Category: Alzheimer’s

Small portions of male DNA, most likely left over in a mother's body by a male fetus can be detected in the maternal brain relatively frequently, according to a report published Sep. 26 in the open access journal PLOS ONE by William Chan of Fred Hutchinson Cancer Research Center and his colleagues.

The process, called fetal 'microchimerism (Mc)', is common in other tissues such as blood, but this is the first evidence of male Mc in the human female brain. Microchimerism can be both beneficial and harmful to maternal health, since it is associated with processes such as tissue repair, as well as to autoimmune diseases.

Testing for the presence of a particular region of the Y-chromosome in autopsied brain tissues, the research team discovered that 63% of their samples showed potentially long-lasting Mc in multiple brain regions. They also found that women with Alzheimer's disease (AD) had less Mc than women without the disease.

According to the authors, this result warrants further investigation because previous reports have suggested that AD may be more prevalent in women with a higher number of pregnancies compared to childless women. The researchers commented that changes to the blood-brain barrier that occur during pregnancy could facilitate the process by which Mc is acquired into the human brain.

"This is the first evidence that microchimerism can cross the blood-brain barrier to establish male fetal tissue in the human female brain" says Chan.

Male DNA is commonly found in the brains of women, most likely derived from prior pregnancy with a male fetus, according to first-of-its-kind research conducted at Fred Hutchinson Cancer Research Center. While the medical implications of male DNA and male cells in the brain are unknown, studies of other kinds of microchimerism — the harboring of genetic material and cells that were exchanged between fetus and mother during pregnancy — have linked the phenomenon to autoimmune diseases and cancer, sometimes for better and other times for worse.

The study findings are published Sept. 26 in PLOS ONE. Lead author William F. N. Chan, Ph.D., in the Department of Biochemistry at the University of Alberta, conducted the research while working in the Hutchinson Center laboratory of J. Lee Nelson, M.D., a member of the Center's Clinical Research Division and a leading international authority on microchimerism. Nelson is senior author on the paper.

Chan said the study is the first description of male microchimerism in the female human brain. The findings support the likelihood that fetal cells frequently cross the human blood-brain barrier and that microchimerism in the brain is relatively common. Until this study, it was not known whether these cells could cross the barrier in humans. For this research, scientists examined brain autopsy specimens from 59 women who had died between the ages of 32 and 101. Male microchimerism was detected in 63 percent of subjects, was distributed in multiple brain regions and was potentially persistent throughout the human lifespan; the oldest female in whom male fetal DNA was detected in the brain was 94.

Twenty six of the women had no neurological disease and 33 had Alzheimer's disease. The brains of women with Alzheimer's had a somewhat lower prevalence of male microchimerism, which appeared in lower concentrations in regions of the brain most affected by the disease. However, the authors noted that the small number of subjects and largely unknown pregnancy history of the women means a link between Alzheimer's disease and level of male cells of fetal origin cannot be established.

The study also does not provide an association between male microchimerism in the female brain and relative health versus disease. "Currently, the biological significance of harboring male DNA and male cells in the human brain requires further investigation," Chan said.

However, other Hutchinson Center studies of male microchimerism in women have found it to impact a woman's risk of developing some types of cancer and autoimmune disease. In some conditions, such as breast cancer, cells of fetal origin are thought to confer protection; in others, such as colon cancer, they have been associated with increased risk. Hutchinson Center studies also have linked lower risk of rheumatoid arthritis to women who previously had given birth at least once as compared to nulliparous women. Grants from the National Institutes of Health and the Canadian Institutes of Health Research funded the study, which also involved researchers from the Department of Pathology and Division of Rheumatology at the University of Washington School of Medicine.

---

Journal Reference:

1. William F. N. Chan, Cécile Gurnot, Thomas J. Montine, Joshua A. Sonnen, Katherine A. Guthrie, J. Lee Nelson. Male Microchimerism in the Human Female Brain. PLOS ONE, 2012; 7 (9): e45592 DOI: 10.1371/journal.pone.0045592

Neurodegenerative diseases such as Alzheimer's or Parkinson's are characterised by the loss of nerve cells and the deposition of proteins in the brain tissue. A group of researchers led by Gabor G. Kovacs from the Clinical Institute of Neurology at the MedUni Vienna has now demonstrated that Alzheimer's disease does not just — as previously believed — involve the proteins that are attributed to Alzheimer's, but instead the condition can involve a mixture of interacting proteins from different neurodegenerative diseases.

