Hippocampal volume, aging, and estrogen

If you're reading this blog, chances are good that you have some concerns about your aging brain. You are certainly not alone; I often field questions and complaints about decreasing memory function associated with advancing years.

The most common memory-related issue is the most difficult to assess, namely when is it time to worry, when does forgetful cross the boundary from normal to pathological. If we set cognitive normal at the level at which one's doctor functions, regular readers and my patients know that I would be inclined to overlook verbal slips and frequent loss of keys and reading glasses as a normal response to aging, stress, and general busyness.

In fact, neurologists have defined mild cognitive impairment or MCI as "a transitional state between the cognitive changes of normal aging and very early dementia"(1) that progresses to full-scale dementia such as Alzheimer's Disease at the rate of 10-16% per year. Well, that's not very helpful because, once again, we're stuck with the question of 'what's normal?' Researchers have stepped forward with clarification that's more or less helpful, citing the following characteristics of MCI:

• Memory complaint preferably confirmed by another person
• Objective memory impairment with a standardized assessment tool
• Normal general cognitive functioning
• Intact activities of daily living
• Not demented

In other words, the person is bothered by memory troubles and, while other people have noticed the deficit, the subject's daily life is unaffected by mental deficits. I start to worry when I hear about troubles in job performance, difficulties with multi-step tasks that were not formerly a problem, frequent missed obligations, and an inability to learn new information. I am especially concerned when the kids call or come in with mom to discuss this issue, and--worst of all--when others are concerned but the patient is not.

Distinguishing so-called normal aging from MCI is, therefore, a bit slippery. One not-ready-for-prime-time technique that identifies slightly confused MCI types at high risk for dementia is the use of MRI brain imaging to measure the size of the hippocampus. This little brain structure sits to the inside of our temporal lobes located just above our ears and is so-named because it's shaped like a seahorse (but NOT like a hippo!). The hippocampus functions as VP in charge of memory formation. Along with everything else in the human body, these centers tend to shrink with age especially in those on the road to dementia. Rochester researchers launched a multi-disciplinary effort between neurologists, psychiatrists, and radiologists to see if measurements of the hippocampi of elderly test subjects with MCI reliably predicted who ended up dazed and confused at the end of nearly three years of observation(2).

In short, it did. The researchers adjusted for head size by computing the volume of the hippocampi as a function of total brain volume, and they compared the size of the subjects' memory centers to a previously studied group of elderly controls with normal mental functioning. A subject with an average hunk of hippocampus received a W score of zero whereas those with itty bitty hippocampi were assigned negative W scores.

The lower a subject's W score, the more likely they were to slip from MCI unto dementia. Those with W scores greater than zero, i.e. endowed with robust hippocampi, progressed to Alzheimer's Disease (AD) at the rate of 15% by study's end which is an average rate of progression as determined by numerous previous studies. On the other hand, among those with itty bitty hippocampi--W scores less than -2.5 which represents a memory center in the 1st percentile of normal size--50% were diagnosed with AD by study's end.

So where does estrogen therapy fit in? This hormone is known to promote neuronal repair and growth, causing rat hippocampal neurons to fairly bristle with spiky connections from one cell to the next. And the more hippocampal neurons connect with one another, the better the rat performs at various rat tricks!

For humans, however, in whom brain biopsies are considered bad form in every venue but TV episodes of House, M.D., MRI imaging was used to measure the size of hippocampi in the brains of post-menopausal women, some on hormones and some without. Researchers found a positive effect on hippocampal size associated with the use of estrogen. But this benefit was not seen in subjects enrolled in the Women's Health Initiative Memory Study who initiated hormone replacement for the first time years past menopause. This disparate effect of estrogen on memory as correlated with the timing of therapy relative to the onset of menopause suggests once again that there is a window of opportunity after which estrogen no longer preserves brain function.
_____
(1)Grundman M, et al. Mild Cognitive Impairment Can Be Distinguished From AlzheimerDisease and Normal Aging for Clinical Trials. Arch Neurol. 2004;61:59-66.
(2) Clifford, R, et al. Prediction of AD with MRI-Based Hippocampal Volume in Mild Cognitive Impairment. Neurology. 1999 April 22; 52(7): 1397-1403.