It is commonly said that the “eyes are the windows to the soul.” What if this was actually true for patients with Alzheimer’s Disease (AD)? What if doctors could look at the eyes of a person who was genetically predisposed to AD and determine whether the patient will actually suffer from it – years before the person begins to experience serious symptoms? Despite AD being the most common neurodegenerative disorder, there are currently no clinical tests to predict its development. This may soon change, as researchers have recently proposed a novel method to predict and track this disease – which would have remarkable consequences for drug development and maybe even finding a reliable cure.

Believe it or not, the pupil could help us track the progression of AD [1]. The pupil is controlled by the pupil sphincter muscles that decrease its diameter, and pupil dilator muscles that increase its diameter. The sphincter muscles receive impulses from the parasympathetic nervous system, and the dilator muscles from the sympathetic nervous system. These muscles work as an antagonistic pair, enabling the pupil to constrict in brighter situations and dilate in darker situations. This is the pupillary light reflex (PLR). The main cognitive hallmark of AD is neural deterioration, and patients with AD have reduced levels of the neurotransmitter acetylcholine. Researchers have found that the pupil sphincter reacts to acetylcholine [1]. Acetylcholine is an important excitatory neurotransmitter with a wide variety of functions in the brain. You may wonder, then, can we detect AD in a patient through pupillary activity?

Pupillometry is a noninvasive technique measuring changes in pupil size. Researchers believe that pupillometry holds potential as a digital tool to detect neurodegenerative diseases like AD [1]. Patients with neurodegenerative diseases often exhibit alterations in their pupillary responses, indicating underlying neuronal dysfunction [2]. In fact, the pupillary light reflex has been found to be altered in AD patients even in a pre-symptomatic stage, and advances in pupillometry techniques have demonstrated high sensitivity and specificity in detecting the loss of function in light-sensitive cells of the retina, therefore indicating deterioration of central vision [2]. All of this suggests the potential of pupillometry in assessing cognitive function in AD patients.

The melanopsin retinal ganglion cells (mRGCs) are intrinsically photosensitive cells that contribute to the maintenance of pupil diameter [2]. Researchers have found that in the early stages of AD, there are abnormalities in the pupillary light reflex which can reflect a pathology affecting mRGC dendrites [2]. This finding opened the door to further studies to clarify whether the pupillary light reflex can be used as a tool to evaluate the progression of AD.

Quantitative Light Reflex Pupillometry (qLRP) is the objective measurement of the pupillary response to external light stimuli [3]. Researchers hypothesized that it may be feasible to detect retinal function in AD patients by using pupillometry with high sensitivity and specificity. Thus, a study was conducted to investigate the test-retest reliability and short-term, intrasubject variability of qLRP in AD patients. The researchers wanted to know if the pupillary light reflex is a reliable biomarker when used successively on a group of patients with AD. If this is the case, then qLRP should be able to perform well as a tool to detect this biomarker in both the early and later stages of the disease [3].

The researchers decided to test their hypothesis by evaluating patients in a memory clinic setting. These patients had mild cognitive impairment or dementia. During the study, researchers observed that most patients were able to tolerate the procedure with minimal discomfort [3]. The results showed that most baseline pupillometry variables yielded moderate to strong positive correlations. Hence, the researchers concluded that qLRP has good-to-excellent test-retest reliability, but limited intra-subject, short-term reliability. In other words, the results pave the way for future research by strongly suggesting that the pupillary light reflex is a useful biomarker in patients with cognitive dysfunction, including potential applications in disease tracking for AD patients. The study also suggests that longitudinal qLRP could perform equally well in both early and later stages of AD. While this is very exciting news, it is important to note that there are still a lot of questions that researchers need to answer before the pupillary light reflex is implemented as a standardized biomarker for AD. This study in particular had a limited follow-up period with the patient cohort. A longitudinal study design is required, which would allow researchers to record individual trajectories by making repeat measurements of qLRP [3]. 

Despite the uncertainty that still surrounds the use of pupillometry as a standardized test for AD, there is a promising future that lies ahead. Pupillometry represents a novel approach in the prediction and detection of mild AD and offers valuable insights into disease progression and management. Further research is needed to fully harness its potential in clinical practice, but researchers are optimistic about the possibility of being able to unlock a new dimension in their understanding and management of AD.

References:

  1. Haj, M. E., Chapelet, G., Moustafa, A. A., & Boutoleau-Bretonnière, C. (2022). Pupil Size as an Indicator of Cognitive Activity in Mild Alzheimer’s Disease. EXCLI Journal, 21. doi.org/10.17179/excli2021-4568 
  2. Romagnoli, M., Stanzani Maserati, M., De Matteis, M., Capellari, S., Carbonelli, M., Amore, G., Cantalupo, G., Zenesini, C., Liguori, R., Sadun, A. A., Carelli, V., Park, J. C., & La Morgia, C. (2020). Chromatic pupillometry findings in alzheimer’s disease. Frontiers in Neuroscience, 14. doi.org/10.3389/fnins.2020.00780 
  3. Gramkow, M. H., Clemmensen, F. K., Waldemar, G., Hasselbalch, S. G., & Frederiksen, K. S. (2023). Test-retest reliability and short-term variability of Quantitative Light Reflex pupillometry in a mixed memory clinic cohort. Journal of the Neurological Sciences, 456, 122856. doi.org/10.1016/j.jns.2023.122856