"As a result, Alzheimer's should not be treated in isolation. According to these latest findings, pure, classical Alzheimer's disease, which involves only the attributed proteins tau and amyloid beta, appears not to be the norm," says Kovacs. There is also a varied regional distribution of nerve cell loss and protein deposits between patients which, taken together, have clinical prognostic significance. As a consequence of this, differentiated strategies need to be developed for personalised therapy that takes account of all the interacting factors.

The new treatment concepts which are currently being developed by the MedUni Vienna's neuropathologists, neurobiologists, neurologists, psychiatrists and neuroimaging experts will divide the patients into "sub-groups." Says Kovacs: "The aim is to define these groups very precisely in future in order to be able to offer them personalised treatment."

Dementia diseases: a growing trend

Around 100,000 Austrians are currently suffering from a dementia-related illness, according to statistics from the Austrian Alzheimer Society. According to estimates, this figure will rise to around 280,000 by 2050 as a result of the increasing age of the general population. Alzheimer's disease is responsible for 60 to 80 per cent of these conditions.

The global Alzheimer's report by "Alzheimer's Disease International" reckons that the prevalence of dementia doubles every 20 years. There are currently around 35 million people worldwide suffering a dementia-related illness. By 2030, their number will rise to 65.7 million and reach as many as 115.4 million by 2050.

Taking Gingko biloba supplements does not improve memory, attention or problem solving in healthy individuals, according to researchers from the University of Hertfordshire.

The paper, published in Human Psychopharmacology: Clinical and Experimental, is the first meta-analytic review examining the effects of Gingko biloba on healthy people across all age groups. The researchers led by Professor Keith Laws found zero impact on the cognitive functions whatever the age of the people, the dose taken or the length of time of taking Gingko biloba supplements.

Gingko biloba, the oldest tree living species, has been used extensively in traditional Chinese herbal medicine for thousands of years.  Today, it is one of the most widely used plant-based products available without prescription in Europe and North America, where is it marketed as a dietary supplement to treat blood disorders and, more specifically, to enhance memory both for healthy individuals and also for those trying to ward off Alzheimer’s Disease.

Keith Laws, Professor of psychology, said: “Gingko biloba has been widely used for a number of years to reduce the mental decline associated with aging.  But more recently it has been marketed as a memory enhancing supplement for healthy individuals – and it is crucial to establish the validity for such claims.

“Our findings show that taking Gingko biloba supplements at any age to boost memory have no impact at all – and may be a waste of time and money.”

The paper, “Is Gingko biloba a cognitive enhancer in healthy individuals? A meta-analysis”, examines the published research of thirteen randomised control trials of over 1000 healthy individuals across all ages. 

Other recently published studies have also shown that there is no evidence to support taking Gingko biloba supplements to protect against developing Alzheimer’s Disease.

A team of neuroscientists and chemists from the U.S. and China September 24 publish research suggesting that a class of currently used anti-cancer drugs as well as several previously untested synthetic compounds show effectiveness in reversing memory loss in two animal models of Alzheimer's disease.

CSHL Professor Yi Zhong, Ph.D., who led the research conducted in fruit flies and mice, says he and his colleagues were surprised with their results, which, he stressed, used two independent experimental approaches "the results of which clearly converged."

Specifically, the research converged on what Zhong's team suggests is a "preferred target" for treating memory loss associated with the amyloid-beta (Aβ) plaques seen in advanced Alzheimer's patients. That target is the epidermal growth factor receptor, often called by its acronym, EGFR.

Overexpression of the EGFR is a characteristic feature of certain cancers, notably a subset of lung cancers. Two targeted treatments, erlotinib (Tarceva) and gefitinib (Iressa), can dramatically, albeit transiently, reverse EGFR-positive cancers, by blocking the EGF receptor and thus preventing its activation.

The newly published research by Zhong's team suggests that the signaling within cells that is induced by EGFR activation also plays a role in the pathology — still poorly understood — involved in Aβ-associated memory loss seen in Alzheimer's patients.

Zhong and colleagues previously had studied Aβ-associated memory loss in fruit flies with brain cells expressing the Aβ-42 peptide (a specific version of the protein, composed of 42 amino acids, seen in Alzheimer's plaques). These fruit flies are regarded as models of the illness in part because the Aβ-42 they manifest is encoded by a human gene, inserted in their genome. In behavioral experiments, such flies have been shown to suffer memory deficiencies analogous to those seen in human Alzheimer's.

