bvFTD, yielding an excellent accuracy in classifying each group of patients. Brain dynamics turned more “viscous” (uncoordinated) in patients and were associated with multimodal disease progression (years of disease, cognitive impairment, atrophy). Then a whole‐brain Jansen & Rit model simulated the functional disturbances in AD and bvFTD. The DTI connectome disintegration (reduced structural integration) and hypoexcitability (altered excitation/inhibition balance) triggered the metaconnectivity dynamics observed in AD and bvFTD. Finally, in‐silico stimulation identified key regions involved in the transition from disease (AD and bvFTD models) to a healthy brain dynamics.ConclusionOur work suggests new possible EEG markers for characterizing AD and bvFTD, linking the functional disturbances in patients to alterations in the connectome and E/I balance, and evidencing possible anatomical targets to restore the normal brain function.

Pathological (Dis)Similarities in Neuronal Exosome-Derived Synaptic and Organellar Marker Levels Between Alzheimer's Disease and Frontotemporal Dementia.

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are pathologically distinct neurodegenerative disorders with certain overlap in cognitive and behavioral symptoms. Both AD and FTD are characterized by synaptic loss and accumulation of misfolded proteins, albeit, in different regions of the brain. To investigate the synaptic and organellar markers in AD and FTD through assessment of the levels of synaptic protein, neurogranin (Ng) and organellar proteins, mitofusin-2 (MFN-2), lysosomal associated membrane protein-2 (LAMP-2), and golgin A4 from neuronal exosomes. Exosomes isolated from the plasma of healthy controls (HC), AD and FTD subjects were characterized using transmission electron microscopy. Neurodegenerative status was assessed by measurement of neurofilament light chain (NfL) using Simoa. The pooled exosomal extracts from each group were analyzed for Ng, MFN-2, LAMP-2, and golgin A4 by western blot analysis using enhanced chemiluminescence method of detection. The densitometric analysis of immunoreactive bands demonstrated a 65% reduction of Ng in AD and 53% in FTD. Mitochondrial protein MFN-2 showed a significant reduction by 32% in AD and 46% in FTD. Lysosomal LAMP-2 and Golgi complex associated golgin A4 were considerably increased in both AD and FTD. Changes in Ng may reflect the ongoing synaptic degeneration that are linked to cognitive disturbances in AD and FTD. Importantly, the rate of synaptic degeneration was more pronounced in AD. Changes to a similar extent in both the dementia groups in organellar proteins indicates shared mechanisms of protein accumulation/degradation common to both AD and FTD.

GABA-Positive Astrogliosis in Sleep-Promoting Areas Associated with Sleep Disturbance in 5XFAD Mice.

Sleep disturbances, a debilitating symptom of Alzheimer's disease (AD), are associated with neuropathological changes. However, the relationship between these disturbances and regional neuron and astrocyte pathologies remains unclear. This study examined whether sleep disturbances in AD result from pathological changes in sleep-promoting brain areas. Male 5XFAD mice underwent electroencephalography (EEG) recordings at 3, 6, and 10 months, followed by an immunohistochemical analysis of three brain regions associated with sleep promotion. The findings showed that 5XFAD mice demonstrated reduced duration and bout counts of nonrapid eye movement (NREM) sleep by 6 months and reduced duration and bout counts of rapid eye movement (REM) sleep by 10 months. Additionally, peak theta EEG power frequency during REM sleep decreased by 10 months. Sleep disturbances correlated with the total number of GFAP-positive astrocytes and the ratio of GFAP- and GABA-positive astrocytes across all three sleep-associated regions corresponding to their roles in sleep promotion. The presence of GABRD in sleep-promoting neurons indicated their susceptibility to inhibition by extrasynaptic GABA. This study reveals that neurotoxic reactive astrogliosis in NREM and REM sleep-promoting areas is linked to sleep disturbances in 5XFAD mice, which suggests a potential target for the treatment of sleep disorders in AD.

