Chromatic Pupillometry Findings in Alzheimer’s Disease

Disturbed sleep cycles are the principal cause of institutionalization in dementia, and therefore represent a major clinical problem. They may arise from dysfunction within the circadian clock of the hypothalamus that times and consolidates wakefulness, or from neuropathology in output pathways and/or target sites of the clock specifically controlling sleep and wakefulness. To determine the relationship of disturbed activity cycles to other circadian clock-controlled rhythms, cross-sectional and longitudinal actigraphy and serial sampling of saliva were used to compare the impact of early Alzheimer's dementia on activity/rest and cortisol rhythms in home-dwelling subjects. Mildly demented subjects had daily activity rhythms comparable to those of healthy age-matched subjects. Moderately demented subjects exhibited a range of disturbances of the activity/rest cycle, with reduced stability, increased fragmentation and loss of amplitude. Within the moderately demented group, however, the degree of circadian disruption was not correlated with the individual severity of dementia. All groups of subjects, mild, moderate with normal activity cycles and moderate with abnormal activity cycles, exhibited robust daily profiles of salivary cortisol, with highest levels in the morning (08:00 h) and an evening nadir (20:00-24:00 h). Salivary cortisol levels tended to be higher in the moderately demented subjects in the afternoon, but this effect was not specific to those with abnormal activity/rest patterns. The actimetric data confirm that deterioration of activity/rest cycles is a common and progressive feature in home-dwelling Alzheimer's patients, occurring early in the disease but after the measurable onset of dementia. The maintenance of highly rhythmic daily cortisol profiles in association with disturbed activity profiles, both on an individual and on a group basis, demonstrates that loss of circadian control to activity/rest cycles is not a consequence of global circadian disruption in early dementia. Rather, pathology may develop in discrete elements of the circadian clockwork and/or its output systems that control activity/rest, sleep and wakefulness. Further characterization of this pathology will facilitate more effective management of sleep patterns in home-dwelling demented patients.

PURPOSE. To better understand the relative contributions of rod, cone, and melanopsin to the human pupillary light reflex (PLR) and to determine the optimal conditions for assessing the health of the rod, cone, and melanopsin pathways with a relatively brief clinical protocol. METHODS. PLR was measured with an eye tracker, and stimuli were controlled with a Ganzfeld system. In experiment 1, 2.5 log cd/m(2) red (640 ± 10 nm) and blue (467 ± 17 nm) stimuli of various durations were presented after dark adaptation. In experiments 2 and 3, 1-second red and blue stimuli were presented at different intensity levels in the dark (experiment 2) or on a 0.78 log cd/m(2) blue background (experiment 3). Based on the results of experiments 1 to 3, a clinical protocol was designed and tested on healthy control subjects and patients with retinitis pigmentosa and Leber's congenital amaurosis. RESULTS. The duration for producing the optimal melanopsin-driven sustained pupil response after termination of an intense blue stimulus was 1 second. PLR rod- and melanopsin-driven components are best studied with low- and high-intensity flashes, respectively, presented in the dark (experiment 2). A blue background suppressed rod and melanopsin responses, making it easy to assess the cone contribution with a red flash (experiment 3). With the clinical protocol, robust melanopsin responses could be seen in patients with few or no contributions from the rods and cones. CONCLUSIONS. It is possible to assess the rod, cone, and melanopsin contributions to the PLR with blue flashes at two or three intensity levels in the dark and one red flash on a blue background.

Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) innervate the hypothalamic suprachiasmatic nucleus (SCN) and the olivary pretectal nucleus (OPN), providing irradiance information for entrainment of circadian rhythms and for stimulating the pupillary light reflex. In this study, mice were used in which the melanopsin gene was replaced with the tau-lacZ gene. Heterozygous (tau-lacZ+/-) mice express both melanopsin and beta-galactosidase. In tau-lacZ+/- mice, only approximately 50% of melanopsin ipRGCs contain beta-galactosidase, and these cells are specifically labeled with a C-terminus melanopsin antibody. Retrograde tracer injection into the SCN labels beta-galactosidase-expressing ipRGCs (termed M1) that comprise approximately 80% of the SCN-projecting ipRGCs. M1 ipRGCs and an additional set of ipRGCs (termed M2) are labeled with a melanopsin antiserum targeted against the N-terminus of the melanopsin protein; M2 ipRGCs do not contain detectable beta-galactosidase, and these cells make up the remainder of the SCN-projecting RGCs. Tracer injection into the OPN labeled non-melanopsin RGCs and both types of melanopsin ipRGC: 45% M1 and 55% M2. Infection of the iris with pseudorabies virus (PRV) results in retrograde transneuronal label of OPN projection neurons that innervate preganglionic parasympathetic neurons of the Edinger-Westphal nucleus; PRV-labeled cells were located almost exclusively within the terminal field of M1 ipRGCs in the periphery (shell) of the OPN. The OPN core receives retinal input, and we hypothesize that the OPN core receives input from the M2 ipRGCs. Two subtypes of melanopsin ipRGCs project differentially to the SCN and OPN; the functional significance of ipRGCs subtypes is currently unknown.