Brendan P. Lucey

Sleep and Alzheimer disease pathology—a bidirectional relationship

Factors other than age and genetics may increase the risk of developing Alzheimer disease (AD). Accumulation of the amyloid-β (Aβ) peptide in the brain seems to initiate a cascade of key events in the pathogenesis of AD. Moreover, evidence is emerging that the sleep–wake cycle directly influences levels of Aβ in the brain. In experimental models, sleep deprivation increases the concentration of soluble Aβ and results in chronic accumulation of Aβ, whereas sleep extension has the opposite effect. Furthermore, once Aβ accumulates, increased wakefulness and altered sleep patterns develop. Individuals with early Aβ deposition who still have normal cognitive function report sleep abnormalities, as do individuals with very mild dementia due to AD. Thus, sleep and neurodegenerative disease may influence each other in many ways that have important implications for the diagnosis and treatment of AD.

Dietary and lifestyle guidelines for the prevention of Alzheimer's disease.

Risk of developing Alzheimers disease is increased by older age, genetic factors, and several medical risk factors. Studies have also suggested that dietary and lifestyle factors may influence risk, raising the possibility that preventive strategies may be effective. This body of research is incomplete. However, because the most scientifically supported lifestyle factors for Alzheimers disease are known factors for cardiovascular diseases and diabetes, it is reasonable to provide preliminary guidance to help individuals who wish to reduce their risk. At the International Conference on Nutrition and the Brain, Washington, DC, July 19-20, 2013, speakers were asked to comment on possible guidelines for Alzheimers disease prevention, with an aim of developing a set of practical, albeit preliminary, steps to be recommended to members of the public. From this discussion, 7 guidelines emerged related to healthful diet and exercise habits.

How amyloid, sleep and memory connect

In a bidirectional relationship, the sleep/wake cycle regulates amyloid-β (Aβ) levels and Aβ accumulation then disrupts sleep. A quantitative three-way model now suggests that Aβ impairs memory via its effect on sleep.

Continuous 24-Hour Leptin, Proopiomelanocortin, and Amino Acid Measurements in Human Cerebrospinal Fluid: Correlations With Plasma Leptin, Soluble Leptin Receptor, and Amino Acid Levels

CONTEXT In order to characterize diurnal changes in central leptin and its target neuropeptide, proopiomelanocortin (POMC), we measured leptin and POMC in cerebrospinal fluid (CSF) as related to changes in plasma leptin and soluble leptin receptor (sOB-R) levels. CSF and plasma levels of 20 amino acids (AA) were also measured because AA can affect brain POMC. DESIGN AND PARTICIPANTS Stored CSF and plasma samples obtained from eight healthy subjects who served as controls for a previous study were evaluated. CSF was collected hourly over 33 h via indwelling subarachnoid catheter. Leptin, sOB-R, and POMC were measured by sensitive ELISA and AA by gas chromatography-mass spectrometry. RESULTS There was a diurnal rhythm for plasma leptin with a peak at 2200 h (144% of baseline) and there was a similar diurnal rhythm for CSF leptin with a peak (117%) 3-5 h after the plasma peak. Plasma sOB-R was lowest at 0300 h and correlated negatively with plasma and CSF leptin. A diurnal rhythm for POMC in CSF was also detected with a peak (125%) at 0100 h. A positive correlation existed between CSF POMC and leptin in individual subjects over time. CSF levels of many AA increased at night. There was a significant correlation between CSF POMC and 10 AA, including leucine, isoleucine, tryptophan, and tyrosine. CONCLUSIONS Diurnal changes occur in leptin and POMC in human CSF that likely reflect changes in central leptin and melanocortin activity. Our results suggest that nocturnal elevations in leptin, AA, and POMC may help to suppress appetite and feeding at night.

Transient encephalopathy in a postoperative non-alcoholic female with Marchiafava-Bignami disease

Marchiafava-Bignami disease (MBD) is historically reported in middle-aged alcoholic men. We describe the presentation, course and radiological findings of a young non-alcoholic woman who developed encephalopathy and MRI findings consistent with MBD postoperatively. She returned to baseline after vitamin supplementation. We believe it is important to diagnose MBD because it is a potentially reversible encephalopathy.

