New Alzheimer’s biomarkers suggest potential for simpler tests

Smell, eye tests can help in detection of memory decline


1 in 3 seniors dies with Alzheimer’s or another dementia

The potential of odor identification testing and physical changes in and around the eye to detect cognitive impairment and Alzheimer’s disease at an early stage was bolstered by new evidence from four studies presented at the Alzheimer’s Association International Conference (AAIC) 2016 in Toronto.

Two studies evaluated changes in odor identification as an early predictor of cognitive decline, or of the transition to dementia, and compared it to two established biological markers for cognitive decline and dementia – brain amyloid PET imaging and thickness of the brain’s cortex in areas important to memory.

Two other studies reported at AAIC 2016 found:

  • A strong association between thinning nerve layers in the retina of the eye and poor cognition, suggesting the potential of retinal imaging as part of early Alzheimer’s testing.
  • The presence of amyloid deposits in the retina of both people with Alzheimer’s and canine models of the disease by non-invasive polarization imaging; this strengthens their utility as a marker of Alzheimer’s, and a possibility for pre-symptomatic detection.

“It’s clear that the science around biological measures in the detection of Alzheimer’s continues to gather pace and validation,” said Heather Snyder, PhD, director of medical and scientific operations, Alzheimer’s Association. “Low cost, non-invasive measures to detect dementia-related changes and evaluate the risk of future decline continue to be refined and tested; this is a positive step forward to earlier detection and intervention.”

Today, it is only possible to clinically detect Alzheimer’s relatively late in its development, when significant brain damage has already occurred. While brain positron emission tomography (PET) imaging can show the buildup of amyloid plaques in the brain years before symptoms appear, PET scans are expensive. Beta amyloid can also be detected in cerebrospinal fluid (CSF) through a lumbar puncture, and brain PET imaging of abnormal tau protein is rapidly advancing through research.

“Using other biomarkers of Alzheimer’s disease to detect the disease at an earlier stage – which have the potential to be lower-cost and non-invasive – could lead to dramatic improvements in early detection and management of the disease,” Snyder said.

Predictive Utility of Entorhinal Cortex Thinning and Odor Identification Test for Transition to Dementia and Cognitive Decline in an Urban Community Population
Growing research evidence suggests that decreased ability to correctly identify odors is a predictor of cognitive decline and an early clinical feature of Alzheimer’s disease. The 40-item University of Pennsylvania Smell Identification Test (UPSIT), can be used to test ability to identify odors.

Seonjoo Lee, PhD, and colleagues from Columbia University Medical Center, administered UPSIT to 397 people average age 80 from a multiethnic community in North Manhattan, all non-demented at baseline, who also had an MRI scan, and followed them over four years. The goal was to better understand the usefulness of UPSIT in detecting the transition to dementia and cognitive decline, and to compare it with thinning of the entorhinal cortex, the first area of the brain to be affected by Alzheimer’s disease.

During follow-up, 50 people (12.6 percent) transitioned to dementia (49 to Alzheimer’s disease), and 19.8 percent were classified as cognitive decliners.

  • Both lower odor identification scores on UPSIT and, to a lesser degree, entorhinal cortical thickness were significantly associated with the transition to dementia and Alzheimer’s disease controlling for age, education, gender, language of UPSIT administration (English or Spanish), functional status and intracranial volume.
  • Lower baseline UPSIT scores, but not entorhinal cortex thickness, predicted cognitive decline in study participants.
  • Entorhinal cortical thickness was significantly associated with UPSIT among participants who transitioned to dementia.

Alzheimer’s kills more people than breast and prostate cancer combined

“Our research showed that odor identification impairment, and to a lesser degree entorhinal cortical thickness, were predictors of the transition to dementia,” said Lee. “These findings support odor identification as an early predictor, indirectly suggesting that impairment in odor identification may precede thinning in the entorhinal cortex in the early clinical stage of Alzheimer’s disease.”

Both Odor Identification and Amyloid Status Predict Memory Decline in Older Adults
William Kreisl, MD, and colleagues from Columbia University Medical Center, sought to assess the utility of odor identification impairment and beta amyloid PET or CSF analysis in predicting memory decline in older adults. They did this by determining both UPSIT scores and amyloid status in 84 participants (58 with amnestic mild cognitive impairment and 26 control subjects, age 68 ± 7 years, 58% female, education 16 ± 3 years) who had either brain amyloid PET or lumbar puncture at baseline, plus at least six months follow-up.

At follow-up, 67 percent of participants showed memory decline. After correcting for age, sex and education, amyloid-positivity determined by PET scan or lumbar puncture predicted decline while UPSIT score did not. However, participants with a UPSIT score less than 35 were more than three times more likely (OR=3.95, p=0.0192) to have memory decline than those with a UPSIT score greater than 35.

“Our research suggests that both UPSIT score and amyloid status predict memory decline,” Kreisl said. “Younger age, higher education, and shorter follow-up may explain why UPSIT did not predict decline as strongly in this study as in previous studies,” Dr. Kreisl said. “While more research is needed, because the UPSIT is much less expensive and easier to administer than PET imaging or lumbar puncture, odor identification testing may prove to be a useful tool in helping physicians counsel patients who are concerned about their risk of memory loss.”

