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Imaging May Offer Alzheimer's Diagnosis Tool


 

FROM JAMA

Positron-emission tomography in combination with the radiolabeled compound florbetapir F-18 detected beta-amyloid plaques with 93% sensitivity and 100% specificity in the brains of 35 elderly patients, most of whom had some form of dementia.

Lead investigator Dr. Christopher Clark and his colleagues wrote that florbetapir-PET imaging could be an important diagnostic tool for Alzheimer's disease – perhaps with the ability to detect brain plaques early in a prodromal stage of the disease – and to measure plaque changes in relation to therapeutic response in future drug studies, according to Dr. Clark, medical director of Avid Radiopharmaceuticals, the company testing the compound (JAMA 2011;305:275-83).

The study also represents the first time an amyloid imaging agent has been tested against autopsy results, said coinvestigator Dr. Marwan N. Sabbagh, founding director of the Cleo Roberts Center for Clinical Research in Sun City, Ariz.

“It's really exciting to be able to correlate imaging so strongly with autopsy findings,” Dr. Sabbagh said.

But Dr. Clark and his coinvestigators cautioned that the study does not make it clear what specific clinical applications the imaging procedure could have, be it the clinical diagnosis of Alzheimer's disease or the prediction of progression to dementia.

The Food and Drug Administration's Peripheral and Central Nervous System Drugs Advisory Committee will meet on Jan. 20 to discuss the compound and the study's findings.

Like Pittsburgh imaging compound B (PiB), florbetapir binds to beta-amyloid plaques in the living brain.

PiB's use, however, has been limited by its short half-life of 20 minutes.

Florbetapir achieves maximum uptake at 30 minutes and remains unchanged for the next 60 minutes, “providing a wide time window to obtain a 10-minute image,” the authors noted.

The prospective study involved 35 patients in hospice or long-term care facilities who were expected to die within 6 months.

Six of the patients were used to validate the imaging procedure while the remaining 29 were used in the primary validation study.

Among the 29 in the validation analysis, the mean age was 80 years.

This group included 13 with a clinical diagnosis of Alzheimer's, 5 with other dementias, 9 with normal cognition, and the rest with mild cognitive impairment.

Their mean Mini-Mental State Examination (MMSE) score was 3.8.

The control group comprised 74 young, healthy subjects, 27 of whom were positive for the APOE e4 allele, which greatly increases the risk of developing Alzheimer's in later life.

The control subjects had a mean age of 27 years and a mean MMSE score of 29.7.

Florbetapir imaging was negative for all 74 subjects, including those with the APOE e4 allele.

Florbetapir-PET imaging in the 35 patients was significantly correlated with both immunohistochemistry and silver stain for beta-amyloid plaques in each of the six brain regions that the investigators examined (frontal, temporal, parietal, anterior and posterior cingulate, precuneus, and cerebellum).

At autopsy, 15 patients in the validation group met pathologic criteria for Alzheimer's disease.

Of these, 14 had positive florbetapir-PET scans, leading to a sensitivity of 93%.

The other 14 patients had low levels of beta-amyloid plaque on autopsy, and did not meet the diagnostic criteria for Alzheimer's.

All 14 also had negative florbetapir-PET scans, giving 100% specificity.

“The neuropathological diagnosis in the participants who did not meet pathological criteria for AD included dementia with Lewy bodies, hippocampal sclerosis, Parkinson's disease, subcortical microscopic infarct, mesial temporal lobe neurofibrillary tangles, neurofibrillary tangles with argyrophilic grains and glial tauopathy, and no neuropathology,” the authors wrote.

Of the 15 patients in the validation cohort who had a clinical diagnosis of dementia during life, 3 did not have the same diagnosis on autopsy.

One of these patients had a clinical diagnosis of probable Alzheimer's but did not have it on autopsy, whereas one with a clinical diagnosis of Parkinson's disease dementia and one with a clinical diagnosis of Lewy body dementia actually had Alzheimer's.

Florbetapir-PET correctly predicted the presence or absence of Alzheimer's disease in these patients.

The authors noted that the patient sample used in the study did not represent a typical clinical population, most of whom would be referred for initial signs of cognitive impairment.

Rather, the cohort was selected “for their unique ability to provide information about the ability of florbetapir-PET imaging to accurately identify and quantify beta-amyloid with the shortest interval between imaging and definitive pathological evaluation possible,” they said.

The study was funded primarily by Avid Radiopharmaceuticals. Dr. Clark and eight of the coauthors are stockholders and/or employees of the company. All of the other coauthors received research grants, and most are educators, paid investigators, or members of the speakers bureau for Avid or for Eli Lilly, which acquired the company last November.

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