Light-Induced Pupillary Responses in Alzheimer's Disease

Abstract

The impact of Alzheimer's disease (AD) on the pupillary light response (PLR) is controversial, being dependent on the stage of the disease and on the experimental pupillometric protocols. The main hypothesis driving pupillometry research in AD is based on the concept that the AD-related neurodegeneration affects both the parasympathetic and the sympathetic arms of the PLR (cholinergic and noradrenergic theory), combined with additional alterations of the afferent limb, involving the melanopsin expressing retinal ganglion cells (mRGCs), subserving the PLR. Only a few studies have evaluated the value of pupillometry as a potential biomarker in AD, providing various results compatible with parasympathetic dysfunction, displaying increased latency of pupillary constriction to light, decreased constriction amplitude, faster redilation after light offset, decreased maximum velocity of constriction (MCV) and maximum constriction acceleration (MCA) compared to controls. Decreased MCV and MCA appeared to be the most accurate of all PLR parameters allowing differentiation between AD and healthy controls while increased post-illumination pupillary response was the most consistent feature, however, these results could not be replicated by more recent studies, focusing on early and pre-clinical stages of the disease. Whether static or dynamic pupillometry yields useful biomarkers for AD screening or diagnosis remains unclear. In this review, we synopsize the current knowledge on pupillometric features in AD and other neurodegenerative diseases, and discuss potential roles of pupillometry in AD detection, diagnosis and monitoring, alone or in combination with additional biomarkers.

Keywords: Alzheimer's disease; Parkinson's disease; cholinergic deficit; chromatic pupillometry; dementia; melanopsin expressing intrinsically photosensitive retinal ganglion cells; post -llumination pupil response; pupillary light response.

Figure 1

Neuronal control of the PLR and affected structures in AD. The pupil size depends on the interplay between antagonistic parasympathetic and sympathetic impulses. The photoreceptors in retina, including the melanopsin expressing retinal ganglion cells (mRGCs), stimulate the OPN, connected to the parasympathetic EWN. mRGCs also project to the SCN, which is connected to the sympathetic LC. EWN is the major cholinergic center subserving the pupillary constriction to light. Light has an inhibitory effect on sympathetic activity and PVN via SCN. This inhibitory effect is attenuated by sympatho-excitation, which is mediated via the SCN and LC (14). The encircled structures are affected in AD. Solid lines, excitatory connections; dashed lines, inhibitory connections; Hypothalamic nuclei: SCN, suprachiasmatic nucleus; PVN, paraventricular nucleus; DMH, dorsomedial hypothalamus. Autonomic premotor nuclei: OPN, olivary pretectal nucleus; LC, locus coeruleus. Parasympathetic nucleus/ganglion: EWN, Edinger Westphal nucleus; CG, Cilliary ganglion. Sympathetic nucleus/ganglion: IML, intermedio-lateral column of spinal cord; SCG, superior cervical ganglia. Neurotransmitters: Glu, glutamate; GABA, γ-amino-butyric acid; VP, vasopressin; Ox, orexin; Ach, acetylcholine; NA, noradrenaline. Adrenoceptors: α1, excitatory; α2, inhibitory.

Figure 2

(A) Representative baseline-adjusted pupillary response to a 1-s bright blue light (480 nm) stimulus of 13.0 Log photons/cm²/s in a healthy individual. Pupil constriction velocity (B) and acceleration (C) curves were computed, respectively, from the trace in (A) as the first and second derivatives of change in pupil constriction with respect to time. Pupillometric features extracted include: a, amplitude of pupillary constriction; b, post-illumination pupillary response after (t) seconds from light offset; c, Maximum constriction velocity (MCV); d, maximum redilation velocity; e, Maximum constriction acceleration (MCA).