Andrew S. Lim

Modification of the Relationship of the Apolipoprotein E ε4 Allele to the Risk of Alzheimer Disease and Neurofibrillary Tangle Density by Sleep

IMPORTANCEnThe apolipoprotein E (APOE [GenBank, 348; OMIM, 107741]) ε4 allele is a common and well-established genetic risk factor for Alzheimer disease (AD). Sleep consolidation is also associated with AD risk, and previous work suggests that APOE genotype and sleep may interact to influence cognitive function.nnnOBJECTIVEnTo determine whether better sleep consolidation attenuates the relationship of the APOE genotype to the risk of incident AD and the burden of AD pathology.nnnDESIGN, SETTING, AND PARTICIPANTSnA prospective longitudinal cohort study with up to 6 years of follow-up was conducted. Participants included 698 community-dwelling older adults without dementia (mean age, 81.7 years; 77% women) in the Rush Memory and Aging Project.nnnEXPOSURESnWe used up to 10 days of actigraphic recording to quantify the degree of sleep consolidation and ascertained APOE genotype.nnnMAIN OUTCOMES AND MEASURESnParticipants underwent annual evaluation for AD during a follow-up period of up to 6 years. Autopsies were performed on 201 participants who died, and β-amyloid (Aβ) and neurofibrillary tangles were identified by immunohistochemistry and quantified.nnnRESULTSnDuring the follow-up period, 98 individuals developed AD. In a series of Cox proportional hazards regression models, better sleep consolidation attenuated the effect of the ε4 allele on the risk of incident AD (hazard ratio, 0.67; 95% CI, 0.46-0.97; P = .04 per allele per 1-SD increase in sleep consolidation). In a series of linear mixed-effect models, better sleep consolidation also attenuated the effect of the ε4 allele on the annual rate of cognitive decline. In individuals who died, better sleep consolidation attenuated the effect of the ε4 allele on neurofibrillary tangle density (interaction estimate, -0.42; SE = 0.17; P = .02), which accounted for the effect of sleep consolidation on the association between APOE genotype and cognition proximate to death.nnnCONCLUSIONS AND RELEVANCEnBetter sleep consolidation attenuates the effect of APOE genotype on incident AD and development of neurofibrillary tangle pathology. Assessment of sleep consolidation may identify APOE+ individuals at high risk for incident AD, and interventions to enhance sleep consolidation should be studied as potentially useful means to reduce the risk of AD and development of neurofibrillary tangles in APOE ε4+ individuals.

Selective enhancement of rapid eye movement sleep by deep brain stimulation of the human pons.

Animal studies suggest that rapid eye movement (REM) sleep is governed by the interaction of REM‐promoting and REM‐inhibiting nuclei in the pontomesencephalic tegmentum. The pedunculopontine nucleus is proposed to be REM promoting. Using polysomnography, we studied sleep in five parkinsonian patients undergoing unilateral pedunculopontine nucleus deep brain stimulation (DBS). We demonstrated a near doubling of nocturnal REM sleep between the DBS “off” and DBS “on” states, without significant changes in other sleep states. This represents the first demonstration that DBS can selectively modulate human sleep, and it supports an important role for the pedunculopontine nucleus region in modulating human REM sleep. Ann Neurol 2009;66:110–114

Sleep is related to neuron numbers in the ventrolateral preoptic/intermediate nucleus in older adults with and without Alzheimer’s disease

Fragmented sleep is a common and troubling symptom in ageing and Alzheimers disease; however, its neurobiological basis in many patients is unknown. In rodents, lesions of the hypothalamic ventrolateral preoptic nucleus cause fragmented sleep. We previously proposed that the intermediate nucleus in the human hypothalamus, which has a similar location and neurotransmitter profile, is the homologue of the ventrolateral preoptic nucleus, but physiological data in humans were lacking. We hypothesized that if the intermediate nucleus is important for human sleep, then intermediate nucleus cell loss may contribute to fragmentation and loss of sleep in ageing and Alzheimers disease. We studied 45 older adults (mean age at death 89.2 years; 71% female; 12 with Alzheimers disease) from the Rush Memory and Aging Project, a community-based study of ageing and dementia, who had at least 1 week of wrist actigraphy proximate to death. Upon death a median of 15.5 months later, we used immunohistochemistry and stereology to quantify the number of galanin-immunoreactive intermediate nucleus neurons in each individual, and related this to ante-mortem sleep fragmentation. Individuals with Alzheimers disease had fewer galaninergic intermediate nucleus neurons than those without (estimate -2872, standard error = 829, P = 0.001). Individuals with more galanin-immunoreactive intermediate nucleus neurons had less fragmented sleep, after adjusting for age and sex, and this association was strongest in those for whom the lag between actigraphy and death was <1 year (estimate -0.0013, standard error = 0.0005, P = 0.023). This association did not differ between individuals with and without Alzheimers disease, and similar associations were not seen for two other cell populations near the intermediate nucleus. These data are consistent with the intermediate nucleus being the human homologue of the ventrolateral preoptic nucleus. Moreover, they demonstrate that a paucity of galanin-immunoreactive intermediate nucleus neurons is accompanied by sleep fragmentation in older adults with and without Alzheimers disease.