Progressive sleep disturbance in various transgenic mouse models of Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of dementia. The relationship between AD and sleep dysfunction has received increased attention over the past decade. The use of genetically engineered mouse models with enhanced production of amyloid beta (Aβ) or hyperphosphorylated tau has played a critical role in the understanding of the pathophysiology of AD. However, their revelations regarding the progression of sleep impairment in AD have been highly dependent on the mouse model used and the specific techniques employed to examine sleep. Here, we discuss the sleep disturbances and general pathology of 15 mouse models of AD. Sleep disturbances covered in this review include changes to NREM and REM sleep duration, bout lengths, bout counts and power spectra. Our aim is to describe in detail the severity and chronology of sleep disturbances within individual mouse models of AD, as well as reveal broader trends of sleep deterioration that are shared among most models. This review also explores a variety of potential mechanisms relating Aβ accumulation and tau neurofibrillary tangles to the progressive deterioration of sleep observed in AD. Lastly, this review offers perspective on how study design might impact our current understanding of sleep disturbances in AD and provides strategies for future research.

APOE ε4 and Alzheimer's disease diagnosis associated differences in L-carnitine, GBB, TMAO, and acylcarnitines in blood and brain

The apolipoprotein E (APOE) ε4 allele, involved in fatty acid (FA) metabolism, is a major genetic risk factor for Alzheimer's disease (AD). This study examined the influence of APOE genotypes on blood and brain markers of the L-carnitine system, necessary for fatty acid oxidation (FAO), and their collective influence on the clinical and pathological outcomes of AD. L-carnitine, its metabolites γ-butyrobetaine (GBB) and trimethylamine-n-oxide (TMAO), and its esters (acylcarnitines) were analyzed in blood from predominantly White community/clinic-based individuals (n = 372) and in plasma and brain from the Religious Order Study (ROS) (n = 79) using liquid chromatography tandem mass spectrometry (LC-MS/MS). Relative to total blood acylcarnitines, levels of short chain acylcarnitines (SCAs) were higher whereas long chain acylcarnitines (LCAs) were lower in AD, which was observed pre-clinically in APOE ε4s. Plasma medium chain acylcarnitines (MCAs) were higher amongst cognitively healthy APOE ε2 carriers relative to other genotypes. Compared to their respective controls, elevated TMAO and lower L-carnitine and GBB were associated with AD clinical diagnosis and these differences were detected preclinically among APOE ε4 carriers. Plasma and brain GBB, TMAO, and acylcarnitines were also associated with post-mortem brain amyloid, tau, and cerebrovascular pathologies. Alterations in blood L-carnitine, GBB, TMAO, and acylcarnitines occur early in clinical AD progression and are influenced by APOE genotype. These changes correlate with post-mortem brain AD and cerebrovascular pathologies. Additional studies are required to better understand the role of the FAO disturbances in AD.

Degeneration of human orexinergic neurons across Braak stages of Alzheimer's disease: Implication for pathogenesis, sleep dysfunction, and therapy.

Sleep disturbances are common precognitive symptoms of Alzheimer's disease (AD). Wake-promoting orexinergic neurons (Oxe) in the lateral hypothalamic area (LHA) are key regulators of sleep-wake states. We recently reported a major loss of Oxe in the terminal stages of AD. This was unexpected, because clinical research shows elevated orexin levels in the cerebrospinal fluid (CSF) of AD patients. In line with this finding, suvorexant, an orexin receptor antagonist, was recently the first drug approved for insomnia in patients with mild-to-moderate AD. The aim of our current study was to understand the biological basis of these findings and elucidate the still unknown pattern of orexinergic neuron degeneration in the course of AD. We performed a postmortem study of 15 subjects with different AD stages and controls. Patients with contributing pathologies other than AD were excluded from the study. Using double immunohistochemistry and unbiased stereology, we estimated the number of total neurons, Oxe and tau-inclusions in the LHA along the Braak stages of AD. Examined participants' mean age was 70± 12 years, 47% female. Along AD progression, there was an increase of tau inclusions in Oxe, with 0.1% of tau-positive neurons at Braak stage 0 and 23% at stage 6 (Fig. 1). Further, we observed a substantial decrease of ONs from Braak stage 0 to stage 6 (Fig. 2). Along other Braak stages the decrease of orexinergic neuronal number was slower. We provide evidence of tau-accumulation in Oxe as early as Braak stage 0 and significant orexinergic neuronal loss from Braak 1. This correlates well with clinical data showing that in many patients sleep-wake disorders precede the cognitive symptoms, which typically emerge with Braak 3-4 stages. Further, we conclude that elevated orexin levels in the CSF of AD patients may represent a compensatory mechanism for the loss of Oxe in the early and middle disease stages, whereas in the terminal stage the compensatory capacity may be lost. The practical consequence is that during treatment, disease stages should be considered and symptomatic therapy should be adjusted accordingly. Further studies are necessary to develop better targeting / therapeutics for sleep disturbances in AD.

