Pupil size is regulated exclusively by the autonomic nervous system, and in darkness is proportional to the level of central sympathetic tone. Spontaneous pupillary movements, while at rest in darkness and quiet, were recorded for a period of 11 min, using infrared video pupillography. Thirteen young adults took part in a 30‐h experiment lasting from 08.00 h to 14.00 h on the following day. Pupillographic testing and completion of a self‐rated scale for the estimate of sleepiness were repeated every two hours. Pupillary unrest index (PUI), as a measure of pupil size instability associated with daytime sleepiness, showed the lowest values at 09.00 h, when pupil size was found to be maximal, and 23.00 h. During the course of the day, amplitude spectrum ≤0.8 Hz and PUI showed increasing values during the afternoon hours, followed by a decrease during the evening. Daytime variations in the pupillary unrest index in healthy normal subjects were found to be positively correlated with the level of alertness. These findings are similar to the daytime variations found by the MSLT (multiple sleep latency test) in young adults.

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Alzheimer’s disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes—aggregation of the amyloid-β (Aβ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)—are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of Aβ plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with Aβ plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than Aβ and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with Aβ and tau.

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