Suprachiasmatic neuron numbers and rest–activity circadian rhythms in older humans

The suprachiasmatic nucleus (SCN) of the hypothalamus, the master mammalian circadian pacemaker, synchronizes endogenous rhythms with the external day–night cycle. Older humans, particularly those with Alzheimer disease (AD), often have difficulty maintaining normal circadian rhythms compared to younger adults, but the basis of this change is unknown. We report that the circadian rhythm amplitude of motor activity in both AD subjects and age‐matched controls is correlated with the number of vasoactive intestinal peptide–expressing SCN neurons. AD was additionally associated with delayed circadian phase compared to cognitively healthy subjects, suggesting distinct pathologies and strategies for treating aging‐ and AD‐related circadian disturbances. Ann Neurol 2015;78:317–322

Increased fragmentation of rest-activity patterns is associated with a characteristic pattern of cognitive impairment in older individuals.

STUDY OBJECTIVESnAging is accompanied by changes in cognitive function, and changes in rest-activity patterns. Previous work has demonstrated associations between global rest-activity measures and cognitive performance on a number of tasks. Recently, we demonstrated that aging is associated with changes in the minute-to-minute fragmentation of rest-activity patterns in addition to changes in amounts of rest and activity. Given the body of experimental evidence linking sleep fragmentation with decrements in cognitive function in animals and humans, we hypothesized that increased fragmentation of rest-activity patterns would be associated with decreased cognitive function in older individuals.nnnDESIGNnCross-sectional.nnnPARTICIPANTSn700 community-dwelling individuals from the Rush Memory and Aging Project.nnnMEASUREMENTS AND RESULTSnWe obtained up to 11 days of actigraphic recordings in subjects home environments and quantified the fragmentation of rest and activity using a recently developed state transition metric. We tested the associations between this metric and performance in 5 cognitive domains. Greater fragmentation of both rest and activity were associated with lower levels of cognitive performance, and this association was independent of total amounts of rest or activity. There was a characteristic pattern of cognitive deficits associated with rest and activity fragmentation, with preferential involvement of perceptual speed, semantic memory, working memory, and visuospatial abilities, and relative sparing of episodic memory.nnnCONCLUSIONSnThe fragmentation of periods of rest and activity is a clinically important characteristic of rest-activity patterns that correlates with cognitive performance in older individuals.

24-Hour Rhythms of DNA Methylation and Their Relation with Rhythms of RNA Expression in the Human Dorsolateral Prefrontal Cortex

Circadian rhythms modulate the biology of many human tissues, including brain tissues, and are driven by a near 24-hour transcriptional feedback loop. These rhythms are paralleled by 24-hour rhythms of large portions of the transcriptome. The role of dynamic DNA methylation in influencing these rhythms is uncertain. While recent work in Neurospora suggests that dynamic site-specific circadian rhythms of DNA methylation may play a role in modulating the fungal molecular clock, such rhythms and their relationship to RNA expression have not, to our knowledge, been elucidated in mammalian tissues, including human brain tissues. We hypothesized that 24-hour rhythms of DNA methylation exist in the human brain, and play a role in driving 24-hour rhythms of RNA expression. We analyzed DNA methylation levels in post-mortem human dorsolateral prefrontal cortex samples from 738 subjects. We assessed for 24-hour rhythmicity of 420,132 DNA methylation sites throughout the genome by considering methylation levels as a function of clock time of death and parameterizing these data using cosine functions. We determined global statistical significance by permutation. We then related rhythms of DNA methylation with rhythms of RNA expression determined by RNA sequencing. We found evidence of significant 24-hour rhythmicity of DNA methylation. Regions near transcription start sites were enriched for high-amplitude rhythmic DNA methylation sites, which were in turn time locked to 24-hour rhythms of RNA expression of nearby genes, with the nadir of methylation preceding peak transcript expression by 1–3 hours. Weak ante-mortem rest-activity rhythms were associated with lower amplitude DNA methylation rhythms as were older age and the presence of Alzheimers disease. These findings support the hypothesis that 24-hour rhythms of DNA methylation, particularly near transcription start sites, may play a role in driving 24-hour rhythms of gene expression in the human dorsolateral prefrontal cortex, and may be affected by age and Alzheimers disease.

A common polymorphism near PER1 and the timing of human behavioral rhythms

Circadian rhythms influence the timing of behavior, neurological diseases, and even death. Rare mutations in homologs of evolutionarily conserved clock genes are found in select pedigrees with extreme sleep timing, and there is suggestive evidence that certain common polymorphisms may be associated with self‐reported day/night preference. However, no common polymorphism has been associated with the timing of directly observed human behavioral rhythms or other physiological markers of circadian timing at the population level.

Quantification of the fragmentation of rest-activity patterns in elderly individuals using a state transition analysis.