The Alzheimer's disease-associated C99 fragment of APP regulates cellular cholesterol trafficking.

The link between cholesterol homeostasis and cleavage of the amyloid precursor protein (APP), and how this relationship relates to Alzheimer's disease (AD) pathogenesis, is still unknown. Cellular cholesterol levels are regulated through crosstalk between the plasma membrane (PM), where most cellular cholesterol resides, and the endoplasmic reticulum (ER), where the protein machinery that regulates cholesterol levels resides. The intracellular transport of cholesterol from the PM to the ER is believed to be activated by a lipid‐sensing peptide(s) in the ER that can cluster PM‐derived cholesterol into transient detergent‐resistant membrane domains (DRMs) within the ER, also called the ER regulatory pool of cholesterol. When formed, these cholesterol‐rich domains in the ER maintain cellular homeostasis by inducing cholesterol esterification as a mechanism of detoxification while attenuating its de novo synthesis. In this manuscript, we propose that the 99‐aa C‐terminal fragment of APP (C99), when delivered to the ER for cleavage by γ‐secretase, acts as a lipid‐sensing peptide that forms regulatory DRMs in the ER, called mitochondria‐associated ER membranes (MAM). Our data in cellular AD models indicates that increased levels of uncleaved C99 in the ER, an early phenotype of the disease, upregulates the formation of these transient DRMs by inducing the internalization of extracellular cholesterol and its trafficking from the PM to the ER. These results suggest a novel role for C99 as a mediator of cholesterol disturbances in AD, potentially explaining early hallmarks of the disease.

Profound degeneration of wake-promoting neurons in Alzheimer's disease

IntroductionSleep-wake disturbances are a common and early feature in Alzheimer's disease (AD). The impact of early tau pathology in wake-promoting neurons (WPNs) remains unclear. MethodsWe performed stereology in postmortem brains from AD individuals and healthy controls to identify quantitative differences in morphological metrics in WPNs. Progressive supranuclear palsy (PSP) and corticobasal degeneration were included as disease-specific controls. ResultsThe three nuclei studied accumulate considerable amounts of tau inclusions and showed a decrease in neurotransmitter-synthetizing neurons in AD, PSP, and corticobasal degeneration. However, substantial neuronal loss was exclusively found in AD. DiscussionWPNs are extremely vulnerable to AD but not to 4 repeat tauopathies. Considering that WPNs are involved early in AD, such degeneration should be included in the models explaining sleep-wake disturbances in AD and considered when designing a clinical intervention. Sparing of WPNs in PSP, a condition featuring hyperinsomnia, suggest that interventions to suppress the arousal system may benefit patients with PSP.

Alteration in sleep architecture and electroencephalogram as an early sign of Alzheimer's disease preceding the disease pathology and cognitive decline

ObjectiveThe present work aims to evaluate the significance of sleep disturbance and electroencephalogram (EEG) alteration in the early stage of Alzheimer's disease (AD). Background and RationaleSleep disturbance is common in patients with AD. It is not known if it can occur at the early stage of AD and if EEG recording may help identify the early sign of the disease. Historical EvolutionSleep disturbance in AD has generally been considered as late consequence of the neurodegenerative process. A growing body of evidence has suggested that the sleep disturbance may occur at the early stage of AD. Updated HypothesisBased on the previous epidemiologic studies and our recent findings, we propose that sleep disturbance may play an important role in the development of AD. Sleep EEG changes may serve as a valuable early sign for AD in the prepathological stage. Early Experimental DataOur data suggested that AβPPswe/PS1ΔE9 transgenic AD mice at preplaque stage (3 and 4 months of age) exhibited different profile of sleep architecture and sleep EEG, which preceded the cognitive deficit and AD neuropathology. Future Experiments and Validation StudiesFuture experiments should focus on sleep EEG changes in patients with mild cognitive impairment and early stage of AD. Follow-up studies in high-risk population of the elderly are equally important. In addition, the exact molecular mechanism underlying the sleep disturbance should be thoroughly investigated. Major Challenges for the HypothesisStudies on human participants with early stage of AD, especially the follow-up studies on the presymptomatic elderly in a large population, are difficult and time-consuming. Linkage to Other Major TheoriesOur hypothesis may link previous theories to establish a bidirectional relationship between sleep disorders and AD, which may finally form a new schematic mechanism to understand the disease pathogenesis and disease progression.

