Study finds that sleep apnea and Alzheimer’s are linked

A new study looking at sleep-disordered breathing (SDB) and markers for Alzheimer’s disease (AD) risk in cerebrospinal fluid (CSF) and neuroimaging adds to the growing body of research linking the two.

But this latest study also poses an interesting question: Could AD in its “preclinical stages” also lead to SDB and explain the increased prevalence of SDB in the elderly?

The study will be presented at the ATS 2013 International Conference.

"It’s really a chicken and egg story," said Ricardo S. Osorio, MD, a research assistant professor at NYU School of Medicine who led the study. "Our study did not determine the direction of the causality, and, in fact, didn’t uncover a significant association between the two, until we broke out the data on lean and obese patients."

When the researchers did consider body mass, they found that lean patients (defined as having a body mass index <25) with SDB did possess several specific and non-specific biomarkers of AD risk (increased P-Tau and T-Tau in CSF, hippocampal atrophy using structural MRI, and glucose hypometabolism using FDG-PET in several AD-vulnerable regions). Among obese patients (BMI >25), glucose hypometabolism was also found in the medial temporal lobe, but was not significant in other AD-vulnerable regions.

"We know that about 10 to 20 percent of middle-aged adults in the United States have SDB [defined as an apnea-hypopnea index greater than 5] and that the number jumps dramatically in those over the age of 65," said Dr. Osorio, noting that studies put the percentage of people over the age of 65 with SDB between 30 and 60 percent. "We don’t know why it becomes so prevalent, but one factor may be that some of these patients are in the earliest preclinical stages of AD."

According to Dr. Osorio, the biochemical harbingers of AD are present 15 to 20 years before any of its currently recognized symptoms become apparent.

The NYU study enrolled 68 cognitively normal elderly patients (mean age 71.4±5.6, range 64-87) who underwent two nights of home monitoring for SDB and were tested for at least one diagnostic indicator of AD. The researchers looked at P-Tau, T-Tau and Aβ42 in CSF, FDG-PET (to measure glucose metabolism), Pittsburgh compound B (PiB) PET to measure amyloid load, and/or structural MRI to measure hippocampal volume. Reduced glucose metabolism in AD-vulnerable regions, decreased hippocampal volume, changes in P-Tau, T-Tau and Aβ42, and increased binding of PiB-PET are recognized as markers of risk for AD and have been reported to be abnormal in healthy subjects before the disease onset.

Biomarkers for AD risk were found only among lean study participants with SDB. These patients showed a linear association between the severity of SDB and CSF levels of the biomarker P-Tau (F = 5.83, t=2.41, β=0.47; p< 0.05) and between SDB and glucose hypometabolism using FDG-PET, in the medial temporal lobe (F=6.34, t=-2.52, β=-0.57,p<0.05), the posterior cingulate cortex/precuneus (F=11.62, t=-3.41, β=-0.69, p<0.01) and a composite score of all AD-vulnerable regions (F=4.48, t=-2.11, β=-0.51, p<0.05). Lean SDB patients also showed smaller hippocampi when compared to lean controls (F=4.2, p<0.05), but no differences were found in measures of amyloid burden such as decreased Aβ42 in CSF or PiB positive scans.

Dr. Osorio and his colleagues are planning to test their hypothesis that very early stage preclinical AD brain injury that associates with these biomarkers can lead to SDB. They have proposed a two-year longitudinal study that would enroll 200 cognitively normal subjects, include AD biomarkers and treat those patients with moderate to severe SDB with continuous positive airway pressure, or CPAP, over time.

The purpose of the new study would be to determine the “direction” of causality between SDB and preclinical AD in elderly patients. After an initial assessment, the patients would be given CPAP to treat their sleep apnea. After six months, they would be evaluated again for biomarker evidence of AD.

"If the biomarkers change, it may indicate that SDB is causing AD," explained Dr. Osorio. "If they don’t change, the probable conclusion is that these patients are going to develop AD with or without CPAP, and that AD may either be causing the apneas or may simply coexist with SDB as part of aging."

Either way, Dr. Osorio believes the relationship between SDB and AD deserves further study.

"Sleep apnea skyrockets in the elderly, and this fact hasn’t been given the attention it deserves by the sleep world or the Alzheimer’s world," Dr. Osorio said. "Sleep particularly suffers from an outmoded perception that it is an inactive physiological process, when, in reality, it is a very active part of the day for the brain."

