A "signature" consisting of three biomarkers in the cerebrospinal fluid was present in 90 percent of patients who had been diagnosed with Alzheimer’s disease but also was found in more than one-third of cognitively normal older adults, according to a report in the August issue of Archives of Neurology.
"The initiation of the Alzheimer’s disease pathogenic process is typically unobserved and has been thought to precede the first symptoms by 10 years or more," the authors write as background information in the article. "Therefore, demonstrating that Alzheimer’s disease biomarkers, such as cerebrospinal fluid beta-amyloid protein 1-42 (CSF Aß1-42), total CSF tau protein and CSF phosphorylated tau181P (P-Tau181P) protein concentrations are true indicators of the pathogenic process at an early stage is a major challenge."
Geert De Meyer, Ph.D., of Ghent University, Ghent, Belgium, and colleagues in the Alzheimer’s disease Neuroimaging Initiative analyzed data from 114 older adults who were cognitively normal, 200 who had mild cognitive impairment and 102 who had Alzheimer's disease. They first modeled the data from all participants, without considering their cognitive status, to identify profiles that had different levels of three biomarkers: CSF Aß1-42, total CSF tau protein and P-Tau181P. One profile or signature was presumed to be associated with Alzheimer’s disease while the other matched a "healthy" status.
When these profiles were applied to the data in the subgroups, the Alzheimer’s disease signature was found in 90 percent of those with Alzheimer's disease, 72 percent of those with mild cognitive impairment and 36 percent of those who were cognitively normal.
"Results were validated on two other data sets," the authors write. "In one study consisting of 68 autopsy-confirmed Alzheimer’s disease cases, 64 of 68 patients (94 percent sensitivity) were correctly classified with the Alzheimer’s disease feature. In another data set with patients (n=57) with mild cognitive impairment followed up for five years, the model showed a sensitivity of 100 percent in patients progressing to Alzheimer's disease."
The results suggest that this signature of biomarkers -- developed independently of data on clinical diagnosis of Alzheimer’s disease -- can correctly classify patients with the condition. "The unexpected presence of the Alzheimer’s disease signature in more than one-third of cognitively normal subjects suggests that Alzheimer’s disease pathology is active and detectable earlier than has heretofore been envisioned," the authors conclude. "Thus, taken together, these data provide further support for the view that revision of current diagnostic criteria for Alzheimer’s disease is needed, or at least as far as early-stage Alzheimer’s disease is concerned."
Editorial: Biomarkers Aid Diagnosis of Alzheimer's Disease
"The article by De Meyer et al in this month's issue of the Archives presents a novel method of analyzing cerebrospinal fluid (CSF) biomarker data and determining how these data map onto the clinical diagnoses of Alzheimer's disease, mild cognitive impairment and healthy control subjects," write A. Zara Herskovits, M.D., Ph.D., of Brigham and Women's Hospital, and John H. Growdon, M.D., of Massachusetts General Hospital, Boston, in an accompanying editorial.
"To date, cerebrospinal fluid analyses have not been a routine component of assessment and care for patients with cognitive impairments and suspected Alzheimer’s disease in the United States. There is now ample evidence that these measurements have value; physicians need to formulate when and how to incorporate cerebrospinal fluid measurements into their practice," they write.
"Gazing into the future when there are neuroprotective medications for Alzheimer's disease, we can envision a recommendation that cerebrospinal fluid analyses be implemented as a screening test to identify clinically healthy individuals at risk for mild cognitive impairment and Alzheimer's disease. The information gained would enable early application of treatments to delay onset of symptoms or slow progression of cognitive impairments."
1. Diagnosis-Independent Alzheimer Disease Biomarker Signature in Cognitively Normal Elderly People.
Geert De Meyer, PhD; Fred Shapiro, MLS; Hugo Vanderstichele, PhD; Eugeen Vanmechelen, PhD; Sebastiaan Engelborghs, MD, PhD; Peter Paul De Deyn, MD, PhD; Els Coart, PhD; Oskar Hansson, MD; Lennart Minthon, MD; Henrik Zetterberg, MD, PhD; Kaj Blennow, MD, PhD; Leslie Shaw, PhD; John Q. Trojanowski, MD, PhD; for the Alzheimer's Disease Neuroimaging Initiative
Archives of Neurology, 2010; 67 (8): 949 – 956 DOI: 10.1001/archneurol.2010.179
Link to Arch Neurol abstract
2. Editorial:Sharpen That Needle.
A. Zara Herskovits. MD and John H. Growdon, MD
Archives of Neurology 2010;67(8):918-920 DOI: 10.1001/archneurol.2010.151
Link to Arch Neurol editorial