Smell and eye tests show potential to detect Alzheimer’s early

A decreased ability to identify odors might indicate the development of cognitive impairment and Alzheimer’s disease, while examinations of the eye could indicate the build-up of beta-amyloid, a protein associated with Alzheimer’s, in the brain, according to the results of four research trials reported today at the Alzheimer’s Association International Conference® 2014 (AAIC® 2014) in Copenhagen.

In two of the studies, the decreased ability to identify odors was significantly associated with loss of brain cell function and progression to Alzheimer’s disease. In two other studies, the level of beta-amyloid detected in the eye (a) was significantly correlated with the burden of beta-amyloid in the brain and (b) allowed researchers to accurately identify the people with Alzheimer’s in the studies.

Beta-amyloid protein is the primary material found in the sticky brain “plaques” characteristic of Alzheimer’s disease. It is known to build up in the brain many years before typical Alzheimer’s symptoms of memory loss and other cognitive problems.

"In the face of the growing worldwide Alzheimer’s disease epidemic, there is a pressing need for simple, less invasive diagnostic tests that will identify the risk of Alzheimer’s much earlier in the disease process," said Heather Snyder, Ph.D., Alzheimer’s Association director of Medical and Scientific Operations. "This is especially true as Alzheimer’s researchers move treatment and prevention trials earlier in the course of the disease."

"More research is needed in the very promising area of Alzheimer’s biomarkers because early detection is essential for early intervention and prevention, when new treatments become available. For now, these four studies reported at AAIC point to possible methods of early detection in a research setting to choose study populations for clinical trials of Alzheimer’s treatments and preventions," Snyder said.

With the support of the Alzheimer’s Association and the Alzheimer’s community, the United States created its first National Plan to Address Alzheimer’s Disease in 2012. The plan includes the critical goal, which was adopted by the G8 at the Dementia Summit in 2013, of preventing and effectively treating Alzheimer’s by 2025. It is only through strong implementation and adequate funding of the plan, including an additional $200 million in fiscal year 2015 for Alzheimer’s research, that we’ll meet that goal. For more information and to get involved, visit http://www.alz.org.

Clinically, at this time it is only possible to detect Alzheimer’s late in its development, when significant brain damage has already occurred. Biological markers of Alzheimer’s disease may be able to detect it at an earlier stage. For example, using brain PET imaging in conjunction with a specialized chemical that binds to beta-amyloid protein, the buildup of the protein as plaques in the brain can be revealed years before symptoms appear. These scans can be expensive and are not available everywhere. Amyloid can also be detected in cerebrospinal fluid through a lumbar puncture where a needle is inserted between two bones (vertebrae) in your lower back to remove a sample of the fluid that surrounds your brain and spinal cord.

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Humans have a nose for gender

The human body produces chemical cues that communicate gender to members of the opposite sex, according to researchers who report their findings in the Cell Press journal Current Biology on May 1. Whiffs of the active steroid ingredients (androstadienone in males and estratetraenol in females) influence our perceptions of movement as being either more masculine or more feminine. The effect, which occurs completely without awareness, depends on both our biological sex and our sexual orientations.

"Our findings argue for the existence of human sex pheromones," says Wen Zhou of the Chinese Academy of Sciences. "They show that the nose can sniff out gender from body secretions even when we don’t think we smell anything on the conscious level."

Earlier studies showed that androstadienone, found in male semen and armpits, can promote positive mood in females as opposed to males. Estratetraenol, first identified in female urine, has similar effects on males. But it wasn’t clear whether those chemicals were truly acting as sexual cues.

In the new study, Zhou and her colleagues asked males and females, both heterosexual and homosexual, to watch what are known as point-light walkers (PLWs) move in place on a screen. PLWs consist of 15 dots representing the 12 major joints in the human body, plus the pelvis, thorax, and head. The task was to decide whether those digitally morphed gaits were more masculine or feminine.

Individuals completed that task over a series of days while being exposed to androstadienone, estratetraenol, or a control solution, all of which smelled like cloves. The results revealed that smelling androstadienone systematically biased heterosexual females, but not males, toward perceiving walkers as more masculine. By contrast, the researchers report, smelling estratetraenol systematically biased heterosexual males, but not females, toward perceiving walkers as more feminine.

