Table 1.

Sleep deficits and cellular stress in neurological disorders with various etiologies.

	Onset of delay	Onset of sleep difficulties	Prevalence of sleep deficits	Sleep phenotypes	Cellular stress and damage in the brain	Cognitive and behavioral phenotypes
Neurodevelopment
Autism spectrum disorder (ASD)	12–18 months	0–6 months [122]	86% [88]	Insomnia, bedtime resistance, parasomnias, sleep disordered breathing, morning rise problems, daytime sleepiness, increased sleep latency, decreased sleep efficiency, decreased REM, increased late-stage NREM [88]	ER stress, altered expression of ER stress genes, accumulation of reactive oxygen species, decreased antioxidant capacity, lipid peroxidation, increased levels of 8-oxo-dG [72–76,80–84]	Restrictive and repetitive behaviors, avoiding physical contact, communication deficits, sometimes non-verbal, social interaction deficits [123]
Fragile X syndrome (FXS)	12–16 months	≤3 years [50]	32% [50]	Increased sleep latency, sleep fragmentation, reduced REM duration, fewer REM bouts, disrupted NREM [50,124]	Decreased expression of DNA repair genes, elevated Aβ levels, elevated NADPH-oxidase activity, altered antioxidant activity, increased lipid and protein oxidation [93,98–101]	Cognitive impairment, hyperactivity, anxiety, social avoidance, hyperarousal to stimuli, attention deficits, increased risk of ASD [125]
Neurodegeneration
Alzheimer’s disease (AD)	∼65 years	often precedes, risk factor (1.49-fold) [70]	45% [126]	Insomnia, sleep fragmentation, sleep disordered breathing, disrupted circadian rhythms, excessive daytime sleepiness, reduced REM and NREM [44,70,127,128]	Cellular oxidative stress, ER stress, mitochondrial dysfunction, upregulation of BACE1, nuclear and mitochondrial DNA oxidation, reduced activity of base excision repair proteins [53–58,60,62–67]	Sundowning (agitation/confusion beginning around dusk), dementia, memory loss, impaired communication, disorientation/confusion, poor judgement, behavioral changes, difficulty swallowing, speaking, and walking [52]
Parkinson’s disease (PD)	∼65–70 years	RBD onset often precedes PD (12.7 ± 7.3 years) [129]	90% [130]	REM sleep behavior disorder (RBD), daytime sleepiness, insomnia, restless leg syndrome, decreased total sleep time, decreased sleep efficiency, decreased NREM and REM, increased wake time after sleep onset, increased REM latency, sleep apnea [130]	Oxidative stress, elevated 8-oxo-G, abasic sites, and nuclear DNA strand breaks, persistent mtDNA abasic sites, impaired mitochondrial complex I, reduced ATP synthesis, increased ROS production, increased mitochondrial mutations and defective mitochondrial repair pathways, decreased GSH levels [131–133]	Problems with movement (tremor, rigidity, bradykinesia, postural instability), dementia, depression, sensory dysfunction, cognitive changes, behavioral changes, autonomic dysfunction [134]
Neurological injury
Traumatic brain injury (TBI)	-	-	30–70% [135]	Sleep apnea, excessive daytime sleepiness, circadian rhythm misalignment, sleep-wake disturbances, fatigue, insomnia, hypersomnia, REM behavior disorder [135–138]	Oxidative stress, ER stress, elevated reactive oxygen species, neuroinflammation, disrupted brain energy metabolism, lipid peroxidation, impaired energy homeostasis, increased Aβ, BACE1, and APP [139–141]	Centralized pain, headaches, negative mood and emotional impacts, depression, anxiety, memory impairment, increased risk of neurodegenerative disease [138,142]
Stroke	-	Risk factor and outcome [143]	20–69% (insomnia) [144]	Insomnia, sleep disordered breathing, circadian rhythm dysfunctions, sleep-related movement disorders, decreased REM, prolonged REM latency, decreased NREM, reduced total sleep time, lower sleep efficiency [145–147]	Excessive ROS production, decreased ROS scavenging (decreased SODs, CATs, GPx, and glutathione), depletion of cellular energy, inflammation, DNA damage (apurinic/apyrimidinic sites, oxidative base modifications, singlestrand breaks, and double strand breaks) [148–150]	Depression, anxiety, impaired mobility, cognition and memory, and speaking, emotional difficulties, social isolation, fatigue [151]

Abbreviations: ROS, reactive oxygen species; REM, rapid eye movement; NREM, non-REM; RBD, REM sleep behavior disorder; ER, endoplasmic reticulum; Aβ, Amyloid beta; GSH, glutathione; BACE1, Beta-secretase 1; APP, Amyloid beta precursor protein; SOD, superoxide dismutase; CAT, catalase; GPx, glutathione peroxidase.