Tuesday, November 24, 2009
MCI Symposium: What Do Autopsy Studies Tell Us?
Summary: The symptoms associated with Mild Cognitive Impairment (MCI) vary from person to person. The same can be said of the pathologies found in the brains of people with MCI. Pathologists often find some level of the plaques and tangles associated with Alzheimer’s disease, but other abnormalities are common. It’s not yet clear how much each pathology might contribute to memory loss, or how those pathologies might interact.
Two presentations at the 7th Annual Mild Cognitive Impairment (MCI) Symposium detailed the complexities of making a definitive diagnosis based on pathologies found in the brains of people who had MCI.
During an autopsy, a pathologist looks at various sections of the brain, and assesses the types and level of brain pathologies, or abnormalities. For patients who had dementia, pathologists look for evidence of structural abnormalities including infarcts (areas damaged by stroke), tumors and demyelinating disease (multiple sclerosis, for example). They also look for the presence of specific degenerative changes in vulnerable brain regions.
Dr. Joseph Parisi, Professor of Laboratory Medicine and Pathology at Mayo Clinic, started his presentation at the MCI Symposium with an overview of these degenerative changes. Neurodegenerative diseases are diverse, he said, but all are associated with aging and involve abnormal protein interactions that form the deposits that serve as the defining features of a specific neurodegenerative disease. These abnormal protein deposits include:
• Beta amyloid
Mixed pathologies in the brains of older people with Amnestic MCI
In a study of the brains of fifteen people with Amnestic MCI (average age 89 years), Dr. Parisi and his colleagues found evidence of medial temporal lobe pathology in all. [The medial temporal lobe is an area of the brain associated with memory function.] The brains were not normal, and showed a variety of pathologies. Many had mixed pathologies.
Most of the brains in the study had features of early Alzheimer’s disease. Plaques and tangles – the hallmarks of Alzheimer’s – were present, but were fewer in number than needed for a diagnosis of Alzheimer’s. The plaques and tangles in these MCI brains were confined to the medial temporal area, instead of distributed widely throughout the brain as they would be in Alzheimer’s, Dr. Parisi said.
In addition to plaques and tangles, the brains in this study had a variety of other pathologies. Of the fifteen brains, there were:
• Seven with argyrophilic grain disease
• Five with infarcts, or signs of stroke
• Three with loss of neurons in a specific part of the medial temporal lobe called the hippocampus
• Two with tangles but no plaques
• One with alpha-synuclein deposits characteristic of Lewy body disease/dementia.
This was a small study with older patients, so the results may not be representative of all patients with MCI.
The limits of autopsy studies
You might have read that the only way to be 100 percent sure of what caused someone’s memory loss is to conduct an autopsy. Many of the things we think we know about dementia are over-simplified, though, and the idea that an autopsy can accurately capture all the processes that caused a person’s memory loss is no exception.
First, an autopsy captures a pathologic process at one point in time, providing a “snap-shot” of the disease process at the time of death. This means the disease process as seen at autopsy is often end-stage. Also, as people age, there may be multiple pathological events going on at the same time, each at different rates. Research suggests that these different pathologies may interact with each other in a synergistic manner. Finally, the presence of the plaques and tangles associated with Alzheimer’s doesn’t always mean the person had problems with memory and thinking.
“Although in general, the number of plaques and tangles correlates with the degree of cognitive impairment, this is not always the case,” Dr. Parisi explained in an email after the conference. “Some patients can compensate for high plaque and tangle burdens, and remain cognitively normal. This may be due to factors such as education, activity or life experience.”
Despite these cautionary notes, this study and related research add to the data about what causes Mild Cognitive Impairment.
Related studies at Mayo Clinic
Researchers at Mayo Clinic are also studying the brains of people with Non-Amnestic MCI. About half of these brains don’t show the level of medial temporal lobe pathology found in the brains of people with Amnestic MCI, and about half show some degree of Alzheimer’s pathology, Dr. Parisi said.
He and his colleagues also examined the brains of 34 people who had been diagnosed with Amnestic MCI and then progressed to dementia before death. He said the majority (71 percent) of patients progressing through MCI to dementia showed pathologic Alzheimer’s at autopsy, confirming final clinical diagnoses. A significant minority (29 percent), however, showed other pathologies including Lewy body disease, loss of neurons in the hippocampus, nonspecific tauopathy, argyrophilic grain disease, frontotemporal dementia with hippocampal sclerosis, and progressive supranuclear palsy.
Mixed pathologies increase the likelihood of cognitive problems
In the second presentation, Dr.Julie Schneider, Assistant Professor of Neurology and Neuropathology at Rush University Medical Center, talked about autopsy results for 134 people from the Religious Orders Study and from Rush’s Memory and Aging Project who were diagnosed with MCI.
Mixed pathologies were common in these brains, with 55 percent meeting criteria for Alzheimer’s, 33 percent meeting the criteria for stroke or vascular disease and 16 percent meeting criteria for Lewy body disease. On average, the amount of these pathologies was higher than in the brains of people with no cognitive impairment, but lower than in those of people with probable Alzheimer’s. When there were infarcts or Lewy bodies in addition to Alzheimer’s pathology, it increased the likelihood of cognitive impairment.
Previously published research has suggested that Alzheimer’s pathology underlies Amnestic MCI, while vascular pathology underlies Non-Amnestic MCI, Dr. Schneider said. However, she and her colleagues found that in the brains they studied, Alzheimer’s was the most common pathology in both Amnestic (59 percent) and Non-Amnestic MCI (49 percent). In brains with only a single pathology, vascular pathology was somewhat higher in Non-Amnestic MCI, though (17 percent vs. 11 percent in Amnestic MCI).
Interestingly, 22 percent of the MCI brains they studied had no Alzheimer’s or Lewy body pathologies, and no signs of stroke.
The role of vascular disease
Dr. Schneider and her colleagues at Rush have started new research into the role of vascular disease in memory loss. They are investigating whether very small infarcts, previously thought to be harmless, are related to poor cognitive function. In studies so far, the cerebral amyloid angiopathy (CAA) my father had was present in 94 percent of the brains of people with dementia, but also in 77 percent of those without dementia. Even in people with no memory loss, CAA was associated with a worsening of perceptual speed in these studies.