Enhanced activation of EGFR exacerbates memory loss in flies

In the current round of experiments, Zhong's team demonstrated that enhanced activation of EGFRs in brain cells exacerbated memory loss in the Aβ-42 fruit fly model of Alzheimer's disease. This led them to dose 3-day-old flies of this type with the two anti-cancer EGFR inhibitors over a week's time, which was shown in behavioral tests on day 11 to prevent memory loss. The results were then confirmed in mouse models of Alzheimer's, also based on the human Aβ-42 gene.

This was remarkable, but even more so, says Zhong, because of a parallel but independent experimental process that also suggested EGFR as a drug target for Alzheimer's. This parallel process consisted of screening, by Zhong's collaborators in China, of some 2,000 synthetic compounds for activity against Aβ-induced memory loss in model fruit flies. Of these, 45 compounds showed positive results in fruit flies after two months of dosing. Nine of these were selected for testing in mouse models, of which four showed positive results after two months.

"We were amazed to find that three of these compounds — designated JKF-006, JKF-011 and JKF-027 — not only showed effective results in rescuing memory loss in the mice, but also, in test-tube-based experiments prevented Aβ-42 from activating human EGFR," Zhong reports.

Blocking EGFR signaling appeared to prevent memory loss

Importantly, a precise mechanism could not be conclusively demonstrated from this and related experiments. But the available evidence leads the scientists to propose in a paper appearing online today in Proceedings of the National Academy of Sciences, that reversal of memory loss occurs when clumps of beta-amyloid proteins are either prevented directly from "docking" with the human EGF receptor, or prevent phosphate groups from attaching to the receptor, a process called phosphorylation. Both hypothesized processes would prevent the initiation of the EGFR intracellular signaling cascade.

Zhong and colleagues note the uncertainty of Alzheimer's pathology. Memory loss stemming from Aβ-induced activation of EGFR "may reflect the acute toxic effects of Aβ, which might be independent of synaptic and neuronal degeneration," they note. To gain more insight, the team tested drug treatment of middle-aged mice (8 months old) with advanced memory loss during an 18-day period — some six weeks shorter than the dosing period initially shown to be effective.

"Eighteen days — the shortest dosing period we tested — was sufficient to reverse loss in these mice, although we should note that these animals had few morphological changes in the brain despite their severe memory loss when treatment began," Zhong says.

Because of the positive results they obtained in reversing memory loss in animal models, the team suggests additional testing with EGFR inhibitors be conducted, as well as testing of "behaviorally screened chemicals in treatments of Alzheimer's patients."

A previously unrecognized system that drains waste from the brain at a rapid clip has been discovered by neuroscientists at the University of Rochester Medical Center. The findings were published online August 15 in Science Translational Medicine.

The highly organized system acts like a series of pipes that piggyback on the brain's blood vessels, sort of a shadow plumbing system that seems to serve much the same function in the brain as the lymph system does in the rest of the body — to drain away waste products.

"Waste clearance is of central importance to every organ, and there have been long-standing questions about how the brain gets rid of its waste," said Maiken Nedergaard, M.D., D.M.Sc., senior author of the paper and co-director of the University's Center for Translational Neuromedicine. "This work shows that the brain is cleansing itself in a more organized way and on a much larger scale than has been realized previously.

"We're hopeful that these findings have implications for many conditions that involve the brain, such as traumatic brain injury, Alzheimer's disease, stroke, and Parkinson's disease," she added.

Nedergaard's team has dubbed the new system "the glymphatic system," since it acts much like the lymphatic system but is managed by brain cells known as glial cells. The team made the findings in mice, whose brains are remarkably similar to the human brain.

Scientists have known that cerebrospinal fluid or CSF plays an important role cleansing brain tissue, carrying away waste products and carrying nutrients to brain tissue through a process known as diffusion. The newly discovered system circulates CSF to every corner of the brain much more efficiently, through what scientists call bulk flow or convection.

"It's as if the brain has two garbage haulers — a slow one that we've known about, and a fast one that we've just met," said Nedergaard. "Given the high rate of metabolism in the brain, and its exquisite sensitivity, it's not surprising that its mechanisms to rid itself of waste are more specialized and extensive than previously realized."

While the previously discovered system works more like a trickle, percolating CSF through brain tissue, the new system is under pressure, pushing large volumes of CSF through the brain each day to carry waste away more forcefully.

