18 December 2009. The December 14 issue of Archives of Neurology features three papers and an editorial from scientists at Washington University in St Louis, Missouri, that, taken together, strengthen the case for using readouts of amyloid in the brain or the spinal fluid as indicators to flag that a cognitively healthy person faces a future with Alzheimer disease. This space has covered the underlying research in conference presentations and elsewhere on Alzforum, but here are brief reminders.
In one paper, Martha Storandt and colleagues took data from 135 cognitively normal people studied between the years of 1985 and 2008, who, besides undergoing annual cognitive testing, had PIB-PET scans to visualize amyloid in their brain as well as volumetric MRI imaging. None of these research volunteers met clinical criteria for even a mild dementia diagnosis, i.e., they all tested within the normal range. All the same, those 29 participants who had significant amyloid in their brains also showed brain atrophy in AD-relevant brain areas, and their performance over time started to dip in episodic and working memory as well as visuospatial tasks (Storandt et al., 2009; for extensive context, see Leonard Berg conference story).
In another paper, John Morris and colleagues report that a longitudinal study of 159 research participants who were cognitively normal at baseline and had PIB-PET and MRI scans showed that being positive for brain amyloid greatly increased a person’s risk of developing symptomatic AD in the next two to five years. This, to the authors, suggests that brain amyloid indicates preclinical AD in an outwardly still-normal person (Morris et al., 2009; see ARF related news story).
A third paper led by Nigel Cairns describes a case report of a man who was unusual in that he underwent numerous CSF, PIB-PET, and cognitive assessments late in life, shortly before and after he became symptomatic for AD. To the authors, his data indicated that in some cases, the characteristic drop in CSFAβ42 may occur soon after diffuse amyloid begins to deposit in the brain but before fibrillar amyloid becomes detectable by PIB somewhat later, rendering CSF Aβ42 perhaps the earliest biomarker available to date (Cairns et al., 2009).
The same issue of the Archives features an editorial by David Holtzman of WashU on a large European study that had tested the CSF biomarker signature for AD in a multicenter, multi-country setting that featured inevitable local variability in how patients were assessed and tests performed. Led by Niklas Mattsson and colleagues at the Sahlgrenska University Hospital in Molndal, Sweden, the study appeared in JAMA this past summer (Mattsson et al., 2009; also ARF related news story; Petersen and Trojanowski, 2009). In his Archives comment, Holtzman noted that this large multicenter study robustly affirmed the biological relevance of these markers, but also that significant hurdles remain before they will be truly useful in routine clinical practice. These include standardization of sample collection and storage, standardization of assay choice and performance, and external quality control. For a detailed description on a new worldwide Quality Control program that is free and open to all, including downloadable protocol and signup information, see ARF Quality Control series Parts 1, 2, and 3.—Gabrielle Strobel.
Storandt M, Mintun MA, Head D, Morris JC. Cognitive decline and brain volume loss as signatures of cerebral amyloid-beta peptide deposition identified with Pittsburgh compound B: cognitive decline associated with Abeta deposition. Arch Neurol. 2009 Dec;66(12):1476-81. Abstract
Morris JC, Roe CM, Grant EA, Head D, Storandt M, Goate AM, Fagan AM, Holtzman DM, Mintun MA. Pittsburgh Compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease. Arch Neurol. 2009 Dec;66(12):1469-75. Abstract
Cairns NJ, Ikonomovic MD, Benzinger T, Storandt M, Fagan AM, Shah AR, Reinwald LT, Carter D, Felton A, Holtzman DM, Mintun MA, Klunk WE, Morris JC. Absence of Pittsburgh Compound B detection of cerebral amyloid beta in a patient with clinical, cognitive, and cerebrospinal fluid markers of Alzheimer disease: a case report. Arch Neurol. 2009 Dec;66(12):1557-62. Abstract
Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, Herukka SK, van der Flier WM, Blankenstein MA, Ewers M, Rich K, Kaiser E, Verbeek M, Tsolaki M, Mulugeta E, Rosén E, Aarsland D, Visser PJ, Schröder J, Marcusson J, de Leon M, Hampel H, Scheltens P, Pirttilä T, Wallin A, Jönhagen ME, Minthon L, Winblad B, Blennow K. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA. 2009 Jul 22;302(4):385-93. Abstract