Brain diseases linked

POSTED 25 DEC 2003

Why Files

Bats, brains, burying grounds

How the brain learns

Stem cells and brain disease

Alzheimer's and stem cells
Alzheimer's begins in the entorhinal cortex, and proceeds to the hippocampus, a key memory structure. Affected regions shrink as neurons die; the brain changes probably start 10 to 20 years before symptoms appear. Image: National Institute on Aging.

Pie chart shows 1,630 Down's syndrome cases per 100,000 births.

In Alzheimer's, plaques and tangles first damage areas that control memory, language and reasoning. Since physical abilities don't decline until later, a person with mild Alzheimer's may seem healthy, but still have trouble making sense of the world. Image from: National Institute on Aging.

Brain scans find similarities in Alzheimer's and Down syndrome.

A part of the brain implicated in Alzheimer's is also abnormal in Down's Syndrome -- but it's hyperactive, not hypoactive.
To many older people, nothing is more frightening than Alzheimer's disease, the destroyer of memory, language, rationality and behavior. Alzheimer's, which affects about four million Americans, sneaks up on its victims, and the fear of dementia lurks in the back of many old, but healthy minds.

Drawing of brain looks almost like normal.As more people survive into their 70s, prime time for Alzheimer's, the clinical picture is mixed. Some drugs can now slow, but not stop, the memory loss, meaning the disease is finally treatable, if not reversible. But because a firm diagnosis requires an autopsy, it's not clear who should get the drugs.

A study of adults with Down's Syndrome published in Neurology this week suggests that brain scans may eventually diagnose Alzheimer's among people who lack symptoms -- and therefore have more brain function to preserve.

The study focused on people with Down's Syndrome because in their 40s or 50s a majority of them get a dementia that looks much like Alzheimer's.

Trouble ahead
Down's Syndrome, a genetic disease caused by extra copy of chromosome 21, delays physical and intellectual development in about 350,000 Americans. Most people with Down's show the neural tangles and plaques that mark Alzheimer's. Although the abnormalities appear in the same part of the brain as in Alzheimer's, not all Down's patients get dementia.

Drawing of brain shows some damage. Using positron emission tomography -- which measures metabolic activity -- researchers lead by Richard Haier, a professor of pediatrics at the University of California at Irvine, observed the brain while a subject did cognitive tasks. One task was a simple test of attention: Subjects were asked to press a button every time a zero appeared as a computer screen flashed random digits.

PET scanners measure metabolism of glucose, a common blood sugar, to show how hard individual cells are working.

A researcher views brain scan at his desk. A scientist works with a PET scan of a brain. Photo: National Institute on Aging.

The Haier study found similarities between people with Down's and patients with mild Alzheimer's. But the picture also reflected a mirror image of typical Alzheimer's: In the entorhinal cortex, where Alzheimer's patients often have massive cell death, the neurons in Down's patients were alive -- and working extra hard. "A part of the brain thought to be related to Alzheimer's is abnormal in Down's Syndrome," says Haier, "but it's abnormal in an interesting way. It's hyperactive, as opposed to hypoactive, as would be expected with brain damage. In the exact spot where people with Alzheimer's have lower glucose metabolism, those are the very areas where Down's Syndrome people have a higher metabolic rate -- before they get demented. "

Pie chart shows 1,630 Down's syndrome cases per 100,000 births.
Down's Syndrome is one of the most common genetic conditions. Numbers are per 100,000 births.

Paddling upstream?
How to explain this bass-ackwards result? Perhaps with the following hypothesis: Because most Down's patients get dementia if they live long enough, the hyperactivity may represent the last gasp of activity by doomed neurons. "We think it reflects a compensatory mechanism," says Haier. "The disease process is underway in the temporal lobes, long before there are clinical symptoms, long before the disease process kills the neurons. We are seeing possibly the very earliest signs of a dementing disease, before the patient is demented."

Graph shows rise from 4.5 to 13.2 million Alzheimer's patientsRates of Alzheimer's disease are expected to soar as the population ages -- unless good preventive strategies can be found.

Hints of a similar phenomenon have appeared in other Down's Syndrome studies, says Haier, whose colleagues in the Neurology study included Michael Alkire, Nathan White, Melina Uncapher, Elizabeth Head, Ira Lott and Carl Cotman. For example, one recent study found neurons -- making new connections -- also in the entorhinal cortex. "The neuron is responding to the disease by overcompensating," he says, "but it can only do this for so long. Sooner or later, the hyperactivity contributes to the cells dying, and it's cell death that contributes to the clinical symptoms of dementia."

The finding will not immediately change how doctors handle potential cases of Alzheimer's, but it may eventually lead to earlier diagnosis for people threatened by garden variety Alzheimer's -- and for the dementia associated with Down's Syndrome.

When it comes to drug treatment for slowing dementia, Haier says the rule is simple: "The earlier, the better."

-- David Tenenbaum

Temporal Cortex Hypermetabolism in Down Syndrome Prior to the Onset of Dementia, Richard Haier et al, Neurology 2003;61:1673-1679

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