Eye Imaging Provides Neurovascular Biomarker In Alzheimer’s Subjects

The relationship between blood flow in the brain and neurodegenerative diseases is well documented and gaining prominence in research circles.

The dysfunction of brain blood flow (neurovascular dysfunction) has been shown to disrupt the removal of the key Alzheimer’s protein amyloid-beta as well as damaging brain cells from leakage of foreign cells into the brain tissue.

Dynamic Vessel Analyser (DVA)

A research group in Germany has attempted to utilise neurovascular dysfunction as a biomarker for Alzheimer’s disease. In the study, a Dynamic Vessel Analyser (DVA) is used to non-invasively measure the reaction of blood vessels (aortic and venous) behind the eye to light stimulation; like an eye test. This is used as a marker for neurovascular dysfunction, with a delayed retinal vessel response being an indicator of Alzheimer’s disease.

From the differences in vessel response the group could establish the most severe group of dementia subjects compared to both the mild cognitive impairment and healthy control groups.

Yearning For Biomarkers

Diagnosis of Alzheimer’s disease is hindered by a lack of biomarkers, with either genetic testing (~5% of cases) or severe symptoms of cognitive impairment in later life being the first signs of dementia. These are often too late for a treatment to be effective in halting disease progression and is thought to be the reason why a lot of drug trials fail in Alzheimer’s disease cohorts.

Arterial and venous reaction in the groups

Relative vessel diameter changes in % to the baseline during flicker stimulation cycle (monochromatic, 12.5 Hz, 20 s).
(A,C) MCI group uniform: (B,D) MCI group divided in two subgroups: MCI-nonAD and MCI-AD.
Grey vertical stripes show the time interval 10–40 s after flicker cessation where arterial constriction and an emphasized decrease of venous diameter are expected in healthy volunteers.
Credit: Kotliar K, et al. CC-BY

Neurovascular dysfunction is a component of Alzheimer’s disease which is gaining increasing attention as a potential therapeutic target or as a disease biomarker. The ease of accessibility to this non-invasive biomarker could be extremely useful in the diagnosis of Alzheimer’s disease and for monitoring progression of the disease.

The non-invasive nature of this biomarker is a stark contrast to intrusive and painful cerebral spinal fluid markers and uncomfortable MRI scans.

Patient Groups

The patient sample used to test the DVA was made up of 15 subjects with mild to moderate dementia due to Alzheimer’s disease, 24 subjects with mild cognitive impairment due to Alzheimer’s disease, and 15 healthy control subjects.

Neurovascular Biomarker In Alzheimer’s Subjects

Some parameters of retinal vessel reaction to flicker reported in the study.
The thin black line shows the median vessel diameter from the 3 flicker cycles.
The superimposed solid black line illustrates the running median (4 s frame and the corresponding back shift) used to smooth the data.
All vessel parameters were calculated using the values from this running median line.
The following parameters were derived from the flicker curve:
(a) mean maximal dilation in response to flicker, [% to the baseline];
(b) area under the reaction curve after flicker cessation, [%×s];
(c) time to reach 30% of maximal dilation at the ascending slope, taking flicker initiation as 0, [s];
(d) time to reach the “center of gravity” of the area under the flicker curve over the baseline between the flicker initiation and the first baseline intersection after the peak dilation, [s].
Credit: Kotliar K, et al. CC-BY

The researchers have named a limitation of their study as the difference in ages between subject groups, with the most cognitively impaired group being slightly older than the other groups, potentially skewing results. Authors also state that this limitation could be confronted with further testing in larger cohorts; and with the non-invasive technique being no more hassle than an eye test, this technique will hopefully be easily integrated to larger studies.

Neurovascular Applications

These results further exemplify the impact of neurovascular dysfunction on Alzheimer’s disease progression; adding evidence to the data already published on this topic. This also highlights the loss of neurovascular integrity as a confounding factor in the pathogenesis of cognitive decline.

The application of this technique to more archetypal vascular neurodegenerative conditions, like vascular dementia or post-stroke degeneration, could be crucial in effective diagnosis of neurovascular dysfunction and ensure the administration of therapeutics which treat the specific disease.

Kotliar K, Hauser C, Ortner M, Muggenthaler C, Diehl-Schmid J, Angermann S, Hapfelmeier A, Schmaderer C, Grimmer T
Altered neurovascular coupling as measured by optical imaging: a biomarker for Alzheimer’s disease
Scientific Reports. 2017 Oct 10. Doi: 10.1038/s41598-017-13349-5

Author: Geoffrey Potjewyd; Regenerative Medicine & Neuroscience PhD student at the University of Manchester. Top Image: Wellcome Images