Colour a constant throughout ageing

Visionary study Age may dim our eyes, but our brains make sure aspects of the rich world of colour experience defy the passing of time, a UK scientist has found.

It’s well known that our colour vision declines with age. Gradual yellowing of the lenses cuts out light in the blue range of the spectrum, while colour-sensing cone receptors on our retinas slowly lose sensitivity.

"Our ability to discriminate small colour differences declines as we age, there is no doubt about that," says neuroscientist Sophie Wuerger from the Department of Psychological Sciences, University of Liverpool.

But she has found our brains apparently compensate for at least some of these physical frailties. Her results are published online this week in the journal PLoS One.

Wuerger explored the colour perception of 185 people aged between 18 and 75 years with normal colour vision, an unusually large and diverse group for a study of this kind.

First, she used well-known data on how the lens changes with age to predict the light signal that would be sent to the brain by the volunteers’ retinas.

She then asked the participants to undertake a variety of tests that required them to select patches of colour representing pure red, green, yellow, or blue, under different lighting conditions.

Constant perception

The idea was to compare the predicted physiological changes in the eye with the participants’ actual experience of colours.

"That’s the surprising bit. If you look just at the lens, it should introduce significant colour changes in older people, but we observed that … most of the time we have a very constant perception and it doesn’t change with age," says Wuerger.

The only age-related effects detected in the study were small changes that became apparent for green hues viewed under daylight.

In other words, although the colour signal being sent from the eye was changing significantly with age, the perception of colour was almost constant regardless of how old the study subject was.

This suggests that somewhere between the retina and the conscious perception of colour, the brain must recalibrate itself, she says.

"Something must be happening to change neural connections to maintain constant colour appearance," Wuerger says.

External standard

Exactly how this happens was not part of this study, but Wuerger offers one possible explanation.

"You could think our brain might be using some external standard like the blue sky or sunlight as a reference. There are things in the environment that don’t change and we could use them to recalibrate our visual system."

One useful clue about the mechanisms involved came from the fact that age did not affect all aspects of the visual system equally. While 18 year olds and 75 year olds were equally good at picking pure red or green and so on, older people were less able to distinguish between subtly different colours, particularly in the bluish range.

Because the recalibration doesn’t affect all our colour vision abilities, Wuerger concludes the adjustment isn’t likely to be taking place in the retina.

"I think that suggests that it must be happening later in the visual processing pathway, closer to the brain. We don’t have any proof of that but the experiments taken together suggest it’s … a kind of plasticity in the adult brain."

The next question might be why the brain performs this recalibration. What benefit is there in ensuring our perception of colours remains constant? For now, answering that question requires entering the realm of speculation.

Perhaps it has to do with a need to communicate colours effectively when describing objects, Wuerger ventures. “After all, to communicate colour meaningfully,” she says with a chuckle, “we all need to be - so to speak - on the same wavelength.”

Boosting ‘cellular garbage disposal’ can delay the aging process

UCLA life scientists have identified a gene previously implicated in Parkinson’s disease that can delay the onset of aging and extend the healthy life span of fruit flies. The research, they say, could have important implications for aging and disease in humans.

The gene, called parkin, serves at least two vital functions: It marks damaged proteins so that cells can discard them before they become toxic, and it is believed to play a key role in the removal of damaged mitochondria from cells.

"Aging is a major risk factor for the development and progression of many neurodegenerative diseases," said David Walker, an associate professor of integrative biology and physiology at UCLA and senior author of the research. "We think that our findings shed light on the molecular mechanisms that connect these processes."

In the research, published today in the early online edition of the journal Proceedings of the National Academy of Sciences, Walker and his colleagues show that parkin can modulate the aging process in fruit flies, which typically live less than two months. The researchers increased parkin levels in the cells of the flies and found that this extended their life span by more than 25 percent, compared with a control group that did not receive additional parkin.

"In the control group, the flies are all dead by Day 50," Walker said. "In the group with parkin overexpressed, almost half of the population is still alive after 50 days. We have manipulated only one of their roughly 15,000 genes, and yet the consequences for the organism are profound."

"Just by increasing the levels of parkin, they live substantially longer while remaining healthy, active and fertile," said Anil Rana, a postdoctoral scholar in Walker’s laboratory and lead author of the research. "That is what we want to achieve in aging research — not only to increase their life span but to increase their health span as well."

Treatments to increase parkin expression may delay the onset and progression of Parkinson’s disease and other age-related diseases, the biologists believe. (If parkin sounds related to Parkinson’s, it is. While the vast majority of people with the disease get it in older age, some who are born with a mutation in the parkin gene develop early-onset, Parkinson’s-like symptoms.)