Preserved Structural Network Organization Mediates Pathology Spread in Alzheimer's Disease Spectrum Despite Loss of White Matter Tract Integrity.

Models of Alzheimer's disease (AD) hypothesize stereotyped progression via white matter (WM) fiber connections, most likely via trans-synaptic transmission of toxic proteins along neuronal pathways. An important question in the field is whether and how organization of fiber pathways is affected by disease. It remains unknown whether fibers act as conduits of degenerative pathologies, or if they also degenerate with the gray matter network. This work uses graph theoretic modeling in a longitudinal design to investigate the impact of WM network organization on AD pathology spread. We hypothesize if altered WM network organization mediates disease progression, then a previously published network diffusion model will yield higher prediction accuracy using subject-specific connectomes in place of a healthy template connectome. Neuroimaging data in 124 subjects from ADNI were assessed. Graph topology metrics show preserved network organization in patients compared to controls. Using a published diffusion model, we further probe the effect of network alterations on degeneration spread in AD. We show that choice of connectome does not significantly impact the model's predictive ability. These results suggest that, despite measurable changes in integrity of specific fiber tracts, WM network organization in AD is preserved. Further, there is no difference in the mediation of putative pathology spread between healthy and AD-impaired networks. This conclusion is somewhat at variance with previous results, which report global topological disturbances in AD. Our data indicates the combined effect of edge thresholding, binarization, and inclusion of subcortical regions to network graphs may be responsible for previously reported effects.

Neural Correlates of Sleep Disturbance in Alzheimer's Disease: Role of the Precuneus in Sleep Disturbance.

Background:Sleep disturbance may affect the development of Alzheimer’s disease (AD), but the neural correlates of sleep disturbance in AD have not been fully clarified.Objective:To examine the factors associated with sleep disturbance in AD.Methods:A retrospective study was performed in 63 patients with AD. None of the patients had been prescribed antidementia or psychoactive drugs, and all underwent brain magnetic resonance imaging (MRI) before medication. Sleep disturbance was defined as a score of at least 1 point on the sleep disturbance subscale of the Neuropsychiatric Inventory (NPI). Whole brain image analysis was performed using SPM8 and VBM8. A two-sample t-test was used to compare patients with AD with (n = 19) and without (n = 44) sleep disturbance, with age and gender included as covariates. The statistical thresholds were set to an uncorrected p-value of 0.001 at the voxel level and a corrected p-value of 0.05 at the cluster level. In addition, pineal gland volume (PGV) measured using MRI, and white matter hyperintensity (WMH) assessed with the modified Fazekas scale were compared between patients with AD with and without sleep disturbance using independent group t-tests.Results:In whole brain analysis, the precuneus volume in patients with AD with sleep disturbance was significantly smaller than those without sleep disturbance. There were no significant differences in PGV and WMH between the two groups.Conclusion:Sleep disturbance in AD was associated with reduction of precuneus volume. This suggests that the precuneus might be an important region in sleep disturbance in AD.

Circadian Rhythms Disturbances in Alzheimer Disease: Current Concepts, Diagnosis, and Management.

The purpose of this review is to provide an overview of the research regarding circadian rhythms in Alzheimer disease (AD). Furthermore, this paper explores the role of melatonin in the pathogenesis of AD and the limitation of trials addressing circadian rhythms disturbances in the AD population. A literature search using Medline with PubMed and Embase was carried out identifying papers focusing on circadian rhythms in AD. Sleep disorders and especially circadian rhythm disturbances are very common in the elderly population but definitely more pronounced in patients with AD. The lack of trials evaluating the management of circadian rhythms disorders in the elderly population and especially in AD should be considered of the utmost importance. Although there is a better understanding about the pathophysiology of AD and its relationship with circadian disorders, further studies in human models need to be conducted.

Semantic Feature Disturbance in Alzheimer Disease: Evidence from an Object Decision Task.

