Researchers find link between concussions and Alzheimer’s disease

Boston University School of Medicine

New research has found concussions accelerate Alzheimer’s disease–related brain atrophy and cognitive decline in people who are at genetic risk for the condition. The findings, which appeared in the journal Brain, show promise for detecting the influence of concussion on neurodegeneration.

Moderate–to–severe traumatic brain injury is one of the strongest environmental risk factors for developing neurodegenerative diseases such as late–onset Alzheimer’s disease, although it is unclear whether mild traumatic brain injury or concussion also increases this risk.

BUSM researchers studied 160 Iraq and Afghanistan war veterans, some who had suffered one or more concussions and some who had never had a concussion. Using MRI imaging, the thickness of their cerebral cortex was measured in seven regions that are the first to show atrophy in Alzheimer’s disease, as well as seven control regions.

“We found that having a concussion was associated with lower cortical thickness in brain regions that are the first to be affected in Alzheimer’s disease,” explained corresponding author Jasmeet Hayes, PhD, assistant professor of psychiatry at BUSM and research psychologist at the National Center for PTSD, VA Boston Healthcare System. “Our results suggest that when combined with genetic factors, concussions may be associated with accelerated cortical thickness and memory decline in Alzheimer’s disease relevant areas.”

Of particular note was that these brain abnormalities were found in a relatively young group, with the average age being 32 years old. “These findings show promise for detecting the influence of concussion on neurodegeneration early in one’s lifetime, thus it is important to document the occurrence and subsequent symptoms of a concussion, even if the person reports only having their “bell rung” and is able to shake it off fairly quickly, given that when combined with factors such as genetics, the concussion may produce negative long–term health consequences,” said Hayes.

The researchers hope that others can build upon these findings to find the precise concussion–related mechanisms that accelerate the onset of neurodegenerative diseases such as Alzheimer’s disease, chronic traumatic encephalopathy, Parkinson’s and others. “Treatments may then one day be developed to target those mechanisms and delay the onset of neurodegenerative pathology,” she added.

Preliminary results from 2 studies presented here at the Alzheimer’s Association International Conference (AAIC) 2014 show that beta-amyloid detected in the eyes significantly correlated with the burden of beta-amyloid in the brain, allowing investigators to accurately identify individuals with AD.

In the first study, researchers at the Commonwealth Scientific and Industrial Research Organization (CSIRO), Australia’s national science agency, used curcumin fluorescence imaging to highlight beta-amyloid in the retina and correlated these results using Pittsburgh compound B (PiB) positron emission tomography (PET) imaging findings in the brain.

“Every single person who tested positive with high levels of plaque in the brain tested positive to the retinal test as well, so we had 100% sensitivity and no false negatives, which is a crucial component on a screen for Alzheimer’s disease because we don’t want to leave anyone behind when it comes to the early signs,” lead investigator Sean Frost said at a press briefing here.

The investigators note that although AD-related pathology in the brain is well documented, the disease has also been reported to affect the retina, a developmental outgrowth of the brain that is more accessible for imaging.

The primary substance in the Asian spice turmeric, curcumin has several properties that make it a good contrast medium ― it binds with high affinity to beta-amyloid, and it has fluorescent properties that enable amyloid plaques to be imaged in the retina. In addition, said Frost, it is safe.

Study participants included individuals with AD, individuals with mild cognitive impairment, and healthy control participants from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) study.

In addition to undergoing PiB PET imaging, participants made 2 visits for retinal fluorescence imaging. During the first visit, they drank a proprietary curcumin supplement. On the second visit, they underwent retinal amyloid imaging (RAI).

Preliminary data from the first 40 participants showed that amyloid levels detected in the retina were significantly correlated with brain amyloid levels, as shown by PiB PET imaging. In addition, RAI differentiated participants with AD from those without AD with 100% sensitivity and 80.6% specificity.

Furthermore, said Frost, longitudinal data showed an average increase of 3.5% in retinal amyloid during a 3.5-month period, suggesting that the technique may be used as a means of monitoring response to therapy.

If these early findings bear out, Frost said, this technology could be used as an initial screen for AD that could potentially be part of regular eye examinations.

“One day we hope there’s going to be better treatments available, and this will definitely provide a frontline screening tool to detect it in the early stages, before cognitive decline, and hopefully change the course of Alzheimer’s disease,” he said.

The full study is expected to be completed later this year.

On-the-Spot Results

In the second study, investigators from Cognoptix Inc, in Acton, Massachusetts, reported findings showing that a novel fluorescent ligand eye scanning (FLES) system that detects beta-amyloid in the lens of the eye also accurately detects amyloid burden and correlates with florbetapir PET brain imaging.

