Sense of Smell’s Links to Brain Diseases

Carl Sherman
March 28, 2012

Some people’s sense of smell is a lot worse than others, and neuroscientists want to know why.

There are practical reasons for their interest. A blunted sense of smell, common with age, lowers quality of life and is linked to depression; because food flavor is largely mediated by smell, it can compromise nutrition. And impaired olfaction gives early warning of neurodegenerative disease, including Alzheimer’s.

And the olfactory system is fascinating in its own right. “Smell is very primitive, but at the same time has direct links to the highest centers of the brain,” says Donald Wilson, professor of child and adolescent psychiatry at New York University. Odor receptors in the nose are actually extensions of the olfactory bulb in the brain, which “has fingers on buttons affecting what we eat, with whom we mate, what we’re afraid of,”

“In studying vision, we have to go through half the brain before we understand how we recognize a face. The olfactory system is doing such tasks in a very reduced neural space: two or three synapses in, it knows what an odor is, whether it likes the odor or not,” Wilson says.

“Olfaction is a good model system for other, more complicated brain circuits,” adds Richard Doty, director of the smell and taste center at University of Pennsylvania. Understanding smell, it seems, could offer broader insights into brain functions—and brain diseases—as well.

How the nose knows

“The human sense of smell is much keener than people give it credit for, and learning and experience play an important role in the process,” says Jay Gottfried, of the Cognitive Neurology and Alzheimer’s Disease Center at Northwestern University. Only recently have researchers begun to appreciate the extent of its educability—for better and worse.

One study in Gottfried’s lab, reported in Science in 2008, offers a dramatic example of how exquisitely keen it can become. Participants repeatedly sniffed two enantiomers—mirror-image molecules of a single chemical—one of which was paired with an electric shock. The training doubled people’s ability to distinguish one enantiomer from another.

Using fMRI analysis, the researchers linked this sharpened acuity to changes in the piriform cortex (PCX), a small area in the cerebral cortex where smell signals go directly from the olfactory bulb.

A study by Wilson and Julie Chapuis showed that training can blunt as well as sharpen the sense of smell. As reported in the Nov. 20, 2011, issue of Nature Neuroscience , the researchers used pairs of chemical mixtures that were either too similar for rats to tell apart or different enough for them to distinguish without difficulty.

The piriform cortex, once more, seemed key: Different chemicals produced different patterns of electrical activity in the olfactory bulb even when the rats treated the odor as identical, but in the PCX, only distinguishable odors produced distinctive patterns. If the rats couldn’t tell the difference between smells, the PCX couldn’t either.

The researchers trained another group of rats to discriminate between the smells that were usually indistinguishable, and now PCX activation patterns became distinctive too.

The process worked in reverse as well. When the researchers rewarded rats for treating  dissimilar odors as if they were the same, they stopped discriminating between them—and the chemicals now produced the same pattern in the PCX.

But now, they couldn’t tell them apart—even for a reward. In real life, says Wilson, such adaptation could mean functional loss.  “I would not be surprised if the training effect—a kind of “use it or lose it” phenomenon—contributes to declining sense of smell with aging,” he says.

Conversely, work like Gottfried’s and Wilson’s suggests that some sort of olfactory rehabilitation—a training regimen for the failing nose—might redress the deficit. “You can tweak up its acuity, as well as bring it down,” Wilson suggests.

The nose as window on the brain

Thus far, however, attempts to restore faltering olfaction through guided practice have had limited success, says Doty: a reflection, he believes, of neurodegenerative damage to which the olfactory system is highly vulnerable.

Why the system is easy prey to Alzheimer’s, Parkinson’s, and Huntington’s disease, and even multiple sclerosis, is not clear, but high metabolic activity and oxidative stress may play a role, he says.

“Receptor cells constantly degenerate and regenerate: the olfactory bulb, which is directly exposed to environmental toxins, may protect itself by shedding damaged cells.” A “remarkable” array of neurotransmitter systems are deployed within the olfactory bulb, in a complex of feedforward and feedback loops, “and perturbation in any of these elements may cause dysfunction.”

In Alzheimer’s disease,  smell loss can precede cognitive symptoms by years, and there is good evidence that amyloid beta (A-beta), its signature protein, is deposited in the olfactory system long before better-known targets like the hippocampus.

Recent research has opened an olfactory window on the Alzheimer’s brain. In a study reported in Brain in 2010, Gottfried and  Wen Li  found that while Alzheimer’s patients could detect odors at the same concentration as  healthy older people, they were far worse at distinguishing one odor from another, and here too, the PCX—the brain area that “codes” smells for identification—appeared to be critical.

In the experiment, fMRI analysis showed that activity in the PCX dwindled more after healthy controls were exposed to similar than dissimilar odors—a phenomenon called cross-adaptation. But in the Alzheimer’s patients, activity dropped equally. “Adaptation was more generalized,” says Gottfried. “there was a reduction in activation irrespective of whether the odor was the same or different.”

Although his study pinpointed the PCX (no differences between patients and controls were seen in “higher” brain areas), it didn’t rule out pathology “earlier in the odor processing pathway, in the olfactory bulb,” Gottfried says. This is a corner of the brain fMRI cannot reveal.

The  bulb, in fact, “may be the major culprit behind olfactory dysfunction in AD,” according to research by Daniel Wesson and Donald Wilson reported in the Nov. 2, 2011, issue of Journal of Neuroscience .

Their earlier studies with a rodent model of Alzheimer’s disease—mice bred to overexpress A-beta— found that the abnormal protein was deposited in the olfactory bulb before other areas, and that the amount of amyloid  corresponded to the degree of olfactory loss. The new paper details a pathological cascade spreading from the bulb through the olfactory system that may provide more general insights into the Alzheimer’s process.

In this study, researchers found that shortly after the protein first appeared in the olfactory bulb, the circuit linking this structure to the PCX became hyperactive.

Within a few months, however, electrical activity in response to odors in the PCX had dwindled to below normal. A-beta was apparently to blame: Treating the mice with a liver-x receptor agonist—a compound that broke down the abnormal protein—improved behavioral response to odor, and restored the PCX to normal activity levels.

“The study suggests that the progression from the normal brain to a damaged system is not on a straight line,” Wilson says: A-beta-linked hyperactivity in the olfactory bulb may induce overactivity downstream in the PCX, which promotes the deposition of A-beta there as well. Ultimately, activity declines as neurons die and the whole network deteriorates.

Whether the shortened pathway of the olfactory system provides a model for similar cascades elsewhere in the Alzheimer’s brain is impossible to know right now, says Doty, but the findings are provocative. The sequence that leads from hyper- to hypoactivity might indicate selective vulnerability of GABA-ergic neurons, the involvement of microglia, and damage to interneurons that modulate neuron activity. “It seems that the more we learn, the more complicated it gets,” he says.

The fact that an A-beta-degrading compound could reverse functional decline may or may not ultimately have clinical implications, but “if nothing else, it’s proof of concept that there are ways to deal with this,” Wilson says. “And it suggests that you want to treat as soon as you can to stop the process—you really want an early marker.”

Might the nose point the way to Alzheimer’s detection? “The problem with smell as such is that it’s sensitive, but not specific,” says Doty: you see similar descreases in other disorders and in apparently normal aging.

But a more detailed understanding of olfactory neuropathology in Alzheimer’s could, perhaps, make it possible to add functional imaging data to psychological and behavioral tests for the disease.  “Because problems show up so early, in combination with other things olfaction could be an early biomarker,” Wilson says.