Intrinsically photosensitive melanopsin retinal ganglion cells (mRGCs) are crucial for nonimage forming functions of the eye, including the photoentrainment of circadian rhythms and the regulation of the pupillary light reflex (PLR). Chromatic pupillometry, using light stimuli at different wavelengths, makes possible the isolation of the contribution of rods, cones, and mRGCs to the PLR. In particular, post-illumination pupil response (PIPR) is the most reliable pupil metric of mRGC function. We have previously described, in post-mortem investigations of AD retinas, a loss of mRGCs, and in the remaining mRGCs, we demonstrated extensive morphological abnormalities. We noted dendrite varicosities, patchy distribution of melanopsin, and reduced dendrite arborization. In this study, we evaluated, with chromatic pupillometry, the PLR in a cohort of mildmoderate AD patients compared to controls. AD and controls also underwent an extensive ophthalmological evaluation. In our AD cohort, PIPR did not significantly differ from controls, even though we observed a higher variability in the AD group and 5/26 showed PIPR values outside the 2 SD from the control mean values. Moreover, we found a significant difference between AD and controls in terms of rod-mediated transient PLR amplitude. These results suggest that in the early stage of AD there are PLR abnormalities that may reflect a pathology affecting mRGC dendrites before involving the mRGC cell body. Further studies, including AD cases with more severe and longer disease duration, are needed to further explore this hypothesis.

Objective. To study the Tree-Drawing Test in a group of demented patients and compare it with a group of mild cognitively impaired patients (MCI) and controls. Methods. Consecutive outpatients were classified as affected by dementia (Alzheimer's disease (AD), frontotemporal dementia (FTD), and vascular dementia (VD)) or by MCI. Patients and controls underwent the Tree-Drawing Test and MMSE. Results. 118 AD, 19 FTD, 46 VD, and 132 MCI patients and 90 controls were enrolled. AD patients draw trees globally smaller than other patients and controls. FTD patients draw trees with a wider space occupation than AD and MCI patients but smaller than controls as well as VD patients. Trees drawn by MCI patients are intermediate in size between AD patients and controls. The trunk-to-crown ratio of trees drawn by cognitive impaired patients is greater than controls while the tree size-relative-to-page space index is significantly smaller. The tree size-relative-to-page space index of trees drawn by AD patients is smaller than that of the other cognitively impaired patients. Tree height and the trunk-to-crown ratio are independent predictors of cognitive impairment. Conclusions. Trees drawn by cognitively impaired patients are different from those drawn by healthy subjects with a progressive differentiation from mild to more relevant degrees of cognitive impairment.

To study human figure drawing in a group of Alzheimer's disease (AD) patients and compare it with a group of patients with mild cognitive impairment (MCI) and controls. We evaluated consecutive outpatients over a one-year period. Patients were classified as affected by AD or by MCI. All patients and controls underwent a simplified version of the human-figure drawing test and MMSE. A qualitative and quantitative analysis of all human figures was obtained. 112 AD, 100 MCI patients and 104 controls were enrolled. AD patients drew human figures poor in details and globally smaller than MCI patients and controls. Human figures drawn by MCI patients are intermediate in body height between those of the AD patients and the healthy subjects. The head-to-body ratio of human figures drawn by AD patients is greater than controls and MCI patients, while the human figure size-relative-to-page space index is significantly smaller. Body height is an independent predictor of cognitive impairment correlating with its severity and with the number of the figure's details. Human figures drawn by AD patients are different from those drawn by healthy subjects and MCI patients. Human figure drawing test is a useful tool for orienting cognitive impairment's diagnosis.

Objective: In Alzheimer's disease (AD), the presence of circadian dysfunction is well-known and may occur early in the disease course. The melanopsin retinal ganglion cell (mRGC) system may play a relevant role in contributing to circadian dysfunction. In this study, we aimed at evaluating, through a multimodal approach, the mRGC system in AD at an early stage of disease. Methods: We included 29 mild-moderate AD (70.9 AE 11 years) and 26 (70.5 AE 8 years) control subjects. We performed an extensive neurophtalmological evaluation including optical coherence tomography with ganglion cell layer segmentation, actigraphic evaluation of the rest-activity rhythm, chromatic pupillometry analyzed with a new data-fitting approach, and brain functional MRI combined with light stimuli assessing the mRGC system. Results: We demonstrated a significant thinning of the infero-temporal sector of the ganglion cell layer in AD compared to controls. Moreover, we documented by actigraphy the presence of a circadian-impaired AD subgroup. Overall, circadian measurements worsened by age. Chromatic pupillometry evaluation highlighted the presence of a pupil-light response reduction in the rod condition pointing to mRGC dendropathy. Finally, brain fMRI showed a reduced occipital cortex activation with blue light particularly for the sustained responses. Interpretation: Overall, the results of this multimodal innovative approach clearly document a dysfunctional mRGC system at early stages of disease as a relevant contributing factor for circadian impairment in AD providing also support to the use of light therapy in AD.