Neurodegenerative Lesions Cause Cognitive Decline, Not "Normal Aging"

Pam Harrison

September 15, 2010

September 15, 2010 — Virtually all decline in cognitive function traditionally associated with aging is not "normal" but is, rather, a reflection of the accumulation of neurodegenerative lesions associated with dementia, a new study suggests.

Robert Wilson, MD, from Rush University Medical Center, Chicago, Illinois, and colleagues found that age-related cognitive decline among 354 participants in the Religious Orders Study was associated with neurofibrillary tangles, cerebral infarction, and Lewy bodies. In the absence of these lesions, decline in cognitive function was not evident.

"It's long been thought that memory and thinking skills gradually decline as we get older, which seems a perfectly reasonable idea," Dr. Wilson told Medscape Medical News. This, however, is probably not true, as experience suggests that although cognition does decline gradually with age in some individuals, "others don't decline at all, and others decline very rapidly," he added.

"What we showed in this study is if you follow a group of people in whom cognitive changes occurred over time, and do a brain autopsy, mild cognitive decline is actually highly correlated with how much neurodegenerative lesions accumulate in the brain, and...all 3 of the pathologies we looked at were very strongly related to cognitive changes," Dr. Wilson said. "This suggests that decline in cognitive function is not the developmental process we assume."

The findings from the study were published online September 15 in Neurology.

Religious Orders Study

Participants involved in the Religious Orders Study were older Catholic nuns, priests, and brothers who completed up to 13 years of annual cognitive testing and agreed to donate their brains for study after their death.

"Summary measures of neurofibrillary tangles, cerebral infarction, and Lewy bodies were derived from a uniform post-mortem examination of the brain," investigators write, "and we tested the association of post-mortem measures of neurodegeneration with each component of change in cognitive function, first using a composite measure of global cognition and then measures of specific cognitive systems."

At study outset, the mean score on a composite measure of global cognition based on all individual tests ranged from −3.4 to 1.4 (mean, −0.3), with higher values indicating better performance, the authors observed. The rate of change in global cognition was also calculated, they add. Using a "change point" of 52 months before death, investigators calculated that global cognition declined at a mean of 0.052 units per year before this point — the so-called "age-related change".

This suggests that decline in cognitive function is not the developmental process we assume.

In contrast, during the last 52 months of life, "this rate increased more than 4-fold to 0.218 unit per year," investigators state — what they called "disease-related change."

Baseline levels of cognitive function were positively correlated with age-related rate of cognitive change, but not with disease-related cognitive change, they added; nor was age-related cognitive change associated with disease-related cognitive change.

Neurodegenerative Lesions

In an analysis of specific neurodegenerative lesions and global cognitive decline, the researchers also observed that higher tangle density was associated with more rapid age-related and disease-related decline in global cognition and that the effect of tangles "was roughly equivalent" for both age-related and disease-related change.

In contrast, "virtually no age-related change in global cognition occurred at low levels of tangles...compared to substantial decline at high levels," they add. On the other hand, significant disease-related global cognitive decline occurred despite low levels of tangles — suggesting the involvement of other pathologic factors, as the authors indicate.

In fact, both gross and microscopic infarction were associated a greater than 2-fold increase in the rate of age-related global cognitive decline, although neither was associated with disease-related cognitive decline.

Investigators also observed that the presence of neocortical Lewy bodies was associated with an approximate doubling of disease-related decline relative to that of patients without Lewy bodies, although nigral/limbic Lewy bodies were not associated with either age-related or disease-related decline in global cognition.

"This indicates that the neurodegenerative lesions traditionally associated with dementia are principally responsible for the gradual age-related cognitive decline that precedes dementia and that AD and related disorders have a much greater impact on late-life cognitive functioning than previously recognized," the authors conclude.

Long Course of Decline

Dr. Wilson also felt that their study — along with other evidence — indicates that Alzheimer's disease starts many years before patients demonstrate global impairment in memory and thinking skills and that if clinicians were able to diagnose the disease at a much earlier stage, before patients develop massive brain damage, interventions may be more effective.

"This research is part of attempts to shed more light on the earliest beginnings of Alzheimer's disease and other conditions that cause cognitive impairment in older age," Dr. Wilson said. "Then, if we do find more effective treatments, we would want to begin them as early as possible in the process, when the disease is more malleable."

Ronald C. Petersen, MD, from the Mayo Clinic, Rochester, Minnesota, agreed with Dr. Wilson that if more effective treatments were ever to become available for Alzheimer's disease and other dementias, then early use of them may elicit more clinically significant responses.

"Presumably, down the road, we will be able to identify biomarkers that tell us which of these pathologic entities is operating in a given patient," he said, commenting for Medscape Medical News, "and then if we could develop focused therapies, then yes, early intervention would make sense."

The study was supported by the National Institutes of Health/National Institute on Aging. Dr. Wilson receives research support from National Institutes of Health, including the National Institute on Aging and the National Institute of Environmental Health Sciences. Dr. Petersen chairs a safety monitoring committee for immunotherapies supported by Janssen and Pfizer and serves as a consultant for GE Healthcare on the development of tracers.

Neurology. 2010;75:1070-1078.