Interacting influences of aging and Alzheimer's disease on circadian rhythms

Aging leads to changes in circadian rhythms, including decreased amplitude or robustness, altered synchrony with the environment, and reduced coordination of rhythms within body. These circadian rhythm alterations are more pronounced in age‐associated neurodegenerative disorders such as Alzheimer's disease (AD), in which they often precede the onset of other symptoms by many years. As well as their early onset, the findings that fragmentation of daily rest‐activity rhythms in non‐demented older subjects is associated earlier cognitive decline, increased risk of incident AD, and preclinical AD neuropathology, suggest that circadian rhythm disruption may contribute to the development and progression of the neuropathological changes occurring in AD. Conversely, other studies have implicated amyloid‐beta, a prominent neurotoxin that accumulates in AD, in the impairment of circadian rhythms. Thus, circadian rhythm disruption and AD‐associated neurodegeneration may interact to form a deleterious cycle. This article reviews the neural and molecular mechanisms underlying the age‐ and AD‐related changes in circadian rhythms. It also explores therapeutic strategies proposed to ameliorate circadian rhythm deficits in elderly and demented individuals.     

Sundowning and circadian rhythm disorders in dementia

Sleep disorders and disruptive nocturnal behaviours are commonly reported in people with senile dementia and present both a significant clinical problem and a cause of increased stress for caregivers. Neuronal degeneration of cholinergic Nucleus basalis Meynert (NBM) neurons promote rest-activity disturbance and Sundowning in Alzheimer's disease. NBM neurons modulate the activity of the mainly cholinergic suprachiasmatic nucleus (SCN) and the induction of NONREM sleep. Sundowning might be explained as a syndrome occurring when arousal is to be processed while the neocortex is already turned "off" to (NONREM) sleep. The therapeutic measures should thus primarily be aimed at the stimulation of the circadian system and enforcing "external Zeitgebers". Pharmacologically, application of cholinergic enhancers i.e. cholinesterase inhibitors and melatonin supports and should stabilize the weakened structures.     

Twenty-four-hour rhythms of sleep-wake cycle and temperature in Alzheimer's disease

The authors aimed to examine the difference in 24-hour rhythms of sleep-wake cycle and temperature between Alzheimer's disease (AD) patients and elderly comparison subjects. The continuous measuring of wrist activity and skin temperature was conducted for 96 hours in seven AD patients (age: 77.0 +/- 4.3) and 11 normal comparison subjects (age: 74.2 +/-5.2). The mean acrophases and amplitudes of the two rhythms in the AD group were not different from those in the comparison group. The mean phase difference between the two rhythms, however, was significantly lower in the AD group than in the comparison group.     

Affective disorders and circadian rhythms

Abnormal circadian rhythms have been associated with affective disorders. A review of this rapidly expanding area of investigation shows that while a clear causal relationship has not yet been proven, a knowledge of the circadian system and its dysfunction can help in understanding unipolar and bipolar depression. Evidence suggests that existing therapies such as lithium and antidepressants act upon the circadian system. Better identification of individuals at risk for affective disorders and the development of new preventive and therapeutic interventions may result from further study of circadian dysfunction.     

Alterations in the circadian rest-activity rhythm in aging and Alzheimer's disease

The suprachiasmatic nucleus, considered to be the endogenous circadian clock in the mammalian brain, shows morphological changes with aging, which become even more pronounced in Alzheimer's disease (AD). In order to assess possible functional implications of these alterations, circadian rest-activity rhythms of 6 young and 13 old volunteers and of 12 AD patients were studied with a recently developed ambulatory rest-activity monitor (RA24). Young and old volunteers showed no differences in their rest-activity rhythm in any of the variables studied. Comparison of old controls versus AD patients revealed that (1) rest-activity rhythm was markedly disturbed in many of the AD patients and tended to be correlated with the severity of the dementia; (2) disturbances were most pronounced in subjects using sedating drugs; (3) disturbances in the latter group did not result from medication as no differences were found in the rest-activity patterns before and after administration of sedating drugs; (4) negative findings reported in the literature concerning circadian disturbances in AD may well have resulted from selection criteria that excluded the group of patients with the most severely affected rest-activity rhythm; and (5) rest-activity monitors offer a practical and fruitful approach for the study of circadian rhythms in humans.     

