Dementia is characterized by the impairment of cognition and behavior of people\nover 65 years. Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in\nthe world, as approximately 47 million people are affected by this disease and the tendency is\nthat this number will increase to 62% by 2030. Two microscopic features assist in the characterization\nof the disease, the amyloid plaques and neurofibrillary agglomerates. All these factors\nare responsible for the slow and gradual deterioration of memory that affect language,\npersonality or cognitive control. For the AD diagnosis, neuropsychological tests are performed\nin different spheres of cognitive functions but since not all cognitive functions may be\naffected, cerebrospinal fluid biomarkers are used along with these tests. To date, cholinesterase\ninhibitors are used as treatment, they are the only drugs that have shown significant improvements\nin the cognitive functions of AD patients. Despite the proven effectiveness of\ncholinesterase inhibitors, an AD carrier, even while being treated, is continually subjected to\nprogressive degeneration of the neuronal tissue. For this reason, other biochemical pathways\nassociated with the pathophysiology of AD have been explored as alternatives to the treatment\nof this condition such as inhibition of β-secretase and glycogen synthase kinase-3β. The present\nstudy aims to conduct a review of the epidemiology, pathophysiology, symptoms, diagnosis\nand treatment of Alzheimer's disease, emphasizing the research and development of new\ntherapeutic approaches.

Autonomic function has received little attention in Alzheimer's disease (AD). AD pathology has an impact on brain regions which are important for central autonomic control, but it is unclear if AD is associated with disturbance of autonomic function.To investigate autonomic function using standardized techniques in patients with AD and healthy age-matched controls.Thirty-three patients with mild to moderate AD and 30 age- and gender-matched healthy controls, without symptoms of autonomic dysfunction, underwent standardized autonomic testing with deep breathing, Valsalva maneuver, head-up tilt, and isometric handgrip test. Brachial pressure curve and electrocardiogram were recorded for off-line analysis of blood pressure and beat-to-beat heart rate (HR).AD patients had impaired blood pressure responses to Vasalva maneuver (p < 0.0001) and HR response to isometric contraction (p = 0.0001). A modified composite autonomic scoring scale showed greater degree of autonomic impairment in patients compared to controls (patient: 2.1 ± 1.6; controls: 0.9 ± 1.1, p = 0.001). HR response to deep breathing and Valsalva ratio were similar in the two groups.We identified autonomic impairment ranging from mild to severe in patients with mild to moderate AD, who did not report autonomic symptoms. Autonomic impairment was mainly related to impairment of sympathetic function and evident by impaired blood pressure response to the Vasalva maneuver. The clinical implications of this finding are that AD may be associated with autonomic disturbances, but patients with AD may rarely report symptoms of autonomic dysfunction. Future research should systematically evaluate symptoms of autonomic function and characterize risk factors associated with autonomic dysfunction.

Older adults do not sleep as well as younger adults. Why? What alterations in sleep quantity and quality occur as we age, and are there functional consequences? What are the underlying neural mechanisms that explain age-related sleep disruption? This review tackles these questions. First, we describe canonical changes in human sleep quantity and quality in cognitively normal older adults. Second, we explore the underlying neurobiological mechanisms that may account for these human sleep alterations. Third, we consider the functional consequences of age-related sleep disruption, focusing on memory impairment as an exemplar. We conclude with a discussion of a still-debated question: do older adults simply need less sleep, or rather, are they unable to generate the sleep that they still need?Copyright © 2017. Published by Elsevier Inc.

This paper reviews the characteristics of sleep disorders found in people at a greater risk of dementia: the elderly adult, patients with mild cognitive impairment (MCI) and those with neurodegenerative diseases. The frequency of sleep architecture modifications and circadian rhythm sleep disturbances increases with age. Although around 40% of older adults complain of poor sleep, true sleep disorders are far less prevalent in healthy older adults and are frequently associated with comorbidities. The sleep disorders observed in Alzheimer's disease (AD) patients are often similar to (but more intense than) those found in non-demented elderly people. Poor sleep results in an increased risk of significant morbidities and even mortality in demented patients and constitutes a major source of stress for caregivers. The prevalence of primary sleep disorders such as rapid eye movement (REM) sleep behavior disorders (RBDs), restless legs syndrome (RLS), periodic limb movements (PLMs) and sleep-disordered breathing increases with age. There are no published data on RLS and PLMs in demented persons but RBDs and sleep apnea syndrome have been studied more extensively. In fact, RBDs are suggestive of Lewy body dementia (LBD) and are predictive for neurodegeneration in Parkinson's disease. Obstructive sleep apnea (OSA) shares common risk factors with AD and may even be an integral part of the pathological process in AD. In MCI patients, the hypotheses in which (i) sleep disorders may represent early predictive factors for progression to dementia and (ii) MCI is symptomatic of a non-diagnosed sleep disorder remain to be elucidated. Guidelines for drug and non-drug treatments of sleep disorders in the elderly and in demented patients are also considered in this review. In healthy but frail elderly people and in early-stage AD patients, sleep should be more thoroughly characterized (notably by using standardized interviews and polysomnographic recording).

