14 July 2007. Is it time for a new diagnostic paradigm for Alzheimer disease? In a position paper published online in Lancet Neurology on July 6, a panel of experts says that when it comes to research studies, the answer is yes. Their proposal to update the current criteria, which date to 1984, is aimed at capturing the knowledge explosion that has occurred since then in understanding the biology of the disease. Combining memory testing with biomarker measurements, including genetic testing, imaging, and CSF protein assessments, the panel writes, will let researchers diagnose AD earlier and with greater accuracy. Nailing the diagnosis at the earliest possible stage with the greatest possible accuracy will be a critical factor in the success or failure of clinical trials of the many new candidate treatments coming down the pipeline.
The paper comes from first authors Bruno Dubois of the Hopital de la Salpetriere in Paris, France, and Howard Feldman of the University of British Columbia in Vancouver, Canada, who write with an additional 15 coauthors from Europe, North America, and Japan. The text presents the consensus recommendations of a working group convened in 2005 to integrate the information explosion in the field of AD biomarkers (see last year’s ARF biomarkers meeting report, for just a start), and the importance of early diagnosis, into a new framework for identifying AD.
The current criteria used to assign a diagnosis of AD were set out 23 years ago by the National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA) working group. The other accepted criteria are those of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). Both start with the finding of dementia, then go through a process of ruling out other causes to arrive at the diagnosis of AD. The clinical standard assigns a probability of AD; definitive diagnosis is only made postmortem based on brain pathology. The DSM criteria set the highest bar, requiring significant impairment in activities of daily living. The looser NINDS criteria allow an earlier diagnosis based on cognitive impairment, but neither of the currently accepted criteria captures the earliest, and presumably treatable, disease stages with high accuracy. (For more information on diagnosis, see ARF Diagnosis page).
The new approach would depend on biomarkers, not dementia, to define AD in patients with narrowly defined memory impairments. Thus, the working group recommends a core criterion of impairment in early episodic memory, bolstered by a second supporting biomarker measure. This could be medial temporal lobe atrophy, measured by MRI, abnormal levels of amyloid-β peptides or tau proteins in cerebrospinal fluid, specific patterns of brain function measured by fMRI, pathological protein deposition measured by PET, or a proven AD mutation in the family. The emphasis on biomarkers would help separate AD from look-alike diseases like frontotemporal dementias, and allow earlier diagnosis.
This approach would represent a “cultural shift” in the way AD is recognized, the authors write, “requiring more biologically focused workup than previous approaches; however, this seems to be the best way to integrate the profound advances into the clinical arena.” Rather than relying on clinical testing alone, the approach begins to define AD as a biological entity.
The devil, as always, is in the details. The recommendations are forward-looking, and much work remains to validate and implement such schemes. As yet, there are no standard procedures, no established cut-off values for normal and abnormal results for the proposed tests, the authors concede. Validation in both retrospective and prospective formats will be needed to establish working parameters. Practical issues limit much of this work to research centers, and the authors advocate an approach of adding on these new measures to ongoing studies to start to accumulate the needed validation data.
These issues are considerable, and some researchers feel it is premature to be talking about revising the diagnostic criteria based on current data. Ron Petersen of the Mayo Clinic in Rochester, Minnesota, told ARF that a meeting held in Miami last April sponsored by the Mt. Sinai Medical Center focused on the question of whether the field was ripe for a consensus conference to revise the 1984 criteria. “There were a lot of good hypotheses proposed,” said Petersen, “But we came away thinking it was too soon, and there was no consensus as to how we would go about revising the guidelines. The bottom line is that we need more longitudinal data.
“Moving to earlier diagnosis based on a single memory test and one biomarker raises the risk of misdiagnosis, and putting the label of AD on a patient has both scientific and sociological consequences,” Petersen told ARF. “We have a responsibility to our patients and the scientific community to be accurate with our labels.”
In an accompanying commentary, Norman Foster of the University of Utah in Salt Lake City writes that while the proposed criteria are not ready for clinical use, they will form a crucial framework for future discussion. He suggests that age should also be incorporated into the diagnostic scheme, since episodic memory loss in someone under 60 is far less likely to be due to AD than the same symptom in an older person.
Like the working group, Foster anticipates that great progress could be made relatively easily by incorporating the evaluation of new criteria in studies that continue to use the NINCDS-ADRDA criteria. Indeed, this kind of add-on goes on in research centers like the Mayo Clinic routinely, Petersen said.
Foster points out that before those guidelines were published, “many clinicians had previously considered [a diagnosis of AD] futile without an autopsy.” The criteria spurred research and enhanced care, but he writes that after 20-plus years, “The time is right to use the advanced technology at our disposal to improve the early, accurate diagnosis of dementia and develop more effective treatments.”—Pat McCaffrey.
Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007 Jul 6; [Epub ahead of print] Abstract
Foster NL. A new framework for the diagnosis of Alzheimer's disease. Lancet Neurol. 2007 Jul 6; [Epub ahead of print] Abstract