27 June 2009. Convincing people that something is wrong with your health can be difficult. Demonstrating that your memory is not up to par can sometimes be impossible. People who complain of troubling memory lapses but show no impairment in standard memory tests may take some solace from a recent European study. Writing in the June 11 Lancet Neurology, Pieter Jelle Visser and colleagues report that about 50 percent of people with subjective cognitive impairment have biomarker signatures that are found in Alzheimer disease (AD). “One interpretation is that these subjects might be in the very early stages of the disease,” Visser, University of Maastricht, The Netherlands, told ARF. That’s not to say that people with minor memory lapses—such as misplacing their car keys—should be concerned that they are on the slippery slope to full-blown dementia. The subjects in question have major forgetfulness. “Something like the children and grandchildren arriving for a Sunday dinner that you have totally forgotten you planned,” suggested Ron Petersen, Mayo Clinic, Rochester, Minnesota. Petersen was not involved in the study but feels it is an important contribution. “It addresses one of the hottest topics in aging and dementia these days—that is, the role of biomarkers in predicting what is going to happen down the road from a clinical perspective,” he said.
Visser and colleagues focused on three cerebrospinal fluid (CSF) biomarkers, amyloid-β42 (Aβ42) and total and phosphorylated tau. A low CSF Aβ42:tau ratio is found in people with AD and is associated with increased risk for cognitive decline in people with mild cognitive impairment, or MCI (see Hansson et al., 2006). But this is the first prospective study to see how the ratio correlates with cognitive decline in people with subjective memory complaint (SCI). The work was part of the multicenter European Union study Development of Screening Guidelines and Criteria for Predementia Alzheimer’s Disease (DESCRIPA).
Visser and colleagues collected CSF samples from people with amnestic MCI, non-amnestic MCI, SCI, and also normal controls. The SCI subjects were people who came to memory clinics with complaints, yet were found to have no impairment in tests of memory, language, executive function, and attention. The first thing the researchers found was that an AD-type CSF profile was prevalent in the three test groups being found in 80 percent of amnestic MCI patients, about 70 percent of non-amnestic MCI, and 52 percent of SCI subjects. In contrast, only 31 percent of controls had an AD-type profile. Next the researchers looked to see if the CSF profile had any correlation with subsequent cognitive decline. They followed patients for three years, repeating the cognitive tests. Patients without an AD-like CSF profile showed a statistically significant improvement in the Mini-Mental State Exam (MMSE) and the Clinical Dementia Rating-Sum-of-Boxes score (CDR-SOB). Patients with either amnestic or non-amnestic MCI and an AD CSF profile showed a significant deterioration in both tests. SCI subjects with the AD CSF profile had no change in the MMSE but trended toward decline in the CDR-SOB. Imaging data for some patients showed that for those with an AD CSF profile, SCI subjects had less medial temporal lobe atrophy than amnestic MCI patients. “It could be that these are very healthy subjects in the very earliest stage of decline,” suggested Visser. That decline might be revealed by longer follow-up studies, which are in the works, he said. But he also said that these patients might represent a specific subgroup in the population, one that may have protective factors that defend against impairments. “How these [CSF] profiles will perform in the general community is a whole other issue,” suggested Petersen. “The point being that we can’t overgeneralize these findings. They need to be interpreted in the context of people coming for clinical advice to a memory disorders clinic.”
This CSF work adds to a growing consensus that AD pathology might start well before any clinical manifestations of the disease. Studies with the amyloid imaging ligand Pittsburgh compound B (PIB) show that amyloid deposits are present in the brains of healthy seniors (see ARF related news story). “I think these two markers are probably giving us the same signal,” suggested Petersen. “The theory is that when the CSF level drops, it is because the Aβ is being deposited in brain, and that, of course, is what the PIB is detecting.” Petersen suggested that what might be more important is which happens first. “If you had a disease-modifying therapy, then you would want to use it as soon as possible, so you would want the earliest possible indicator,” he said. “That may be CSF markers, but we don’t know that for sure.”
Of course, neither PIB binding nor an AD CSF profile is necessarily a guarantee that dementia will follow (see ARF related news story). “In fact, people who have abnormal markers or positive PIB may not become demented in their lifetime. These are risk factors, they are not deterministic,” said Petersen. “I’d rather not have a head full of amyloid, but it is not necessarily a death sentence.”—Tom Fagan.
Visser PJ, Verhey F, Knol DL, Scheltens P, Wahlund LO, Freund-Levi Y, Tsolaki M, Minthon L, Wallin AK, Hampel H, Bürger K, Pirttila T, Soininen H, Rikkert MO, Verbeek MM, Spiru L, Blennow K. Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study. Lancet Neurol. 2009 Jul;8(7):619-27. Abstract