The aim of this research, based on 7 years of observations, was to assess the relationship between the dynamics of changes in the realm of cognitive functions in the early stages of observations and the presence of neuropsychiatric symptoms as well as further progression of cognitive function impairments in people diagnosed with mild cognitive impairment (MCI).One hundred and ninety three individuals were included in the study, all of whom referred themselves to the Mental Health Clinic and were diagnosed with MCI based on the criteria of the Working Group on MCI. It was assumed that these individuals would be subjected to systematic psychiatric and neuropsychological observation until they were diagnosed with dementia. This report concerns a completed 7-year period of these observations. Participants were assessed based on the following scales: MMSE, NPI and GDS.The obtained results indicate statistically significant differences between groups of subjects at the time of inclusion in the study, regarding the frequency of occurrence and severity of the following categories of impairments: thought impairments (< 0.001), arousal/aggression (< 0.001), depression/dysphoria (< 0.001), disinhibition (< 0.03), irritability/lability (< 0.001), abnormal motor behaviors (< 0.02), as well as sleep and night-time behavior disorders (< 0.01) Moreover, individuals who developed dementia during observation exhibited greater progression in cognitive function impairment assessed with the MMSE scale in the first year of observation (< 0.01).The accruing of cognitive function impairments and the presence of neuropsychiatric symptoms seem to be important risk factors for the development of dementia.

The NINCDS-ADRDA and the DSM-IV-TR criteria for Alzheimer's disease (AD) are the prevailing diagnostic standards in research; however, they have now fallen behind the unprecedented growth of scientific knowledge. Distinctive and reliable biomarkers of AD are now available through structural MRI, molecular neuroimaging with PET, and cerebrospinal fluid analyses. This progress provides the impetus for our proposal of revised diagnostic criteria for AD. Our framework was developed to capture both the earliest stages, before full-blown dementia, as well as the full spectrum of the illness. These new criteria are centred on a clinical core of early and significant episodic memory impairment. They stipulate that there must also be at least one or more abnormal biomarkers among structural neuroimaging with MRI, molecular neuroimaging with PET, and cerebrospinal fluid analysis of amyloid beta or tau proteins. The timeliness of these criteria is highlighted by the many drugs in development that are directed at changing pathogenesis, particularly at the production and clearance of amyloid beta as well as at the hyperphosphorylation state of tau. Validation studies in existing and prospective cohorts are needed to advance these criteria and optimise their sensitivity, specificity, and accuracy.

Despite the prevalence of sleep complaints among psychiatric patients, few questionnaires have been specifically designed to measure sleep quality in clinical populations. The Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire which assesses sleep quality and disturbances over a 1-month time interval. Nineteen individual items generate seven "component" scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of scores for these seven components yields one global score. Clinical and clinimetric properties of the PSQI were assessed over an 18-month period with "good" sleepers (healthy subjects, n = 52) and "poor" sleepers (depressed patients, n = 54; sleep-disorder patients, n = 62). Acceptable measures of internal homogeneity, consistency (test-retest reliability), and validity were obtained. A global PSQI score greater than 5 yielded a diagnostic sensitivity of 89.6% and specificity of 86.5% (kappa = 0.75, p less than 0.001) in distinguishing good and poor sleepers. The clinimetric and clinical properties of the PSQI suggest its utility both in psychiatric clinical practice and research activities.

