ARTICLE IN BRIEF
Investigators evaluated the association of CSF biomarkers of AD to amyloid and tau pathologies in brain biopsies of living patients, finding that that the concentration of amyloid beta-42 in ventricular CSF differentiates the groups between the presence of amyloid and tau in cortical brain biopsy.
For the first time researchers have confirmed that levels of certain proteins found in ventricular and lumbar CSF correlate with pathological changes in the brain characteristic of Alzheimer disease (AD) in living patients.
A number of imaging studies have indicated that certain AD biomarkers in CSF appear to be associated with AD. Linking potential CSF markers to the disease's characteristic amyloid beta (Abeta) plaques and neurofibrillary tangles caused by excessive levels of total tau (t-tau) and phosphorylated tau (p-tau, especially p-tau-181) in living patients is viewed as a critical step toward both early diagnosis and testing possible interventional strategies.
Reporting in the May 15 edition of Neurology, a team led by Toni T. Seppälä, MD, a researcher at the University of Eastern Finland School of Medicine's Brain Research Unit in Kuopio, Finland, studied 182 patients, including 152 carriers of a genetic variant that has been linked to AD — apolipoprotein E 4 (APOE4).
Cortical biopsies were possible because all of the patients were being treated for normal pressure hydrocephalus (NPH), which requires brain shunting. Many of the symptoms of NPH are similar to those in AD patients, including memory disturbances, gait problems, and urinary incontinence. Lumbar and ventricular CSF analysis was performed to see if the presence of known AD biomarkers correlated with biopsy evidence of plaques and tangles. At a median follow-up of two years, 51 of the patients had developed AD dementia.
AN INVERSE CORRELATION
Individuals with tau in their cortical biopsy had lower levels of the 42 isotope of Abeta (Abeta-42), but higher levels of p-tau-181 in their CSF. Low levels of Abeta-42 and high levels of CSF tau and p-tau-181 were linked to both amyloid plaques and the presence of neurofibrillary tangles in cortical samples, especially in patients who went on to develop AD dementia.
“There was an inverse correlation between the CSF concentrations of Abeta-42 and the quantitative amount of amyloid in biopsy specimens,” Dr. Seppälä told Neurology Today in an e-mail. “We found that the known CSF biomarkers of Alzheimer disease, Abeta-42 and tau, correlated with neuropathological findings in our cortical brain biopsies.”
Patients with amyloid plaques and concentrations of tau in biopsy samples had the lowest Abeta-42 and highest tau and p-tau-181 levels in the CSF. The Abeta-42 levels were also lower, and the tau and p-tau-181 higher, in ventricular vs. corresponding lumbar CSF samples. In a multivariate analysis, the presence of cortical Abeta was independently predicted by the APOE4 carrier status and age.
“The study shows that CSF Abeta-42 accurately reflects the neuropathological findings that take place in the living brain, which corroborates the findings that have been seen with PIB-PET [Pittsburgh compound B-positron emission tomography] imaging,” Dr. Seppälä explained. “Secondly, brain biopsy samples taken from the frontal cortex, a routine diagnostic procedure for patients with NPH, can effectively show whether there are any neuropathological signs of AD in the brain. Together with CSF biomarkers, this information may provide assistance in making differential diagnoses so that patients may get an earlier and more accurate diagnosis of AD.”
The main limitation in the study was that most patients had NPH but not AD, he said, however the results were clear in the AD subgroup.
“The usefulness of CSF biomarkers seems to be verified quite undeniably here, and the use of cortical brain biopsy should be considered at least for research purposes,” Dr. Seppälä said. “Still, more information is needed on the reliability of a single cortical brain biopsy and CSF biomarkers, compared with full post-mortem autopsy.”
Other biomarkers for AD are also being studied and some very promising candidates have been identified in the blood, Dr. Seppälä said, although developing a blood test for them will take time.
“I'm certain that in the near future we are going to have a combination of routine clinical tests [for AD] that can be easily conducted. However, therapeutics must also take a major forward because a test for preclinical AD is useless if there is no treatment available that could be aimed at the disease process.”
The team's studies on blood and CSF biomarkers for AD and the NPH brain biopsies are ongoing.
THE IMPORTANCE OF THE STUDY
The research helps provide further evidence that accurate CSF biomarkers for diagnosing early AD in living patients are possible, said John Q. Trojanowski, MD, PhD, co-director of the Center for Neurodegenerative Disease Research, and director of the Institute on Aging Alzheimer's Disease Core Center at the University of Pennsylvania Institute of Neurological Sciences in Philadelphia.
“This is a very interesting and well-done study,” he told Neurology Today in a telephone interview. “What makes it special is that it demonstrates gradients for Abeta and tau in both lumbar and ventricular CSF, and correlates these values with Abeta plaque and tau deposits. The study provides solid examples of changes in CSF Abeta and tau in the CSF.”
“Of course, there are a number of planning issues to be considered in fully evaluating any of these diagnostic tests, but identifying useful CSF biomarkers would be a boon for drug discovery efforts and clinical trials. This study adds additional credence to CSF testing. Having a blood test would be much more attractive, however a credible link between levels of Abeta or tau in the blood and brain deposits has yet to be established.”
Dr. Trojanowski is part of the Alzheimer's Disease Neuroimaging Initiative (ADNI), an ongoing, longitudinal, multicenter study to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of AD.
• Seppälä TT, Nerg O, Koivisto AM, et al. CSF biomarkers for Alzheimer's disease correlate with cortical brain biopsy findings. Neurology
• Seppälä TT, Koivisto AM, Hartikainen P, et al. Longitudinal changes of CSF biomarkers in Alzheimer's disease. J Alzheim Dis
• Weinera MW, Veitcha DP, Trojanowski JQ, et al. The Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception. Alzheimers Dement
• Aisen PS. Q&A: The Alzheimer's disease neuroimaging initiative. BMC Med