The glymphatic system is like a layer of piping that surrounds the brain's existing blood vessels. The team found that glial cells called astrocytes use projections known as "end feet" to form a network of conduits around the outsides of arteries and veins inside the brain — similar to the way a canopy of tree branches along a well-wooded street might create a sort of channel above the roadway.

Those end feet are filled with structures known as water channels or aquaporins, which move CSF through the brain. The team found that CSF is pumped into the brain along the channels that surround arteries, then washes through brain tissue before collecting in channels around veins and draining from the brain.

How has this system eluded the notice of scientists up to now?

The scientists say the system operates only when it's intact and operating in the living brain, making it very difficult to study for earlier scientists who could not directly visualize CSF flow in a live animal, and often had to study sections of brain tissue that had already died. To study the living, whole brain, the team used a technology known as two-photon microscopy, which allows scientists to look at the flow of blood, CSF and other substances in the brain of a living animal.

While a few scientists two or three decades ago hypothesized that CSF flow in the brain is more extensive than has been realized, they were unable to prove it because the technology to look at the system in a living animal did not exist at that time.

"It's a hydraulic system," said Nedergaard. "Once you open it, you break the connections, and it cannot be studied. We are lucky enough to have technology now that allows us to study the system intact, to see it in operation."

First author Jeffrey Iliff, Ph.D., a research assistant professor in the Nedergaard lab, took an in-depth look at amyloid beta, the protein that accumulates in the brain of patients with Alzheimer's disease. He found that more than half the amyloid removed from the brain of a mouse under normal conditions is removed via the glymphatic system.

"Understanding how the brain copes with waste is critical. In every organ, waste clearance is as basic an issue as how nutrients are delivered. In the brain, it's an especially interesting subject, because in essentially all neurodegenerative diseases, including Alzheimer's disease, protein waste accumulates and eventually suffocates and kills the neuronal network of the brain," said Iliff.

"If the glymphatic system fails to cleanse the brain as it is meant to, either as a consequence of normal aging, or in response to brain injury, waste may begin to accumulate in the brain. This may be what is happening with amyloid deposits in Alzheimer's disease," said Iliff. "Perhaps increasing the activity of the glymphatic system might help prevent amyloid deposition from building up or could offer a new way to clean out buildups of the material in established Alzheimer's disease," he added.

In addition to Iliff and Nedergaard, other authors from Rochester include Minghuan Wang, Yonghong Liao, Benjamin Plogg, Weiguo Peng, Edward Vates, Rashid Deane, and Steven Goldman. Also contributing were Erlend Nagelhus and Georg Gundersen of the University of Oslo, and Helene Benveniste of the Health Science Center at Stony Brook University.

The work was funded by the National Institutes of Health (grant numbers R01NS078304 and R01NS078167), the U.S. Department of Defense, and the Harold and Leila Y. Mathers Charitable Foundation.

---

Journal Reference:

1. Jeffrey J. Iliff, Minghuan Wang, Yonghong Liao, Benjamin A. Plogg, Weiguo Peng, Georg A. Gundersen, Helene Benveniste, G. Edward Vates, Rashid Deane, Steven A. Goldman, Erlend A. Nagelhus, and Maiken Nedergaard. A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β. Science Translational Medicine, 2012; DOI: 10.1126/scitranslmed.3003748

One might expect that ridding a brain cell of damaged proteins would be a universally good thing, and that impairing the cell's ability to do this would allow the faulty proteins to accumulate within the cell, possibly to toxic levels. So a lot of scientific effort has gone into looking for ways to enhance the process by which cells dispose of banged-up proteins.

But this thinking may need some revision, according to a new study from the Stanford University School of Medicine. Senior author Thomas Sudhof, MD, professor of molecular and cellular physiology, and his fellow researchers have unexpectedly found that inhibiting the process by which damaged proteins are ordinarily broken down within cells both delayed the onset of symptoms in laboratory mice that are highly prone to neurodegeneration and significantly increased their longevity.

The study, published online Aug. 15 in Science Translational Medicine, also showed that blocking the activity of cells' in-house garbage disposals — known in the biology business as proteasomes — in nerve cells taken from the neurodegeneration-prone mice restored several key biochemical characteristics necessary for the cells' healthy function.

Although Sudhof cautions that more research is needed, the findings pose a challenge to prevailing beliefs about the pathology of certain neurodegenerative disorders.

