Robinson, RichardBack to top
An analysis of autopsies from the Honolulu-Asian Aging Study revealed multiple, diverse, pathological changes in the brains of older decedents, with high rates of lesion co-prevalence, and major difficulties related to attribution of dementia or impairment to single pathologies.
DR. DAVID S. KNOPMAN: “Our idea of thinking about Alzheimer disease as a single clinicopathologic entity simply doesn't work. There is the pathology and the clinical syndrome, and they are dissociable.”
HONOLULU — Amyloid plaques and neurofibrillary tangles are the pathological hallmarks of Alzheimer disease (AD), and neurologists have invested a great deal of effort devising clinical diagnostic criteria for AD that are meant to align the clinical diagnosis with the presumed underlying pathology. But according to a major new study, the pathology of the brain in decline is more complex and less predictable than those criteria assume.
“We found that there are at least five specific independent brain lesions that can produce dementia, that really pretty much look the same clinically,” said the lead author Lon White, MD, principal researcher of the Honolulu-Asia Aging Study, and clinical professor of geriatric medicine at the University of Hawaii John A. Burns School of Medicine in Honolulu, in a plenary session here at the AAN annual meeting. This is “something unharmonious that we have to face,” he said.
Begun in 1991, the Honolulu-Asia Aging Study's purpose was to look at risk factors for common brain aging diseases. The study has enrolled 3,734 men of Japanese ancestry, who undergo careful clinical, cognitive, and motor assessments every three years.
“Early on, we decided we needed to confirm our diagnoses, and we thought that would be an easy matter, so we began to do autopsies,” Dr. White said. But instead of depending on the autopsies “to give us the diagnosis, we wanted to measure every kind of lesion we could.”
To date, the investigators have performed 593 standardized brain autopsies. Of the 593 patients, 262 were cognitively normal at the time of the final exam before death, 147 had some degree of cognitive impairment, 100 had a clinical diagnosis of probable AD, and 79 had non-AD dementia. About 20 percent of the entire sample was apolipoprotein E-positive, equally distributed between demented and non-demented patients. The average age of death was 88 years.
The autopsy results, Dr. White said, while consistent with smaller studies, were nonetheless “in some ways startling and disturbing.”
The autopsies revealed “multiple, diverse, pathological changes in the brains of older decedents, with high rates of lesion co-prevalence, and major difficulties related to attribution of dementia or impairment to single pathologies.”
The investigators saw five kinds of lesions — amyloid plaques and neurofibrillary tangles, cortical Lewy bodies, microvascular lesions, hippocampal sclerosis, and atrophy. Atrophy occurred in the context of both AD lesions and microvascular lesions, but was also seen independent of any other pathology.
Dr. White noted that of the 593 patients, 359 had moderate or severe lesions of one or more types, including 136 with AD lesions, 104 with Lewy bodies, and 220 with microvascular lesions. A proportion of patients had more than one type, though none had all three. “The key thing is that there is an enormous overlap,” he said.
That overlap appeared to have clinical consequences. Cognitive ability was measured using the Cognitive Ability Screening Instrument (CASI), with low scores being worse than high ones. “What is most striking is that when there was co-prevalence of lesion types, the CASI score was lowest,” Dr. White said. “This probably tells us that if you have one lesion, you cannot afford to have a second. This should tell you that when you look at patients, and you don't know what is going on in their brain, the degree of impairment may be related to patterns of co-prevalence.”
But lesions also occurred in about 40 percent of patients who tested entirely cognitively normal within two years of death. “Being cognitively normal certainly does not mean there is no Alzheimer disease process in the brain,” he said.
The most sobering results came from analysis of the 58 patients judged clinically to have “pure Alzheimer disease,” with no evidence of any other disease process. Based on the autopsies, “we got it right, in the sense that there were enough Alzheimer's lesions to attribute them to the Alzheimer disease process, about half the time. And in half of those, they were the only lesion,” Dr. White said. “But in the other half, there was substantial overlap. These are the cases we thought were pure, probable Alzheimer disease. It is very disappointing that we did not have better correspondence. We need to recognize that the clinical diagnosis is not secure. It is more appropriate to think of a syndrome, and not a single pathological entity.”
The major implication of the study as a whole, Dr. White said, “is that when we look forward to trying to reduce the rates of incidence of dementia, we cannot assume that an attack on one kind of process,” whether Alzheimer plaques or one of the other lesion types, “is really going to do it. To have an impact, we must look at multiple kinds of lesions.”
The study reinforced some important lessons that had been raised in previous work, according to David S. Knopman, MD, professor of neurology at the Mayo Clinic in Rochester, MN. “These were more detailed pathological assessments than many previous studies,” he said. Another strength is that the Honolulu-Asia Aging Study is population-based. “They took all comers. They didn't cherry pick the easiest-to-diagnose cases,” he added.
The false-positive rate of the clinical diagnostic criteria, arising from patients with clinical dementia who lacked Alzheimer pathology, was high. “This hits to the heart of the problem,” Dr. Knopman said. “Non-Alzheimer dementing illnesses can produce a clinical syndrome that looks like Alzheimer disease.”
Conversely, he pointed out, a diagnosis of non-Alzheimer dementia cannot rule out AD pathology. “Our idea of thinking about Alzheimer disease as a single clinicopathologic entity simply doesn't work. There is the pathology and the clinical syndrome, and they are dissociable.”
“This points out the need for biomarkers in the diagnosis of Alzheimer disease,” which new criteria, due out this year, are expected to include. “As a clinician I hate to say this, but the clinical diagnostic criteria can only go so far.”
Regarding the multiple pathologies seen in many patients, Dr. Knopman said, “We need a new conceptual approach to combined pathology that doesn't rely on Occam's razor to be able to handle this multiplicity of causes of dementing illness.”
As for Dr. White's belief that it won't be enough to target a single kind of pathology, Dr. Knopman said, “I would take a slightly different view. Therapy for any of the big three — Alzheimer's lesions, Lewy bodies, and microvascular lesions — might be effective. If we could treat multiple pathologies, that will be better, but even one might have an impact on incidence and severity of disease.”Back to top