Abstract
Melanopsin-expressing retinal ganglion cells (mRGCs), intrinsically photosensitive RGCs, mediate the light-based pupil response and the light entrainment of the body's circadian rhythms through their connection to the pretectal nucleus and hypothalamus, respectively. Increased awareness of circadian rhythm dysfunction in neurological conditions including Alzheimer's disease (AD), has led to a wave of research focusing on the role of mRGCs in these diseases. Postmortem retinal analyses in AD patients demonstrated a significant loss of mRGCs, and in vivo measurements of mRGC function with chromatic pupillometry may be a potential biomarker for early diagnosis and progression of AD. We performed a prospective case-control study in 20 cognitively healthy study participants: 10 individuals with pre-symptomatic AD pathology (pre-AD), identified by the presence of abnormal levels of amyloid β42 and total Tau proteins in the cerebrospinal fluid, and 10 age-matched controls with normal CSF amyloid β42 and Tau levels. To evaluate mRGC function, we used a standardized protocol of chromatic pupillometry on a Ganzfeld system using red (640 nm) and blue (450 nm) light stimuli and measured the pupillary light response (PLR). Non-invasive wrist actigraphy and standardized sleep questionnaires were also completed to evaluate rest-activity circadian rhythm. Our results did not demonstrate a significant difference of the PLR between pre-AD and controls but showed a variability of the PLR in the pre-AD group compared with controls on chromatic pupillometry. Wrist actigraphy showed variable sleep-wake patterns and irregular circadian rhythms in the pre-AD group compared with controls. The variability seen in measurements of mRGC function and sleep-wake cycle in the pre-AD group suggests that mRGC dysfunction occurs in the pre-symptomatic AD stages, preceding cognitive decline. Future longitudinal studies following progression of these participants can help in elucidating the relationship between mRGCs and circadian rhythm dysfunction in AD.
Highlights
Alzheimer’s disease (AD) is the most frequent type of dementia, characterized by abnormal accumulation of misfolded amyloid-ß (Aß) protein and hyperphosphorylated-Tau in the brain, in the form of amyloid plaques and neurofibrillary tangles respectively
The variability seen in measurements of Melanopsin-expressing retinal ganglion cells (mRGCs) function and sleep-wake cycle in the preAD group suggests that mRGC dysfunction occurs in the pre-symptomatic AD stages, preceding cognitive decline
Future longitudinal studies following progression of these participants can help in elucidating the relationship between mRGCs and circadian rhythm dysfunction in AD
Summary
Alzheimer’s disease (AD) is the most frequent type of dementia, characterized by abnormal accumulation of misfolded amyloid-ß (Aß) protein and hyperphosphorylated-Tau in the brain, in the form of amyloid plaques and neurofibrillary tangles respectively. The search for additional in vivo markers to improve early diagnosis of AD or measure progression is expanding and the eye represents a promising field of research [5]. In human postmortem specimens and animal models, histological studies demonstrated the characteristic Aß deposits and Tauopathy in the inner retina, which are associated with degeneration of retinal ganglion cells (RGCs) and macular and optic nerve thinning with predominant loss of larger fibers in the superior quadrant [7,8,9]. Postmortem retinal analyses in AD patients demonstrated a significant loss of mRGCs, and in vivo measurements of mRGC function with chromatic pupillometry may be a potential biomarker for early diagnosis and progression of AD
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