Associations Between β-Amyloid Kinetics and the β-Amyloid Diurnal Pattern in the Central Nervous System

Importance Recent studies found that the concentration of amyloid-&bgr; (A&bgr;) fluctuates with the sleep-wake cycle. Although the amplitude of this day/night pattern attenuates with age and amyloid deposition, to our knowledge, the association of A&bgr; kinetics (ie, production, turnover, and clearance) with this oscillation has not been studied. Objective To determine the association between A&bgr; kinetics, age, amyloid levels, and the A&bgr; day/night pattern in humans. Design, Setting, and Participants We measured A&bgr; concentrations and kinetics in 77 adults aged 60 to 87 years with and without amyloid deposition by a novel precise mass spectrometry method at the Washington University School of Medicine in St Louis, Missouri. We compared findings of 2 orthogonal methods, enzyme-linked immunosorbent assay and mass spectrometry, to validate the day/night patterns and determine more precise estimates of the cosinor parameters. In vivo labeling of central nervous system proteins with stable isotopically labeled leucine was performed, and kinetics of A&bgr;40 and A&bgr;42 were measured. Interventions Serial cerebrospinal fluid collection via indwelling lumbar catheter over 36 to 48 hours before, during, and after in vivo labeling, with a 9-hour primed constant infusion of 13C6-leucine. Main Outcomes and Measures The amplitude, linear increase, and other cosinor measures of each participant’s serial cerebrospinal fluid A&bgr; concentrations and A&bgr; turnover rates. Results Of the 77 participants studied, 46 (59.7%) were men, and the mean (range) age was 72.6 (60.4-87.7) years. Day/night patterns in A&bgr; concentrations were more sharply defined by the precise mass spectrometry method than by enzyme-linked immunosorbent assay (mean difference of SD of residuals: A&bgr;40, −7.42 pM; P < .001; A&bgr;42, −3.72 pM; P < .001). Amyloid deposition diminished day/night amplitude and linear increase of A&bgr;42 but not of A&bgr;40. Increased age diminished day/night amplitude of both A&bgr;40 and A&bgr;42. After controlling for amyloid deposition, amplitude of A&bgr;40 was positively associated with production rates (r = 0.42; P < .001), while the linear rise was associated with turnover rates (r = 0.28; P < .05). The amplitude and linear rise of A&bgr;42 were both associated with turnover (r = −0.38; P < .001) and production (r = 0.238; P < .05) rates. Conclusions and Relevance Amyloid deposition is associated with premature loss of normal A&bgr;42 day/night patterns in older adults, suggesting the previously reported effects of age and amyloid on A&bgr;42 amplitude at least partially affect each other. Production and turnover rates suggest that day/night A&bgr; patterns are modulated by both production and clearance mechanisms active in sleep-wake cycles and that amyloid deposition may impair normal circadian patterns. These findings may be important for the designs of future secondary prevention trials for Alzheimer disease.

Comparison of a single-channel EEG sleep study to polysomnography.

An accurate home sleep study to assess electroencephalography (EEG)‐based sleep stages and EEG power would be advantageous for both clinical and research purposes, such as for longitudinal studies measuring changes in sleep stages over time. The purpose of this study was to compare sleep scoring of a single‐channel EEG recorded simultaneously on the forehead against attended polysomnography. Participants were recruited from both a clinical sleep centre and a longitudinal research study investigating cognitively normal ageing and Alzheimers disease. Analysis for overall epoch‐by‐epoch agreement found strong and substantial agreement between the single‐channel EEG compared to polysomnography (κ = 0.67). Slow wave activity in the frontal regions was also similar when comparing the single‐channel EEG device to polysomnography. As expected, Stage N1 showed poor agreement (sensitivity 0.2) due to lack of occipital electrodes. Other sleep parameters, such as sleep latency and rapid eye movement (REM) onset latency, had decreased agreement. Participants with disrupted sleep consolidation, such as from obstructive sleep apnea, also had poor agreement. We suspect that disagreement in sleep parameters between the single‐channel EEG and polysomnography is due partially to altered waveform morphology and/or poorer signal quality in the single‐channel derivation. Our results show that single‐channel EEG provides comparable results to polysomnography in assessing REM, combined Stages N2 and N3 sleep and several other parameters, including frontal slow wave activity. The data establish that single‐channel EEG can be a useful research tool.

