Imaging Suggests Wide Window for Alzheimer’s Tx

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Alzheimer’s Disease

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By Charles Bankhead, Staff Writer, MedPage Today

Published: February 27, 2013

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

Action Points

  • This study used serial amyloid PET imaging to model rates of beta-amyloid accumulation.
  • Low rates of accumulation were observed in those with the lowest and highest baseline amyloid burden, whereas amyloid accumulation was highest in those with mid-range baseline amyloid levels.

The biological path to Alzheimer’s disease might continue for more than a decade, suggesting a broad window of opportunity for intervention, according to a study of amyloid plaque accumulation.

Longitudinal measurement by PET imaging showed that plaque buildup reached a plateau at 2.7 times baseline values, a process that required about 15 years.

The results not only suggest ample opportunity for secondary prevention but imply that therapies with the potential to block plaque accumulation would be less effective when the plateau has been reached, investigators reported in the March 5 issue of Neurology.

“Given that the time course of the disease evaluable by currently available biomarkers may span 30 or more years, it will take decades to collect such an idealized dataset,” Clifford Jack, MD, of the Mayo Clinic in Rochester, Minn., and colleagues noted in their discussion of the findings. “An alternative, however, is to piece together shorter time-interval data in many participants to create plausible long-term disease models.”

“We believe that indexing individual participants by amyloid PET standardized uptake value ratio (SUVR) provides a valid solution to this problem in the current context where we are evaluating an amyloid biomarker,” they added.

The most established biomarkers of Alzheimer’s disease fall into two categories: 1) measures of neuronal injury and degeneration and 2) measures of beta-amyloid accumulation in the brain, including cerebrospinal fluid.

Jack and colleagues have proposed a model of the evolution of Alzheimer’s disease biomarkers. They hypothesized that amyloid accumulation follows an inverted-U (sigmoid) trajectory over time, initially accelerating and then decelerating (Lancet Neurol 2010; 9: 119-128).

The authors conducted a study to test the hypothesis that PET-derived amyloid load versus time can be modeled by a sigmoid function.

The study involved 260 participants in Mayo studies of aging and Alzheimer’s research. The participants had an age range of 70 to 92 at enrollment, and all of them underwent two or more PET studies of brain amyloid.

The study population consisted of 205 participants with normal cognitive function, 47 with mild cognitive impairment, and eight with Alzheimer’s disease.

For each participant, investigators measured baseline amyloid SUVR and estimated the slope of annual rate of amyloid accumulation. They also developed regression models to predict the annual rate of amyloid accumulation on the basis of baseline amyloid SUVR and evaluated age, sex, cognition classification, and apolipoprotein E4 genotype as covariates.

Lastly, investigators integrated the association between amyloid accumulation rate and baseline amyloid SUVR into an amyloid PET-SUVR-versus-time association.

The participants’ PET scans occurred over an average of 1.3 years. Low baseline amyloid SUVR was associated with low rates of amyloid accumulation. The accumulation rates increased with SUVR to a baseline maximum of about 2.0. Thereafter, the rate of accumulation declined and reached 0 at a baseline SUVR of about 2.7.

The rate of amyloid accumulation as a function of baseline SUVR resulted in an inverted U-shaped curve. The estimated time span from an SUVR of 1.5 to 2.5 was about 15 years.

“This roughly 15-year interval where the slope of the amyloid SUVR versus time curve is greatest and roughly linear represents a large therapeutic window for secondary preventive interventions,” the authors concluded.

The study “breaks new ground in providing insight into the nature of amyloid accumulation,” Jeffrey M. Burns, MD, and Russell H. Swerdlow, MD, said in an accompanying editorial. However, application of the results remains limited by an imprecise understanding of amyloid’s clinical relevance to Alzheimer’s disease.

“The study does not examine how amyloid burden or the apparent kinetics of amyloid accumulation … relates to clinical outcomes,” said Burns and Swerdlow, of the University of Kansas in Kansas City. “In fact, the rate of accumulation was not clearly different between impaired and cognitively normal groups, and many individuals with the highest levels of amyloid were cognitively normal.”

The incongruity between amyloid burden and cognitive impairment is consistent with autopsy studies suggesting that amyloid burden has at best a loose association with dementia.

“If the amyloid cascade hypothesis is correct, pharmacologically targeting amyloid accumulation after the amyloid accumulation process burns itself out is probably too little too late,” Burns and Swerdlow added. “Because the period of accelerated amyloid deposition frequently occurs before clinical symptoms manifest, this view supports the assumption that robust disease modification will only be accomplished when initiated very early in the course of the disease.

“It is also important to consider, however, that if amyloid turns out to be only a secondary biomarker of the disease, as opposed to its cause, then targeting its accumulation at any stage will have, at most, a limited effect on clinical outcomes.”

The study was supported by the National Institutes of Health, the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Foundation, the Robert H. and Clarice Smith Alzheimer’s Disease Research Program of the Mayo Foundation, and General Electric.

Jack disclosed relationships with Janssen, Bristol-Myers Squibb, General Electric, Johnson & Johnson, Allon, and Baxter. Co-authors disclosed relationships with Lilly Pharmaceuticals, Janssen, Bayer Schering, GE Healthcare, Siemens Molecular Imaging, MN Partnership for Biotechnology, Medical Genomics, Pfizer, Elan Pharmaceuticals, Cephalon, and the Mangurian Foundation. One or more authors disclosed royalty interests related to book publication.

Burns disclosed relationships with PRA International, Janssen, Wyeth, Danone, and Baxter. Swerdlow disclosed a relationship with PhotoThera.

Primary source: Neurology
Source reference:
Jack CR Jr, et al “Brain ß-amyloid load approaches a plateau” Neurology 2013; 80: 890-896.

Additional source: Neurology
Source reference:
Burns JM, Swerdlow RH “Backwaters and rapids on the amyloid river” Neurology 2013; 80: 878-879.

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