It is widely held that semantic disturbance in Alzheimer disease (AD) involves the loss of distinctive features but the relative sparing of nondistinctive features. Many previous studies of semantic feature disturbance have used cognitively challenging tasks with verbal stimuli that allow for potential cognitive confounds. Our objective was to use a task with lower memory demands to investigate distinctive feature disturbance in AD. We used an object decision task to compare the processing of distinctive and nondistinctive semantic features in people with AD and age-matched controls. The task included six conditions based on the relationship between each prime and target object. We tested the processing of distinctive and nondistinctive features by selectively altering distinctive and nondistinctive semantic features between prime and target pairs. Performance accuracy was significantly lower for participants with AD than for age-matched controls when distinctive features were manipulated, but no difference was found when nondistinctive features were manipulated. Our results provide evidence of semantic content disturbance in AD in the context of a task with low cognitive demands.

Sleep-Wake Profile in Dementia with Lewy Bodies, Alzheimer's Disease, and Normal Aging.

Alterations of the sleep-wake cycle are common features of neurodegenerative dementia. To study differences in sleep-wake profiles in dementia with Lewy bodies (DLB), Alzheimer's disease (AD), and healthy controls. 30 DLB and 32 AD patients, and 33 healthy elderly participants were studied. Patients were evaluated for global cognitive impairment, extrapyramidal signs, fluctuations of attention, and behavioral disorders. A comprehensive sleep-wake profile was obtained including a set of questionnaires [Pittsburgh Sleep Quality Index (PSQI), REM Sleep Behavior Disorder Single-Question screen (RBD1Q), Epworth Sleepiness Scale (ESS)] and 12-day sleep diaries. Patients were matched for age, gender, and disease severity. DLB patients showed more severe daytime somnolence/dysfunction due to somnolence, and a higher proportion of RBD-like symptoms (70%) compared to AD and controls (p < 0.001), regardless of the presence of psychoactive drug treatment. As for sleep timing, DLB patients had a greater number of daytime naps and longer night sleep, with the latter being associated with use of clonazepam. The severity of fluctuations was associated with the presence of RBD (Clinician Assessment of Fluctuation score = RBD+: 5.2±3.7; RBD-: 2.1±3.2, p = 0.04). AD patients reported the best sleep-wake profile, while healthy controls declared the poorest sleep quality, although sleep timing and the quality of wakefulness were comparable between AD and controls. RBD and daytime fluctuations of attention may coexist in DLB and even reciprocally potentiate each other. Self-reports of sleep quality may lead to an underestimation of sleep disturbances in AD, possibly influenced by anosognosia, compared to normal elderly individuals who complain mainly of insomnia.

Aberrant Axonal Arborization of PDF Neurons Induced by Aβ42-Mediated JNK Activation Underlies Sleep Disturbance in an Alzheimer's Model.

Impaired sleep patterns are common symptoms of Alzheimer's disease (AD). Cellular mechanisms underlying sleep disturbance in AD remain largely unknown. Here, using a Drosophila Aβ42 AD model, we show that Aβ42 markedly decreases sleep in a large population, which is accompanied with postdevelopmental axonal arborization of wake-promoting pigment-dispersing factor (PDF) neurons. The arborization is mediated in part via JNK activation and can be reversed by decreasing JNK signaling activity. Axonal arborization and impaired sleep are correlated in Aβ42 and JNK kinase hemipterous mutant flies. Image reconstruction revealed that these aberrant fibers preferentially project to pars intercerebralis (PI), a fly brain region analogous to the mammalian hypothalamus. Moreover, PDF signaling in PI neurons was found to modulate sleep/wake activities, suggesting that excessive release of PDF by these aberrant fibers may lead to the impaired sleep in Aβ42 flies. Finally, inhibition of JNK activation in Aβ42 flies restores nighttime sleep loss, decreases Aβ42 accumulation, and attenuates neurodegeneration. These data provide a new mechanism by which sleep disturbance could be induced by Aβ42 burden, a key initiator of a complex pathogenic cascade in AD.