"Our research may be telling us that parkin could be an important therapeutic target for neurodegenerative diseases and perhaps other diseases of aging," Walker said. "Instead of studying the diseases of aging one by one — Parkinson’s disease, Alzheimer’s disease, cancer, stroke, cardiovascular disease, diabetes — we believe it may be possible to intervene in the aging process and delay the onset of many of these diseases. We are not there yet, and it can, of course, take many years, but that is our goal."

'The garbage men in our cells go on strike'

To function properly, proteins must fold correctly, and they fold in complex ways. As we age, our cells accumulate damaged or misfolded proteins. When proteins fold incorrectly, the cellular machinery can sometimes repair them. When it cannot, parkin enables cells to discard the damaged proteins, said Walker, a member of UCLA’s Molecular Biology Institute.

"If a protein is damaged beyond repair, the cell can recognize that and eliminate the protein before it becomes toxic," he said. "Think of it like a cellular garbage disposal. Parkin helps to mark damaged proteins for disposal. It’s like parkin places a sticker on the damaged protein that says ‘Degrade Me,’ and then the cell gets rid of this protein. That process seems to decline with age. As we get older, the garbage men in our cells go on strike. Overexpressed parkin seems to tell them to get back to work."

Rana focused on the effects of increased parkin activity at the cellular and tissue levels. Do flies with increased parkin show fewer damaged proteins at an advanced age? “The remarkable finding is yes, indeed,” Walker said.

Parkin has recently been shown to perform a similarly important function with regard to mitochondria, the tiny power generators in cells that control cell growth and tell cells when to live and die. Mitochandria become less efficient and less active as we age, and the loss of mitochondrial activity has been implicated in Alzheimer’s, Parkinson’s and other neurodegenerative diseases, as well as in the aging process, Walker said.

Parkin appears to degrade the damaged mitochondria, perhaps by marking or changing their outer membrane structure, in effect telling the cell, “This is damaged and potentially toxic. Get rid of it.”

If parkin is good, is more parkin even better?

While the researchers found that increased parkin can extend the life of fruit flies, Rana also discovered that too much parkin can have the opposite effect — it becomes toxic to the flies. When he quadrupled the normal amount of parkin, the fruit flies lived substantially longer, but when he increased the amount by a factor of 30, the flies died sooner.

"If you bombard the cell with too much parkin, it could start eliminating healthy proteins," Rana said.

In the lower doses, however, the scientists found no adverse effects. Walker believes the fruit fly is a good model for studying aging in humans — who also have the parkin gene — because scientists know all of the fruit fly’s genes and can switch individual genes on and off.

Previous research has shown that fruit flies die sooner when you remove parkin, Walker noted.

Walker and Rana do not know what the optimal amount of parkin would be in humans.

While the biologists increased parkin activity in every cell in the fruit fly, Rana also conducted an experiment in which he increased parkin expression only in the nervous system. That, too, was sufficient to make the flies live longer.

"This tells us that parkin is neuroprotective during aging," Walker said. "However, the beneficial effects of parkin are greater — twice as large — when we increased its expression everywhere."

"We were excited about this research from the beginning but did not know then that the life span increase would be this impressive," Rana said.

The image that accompanies this news release shows clumps or aggregates of damaged proteins in an aged brain from a normal fly (left panel) and an age-matched brain with increased neuronal parkin levels (right panel). As can be seen, increasing parkin levels in the aging brain reduces the accumulation of aggregated proteins.

Scientists have found that this kind of protein aggregation occurs in mammals as well, including humans, Rana said.

"Imagine the damage the accumulation of protein trash is doing to the cell," Walker said. "With increased Parkin, the trash has been collected. Without it, the garbage that should be discarded is accumulating in the cells."

A little brain training goes a long way

People who use a ‘brain-workout’ program for just 10 hours have a mental edge over their peers even a year later, researchers report today in PLoS ONE.

The search for a regimen of mental callisthenics to stave off age-related cognitive decline is a booming area of research — and a multimillion-dollar business. But critics argue that even though such computer programs can improve performance on specific mental tasks, there is scant proof that they have broader cognitive benefits.

For the study, adults aged 50 and older played a computer game designed to boost the speed at which players process visual stimuli. Processing speed is thought to be “the first domino that falls in cognitive decline”, says Fredric Wolinsky, a public-health researcher at the University of Iowa in Iowa City, who led the research.

