Warning: AD Ahead
A shrinking hippocampus and signs of MCI signal destruction of brain cells that may be irreversible, so one goal of biomarker research is to move diagnosis forward to even earlier phases. One approach has been to look for protein markers in cerebrospinal fluid, including the neurotoxic Aβ and phospho-tau peptides, to get a window into ongoing brain pathology. A new paper from Washington University researchers Anne Fagan, David Holtzman, and colleagues advances this technique by showing that CSF levels of Aβ42 and tau proteins, in particular an elevated total tau/Aβ42 or p-tau181/Aβ42 ratio, mark cognitively normal individuals who are heading for dementia.
Previous studies by this group and others have shown that in patients with AD, CSF concentrations of Aβ40 and Aβ42 peptides are lower than normal, while total tau and phospho-tau levels are increased (see ARF related news story). This new study, published online January 8 in the Archives of Neurology, extends those findings by showing that people in even the earliest stages of AD (very mild to mild cognitive symptoms) already show changes in these biomarkers that resemble those seen in people with AD.
Moreover, in a prospective study, the researchers show elevation of total tau/Aβ42 or p-tau181/Aβ42 in cognitively normal people was associated with an increased risk of conversion to dementia during a follow-up period, which averaged 3-4 years. Of 61 people who started the study in the cognitively normal group, 13 went on to develop measurable impairment. The subjects in the top 15 percent of values for tau/Aβ42 or p-tau181/Aβ42 had a 4-5 times higher risk of conversion during the follow-up period. The lowest 15 percent had a lower rate. The results support the idea that CSF levels of plaque and tangle-derived peptides are potentially useful antecedent markers of future dementia, the authors conclude.
The study also strengthened the relationship between CSF Aβ42 concentrations and brain amyloid load as measured by PET imaging with Pittsburgh compound B. A previous study by the same group, in a small number of people, showed that lower CSF Aβ42 correlated with higher amyloid in the brain, suggesting that brain amyloid may represent an Aβ sink (see ARF related news story). The present paper contains results from PET imaging of 50 people, and the relationship holds up, indicating that low CSF Aβ42 levels can be a useful surrogate for brain amyloid load.
Watching Statins at Work
One application of CSF and imaging markers is to clinical trials. There they can help with patient selection and also serve as potential surrogate markers of the clinical effects of the drug at hand. A study in the January Journal of Alzheimer’s Disease shows just such a use. Robert Riekse, working with Elaine Peskind and coworkers at the University of Washington and the VA Puget Sound Healthcare System in Seattle, measured CSF Aβ40 and 42, tau and phospho-tau, as well as soluble amyloid precursor protein (APP) α and β fragments and F2 isoprostanes to assess the effects of statin treatment on Alzheimer-related proteins in the brain.
In a small trial of 23 healthy adults between 34 and 87 years old, the researchers treated 10 people for 14 weeks with simvastatin, which penetrates the brain well, and 13 with pravastatin, which stays outside the CNS. They then assessed CSF marker levels. The researchers found no change in Aβ or any amyloid marker, but did see a decrease in p-tau181 in all subjects treated with simvastatin. In the pravastatin group, half the subjects showed declines in p-tau181, while half showed increases. There were no changes in any other markers in either group.
The differences in the effects of the two statins may have been due to differences in brain penetration. Interestingly, the decline in phospho-tau in some patients on the impermeant pravastatin correlated with their CSF serum albumin ratio, a measure of blood-brain barrier integrity, suggesting that in those patients with lower p-tau, pravastatin might have had access to the brain. The results point to CNS penetration as a critical determinant of whether a statin will affect markers, and support the idea that differences in accessibility could cause some of the variation seen with these agents in epidemiological and clinical trials for AD.
The changes in p-tau after simvastatin treatment were small, and in this group of healthy people, they were not consistent with all previous studies done in AD patients. Nonetheless, the results support a role for cholesterol metabolism in the formation of neurofibrillary tangles, and suggest that CNS-permeant statins might affect AD pathology.
As Simple as a Blood Test?
Finally, there is a new paper from Boston researchers who combed through gene expression profiles in blood cells to find tell-tale signs of neurodegeneration in early Parkinson disease (PD). First author Clemens Scherzer presented some of this work at the Society for Neuroscience Meeting in 2005 (see ARF related news story), and the paper appeared this week in PNAS online.
The course of PD resembles AD in that the target neurons degenerate for years before symptoms appear, early disease is hard to identify, and there is no test for risk of future disease. The same rationale, then, drives the search for biomarkers, a search that has some researchers looking outside the brain at more easily accessible tissues.
To do that, Scherzer and colleagues assembled blood samples from 105 people, half of them with early PD, and the rest either healthy controls or people with other neurodegenerative diseases. From computer analysis of the gene expression profiles of each, they built a set of eight marker genes whose expression highly correlated with early PD. By measuring expression levels in any person, they could then calculate an individual PD risk score. Application of this risk marker to a separate population of 39 people predicted PD better than current risk factors.
Similar approaches looking at gene expression in peripheral tissue have been undertaken for AD (see ARF related news story and meeting coverage on Tony Wyss-Coray’s work). In fact, a study by Scherzer with James Lah at Emory University in Atlanta was the first to find low expression of the apolipoprotein E receptor LR11/SorLa gene in blood cells from AD patients (Scherzer et al., 2004). That study provided insight into the AD disease process, as the researchers showed subsequently that the protein is a modifier of APP processing, and an imminent genetics study identifies the SorLa gene as a new LOAD risk gene.
In the PD study, a closer consideration of the eight marker genes showed they do not appear to be functionally related in any one pathway or process. However, each one is expressed in brain, and three have been linked to PD or neurodegeneration previously. In addition to those eight, the investigators looked at an additional 22 genes that showed significant changes in PD vs. control to present some new insights into potential disease processes. Some of these genes could represent molecular surrogates of the disease, the authors write, but more work will be needed to confirm that.—Pat McCaffrey.
Decarli C, Frisoni GB, Clark CM, Harvey D, Grundman M, Petersen RC, Thal LJ, Jin S, Jack CR Jr, Scheltens P. Qualitative estimates of medial temporal atrophy as a predictor of progression from mild cognitive impairment to dementia. Arch Neurol. 2007 Jan;64(1):108-15. Abstract
Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal Fluid tau/beta-Amyloid42 Ratio as a Prediction of Cognitive Decline in Nondemented Older Adults. Arch Neurol. 2007 Jan 8; [Epub ahead of print] Abstract
Riekse RG, Li G, Petrie EC, Leverenz JB, Vavrek D, Vuletic S, Albers JJ, Montine TJ, Lee VM, Lee M, Seubert P, Galasko D, Schellenberg GD, Hazzard WR, Peskind ER. Effect of statins on Alzheimer's disease biomarkers in cerebrospinal fluid. J Alzheimer’s Dis. 2006 Dec;10(4):399-406. Abstract
Scherzer CR, Eklund AC, Morse LJ, Liao Z, Locascio JJ, Fefer D, Schwarzschild MA, Schlossmacher MG, Hauser MA, Vance JM, Sudarsky LR, Standaert DG, Growdon JH, Jensen RV, Gullans SR. Molecular markers of early Parkinson's disease based on gene expression in blood. Proc Natl Acad Sci U S A. 2007 Jan 10; [Epub ahead of print] Abstract