Amyloid‐β induces sleep fragmentation that is rescued by fatty acid binding proteins in Drosophila

Disruption of sleep/wake activity in Alzheimer's disease (AD) patients significantly affects their quality of life and that of their caretakers and is a major contributing factor for institutionalization. Levels of amyloid-β (Aβ) have been shown to be regulated by neuronal activity and to correlate with the sleep/wake cycle. Whether consolidated sleep can be disrupted by Aβ alone is not well understood. We hypothesize that Aβ42 can increase wakefulness and disrupt consolidated sleep. Here we report that flies expressing the human Aβ42 transgene in neurons have significantly reduced consolidated sleep compared with control flies. Fatty acid binding proteins (Fabp) are small hydrophobic ligand carriers that have been clinically implicated in AD. Aβ42 flies that carry a transgene of either the Drosophila Fabp or the mammalian brain-type Fabp show a significant increase in nighttime sleep and long consolidated sleep bouts, rescuing the Aβ42-induced sleep disruption. These studies suggest that alterations in Fabp levels and/or activity may be associated with sleep disturbances in AD. Future work to determine the molecular mechanisms that contribute to Fabp-mediated rescue of Aβ42-induced sleep loss will be important for the development of therapeutics in the treatment of AD. © 2016 Wiley Periodicals, Inc.

Sleep disturbances are key symptoms of very early stage Alzheimer disease with behavioral and psychological symptoms: a Japan multi-center cross-sectional study (J-BIRD).

Sleep disturbances in Alzheimer disease (AD) may affect behavioral and psychological symptoms of dementia (BPSD). Our aim was to elucidate the associations between sleep disturbances and other BPSD at different stages of AD. This investigation was part of a multicenter-retrospective study in Japan (J-BIRD). Eligible for final analyses were 684 AD patients. Global severity of dementia was estimated using the Clinical Dementia Rating (CDR) scale. BPSD were assessed using the Neuropsychiatric Inventory (NPI). We analyzed the relationships between sleep disturbances and BPSD at different stages of AD according to the CDR score. Among the 684 AD patients, 146 (21.3%) had sleep disturbances. Patients with very early AD (CDR 0.5) and sleep disturbances had significantly more BPSD than those without sleep disturbances, as indicated by the higher prevalence of the following four NPI items: anxiety, euphoria, disinhibition, and aberrant motor behavior. In AD at CDR 2, (moderate AD) only one NPI item (irritability) was affected, while none was affected at CDR 1 (mild AD) and 3 (severe AD). Multiple regression analyses were performed in those with AD having various CDR scores. At CDR 0.5, the presence of sleep disturbances was associated with a high total NPI score (β = 0.32, p < 0.001). However, other factors, including cognitive decline, age, gender, and years of education, were not significantly associated with the NPI score. At CDR 1 and 2, no factor was significantly related to BPSD. Sleep disturbances were strongly associated with other BPSD in the very early stage of AD. Copyright © 2016 John Wiley & Sons, Ltd.

Non-pharmacological interventions for people with Alzheimer's Disease: A critical review of the scientific literature from the last ten years

Currently, non-pharmacological interventions are useful, versatile and potentially cost-effective tools for managing the care of people suffering from Alzheimer's Disease (AD). The aim of the present study is to examine non-pharmacological interventions in terms of their theoretical basis and empirical evidence in improving cognition and autonomy of daily living and reducing neuropsychiatric symptoms in people with AD. We searched the electronic databases from January 2005 until 15 November 2015 using a combination of the terms “Alzheimer's Disease and Reality Orientation”, “Cognitive Stimulation Therapy”, “Reminiscence”, “Psychodynamic therapy”, “Spaced retrieval”, “Music Therapy”, “Bright light therapy”. Non-pharmacological interventions can be grouped into four categories: Holistic techniques, Brief psychotherapies, Cognitive methods and Alternative strategies. Reality orientation and Cognitive stimulation therapy (CST) were associated with a significant improvement in cognition and behaviour in mild to moderate AD patients and in reinforcing concomitant pharmacological treatment. Reminiscence was found to enhance cognition and reduce depressive symptoms. Spaced retrieval may facilitate retention and recall of meaningful items. Further research needs to be conducted to establish the impact of Bright light therapy on neuropsychiatric disturbances in AD, while the use of Music Therapy may lead to a reduction of the frequency and the extent of them. Methodological limitations such as the paucity of randomized-controlled trials and small samples size have been observed. Non-pharmacological interventions represent complementary techniques and should be tailored case by case, according to patients’ medical condition and resilience, compliance to treatment, AD severity, available sanitary and professional resources and caregiver care commitment and support.