OBJECTIVESnRecent interest in the temporal dynamics of behavioral states has spurred the development of analytical approaches for their quantification. Several analytical approaches for polysomnographic data have been described. However, polysomnography is cumbersome, perturbs behavior, and is limited to short recordings. Although less physiologically comprehensive than polysomnography, actigraphy is nonintrusive, amenable to long recordings, and suited to use in subjects natural environments, and provides an indirect measure of behavioral state. We developed a probabilistic state transition model to quantify the fragmentation of human rest-activity patterns from actigraphic data. We then applied this to the study of the temporal dynamics of rest-activity patterns in older individuals.nnnDESIGNnCross-sectional.nnnSETTINGnCommunity-based.nnnPARTICIPANTSn621 community-dwelling individuals without dementia participating in the Rush Memory and Aging Project.nnnMEASUREMENTS AND RESULTSnWe analyzed actigraphic data collected for up to 11 days. We processed each record to give a series of transitions between the states of rest and activity, calculated the probabilities of such transitions, and described their evolution as a function of time. From these analyses, we derived metrics of the fragmentation of rest or activity at scales of seconds to minutes. Regression modeling of the relationship of these metrics with clinical variables revealed significant associations with age, even after adjusting for sex, body mass index, and a broad range of medical comorbidities.nnnCONCLUSIONSnProbabilistic analyses of the transition dynamics of rest-activity data provide a high-throughput, automated, quantitative, and noninvasive method of assessing the fragmentation of behavioral states suitable for large scale human and animal studies; these methods reveal age-associated changes in the fragmentation of rest-activity patterns akin to those described using polysomnographic methods.

Global Hemispheric CT Hypoperfusion May Differentiate Headache With Associated Neurological Deficits and Lymphocytosis From Acute Stroke

Headache with associated neurological deficits and lymphocytosis (HaNDL) is characterized by temporary recurrent neurological deficits, moderate–severe headache, cerebrospinal fluid lymphocytosis, elevated protein, and increased opening pressure.1 Although CT and MRI should be normal, single photon emission CT may indicate focal hypoperfusion and electroencephalogram may reveal slowing or even epileptiform activity2 resolving once the patient is symptom-free (3 months). Catheter angiography also yields normal results but may trigger an acute neurological episode.3,4nnBecause HaNDL is a benign, self-limited syndrome, it is important to differentiate it from cerebrovascular disease to avoid unnecessary interventions such as catheter angiography and thrombolysis. We present a case initially thought to be acute stroke in which the patient was considered for thrombolysis. CT perfusion changes atypical for stroke made stroke diagnosis questionable and thrombolysis was withheld.nnA 31-year-old man with hypertension, dyslipidemia, and sleep apnea (treated with continuous positive airway pressure), but no history of prior migraine, was brought into our emergency department by ambulance with suspected acute ischemic stroke. He had become aphasic at work so his coworkers called 911. On examination, he was globally aphasic without focal weakness or obvious sensory changes aside from questionable mild right facial paresis (National Institutes of Health Stroke Scale score 6). A noncontrast CT and CT angiogram (CTA) were normal, but CT perfusion revealed a striking pattern of …

Regional Neocortical Gray Matter Structure and Sleep Fragmentation in Older Adults.

STUDY OBJECTIVESnTo test the hypothesis that greater sleep fragmentation is associated with regionally decreased cortical gray matter volume in older community-dwelling adults without cognitive impairment.nnnMETHODSnWe studied 141 community-dwelling older adults (median age 82.9; 73% female) without cognitive impairment or stroke, and not using sedative/ hypnotic medications, participating in the Rush Memory and Aging Project. We quantified sleep fragmentation from 7 d of actigraphy using the metric kRA and related this to total cortical gray matter volume, and regional gray matter volume in 34 cortical regions quantified by automated segmentation of magnetic resonance imaging data. We determined statistical significance and accounted for multiple comparisons by empirically estimating the false discovery rate by permutation.nnnRESULTSnLower total cortical gray matter volume was associated with higher sleep fragmentation (coefficient +0.23, standard error [SE] 0.11, P = 0.037). Lower gray matter volumes in four cortical regions were accompanied by higher sleep fragmentation with a false discovery rate < 0.05: the left (coefficient +0.36, SE 0.10, P = 2.7 × 10(-4)) and right (coefficient +0.31, SE 0.10, P = 4.0 × 10(-3)) lateral orbitofrontal cortices, and the adjacent left (coefficient +0.31, SE 0.10, 5.4 × 10(-4)) and right (coefficient +0.39, SE 0.10, P = 1.2 × 10(-4)) inferior frontal gyri pars orbitalis. These associations were unchanged after accounting for age, sex, education, depression, cognitive function, and a number of medical comorbidities.nnnCONCLUSIONSnLower cortical gray matter volume in the lateral orbitofrontal cortex and inferior frontal gyrus pars orbitalis is associated with greater sleep fragmentation in older community-dwelling adults. Further work is needed to clarify whether this is a consequence of or contributor to sleep fragmentation.nnnCOMMENTARYnA commentary on this article appears in this issue on page 15.