Sleep and circadian rhythms in mood disorders

OBJECTIVE: Self-reported sleep disturbances are present in over 80% of patients with depression. However, sleep electroencephalography (EEG) findings, based on overnight polysomnography have not always differentiated depressed patients from healthy individuals. METHOD: The present paper will review the findings on sleep EEG studies in depression highlighting how recent technological and methodological advances have impacted on study outcomes. RESULTS: The majority of studies, including our own work, do indicate that sleep homeostasis and sleep EEG rhythms are abnormal in depression, but the sleep disturbances were strongly moderated by gender and age. Melancholic features of depression correlated significantly with low slow-wave activity in depressed men, but not in depressed women. Women with depression showed low temporal coherence of sleep EEG rhythms but the presence or absence of melancholic features did not influence correlations. CONCLUSION: Diagnostic classification schemas and clinical features of depression may influence sleep EEG findings, but gender may be a more important consideration.     

Cortisol circadian rhythms and stress responses in infants at risk of allergic disease

Altered hypothalamic-pituitary-adrenal function associated with allergic disease has generally been thought to be secondary to the stress of chronic disease. However, recent studies suggest that altered cortisol circadian rhythm and cortisol stress hyper-responsiveness precede the inception of allergic disease and are possible links between preventive factors associated with the hygiene hypothesis and the development of allergies. Elevated endogenous cortisol responses to stressful stimuli could predispose susceptible hosts to atopy and allergic disease by biasing the developing immune system to a T helper 2-predominant immune response, greater total and allergen-specific serum immunoglobulin E responses, and/or inhibition of peripheral immune tolerance. Because glucocorticoid receptors are present throughout the human body and many genes contain glucocorticoid response elements, variances in endogenous cortisol concentrations could have an impact on the phenotypic plasticity of a wide range of immunologically active genes during early human immune development. Here, recent findings related to hypothalamic-pituitary-adrenal function in infants predisposed to developing allergic disease are discussed along with speculation regarding the potential causal role of endogenous cortisol in the inception of allergic disease.     

Hormonal circadian rhythms in eating disorders

The circadian rhythm of several plasma hormones (prolactin, growth hormone, adrenocorticotropic hormone (ACTH), cortisol, and melatonin) was simultaneously evaluated in 23 women with anorexia nervosa (AN), in 27 obese (OB) women, and in gender and age-matched healthy controls. A trend toward similar alterations of the circadian pattern of the different hormones was observed in the two groups of patients, with the exception of plasma growth hormone (GH), which exhibited nutrition-dependent impairments. The timing of the peaks for each hormonal rhythm revealed the existence of an internal desynchronization in both eating disorders.     

ADHD,circadian rhythms and seasonality

ObjectiveWe evaluated whether the association between Adult Attention-Deficit/Hyperactivity Disorder (ADHD) and Seasonal Affective Disorder (SAD) was mediated by the circadian rhythm.MethodData of 2239 persons from the Netherlands Study of Depression and Anxiety (NESDA) were used. Two groups were compared: with clinically significant ADHD symptoms (N = 175) and with No ADHD symptoms (N = 2064). Sleep parameters were sleep-onset and offset times, mid sleep and sleep duration from the Munich Chronotype Questionnaire. We identified the prevalence of probable SAD and subsyndromal SAD using the Seasonal Pattern Assessment Questionnaire (SPAQ). Clinically significant ADHD symptoms were identified by using a T score>65 on the Conners Adult ADHD Rating Scale.ResultsThe prevalence of probable SAD was estimated at 9.9% in the ADHD group (vs. 3.3% in the No ADHD group) and of probable s-SAD at 12.5% in the ADHD group (vs 4.6% in the No ADHD group). Regression analyses showed consistently significant associations between ADHD symptoms and probable SAD, even after adjustment for current depression and anxiety, age, sex, education, use of antidepressants and benzodiazepines (B = 1.81, p < 0.001). Late self-reported sleep onset was an important mediator in the significant relationship between ADHD symptoms and probable SAD, even after correction for confounders (total model effects: B = 0.14, p ≤ 0.001).ConclusionBoth seasonal and circadian rhythm disturbances are significantly associated with ADHD symptoms. Delayed sleep onset time in ADHD may explain the increase in SAD symptoms. Treating patients with SAD for possible ADHD and delayed sleep onset time may reduce symptom severity in these complex patients.     