Interestingly, the researchers found that homosexual males responded to gender pheromones more like heterosexual females did. Bisexual or homosexual female responses to the same scents fell somewhere in between those of heterosexual males and females.

"When the visual gender cues were extremely ambiguous, smelling androstadienone versus estratetraenol produced about an eight percent change in gender perception," Zhou says, a statistically very significant effect.

"The results provide the first direct evidence that the two human steroids communicate opposite gender information that is differentially effective to the two sex groups based on their sexual orientation," the researchers write. "Moreover, they demonstrate that human visual gender perception draws on subconscious chemosensory biological cues, an effect that has been hitherto unsuspected."

Why your nose can be a pathfinder

When I was a child I used to sit in my grandfather’s workshop, playing with wood shavings. Freshly shaven wood has a distinct smell of childhood happiness, and whenever I get a whiff of that scent my brain immediately conjures up images of my grandfather at his working bench, the heat from the fireplace and the dog next to it.

Researchers at the Kavli Institute for Systems Neuroscience have recently discovered the process behind this phenomenon. The brain, it turns out, connects smells to memories through an associative process where neural networks are linked through synchronised brain waves of 20-40 Hz.

– We all know that smell is connected to memories, Kei Igarashi, lead author, explains.– We know that neurons in different brain regions need to oscillate in synchrony for these regions to speak effectively to each other. Still, the relationship between interregional coupling and formation of memory traces has remained poorly understood. So we designed a task to investigate how odour-place representation evolved in the entorhinal and hippocampal region, to figure out whether learning depends on coupling of oscillatory networks.

Smell guides the way in maze
The researchers designed a maze for rats, where a rat would see a hole to poke its nose into. When poking into the hole, the rat was presented with one of two alternative smells. One smell told the rat that food would be found in the left food cup behind the rat. The other smell told it that there was food in the right cup. The rat would soon learn which smell would lead to a reward where. After three weeks of training, the rats chose correctly on more than 85% of the trials. In order to see what happened inside the brain during acquisition, 16–20 electrode pairs were inserted in the hippocampus and in different areas of the entorhinal cortex.

After the associations between smell and place were well established, the researchers could see a pattern of brain wave activity (the electrical signal from a large number of neurons) during retrieval.

Coherent brain activity evolves with learning
– Immediately after the rat is exposed to the smell there is a burst in activity of 20–40 Hz waves in a specific connection between an area in the entorhinal cortex, lateral entorhinal cortex (LEC), and an area in the hippocampus, distal CA1 (dCA1), while a similar strong response was not observed in other connections, Igarashi explains.

This coherence of 20–40 Hz activity in the LEC and dCA1 evolved in parallel with learning, with little coherence between these areas before training started. By the time the learning period was over, cells were phase locked to the oscillation and a large portion of the cells responded specifically to one or the other of the smell-odour pairs.

Long distance communication in brain mediated by waves
– This is not the first time we observe that the brain uses synchronised wave activity to establish network connections, Edvard Moser, director of the Kavli Institute for Systems Neuroscience says. – Both during encoding and retrieval of declarative memories there is an interaction between these areas mediated through gamma and theta oscillations. However, this is the first study to relate the development of a specific band of oscillations to memory performance in the hippocampus. Together, the evidence is now piling up and pointing in the direction of cortical oscillations as a general mechanism for mediating interactions among functionally specialised neurons in distributed brain circuits.

So, there you have it – the signals from your nose translate and connect to memories in an orchestrated symphony of signals in your head. Each of these memories connects to a location, pinpointed on your inner map. So when you feel a wave of reminiscence triggered by a fragrance, think about how waves created this connection in the first place.

Sniff study suggests humans can distinguish more than 1 trillion scents

The human sense of smell does not get the respect it deserves, new research suggests. In an experiment led by Andreas Keller, of Rockefeller’s Laboratory of Neurogenetics and Behavior, researchers tested volunteers’ ability to distinguish between complex mixtures of scents. Based on the sensitivity of these people’s noses and brains, the team calculated the human sense of smell can detect more than 1 trillion odor mixtures, far more discrete stimuli than previous smell studies have estimated.

The existing generally accepted number is just 10,000, says Leslie Vosshall, Robert Chemers Neustein Professor and head of the laboratory. “Everyone in the field had the general sense that this number was ludicrously small, but Andreas was the first to put the number to a real scientific test,” Vosshall says.