Retinal Nerve Fiber Layer Thinning Associated with Poor Cognitive Function Among a Large Cohort
Fang Ko, MD, and colleagues from the Moorfields Eye Hospital, UCL Institute of Ophthalmology, London, in collaboration with members of the Topcon Advanced Biomedical Imaging Laboratory in Oakland, New Jersey, and the University of Oxford explored associations between cognition and retinal nerve fiber layer (RNFL) thickness using spectral domain optical coherence tomography (SD-OCT).

The retinal nerve fiber layer is formed by the expansion of the fibers of the optic nerve, which transmits visual information from the retina to the brain. Thickness of the RNFL is known to decrease with age. Findings from several small clinical studies suggest that RNFL may be associated with cognitive performance. The researchers used the United Kingdom Biobank study to test this hypothesis in a large community-based population sample.

In this study, 33,068 participants underwent macular SD-OCT, physical examination, cognitive testing and answered a questionnaire. Cognitive measures were prospective memory, pairs matching, numeric and verbal reasoning, and reaction time.

The researchers found a significant association between thinner macular RNFL and poor cognition:

  • RNFL was thinner among those with any one abnormal cognitive test.
  • For the prospective memory test, mean RNFL thickness was 53.3μm among those who recalled correctly on first attempt versus 52.5μm on second attempt, and 51.9μm for those who did not recall.
  • Thinner RNFL was associated with poorer pairs matching, numeric and verbal reasoning, and reaction time on univariate regression.
  • Effects appeared additive for each additional cognitive test failed; RNFL was significantly thinner by 1.0μm.

“Our findings show a clear association between thinner macular RNFL and poor cognition in the study population,” Ko said. “This demonstrates the potential utility of the eye as a non-invasive measure of neuronal loss which is linked to cognitive performance, and provides a possible new biomarker for studies of neurodegeneration.”

“These exciting findings show the value of large-scale studies for identifying new biomarkers, strengthening considerably the evidence for neuronal loss in the eye being an indicator of neuronal loss more generally, and may lead to the discovery of new mechanisms of neurodegeneration,” said Praveen Patel, MB, BChir, MA, FRCOphth, MD(Res), of Moorfields Eye Hospital, UCL Institute of Ophthalmology, London, and senior author of this study.

“Many older adults routinely visit their ophthalmologist, so incorporating this technology – once proven – into annual eye care visits could aid in assessing cognitive status and identifying individuals that should have further evaluation by a healthcare professional,” Snyder added.

Amyloid as a Biomarker of Alzheimer’s Disease in Post-Mortem Retinas in Human and the Canine Model of Alzheimer’s Disease
Currently, the presence of amyloid in the brain is measured using PET brain scans that are expensive, not generally covered by insurance, and not always locally available. After death, evidence of beta amyloid in the brain in association with a history of dementia is the gold standard for diagnosis of Alzheimer’s disease. As an inexpensive alternative to PET scans, polarized light may detect protein deposits in the retina. This method requires no dyes or invasive testing.

Melanie Campbell, Ph.D., and colleagues from the University of Waterloo, Ontario, Canada, the University of Rochester, University of British Columbia, Massachusetts General Hospital, Vivocore Inc. and Intervivo Solutions, compared amyloid deposits in the neural retina of humans and in a canine model of Alzheimer’s to assess their visibility using several different imaging methods, and reported the results at AAIC 2016.

The researchers analyzed diseased eyes from 20 humans and six canines, alongside 22 control human retinas and seven control canine retinas. Atomic force, confocal and polarization microscopes were used. Retinas of five canines were imaged in vivo in amyloid fluorescence and clinical optical coherence tomography (OCT) for comparison.

Retinal amyloid deposits were seen using a polarized microscope that did as well as the more invasive fluorescence imaging technique in detecting the amyloid. A fluorescence marker for amyloid crossed the blood retinal barrier in vivo in the canine model of AD and identified amyloid deposits that did not appear in the OCT contrast images.

“Polarization imaging is promising for noninvasive imaging of retinal amyloid deposits as a biomarker of Alzheimer’s,” Campbell said. “The ability to detect amyloid deposits in the retina prior to disease symptoms may be an essential tool for the development of preventative strategies for Alzheimer’s and other dementias.”

“Cognitive dysfunction syndrome is a naturally occurring condition in canines with similar changes in the brain to those in humans with Alzheimer’s, including the accumulation of beta amyloid with increasing age. The amyloid deposits in canine retinas had very similar properties to the deposits imaged in human retinas, such as being located close to nerve cells and exhibiting interaction with polarized light. Studying cognitive dysfunction syndrome in this animal may give improved understanding of Alzheimer’s in humans,” Campbell added.

About the Alzheimer’s Association International Conference (AAIC)
The Alzheimer’s Association International Conference (AAIC) is the world’s largest gathering of researchers from around the world focused on Alzheimer’s and other dementias. As a part of the Alzheimer’s Association’s research program, AAIC serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community. – CNW

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