This phase 2 study included 20 individuals with probable mild to moderate AD and 20 healthy, age-matched control participants.

For the study, participants had a small molecule applied to the eye in the form of a sterile ophthalmic ointment. The compound is left to diffuse into the eye overnight; the next day, the eye is scanned with the laser and results are computed.

All 40 participants also underwent PET amyloid brain imaging.

According to Paul D. Hartung, president and CEO of Cognoptix Inc, who presented the findings, the study showed that the test was able to differentiate individuals with Alzheimer’s from healthy control participants with 85% sensitivity and 95% specificity (P < .001). In addition, amyloid levels in the lens significantly correlated with PET imaging results.

Hartung pointed out that at approximately $300, the test is about 10 times less expensive than PET imaging and much less invasive than cerebrospinal fluid testing.

In addition, he said, a single scan takes less than a second, and the instrument can compute a score, known as a fluorescence uptake value, in less than 5 minutes.

Furthermore, he said, the technology requires minimal training and has the potential to be used by general practitioners, nurses, and other healthcare practitioners in clinics and offices. It is also safe and could be administered on a regular basis to track disease progression and to monitor treatment.

“Early detection is critical. We are hoping the treatments that are being developed will be more effective if they are administered earlier, and we need something that can be made accessible to doctors everywhere,” he said.

With principal investigator Pierre Tariot, MD, director of the Banner Alzheimer’s Institute, Phoenix, Arizona, Hartung said the investigators are currently conducting a pivotal phase 3, multicenter, US-based study to support US Food and Drug Administration approval of the FLES system as an aid in the diagnosis of probable AD.

Exciting Findings

Commenting on the studies for Medscape Medical News, David Knopman, MD, professor of neurology at the Mayo Clinic College of Medicine, consultant in neurology at the Mayo Clinic in Rochester, Minnesota, and a member of the Alzheimer’s Association Medical and Scientific Advisory Council, who moderated a press conference on this topic, said he was “very impressed” by both papers and particularly the retina paper.

“I thought the data were very interesting, and if it is the case that the amyloid in the retina parallels the amyloid in the brain ― and that’s what they were showing ― that’s really an exciting finding.

“I think that brain amyloid imaging at this point has been of tremendous scientific value in allowing us to understand who is either at risk, or who actually has the pathology of Alzheimer’s disease in life, but it’s so expensive. At my institution, to do an Amyvid [Avid Radiopharmaceuticals, Inc] scan is somewhere between $5000 and $7000.

“The Center for Medicare and Medicaid Services doesn’t pay for amyloid imaging. We’re looking into that for research purposes, but if this actually could substitute for that, say, in clinical trials or under appropriate circumstances if there were therapies to identify people who would benefit from the therapies, that would be a tremendous advance.”

Unfortunately, said Dr. Knopman, at this point, the Alzheimer’s field lacks a powerful therapy to prevent the disease or stop it in its tracks.

“At this point, we understand that, but the kind of approaches described here are the kind of approaches we need to have in place when we have those effective therapies,” he said.

“This increase is due to an aging baby boom generation. It will place a huge burden on society, disabling more people who develop the disease, challenging their caregivers, and straining medical and social safety nets,” said co-author Jennifer Weuve, MPH, ScD, assistant professor of medicine, Rush Institute for Healthy Aging at Rush University Medical Center in Chicago. “Our study draws attention to an urgent need for more research, treatments and preventive strategies to reduce this epidemic.”

For the study, researchers analyzed information from 10,802 African-American and Caucasian people living in Chicago, ages 65 and older, between 1993 and 2011. Participants were interviewed and assessed for dementia every three years. Age, race and level of education were factored into the research.

The data were combined with US death rates, education and current and future population estimates from the US Census Bureau.

The study found that the total number of people with Alzheimer’s dementia in 2050 is projected to be 13.8 million, up from 4.7 million in 2010. About 7 million of those with the disease would be age 85 or older in 2050.

“Our detailed projections use the most up-to-date data, but they are similar to projections made years and decades ago. All of these projections anticipate a future with a dramatic increase in the number of people with Alzheimer’s and should compel us to prepare for it,” said Weuve.

Liesi Hebert, ScD, assistant professor, Rush University Medical Center, is lead author of the study.

The study was supported by the Alzheimer’s Association and the National Institute on Aging of the National Institutes of Health.

To learn more about Alzheimer’s disease, visit http://www.aan.com/patients.