\n Accumulation of amyloid-β (Aβ) in the brain is thought to be the initiating event in the pathogenesis of Alzheimer's disease (AD). Aβ is a peptide secreted in a soluble monomeric form predominantly by neurons and its aggregation into toxic forms is concentration dependent. Synaptic activity regulates the release of Aβ in vivo. However, how physiological and environmental processes are involved in regulation of Aβ levels is not understood.\n \n Kang\n et al.\n \n (p.\n 1005\n, published online 24 September), by performing sleep-wake studies in freely behaving animals concomitant with in vivo microdialysis, found that brain interstitial fluid levels of Aβ were significantly correlated with wakefulness and negatively correlated with sleep. Furthermore, relatively short-term (3 weeks) sleep deprivation markedly accelerated amyloid plaque deposition in amyloid precursor protein transgenic mice. Thus, sleep-wake behavior is linked to Aβ levels and abnormal sleep may be linked to AD pathogenesis.\n

It is becoming increasingly recognized that patients with a variety of neurodegenerative diseases exhibit disordered sleep/wake patterns. While sleep impairments have typically been thought of as sequelae of underlying neurodegenerative processes in sleep-wake cycle regulating brain regions, including the brainstem, hypothalamus, and basal forebrain, emerging evidence now indicates that sleep deficits may also act as pathophysiological drivers of brain-wide disease progression. Specifically, recent work has indicated that impaired sleep can impact on neuronal activity, brain clearance mechanisms, pathological build-up of proteins, and inflammation. Altered sleep patterns may therefore be novel (potentially reversible) dynamic functional markers of proteinopathies and modifiable targets for early therapeutic intervention using non-invasive stimulation and behavioral techniques. Here we highlight research describing a potentially reciprocal interaction between impaired sleep and circadian patterns and the accumulation of pathological signs and features in Alzheimer's disease, the most prevalent neurodegenerative disease in the elderly.© 2021. Springer Nature Switzerland AG.

Sleep is evolutionarily conserved across all species, and impaired sleep is a common trait of the diseased brain. Sleep quality decreases as we age, and disruption of the regular sleep architecture is a frequent antecedent to the onset of dementia in neurodegenerative diseases. The glymphatic system, which clears the brain of protein waste products, is mostly active during sleep. Yet the glymphatic system degrades with age, suggesting a causal relationship between sleep disturbance and symptomatic progression in the neurodegenerative dementias. The ties that bind sleep, aging, glymphatic clearance, and protein aggregation have shed new light on the pathogenesis of a broad range of neurodegenerative diseases, for which glymphatic failure may constitute a therapeutically targetable final common pathway.Copyright © 2020, American Association for the Advancement of Science.

The glymphatic (glial-lymphatic) pathway is a fluid-clearance pathway identified in the rodent brain in 2012. This pathway subserves the flow of CSF into the brain along arterial perivascular spaces and subsequently into the brain interstitium, facilitated by aquaporin 4 (AQP4) water channels. The pathway then directs flow towards the venous perivascular and perineuronal spaces, ultimately clearing solutes from the neuropil into meningeal and cervical lymphatic drainage vessels. In rodents, the glymphatic pathway is predominantly active during sleep, when the clearance of harmful metabolites such as amyloid β (Aβ) increases two-fold relative to the waking state. Glymphatic dysfunction, probably related to perturbed AQP4 expression, has been shown in animal models of traumatic brain injury, Alzheimer's disease, and stroke. The recent characterisations of the glymphatic and meningeal lymphatic systems in rodents and in humans call for revaluation of the anatomical routes for CSF-interstitial fluid flow and the physiological role that these pathways play in CNS health.Several features of the glymphatic and meningeal lymphatic systems have been shown to be present in humans. MRI scans with intrathecally administered contrast agent show that CSF flows along pathways that closely resemble the glymphatic system outlined in rodents. Furthermore, PET studies have revealed that Aβ accumulates in the healthy brain after a single night of sleep deprivation, suggesting that the human glymphatic pathway might also be primarily active during sleep. Other PET studies have shown that CSF clearance of Aβ and tau tracers is reduced in patients with Alzheimer's disease compared with healthy controls. The observed reduction in CSF clearance was associated with increasing grey-matter concentrations of Aβ in the human brain, consistent with findings in mice showing that decreased glymphatic function leads to Aβ accumulation. Altered AQP4 expression is also evident in brain tissue from patients with Alzheimer's disease or normal pressure hydrocephalus; glymphatic MRI scans of patients with normal pressure hydrocephalus show reduced CSF tracer entry and clearance. WHERE NEXT?: Research is needed to confirm whether specific factors driving glymphatic flow in rodents also apply to humans. Longitudinal imaging studies evaluating human CSF dynamics will determine whether a causal link exists between reduced brain solute clearance and the development of neurodegenerative diseases. Assessment of glymphatic function after stroke or traumatic brain injury could identify whether this function correlates with neurological recovery. New insights into how behaviour and genetics modify glymphatic function, and how this function decompensates in disease, should lead to the development of new preventive and diagnostic tools and novel therapeutic targets.Copyright © 2018 Elsevier Ltd. All rights reserved.