The game was developed by academic researchers but is now sold under the name Double Decision by Posit Science, based in San Francisco, California. (Posit did not fund the study.) Players are timed on how fast they click on an image in the centre of the screen and on others that appear around the periphery. The program ratchets up the difficulty as a player’s performance improves.

Participants played the training game for 10 hours on site, some with an extra 4-hour ‘booster’ session later, or for 10 hours at home. A control group worked on computerized crossword puzzles for 10 hours on site. Researchers measured the mental agility of all 621 subjects before the brain training began, and again one year later, using eight well-established tests of cognitive performance.

The control group’s scores did not increase over the course of that year, but all the brain-training groups significantly upped their scores in the Useful Field of View test — which requires a subject to identify items in a scene with just a quick glance — and four others. When they compared the study participants’ scores to those expected for people their ages, the researchers found improvements that translated to 3-4.1 years of protection in age-related decline for the field-of-view test and from 1.5-6.6 years for the other tasks.

“It was interesting that it didn’t matter whether you were on site at the clinic or just did this at home — you got basically the same bang for your buck,” says Frederick Unverzagt, a neuropsychologist at the Indiana University School of Medicine in Indianapolis, who was not involved with the study.

But Peter Snyder, a neuropsychologist at Brown University in Providence, Rhode Island, points out that players’ performance could have improved simply because they were familiar with the game — not because their cognitive skills improved. “To me, that makes it hard to interpret the results with the same degree of certainty” that the authors have, he says.

Snyder also doubts that 10 hours of training could affect brain wiring enough to provide long-lasting general benefits, but Henry Mahncke, chief executive of Posit Science, disagrees. “If you’ve never played piano before and spend 10 hours practising, a year later you will be better than when you started,” he says. “The new study shows that there’s science to be done here. Some things you can do with your brain are highly productive and others are not.”

Producing new neurones under all circumstances: a challenge that is just a mouse away …

Improving neurone production in elderly persons presenting with a decline in cognition is a major challenge facing an ageing society and the emergence of neuro-degenerative conditions such as Alzheimer’s disease. INSERM and CEA researchers recently showed that the pharmacological blocking of the TGFβ molecule improves the production of new neurones in the mouse model. These results incentivise the development of targeted therapies enabling improved neurone production to alleviate cognitive decline in the elderly and reduce the cerebral lesions caused by radiotherapy.

The research is published in the journal EMBO Molecular Medicine.

New neurones are formed regularly in the adult brain in order to guarantee that all our cognitive capacities are maintained. This neurogenesis may be adversely affected in various situations and especially:

- in the course of ageing,
- after radiotherapy treatment of a brain tumour. (The irradiation of certain areas of the brain is, in fact, a central adjunctive therapy for brain tumours in adults and children).

According to certain studies, the reduction in our “stock” of neurones contributes to an irreversible decline in cognition. In the mouse, for example, researchers reported that exposing the brain to radiation in the order of 15 Gy is accompanied by disruption to the olfactive memory and a reduction in neurogenesis. The same happens in ageing in which a reduction in neurogenesis is associated with a loss of certain cognitive faculties. In patients receiving radiotherapy due to the removal of a brain tumour, the same phenomena can be observed.

Researchers are studying how to preserve the “neurone stock”. To do this, they have tried to discover which factors are responsible for the decline in neurogenesis.

Contrary to what might have been believed, their initial observations show that neither heavy doses of radiation nor ageing are responsible for the complete disappearance of the neural stem cells capable of producing neurones (and thus the origin of neurogenesis). Those that survive remain localised in a certain small area of the brain (the sub-ventricular zone (SVZ)). They nevertheless appear not to be capable of working correctly.

Additional experiments have made it possible to establish that in both situations, irradiation and ageing, high levels of the cytokine TGFβ cause the stem cells to become dormant, increasing their susceptibility to apoptosis (PCD) and reducing the number of new neurones.

“Our study concluded that although neurogenesis reduced in ageing and after a high dose of radiation, many stem cells survive for several months, retaining their ‘stem’ characteristics”, explains Marc-Andre Mouthon, one of the main authors of the research, that was conducted in conjunction with José Piñeda and François Boussin.

The second part of the project demonstrated that pharmacological blocking of TGFβ restores the production of new neurones in irradiated or ageing mice.

For the researchers, these results will encourage the development of targeted therapies to block TGFβ in order to reduce the impact of brain lesions caused by radiotherapy and improving the production of neurones in the elderly presenting with a cognitive decline.