Altered circadian cortisol secretion in Alzheimer's disease: clinical and neuroradiological aspects

We determined circadian salivary cortisol levels in 18 outpatients affected by probable Alzheimer's disease (AD) and looked for a possible correlation with both cognitive impairment and brain CT scan findings. The diagnosis of probable AD was made according to the NINCDS-ADRDA criteria. The severity of cognitive impairment was quantified using the Mini Mental State Examination (MMSE) and the Global Deterioration Scale (GDS). Cortisol levels were measured on saliva samples collected at 08:00 AM and 08:00 PM. For each sample, a duplicate cortisol measurement was performed on 50 microl of saliva by means of a modified commercial radioimmunoassay kit. At the same time, 11 of the 18 AD patients enrolled also underwent a brain CT scan to estimate cerebral atrophy by using linear indexes. The mean value of cortisol levels was significantly higher in AD patients than in controls at both the morning and the evening measurements, and the circadian fluctuation of cortisol was less marked in AD patients than in controls, although this difference did not reach statistical significance. Morning cortisol levels were significantly correlated to both the MMSE and the GDS scores. A significant correlation was also found between morning cortisol levels and all the cerebral atrophy indexes. By contrast, no correlation was observed between evening cortisol levels or cortisol circadian fluctuations and either cognitive impairment or cerebral atrophy. In conclusion, despite the potential biases deriving from the small sample and the limitations of the CT scan study, our results suggest that, in AD patients, hypercortisolemia is correlated with severity of the disease.     

Food-anticipatory circadian rhythms: concepts and methods

Rats, mice and other species can behaviorally anticipate a predictable daily mealtime by entrainment of circadian oscillators (food-entrainable oscillators) distinct from those (light-entrainable oscillators) that regulate light-dark entrained rhythms of behavior and physiology. Neurobiological analysis of food-anticipatory rhythms has progressed slowly but is gaining pace. Food-anticipatory rhythms have proven to be surprisingly robust to many neural and circadian clock gene perturbations. A few neural ablation sites or gene mutations have been associated with loss or marked attenuation of anticipatory rhythms, but in each case there are apparently conflicting reports. Attenuation of food-anticipatory rhythms following neural or genetic perturbations could result from actions upstream or downstream from the clock mechanism, and could be limited to certain behavioral endpoints or recording conditions. Failure to observe attenuation could reflect compensation by alternate timing mechanisms that do not involve food-entrainable oscillators. To facilitate progress in neurobiological analysis of food-anticipatory rhythms, criteria for distinguishing among formally distinct mechanisms by which animals might anticipate a daily meal are reviewed, and procedural variables that can affect the expression of food-anticipatory rhythms in neurobiologically intact or compromised animals are identified.     

Functional neuroanatomy of sleep and circadian rhythms

The daily sleep–wake cycle is perhaps the most dramatic overt manifestation of the circadian timing system, and this is especially true for the monophasic sleep–wake cycle of humans. Considerable recent progress has been made in elucidating the neurobiological mechanisms underlying sleep and arousal, and more generally, of circadian rhythmicity in behavioral and physiological systems. This paper broadly reviews these mechanisms from a functional neuroanatomical and neurochemical perspective, highlighting both historical and recent advances. In particular, I focus on the neural pathways underlying reciprocal interactions between the sleep-regulatory and circadian timing systems, and the functional implications of these interactions. While these two regulatory systems have often been considered in isolation, sleep–wake and circadian regulation are closely intertwined processes controlled by extensively integrated neurobiological mechanisms.     

Glial cell modulation of circadian rhythms

Studies of Drosophila and mammals have documented circadian changes in the morphology and biochemistry of glial cells. In addition, it is known that astrocytes of flies and mammals contain evolutionarily conserved circadian molecular oscillators that are similar to neuronal oscillators. In several sections of this review, I summarize the morphological and biochemical rhythms of glia that may contribute to circadian control. I also discuss the evidence suggesting that glia-neuron interactions may be critical for circadian timing in both flies and mammals. Throughout the review, I attempt to compare and contrast findings from these invertebrate and vertebrate models so as to provide a synthesis of current knowledge and indicate potential research avenues that may be useful for better understanding the roles of glial cells in the circadian system.     