阿尔茨海默病是以进行性认知功能障碍和精神行为异常为特征的神经变性病。睡眠障碍既是阿尔茨海默病的常见临床症状，又是加速疾病进展和认知功能障碍的危险因素，二者存在交互作用。由于目前阿尔茨海默病尚无有效干预靶点，睡眠障碍作为其可控危险因素，早期准确诊断并管理睡眠障碍对延缓阿尔茨海默病进展具有重要作用。本文综述阿尔茨海默病睡眠障碍的临床表现、危险因素、早期筛查及管理，以期从睡眠角度探索阿尔茨海默病治疗的新靶点。

To describe the stability of the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS) scores over 1 year among a population-based sample of black and white early middle-aged adults.More than 600 participants, aged 38 to 50 years, from the Chicago site of the Coronary Artery Risk Development in Young Adults (CARDIA) Study.The PSQI and ESS were completed twice, approximately 1 year apart, between 2003 and 2005. Seven PSQI 4-level component scores, a global PSQI score, and the ESS scores were calculated. A PSQI global score greater than 5 was classified as poor quality sleep, and an ESS score greater than 10 was classified as high daytime sleepiness.The mean+/-SD PSQI score was 5.7+/-3.1 in Year 1 and 5.9+/-3.1 in Year 2. The mean ESS score was 7.4+/-4.3 in Year 1 and 7.2+/-4.2 in Year 2. The Pearson correlation coefficient for the PSQI score in both years in the full sample was.68 and ranged from.54 among black men to.72 among black women. The Pearson correlation coefficient for the ESS score in both years in the full sample was.76 and ranged from.70 among black men to.80 among white men. In the full sample, 76% had the same PSQI dichotomous classification, and 85% had the same ESS dichotomous classification in both years.These results suggest that the PSQI and ESS are stable measures of sleep quality and sleepiness over the past year in early middle-aged adults.

Several studies report an association between REM Sleep Behavior Disorder (RBD) and neurodegenerative diseases, in particular synucleinopathies. Interestingly, the onset of RBD precedes the development of neurodegeneration by several years. This review and meta-analysis aims to establish the rate of conversion of RBD into neurodegenerative diseases. Longitudinal studies were searched from the PubMed, Web of Science, and SCOPUS databases. Using random-effect modeling, we performed a meta-analysis on the rate of RBD conversions into neurodegeneration. Furthermore, we fitted a Kaplan-Meier analysis and compared the differences between survival curves of different diseases with log-rank tests. The risk for developing neurodegenerative diseases was 33.5% at five years follow-up, 82.4% at 10.5 years and 96.6% at 14 years. The average conversion rate was 31.95% after a mean duration of follow-up of 4.75 ± 2.43 years. The majority of RBD patients converted to Parkinson's Disease (43%), followed by Dementia with Lewy Bodies (25%). The estimated risk for RBD patients to develop a neurodegenerative disease over a long-term follow-up is more than 90%. Future studies should include control group for the evaluation of REM sleep without atonia as marker for neurodegeneration also in non-clinical population and target RBD as precursor of neurodegeneration to develop protective trials.Copyright © 2018 Elsevier Ltd. All rights reserved.

Sleep in the nursing home environment is extremely fragmented, possibly in part as a result of decreased light exposure. This study examined the effect of light on sleep and circadian activity rhythms in patients with probable or possible Alzheimer's disease. Results showed that both morning and evening bright light resulted in more consolidated sleep at night, as measured with wrist actigraphy. Evening light also increased the quality of the circadian activity rhythm, as measured by a 5-parameter extended cosine model (amplitude, acrophase, nadir, slope of the curve, and relative width of the peak and trough). Increasing light exposure throughout the day and evening is likely to have the most beneficial effect on sleep and on circadian rhythms in patients with dementia. It would behoove nursing homes to consider increasing ambient light in multipurpose rooms where patients often spend much of their days.

随着Aβ单抗药物研究的不断进展和疾病修饰治疗理念的不断深入，近期Aβ单抗治疗阿尔茨海默病的临床试验及临床研究取得了重要进展，以Aducanumab、Lecanemab（BAN2401）为代表的药物相继获批，在临床上获得试用。2022年12月11日，由作者团队在海南博鳌乐城医疗先行区首次采用 Aducanumab单抗治疗轻度阿尔茨海默病的临床用药，从而在国内正式开启了Aβ单抗治疗阿尔茨海默病的序幕。本文拟就Aβ单抗治疗阿尔茨海默病的研究进展和临床实践进行一系统述评。