JNM: PET emerges as biomarker for Alzheimer's progression

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18F-FDG PET may provide a quantitative measure to detect progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD), and could offer a mechanism to streamline clinical trials, according to a study published in this month's Journal of Nuclear Medicine.

The study precedes proposed National Institute on Aging (NIA) and the Alzheimer's Association guidelines for detecting Alzheimer's-related brain changes expected in September. The proposed guidelines available this fall will offer additional information regarding the development of tests to measure biological changes in the brain, blood or spinal fluid to diagnose AD at an earlier stage.

"We urgently need tools for conducting drug trials for MCI more efficiently," noted the study's lead author Karl Herholz, MD, of Wolfson Molecular Imaging Centre at University of Manchester in Manchester, England.

"Clinical outcome parameters show large variability and little sensitivity to progression at that stage, making these trials extremely costly and cumbersome," he continued. "By using imaging biomarkers as primary outcome parameters, clinical trials can be performed with smaller sample sizes or shorter trial duration without loss of study power."

However, before an imaging biomarker can be employed, it needs to demonstrate a close link with clinically relevant outcomes.

Previous studies of PET imaging showed impaired activity in AD as reduced FDG uptake in the temporoparietal association areas. Changes were detected as a significant deviation from controls one to two years prior to the onset of dementia.

The current study evaluated a predefined quantitative measure—PET score—that was extracted automatically from 18F-FDG PET scans using a sample of controls, patients with MCI and patients with AD.

The study cohorts, 44 controls, 94 patients with MCI and 40 patients with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI), underwent four PET studies and clinical assessments over two years.

The number of patients diagnosed with AD increased over the course of the study, reported the authors. Between the baseline exam and follow-up at 24 months, two controls progressed to MCI. Furthermore, of the 94 patients with MCI, seven reverted to controls, 57 remained MCI and 30 progressed to AD.

PET scores were significantly higher for AD patients and those who progressed to a more severe diagnostic group, reported Herholz et al. “Subjects who had a baseline above 1 had a significantly increased risk for progression. The sensitivity to predict progression was 0.57; specificity, 0.67; positive predictive value, 0.45; and negative predictive value, 0.77,” wrote the authors. Meanwhile, PET scores in stable subjects did not change significantly.

Although PET scores provided a much higher test-retest reliability than standard neuropsychologic test scores (Alzheimer's Disease Assessment Scale-Cognitive [ADAS-cog] and Mini-Mental State Examination) and superior strength for measuring progression, the researchers found close and highly significant correlation between the measures. After completing a power analysis, Herholz and colleagues estimated that the sample size for a clinical study using ADAS-cog as the primary outcome would require a cohort three times that of a study using PET scores.

Alternatively, the follow-up time could be shortened by approximately half. “PET scores may provide a power for one-year studies in MCI patients similar to what they provide for two-year studies based on progression of ADAS-cog scores,” Herholz wrote.

As such, the PET scores can be considered a valid imaging biomarker to monitor the progression of MCI to AD and fulfill several regulatory requirements for biomarkers, including high test-retest reliability and representation of prodromal and early AD.

However, the link between the biomarker and desired clinical outcome still needs to be clearly established, cautioned Herholz et al. This could occur with two positive phase III trials in which PET scores correlated with clinical outcomes or similar findings in phase II trials.

In addition to the clinical and practical advantages afforded by the PET score, the researchers pointed to a final benefit. "18F-FDG PET as a technical procedure that is independent of language and educational and cultural background may offer an advantage especially in studies performed across multiple countries,” they explained.

Herholz and colleagues affirmed the validity of PET scores