In fact, even 1 trillion may be understating it, says Keller. “The message here is that we have more sensitivity in our sense of smell than for which we give ourselves credit. We just don’t pay attention to it and don’t use it in everyday life,” he says.

The quality of an odor has multiple dimensions, because the odors we encounter in real life are composed of complex mixes of molecules. For instance, the characteristic scent of rose has 275 components, but only a small percentage of those dominate the perceived smell. That makes odor much more difficult to study than vision and hearing, which require us to detect variations in a single dimension. For comparison, researchers estimate the number of colors we can distinguish at between 2.3 and 7.5 million and audible tones at about 340,000.

To overcome this complexity, Keller combined odors and asked volunteers whether they could distinguish between mixtures with some components in common. “Our trick is we use mixtures of odor molecules, and we use the percentage of overlap between two mixtures to measure the sensitivity of a person’s sense of smell,” Keller says. To create his mixtures, Keller drew upon 128 odor molecules responsible for scents such as orange, anise and spearmint. He mixed these in combinations of 10, 20 and 30 with different proportions of components in common. The volunteers received three vials, two of which contained identical mixes, and they were asked to pick out the odd one.

This approach was inspired by previous work at the Weizmann Institute in Israel, in which researchers combined odors at similar intensities to create neutral smelling “olfactory white.” In that experiment and in Keller’s study, the researchers were interested in the perception of odor qualities, such as fishy, floral or musky — not their intensity. But since intensity can interfere with the perceived qualities, both had to account for it.

The results, published this week in Science, show that while individual volunteers’ performance varied greatly, on average they could tell the difference between mixtures containing as much as 51 percent of the same components. Once the mixes shared more than half of their components, fewer volunteers could tell the difference between them. This was true for mixes of 10, 20 and 30 odors.

By analyzing the data, the researchers could calculate the total number of distinguishable mixtures.

“It turns out that the resolution of the olfactory system is not extraordinary – you need to change a fair fraction of the components before the change can be reliably detected by more than 50 percent of the subjects,” says collaborator Marcelo O. Magnasco, head of the Laboratory of Mathematical Physics at Rockefeller. “However, because the number of combinations is quite literally astronomical, even after accounting for this limitation the total number of distinguishable odor combinations is quite large.” The 1 trillion estimate is almost certainly too low, the researchers say, because there are many, many more odor molecules in the real world that can be mixed in many more ways.

Keller theorizes that our ancestors had much more use and appreciation for our sense of smell than we do. Humans’ upright posture lifted our noses far from the ground where most smells originate, and more recently, conveniences such as refrigerators and daily showers, have effectively limited odors in the modern world. “This could explain our attitude that smell is unimportant, compared to hearing and vision,” he says.

Nevertheless, the sense of smell remains closely linked to human behavior, and studying it can tell us a lot about how our brains process complex information. The results of this study are a step toward an elusive quantitative science of odor perception that can help drive further research, Keller says.

No Two People Smell the Same

A difference at the smallest level of DNA — one amino acid on one gene —  can determine whether you find a given smell pleasant. A different amino acid on the same gene in your friend’s body could mean he finds the same odor offensive, according to researchers at Duke University.

There are about 400 genes coding for the receptors in our noses, and according to the 1000 Genomes Project, there are more than 900,000 variations of those genes. These receptors control the sensors that determine how we smell odors. A given odor will activate a suite of receptors in the nose, creating a specific signal for the brain. 

But the receptors don’t work the same for all of us, said Hiroaki Matsunami, Ph.D., associate professor of molecular genetics and microbiology at the Duke University School of Medicine. In fact, when comparing the receptors in any two people, they should be about 30 percent different, said Matsunami, who is also a member of the Neurobiology Graduate Program and the Duke Institute for Brain Sciences. 

"There are many cases when you say you like the way something smells and other people don’t. That’s very common," Matsunami said. But what the researchers found is that no two people smell things the same way. "We found that individuals can be very different at the receptor levels, meaning that when we smell something, the receptors that are activated can be very different (from one person to the next) depending on your genome."

The study didn’t look at the promoter regions of the genes, which are highly variable, or gene copy number variation, which is very high in odor receptors, so the 30 percent figure for the difference between individuals is probably conservative, Matsunami said.

