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Hopkins Study Suggests CSF Markers Can Help Predict Onset of MCI in Cognitively Normal Patients


A team led by researchers at Johns Hopkins University has demonstrated that the cerebrospinal fluid markers β-amyloid, tau, and phosphorylated tau can be used to predict the onset of mild cognitive impairment in cognitively normal patients.

Tracking 265 patients from the National Institutes of Health's Biomarkers for Older Controls at Risk for Dementia (BIOCARD) study, the researchers found that baseline differences in CSF Aβ, tau, and phospho-tau levels as well as total tau/Aβ ratios and phospho-tau/Aβ ratios can predict patient outcomes more than five years before the appearance of clinical symptoms.

While previous studies have identified CSF marker expression changes in asymptomatic subjects, the Johns Hopkins effort, detailed in a paper published last week in the journal Neurology, is one of the first to actually link these changes to a diagnosis of mild cognitive impairment, Marilyn Albert, professor of neurology at Johns Hopkins and one of the authors of the study, told ProteoMonitor.

"We know from previous studies [using] both cerebrospinal fluid and amyloid imaging that we can pick up changes very early," she said. "What we haven't known so well is how much these changes are tied to diagnosis."

Typically, she said, researchers have done cross-sectional analyses, tracking changes in CSF markers not against a diagnosis of Alzheimer's or MCI, but against some other aspect of behavior, like memory.

This, Albert said, is because few studies have tracked patients for as long as the BIOCARD study. Launched by the NIH in 1995 and reestablished by Albert and her colleagues in 2009 after a four year hiatus, the study has tracked its longest participating subjects for 18 years. The minimum length of participation for any subject is eight years.

Most other Alzheimer's studies, on the other hand, "started in 2004 at the earliest," Albert said. "So ours is by far the longest running study, and so we've been able to look at the long-term follow-up of these people."

Additionally, Albert said, the BIOCARD featured a significantly younger cohort than most Alzheimer's trials. As she and her co-authors noted, "most subjects in previous studies were older than 70 years of age," making them unsuited for determining if CSF changes predictive of MCI could be identified in younger patients. The average age of the BIOCARD cohort, on the other hand, was 56.8 years at baseline.

The study collected baseline CSF samples, MRI scans, and cognitive and clinical testing data, following this up with annual neuropsychological batteries and additional MRI scans and CSF and blood sampling every two years. Of the 265 patients followed by Albert and her colleagues, 53 progressed to MCI or Alzheimer's, with the average time from baseline to the onset of MCI being 5.41 years.

The longitudinal data has been particular valuable, Albert said, in that it provides researchers with new insights into measures that could be useful for tracking in clinical trials.

"For example, it wasn't previously known that these [tau/Aβ] ratios were related to the onset of symptoms," she said. With that knowledge, "if you were designing a clinical trial, you might look at these ratios and see if the people who were being treated changed [in terms of their tau/Aβ ratios] in a different way from those who weren't being treated. You might use that as a secondary piece of information as you were conducting the trial."

Improving Alzheimer's drug trials is, of course, a primary aim of research into biomarkers for early detection of the disease – the thinking being that they can be helpful in selecting cohorts of patients early enough in the disease process for therapy to be effective.

According to Albert, use of either CSF markers or amlyoid imaging is "starting to be almost routine in clinical trials with patients with symptoms." And, she noted, a team led by Harvard University researcher Reisa Sperling is launching a clinical trial called the Anti-Amyloid Treatment in Asymptomatic AD, or A4 Trial, that will test anti-amyloid therapy in asymptomatic patients who have demonstrated positive amyloid burdens as determined by PET imaging.

Going forward, the Johns Hopkins team aims to improve the predictive power of its measurements by adding parameters, including amyloid imaging, Albert said. She noted that while the baseline and longitudinal CSF tau and Aβ measurements combined with the MRI and cognitive and clinical data can identify groups of patients likely to develop MCI, "on an individual patient basis, we are still not accurate enough at knowing who is at high risk."

The researchers have continued to add patients to the study, as well, and are currently following almost 300 subjects, Albert said. The majority – roughly three-quarters – have a strong family history of dementia, she noted. While this perhaps limits the breadth of conclusions that can be drawn from the data, the study was constructed in this way so as to increase the researchers' odds of observing patient changes.

"The sample obviously isn't representative of everybody in the world, but it was done that way to try to maximize the chances that we would see changes," Albert said. "The thinking was that if they didn't have [family history of dementia], we would have to follow them even longer."