Effects of aging and genotype on circadian rhythms, sleep, and clock gene expression in APPxPS1 knock-in mice, a model for Alzheimer's disease

Profound disruptions of circadian rhythms and sleep/wake cycles constitute a major cause of institutionalization of AD patients. This study investigated whether a rodent model of AD, APP(NLH/NLH)/PS-1(P264L/264L) (APPxPS1) mice, exhibits circadian alterations. The APPxPS1 mice were generated using CD-1/129 mice and Cre-lox knock-in technology to "humanize" the mouse amyloid (A)β sequence and create a presenilin-1 mutation identified in familial early-onset AD patients. APPxPS1 and WT mice of several ages (~4, 11, and 15 months) were monitored for circadian rhythms in wheel running, cage activity, and sleep:wake behavior. After rhythm assessment, the mice were euthanized at zeitgeber time (ZT) 2 or 10 (i.e., 2 or 10 h after lights-on) and brains were dissected. Amyloidβ levels were measured in cortical samples and brain sections of the hypothalamus and hippocampus were prepared and used for in situ hybridization of circadian or neuropeptide genes. The most significant effects of the APPxPS1 transgenes were phase delays of ~2 h in the onset of daytime wakefulness bouts (P<0.005) and peak wakefulness (P<0.02), potentially relevant to phase delays previously reported in AD patients. However, genotype did not affect the major activity peaks or phases of wheel running, wake, or general movement, which were bimodal with dominant dawn and dusk activity. Expression of Period 2 in the suprachiasmatic nucleus was affected by ZT (P<0.0001) with a marginal interaction effect of age, genotype, and ZT (P<0.08). A separate analysis of the old animals indicated a robust interaction between ZT and genotype, as well as main effects of these parameters. Aging also altered sleep (e.g., bout length and amount of daytime sleep) and the amount of wheel running and cage activity. In conclusion, the APPxPS1 knock-in mice exhibit some alterations in their sleep:wake rhythm and clock gene expression, but do not show robust, genotype-related changes in activity rhythms. The prominent daytime activity peaks shown by the background strain complicate the use of these APPxPS1 knock-in mice for investigations of circadian activity rhythms in AD. In addition to this unusual activity pattern, lack of hyperactivity differentiates the APPxPS1 knock-in mice from other transgenic AD models.     

The hypothalamic integrator for circadian rhythms

Although the suprachiasmatic nucleus (SCN) is well established as providing a genetically based clock for timing circadian rhythms, the mechanisms by which the timing signal is translated into circadian rhythms of behavior and underlying physiology have only recently come to light. The bulk of the SCN outflow terminates in a column of tissue that arches upward and backward from the SCN, and which includes the subparaventricular zone (SPZ) and the dorsomedial nucleus of the hypothalamus. Neurons within the dorsal SPZ are necessary for organizing circadian rhythms of body temperature, whereas neurons in the ventral SPZ are needed for circadian rhythms of sleep and waking. Ventral SPZ neurons in turn relay to the dorsomedial nucleus, which is crucial for producing circadian rhythms of sleep and waking, locomotor activity, feeding and corticosteroid production. This multistage processor provides the animal with flexibility so that environmental cues, such as food availability, ambient temperature and social interactions, can be integrated with the clock signal to sculpt an adaptive pattern of rhythmic daily activities that maximize the chances of survival and reproduction.     

Resting state cortical rhythms in mild cognitive impairment and Alzheimer's disease: electroencephalographic evidence

Physiological brain aging is characterized by a combination of synaptic pruning, loss of cortico-cortical connections and neuronal apoptosis that provoke age-dependent decline of cognitive functions. Neural/synaptic redundancy and plastic remodeling of brain networking, also secondary to mental and physical training, promotes maintenance of brain activity in healthy elderly for everyday life and fully productive affective and intellectual capabilities. Unfortunately, in pathological situations, aging triggers neurodegenerative processes that impact on cognition, like Alzheimer's disease (AD). Oscillatory electromagnetic brain activity is a hallmark of neuronal network function in various brain regions. Modern neurophysiological techniques including digital electroencephalography (EEG) allow non-invasive analysis of cortico-cortical connectivity and neuronal synchronization of firing, and coherence of brain rhythmic oscillations at various frequencies. The present review of field EEG literature suggests that discrimination between physiological and pathological brain aging clearly emerges at the group level, with some promising result on the informative value of EEG markers at the individual level. Integrated approaches utilizing neurophysiological techniques together with biological markers and structural and functional imaging are promising for large-scale, low-cost, widely available on the territory and non-invasive screening of at-risk populations.