"The current consensus in neuroscience favors a therapeutic strategy of trying to accelerate, rather than impede, the disposal of damaged proteins that accumulate in the brains of patients with Alzheimer's, Parkinson's, Huntington's and other neurodegenerative diseases," said Sudhof, who is also the Avram Goldstein Professor in the School of Medicine.

Proteasomes are cell components that destroy damaged proteins. Not just nerve cells but virtually all cells in creatures ranging from yeast to humans contain multitudes of these tiny tube-shaped machines, which suck the defective proteins into their holes and chop them into smithereens.

Examining brain tissue from deceased Alzheimer's and Parkinson's patients, Sudhof's team observed that an aspect of the degenerative process identical to the one they had prevented in lab mice was occurring, suggesting that their findings in the animal model might prove relevant to these and other human diseases as well.

The particular defective protein whose demolition was staved off in Sudhof's study, called SNAP-25, plays a key role in the release of chemical signals that nerve cells use to communicate with one another. But like all proteins, SNAP-25 can't do its job until it is slapped into shape.

"Structure equals function" is a watchword of biochemistry. Proteins — the molecular creatures that do the bulk of the work in every living cell — are initially produced as long linear sequences of small chemical subunits that progressively get strung together like beads on a string. But the string is just a string until it assumes a specific structure, typically with help from one or more "chaperone" molecules that midwife it into its correct conformation.

Like a mail carrier's feet, overworked proteins can eventually go flat. Misfolded and therefore no longer functional proteins may, alternatively, be quickly reconditioned and put back on the job or get chemically "barcoded" for demolition at the hands of proteasomes.

SNAP-25 is used by many types of cells but works particularly hard in nerve cells, or neurons. To transmit signals to one another, neurons release specialized chemicals into small gaps called synapses that separate one neuron from the next in a relay. Prior to release, those chemicals are sequestered within membrane-bound packets, or vesicles, inside the neuron. Every time one neuron transmits a signal to the next — which can be more than 100 times a second — hundreds of tiny chemical-packed vesicles approach the edge of the first neuron and fuse with its outer membrane. A fused vesicle's inner surface becomes part of the neuron's outer surface (just as would happen if a small bubble merged with a larger one surrounding it), and its stored contents spill out into the synapse.

To make this happen, vesicles must be actively coerced into close contact with neurons' membranes. This is accomplished by a cluster of proteins that serves as the molecular equivalent of a clamp. In the course of repeated bouts of neuronal firing, SNAP-25 — a key constituent of this clamping complex — can get bent out of shape, rendering the entire clamp assembly useless. The more a neuron fires, the more molecules of SNAP-25 get deformed over time.

Some years ago, Sudhof's group used a sophisticated genetics technique to create a strain of laboratory mice lacking a chaperone molecule that assists in the proper refolding of SNAP-25. These mice seem quite normal early in life. But the gradual failure of the clamping action necessary for vesicle fusion and neuronal signaling causes the neurons to die off, eventually triggering behavioral symptoms and early death. Sudhof has used these mice extensively as a model system for understanding misfolded proteins and degenerative disease.

In the new study, giving the chaperone-deficient mice injections of either of two proteasome-inhibiting drugs (lactacystin and epoxomicin) once every five days — probably far from an optimal regimen, but at least a feasible animal experiment, Sudhof said — delayed typical outward symptoms of their neurodegenerative disorder by as much as 30 percent and prolonged their survival by close to 20 percent. Next, the researchers incubated neurons from the experimental mice in solutions with or without proteasome-inhibiting drugs. Biochemical measurements showed that, while overall stores of SNAP-25 in the neurons incubated with or without drugs were the same, the activity of the clamping complex was restored to normal levels in the drug-soaked neurons. (In the drug-free neurons, clamp activity remained hugely impaired.)

Clearly, preventing the breakdown of misfolded SNAP-25 molecules increased their levels in neurons — an outcome that one would intuitively think would be toxic, Sudhof said. But the experiments in the new study instead suggest that misfolded proteins, either randomly just from being bounced around in the surrounding environment or with the active assistance of "generic" chaperone molecules, can revert to normal shapes and jump back into the fray. As faulty SNAP-25 accumulates in the cell, more of it gets repaired, with beneficial downstream implications for molecular-clamp activity, vesicle-membrane fusion and better chemical signaling by neurons. Because neurons have to signal effectively in order to survive, fewer of them die.

A number of neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases are associated with the occurrence of damaged proteins. It is a widely held view among investigators in the field that the buildup of these damaged proteins substantially contributes to the disease process.