While researchers had earlier identified the genes that encode for odor receptors, it has been a mystery how the receptors are activated, Matsunami said. To determine what turns the receptors on, his team cloned more than 500 receptors each from 20 people that had slight variations of only one or two amino acids and systematically exposed them to odor molecules that might excite the receptors. 

By exposing each receptor to a very small concentration — 1, 10, or 100 micromoles — of 73 odorants, such as vanillin or guaiacol, the group was able to identify 27 receptors that had a significant response to at least one odorant. This finding, published in the December issue of Nature Neuroscience, doubles the number of known odorant-activated receptors, bringing the number to 40.

Matsunami said this research could have a big impact for the flavors, fragrance, and food industries.

"These manufacturers all want to know a rational way to produce new chemicals of interest, whether it’s a new perfume or new-flavored ingredient, and right now there’s no scientific basis for doing that," he said. "To do that, we need to know which receptors are being activated by certain chemicals and the consequences of those activations in terms of how we feel and smell."

How neurons enable us to know smells we like and dislike, whether to approach or retreat

Think of the smell of freshly baking bread. There is something in that smell, without any other cues – visual or tactile – that steers you toward the bakery.  On the flip side, there may be a smell, for instance that of fresh fish, that may not appeal to you. If you haven’t eaten a morsel of food in three days, of course, a fishy odor might seem a good deal more attractive.

How, then, does this work? What underlying biological mechanisms account for our seemingly instant, almost unconscious ability to determine how attractive (or repulsive) a particular smell is?  It’s a very important question for scientists who are trying to address the increasingly acute problem of obesity: we need to understand much better than we now do the biological processes underlying food selection and preferences.

New research by neuroscientists at Cold Spring Harbor Laboratory (CSHL), published in The Journal of Neuroscience, reveals a set of cells in the fruit fly brain that respond specifically to food odors. Remarkably, the team finds that the degree to which these neurons respond when the fly is presented different food odors – apple, mango, banana – predicts “incredibly well how much the flies will ‘like’ a given odor,” says the lead author of the research paper, Jennifer Beshel, Ph.D., a postdoctoral investigator in the laboratory of CSHL Professor Yi Zhong, Ph.D.

“We all know that we behave differently to different foods – have different preferences. And we also all know that we behave differently to foods when we are hungry,” explains Dr. Beshel. “Dr. Zhong and I wanted to find the part of the brain that might be responsible for these types of behavior. Is there somewhere in the brain that deals with food odors in particular? How does brain activity change when we are hungry? Can we manipulate such a brain area and change behavior?”

When Beshel and Zhong examined the response of neurons expressing a peptide called dNPF to a range of odors, they saw that they only responded to food odors. (dNPF is the fly analog of appetite-inducing Neuropeptide Y, found in people.) Moreover, the neurons responded more to these same food odors when flies were hungry. The amplitude of their response could in fact predict with great accuracy how much the flies would like a given food odor – i.e., move toward it; the scientists needed simply to look at the responses of the dNPF-expressing neurons. 

When they “switched off” these neurons, the researchers were able to make flies treat their most favored odor as if it were just air. Conversely, if they remotely turned these neurons “on,” they could make flies suddenly approach odors they previously had tried to avoid. 

As Dr. Beshel explains: “The more general idea is that there are areas in the brain that might be specifically involved in saying: ‘This is great, I should really approach this.’ The activity of neurons in other areas in the brain might only take note of what something is – is it apple? fish? — without registering or ascribing to it any particular value, whether about its intrinsic desirability or its attractiveness at a given moment.

Finding “Mr. Right,” How Insects Sniff Out the Perfect Mate

Unlike humans, most insects rely on their sense of smell when looking for a mate. Scientists have found that sex pheromones play an important role in finding a suitable partner of the same species; yet, little is known about the evolution and genetic basis of these alluring smells.

A team of researchers from Arizona State University and Germany found that one wasp species has evolved a specific scent, or pheromone, which keeps it from mating with other species. In addition, they discovered that the genetic basis of the new scent is simple, which allows the males to change an existing scent into a new one. Over time, the females recognize and use this new scent to distinguish their own species from others.

Scientists from ASU, the University of Regensburg, the Zoological Research Museum Alexander Koenig Bonn, and the Technical University Darmstadt in Germany, present their findings in an article published Feb. 13 online in the journal Nature.