A team led by Massachusetts General Hospital (MGH) investigators has confirmed that the imaging agent Pittsburgh Compound B (PiB) binds to the protein in amyloid plaques that characterize Alzheimer's disease in the human brain. Their report in the March Archives of Neurology describes the first postmortem neuropathological study of a dementia patient who had previously participated in a PET imaging study using PiB.
"This report is an essential validation of the use of PET imaging with PiB to identify amyloid-beta deposits in the brain and as a marker of disease progression that could be used to track the benefit of new treatments," says John Growdon, MD, director of the MGH Memory Disorders Unit, the paper's senior author. "It also indicates that the interpretation of PiB PET scanning needs to be done in the context of a patient's clinical symptoms and other diagnostic studies."
Alzheimer's disease is characterized by plaques within the brain of amyloid-beta protein, which is toxic to brain cells. Previous studies have shown that PiB, invented by researchers at the University of Pittsburgh School of Medicine, binds to amyloid-beta in the brains of mice and can be detected by PET scan in the brains of human patients with a diagnosis of probable Alzheimer's disease. But since a definitive Alzheimer's diagnosis can be made only on autopsy, there had been no confirmation that PiB in human brains was detecting amyloid-beta deposits.
The Archives of Neurology report describes the case of an elderly man with symptoms that could indicate several neurological disorders. He was evaluated numerous times over a period of three years, including a standard PET scan that produced results suggesting Alzheimer's disease. His eventual diagnosis was dementia with Lewy bodies, a condition that can exist along with Alzheimer's. He also enrolled in a research study involving PiB imaging, and the results of his scan showed the imaging compound had been taken up throughout the cerebral cortex, the outer layer of the brain. Three months after participating in the imaging study, the patient died at the age of 76 following a head injury, and an autopsy was performed.
The autopsy confirmed the diagnosis of dementia with Lewy bodies and had several findings characteristic of Alzheimer's disease. While some plaques that typify Alzheimer's were seen, most amyloid-beta was found in the walls of blood vessels, a condition known as cerebral amyloid angiopathy.
"The distribution of amyloid seen at autopsy matched the overall distribution seen in the PiB imaging study; levels were higher in the cerebral cortex than in other areas of the brain," says Matthew Frosch, MD, PhD, of the MassGeneral Institute for Neurodegenerative Diseases (MGH-MIND), a study co-author. "Features of Alzheimer's pathology, amyloid plaques and neurofibrillary tangles, were observed, but not at a level that would support a separate diagnosis of Alzheimer's disease."
The researchers note that, while their results confirm that uptake of PiB indicates the presence of amyloid in the brain, a positive PiB PET scan cannot be equated with a definitive Alzheimer's diagnosis. "About 15 percent of control participants in previous PiB studies, people with no cognitive impairment, had some level of PiB uptake," says Brian Bacskai, PhD, of MGH-MIND, the paper's lead author. "Some participants who probably had Alzheimer's had low uptake, and uptake levels varied for those with a diagnosis of mild cognitive impairment. Once a safe and effective drug for removing amyloid from the brain or preventing its accumulation is developed, it will be important to see how closely PiB PET scans can track those effects."
Additional co-authors of the Archives of Neurology report are Stefanie Freeman, MD, Scott Raymond, Jean Augustinack, PhD, Keith Johnson, MD, Michael Irizarry, MD, and Bradley Hyman, MD, PhD, of the MGH; William Klunk, MD, PhD, and Chester Mathis, PhD, of University of Pittsburgh School of Medicine, the co-inventors of PiB; and Steven DeKosky, MD, also of the University of Pittsburgh. The study was supported by grants from the National Institutes of Health, the Massachusetts Alzheimer's Disease Reseach Center, and the MGH/Massachusetts Institute of Technology Udall Center of Excellence in Parkinson's Disease Research.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of nearly $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, transplantation biology and photomedicine. MGH and Brigham and Women's Hospital are founding members of Partners HealthCare System, a Boston-based integrated health care delivery system.
Archives of Neurology