New exploratory research led by Dr. Bryan Wong, an optometrist and medical doctor currently completing a residency in ophthalmology at the University of Toronto, provides insights into this developing story and builds on inconsistent findings in past studies.
Neurodegenerative diseases (NDDs) such as Alzheimer’s disease, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are highly challenging to diagnose in life. Researchers are working hard to find markers of these diseases that can be easily accessed in day-to-day life.
Wong et al’s study, “Retinal nerve fibre layer in frontotemporal lobar degeneration and amyotrophic lateral sclerosis”, was recently published in Frontiers in Neuroscience.
The study employed a highly rigorous methodology focused on distinguishing between NDDs based on their protein signatures. The hypothesis was that the existence of specific protein abnormalities in brain tissue could cause different patterns of retinal thinning, and that these could be distinguished between one set of study participants and another.
Researchers leveraged ONDRI’s foundational study data to focus on two groups:
- Tauopathy group – a protein abnormality associated with progressive supranuclear palsy (PSP), a variant of FTD
- TDP-43 proteinopathy group – a protein abnormality associated with ALS and semantic variant primary progressive aphasia (svPPA) – a sub-type of frontotemporal lobar dementia
The ONDRI foundational study protocol included measures of thickness of different parts of participants’ retinas. The researchers studied the differences in thickness between different parts of the retina of participants who were presumed to have these proteinopathies.*
Preliminary results found that a portion of the retinal nerve fibre layer around the optic nerve in the TDP43 group was thinner than that in the tauopathy group. After more rigorous statistical analysis, however, these differences were not found to be statistically significant, in that they could have happened by chance. Larger sample sizes would have added to the confidence of these results. No other statistically significant differences were found between retinal thicknesses of the groups outlined.
*Proteinopathy and NDDs
Scientists working to help solve the complexities of neurodegeneration believe that NDDs are caused, at least in part, by molecular and protein abnormalities. Proteinopathies, or protein misfolding diseases, occur when certain proteins aggregate or bind to each other; these protein clusters can result in disruption to the function of cells, tissues, and organs of the body, such as those that occur with NDDs.
There are no biomarkers for the proteinopathies of TDP-43 and the Tau of PSP so proteinopathy patterns were presumed for study participants based on their clinical presentation. As study participants in ONDRI were deeply characterized, the participant-level clinical data was available from which to draw expert inferences.
Team Science at ONDRI
This study represented a perfect example of the team science approach to research embodied by ONDRI and its funder the Ontario Brain Institute. In following a highly rigorous methodology to focus exclusively on factors to do with neurodegeneration, study authors consulted with optometrists, ophthalmologists, neurologists, statisticians, and molecular researchers. ONDRI’s cross-disease cross-platform study design, which addresses the complexity of the diseases studied, enabled this approach to be utilized effectively, improving the rigour and quality of the study.
Why this study is important
This study represents an important step forward in an emerging area of NDD research for many reasons. Just two are outlined below.
- The eyes are a window to the brain. Technologies like optical coherence tomography (OCT), utilized in this study, are readily accessible in eye care clinics in communities. These technologies allow clinicians and researchers to see three dimensional structures deep in the eye, and by extension the brain. These non-invasive technologies use light to image the retina, representing an attractive option to aid in acceleration of diagnosis of brain conditions in future.
- It is important to understand that many NDDs are on a spectrum. They have frequent overlaps in symptomology, and there are virtually no existing biomarkers to help in their differential diagnosis. Differences in protein signatures and resultant impacts on parts of the body (such as retinal thickness) may become one of the most inexpensive, quick and accessible ways to differentiate them in future.
“A more definitive diagnosis of neurodegeneration earlier in the disease process could ultimately lead to early interventions,” said Wong. “We believe that this small study has contributed to the science and look forward to continued research in this area,” he continued.