An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-β concentrations collected by lumbar puncture and indwelling lumbar catheter

IntroductionAmyloid-β (Aβ) has been investigated as a diagnostic biomarker and therapeutic drug target. Recent studies found that cerebrospinal fluid (CSF) Aβ fluctuates over time, including as a diurnal pattern, and increases in absolute concentration with serial collection. It is currently unknown what effect differences in CSF collection methodology have on Aβ variability. In this study, we sought to determine the effect of different collection methodologies on the stability of CSF Aβ concentrations over time.MethodsGrouped analysis of CSF Aβ levels from multiple industry and academic groups collected by either lumbar puncture (n=83) or indwelling lumbar catheter (n=178). Participants were either placebo or untreated subjects from clinical drug trials or observational studies. Participants had CSF collected by lumbar puncture or lumbar catheter for quantitation of Aβ concentration by enzyme linked immunosorbent assay. Data from all sponsors was converted to percent of the mean for Aβ40 and Aβ42 for comparison. Repeated measures analysis of variance was performed to assess for factors affecting the linear rise of Aβ concentrations over time.ResultsAnalysis of studies collecting CSF via lumbar catheter revealed tremendous inter-subject variability of Aβ40 and Aβ42 as well as an Aβ diurnal pattern in all of the sponsors’ studies. In contrast, Aβ concentrations from CSF samples collected at two time points by lumbar puncture showed no significant differences. Repeated measures analysis of variance found that only time and draw frequency were significantly associated with the slope of linear rise in Aβ40 and Aβ42 concentrations during the first 6 hours of collection.ConclusionsBased on our findings, we recommend minimizing the frequency of CSF draws in studies measuring Aβ levels and keeping the frequency standardized between experimental groups. The Aβ diurnal pattern was noted in all sponsors’ studies and was not an artifact of study design. Averaging Aβ concentrations at each time point is recommended to minimize the effect of individual variability. Indwelling lumbar catheters are an invaluable research tool for following changes in CSF Aβ over 24-48 hours, but factors affecting Aβ concentration such as linear rise and diurnal variation need to be accounted for in planning study designs.

Effect of sleep on overnight cerebrospinal fluid amyloid β kinetics

Sleep disturbances are associated with future risk of Alzheimer disease. Disrupted sleep increases soluble amyloid β, suggesting a mechanism for sleep disturbances to increase Alzheimer disease risk. We tested this response in humans using indwelling lumbar catheters to serially sample cerebrospinal fluid while participants were sleep‐deprived, treated with sodium oxybate, or allowed to sleep normally. All participants were infused with 13C6‐leucine to measure amyloid β kinetics. We found that sleep deprivation increased overnight amyloid β38, amyloid β40, and amyloid β42 levels by 25 to 30% via increased overnight amyloid β production relative to sleeping controls. These findings suggest that disrupted sleep increases Alzheimer disease risk via increased amyloid β production. Ann Neurol 2018;83:197–204

A New Model to Study Sleep Deprivation-Induced Seizure

BACKGROUND AND STUDY OBJECTIVES A relationship between sleep and seizures is well-described in both humans and rodent animal models; however, the mechanism underlying this relationship is unknown. Using Drosophila melanogaster mutants with seizure phenotypes, we demonstrate that seizure activity can be modified by sleep deprivation. DESIGN Seizure activity was evaluated in an adult bang-sensitive seizure mutant, stress sensitive B (sesB(9ed4)), and in an adult temperature sensitive seizure mutant seizure (sei(ts1)) under baseline and following 12 h of sleep deprivation. The long-term effect of sleep deprivation on young, immature sesB(9ed4) flies was also assessed. SETTING Laboratory. PARTICIPANTS Drosophila melanogaster. INTERVENTIONS Sleep deprivation. MEASUREMENTS AND RESULTS Sleep deprivation increased seizure susceptibility in adult sesB(9ed4)/+ and sei(ts1) mutant flies. Sleep deprivation also increased seizure susceptibility when sesB was disrupted using RNAi. The effect of sleep deprivation on seizure activity was reduced when sesB(9ed4)/+ flies were given the anti-seizure drug, valproic acid. In contrast to adult flies, sleep deprivation during early fly development resulted in chronic seizure susceptibility when sesB(9ed4)/+ became adults. CONCLUSIONS These findings show that Drosophila is a model organism for investigating the relationship between sleep and seizure activity.