Sudhof cautioned that, while it is possible that proteasome-inhibiting drugs could, paradoxically, turn out to slow the progress of these and other human degenerative conditions, this was far from proven. However, far more powerful proteasome-inhibiting drugs than the old, off-patent drugs Sudhof and his teammates gave their experimental mice are already in clinical use for certain cancer indications, so they could rapidly be deployed in preclinical studies testing this possibility.

Postdoctoral scholar Manu Sharma, PhD, is the first author of the study, which was funded by the National Institute on Aging. Postdoctoral researcher Jacqueline Burre, PhD, was an additional co-author.

Information about the medical school's Department of Molecular and Cellular Physiology, which also supported this work, is available at http://mcp.stanford.edu/.

The underlying causes of Alzheimer's disease are not fully understood, but a good deal of evidence points to the accumulation of β-amyloid, a protein that's toxic to nerve cells. β-amyloid is formed by the activity of several enzymes, including one called BACE1. Most Alzheimer's disease patients have elevated levels of BACE1, which in turn leads to more brain-damaging β-amyloid protein. In a paper published August 15 in The Journal of Neuroscience, researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) found that BACE1 does more than just help produce β-amyloid — it also regulates another cellular process that contributes to memory loss. This means that just inhibiting BACE1's enzymatic activity as a means to prevent or treat Alzheimer's disease isn't enough — researchers will have to prevent cells from making it at all.

"Memory loss is a big problem — not just in Alzheimer's disease, but also in the normal aging population," said Huaxi Xu, Ph.D., professor in Sanford-Burnham's Del E. Webb Neuroscience, Aging, and Stem Cell Research Center and senior author of the study. "In this study, we wanted to better understand how BACE1 plays a role in memory loss, apart from β-amyloid production."

To do this, Xu and his team used a mouse model that produces human BACE1. Mice produce a different type of β-amyloid, one that's far less toxic than the human version. So, in this system, they could look solely at how BACE1 functions independent from β-amyloid formation. If BACE1 only acted to produce β-amyloid, the researchers would expect to see no effect when mice produce human BACE1 — since mouse β-amyloid isn't very toxic, extra BACE1 would be no big deal. Instead, they saw that the enzyme still impaired learning and memory, indicating a secondary function at work.

If it's not producing β-amyloid, what is BACE1 doing? Many years ago, scientists found that a protein in the brain — protein kinase A (PKA), better known for directing cellular metabolism — also plays an important role in memory formation. In this study, Xu and colleagues found that BACE1 disrupts the cell's production of other molecules required for PKA function. By that mechanism, BACE1 inactivates PKA and therefore inhibits memory formation in mice, even in the absence of neurotoxic β-amyloid.

"So BACE1 is a double whammy when it comes to memory," Xu said. "But that also means that a therapy that targets BACE1 could be a double punch against Alzheimer's disease, and even just normal aging-related memory loss. That's why we're now looking for ways to block BACE1 expression in the brain."

---

Journal Reference:

1. Y. Chen, X. Huang, Y.-w. Zhang, E. Rockenstein, G. Bu, T. E. Golde, E. Masliah, H. Xu. Alzheimer's  -Secretase (BACE1) Regulates the cAMP/PKA/CREB Pathway Independently of  -Amyloid. Journal of Neuroscience, 2012; 32 (33): 11390 DOI: 10.1523/JNEUROSCI.0757-12.2012

High baseline levels of neuronal activity in the best connected parts of the brain may play an important role in the development of Alzheimer's disease. This is the main conclusion of a new study appearing in PLoS Computational Biology from a group at VU University Medical Center in Amsterdam, the Netherlands.

In recent times, it has become clear that brain activity patterns change at an early stage in Alzheimer's disease. Moreover, there is reason to believe that, instead of being the consequence of structural damage, they might be the cause: recently, a direct influence of excessive regional neuronal activity on Alzheimer pathology was found in animal experiments. By showing that highly connected 'hub' regions (which display most Alzheimer pathology) indeed possess the highest levels of activity, the present study offers support for the unconventional view that brain dynamics may play a causal role in Alzheimer. As first author, Willem de Haan, says, "this implies that the investigation of factors regulating neuronal activity may open up novel ways to detect, elucidate and counter the disease."

Using a realistic computational model of the human cortex, the authors simulated progressive synaptic damage to brain regions based on their level of activity, and subsequently investigated the effect on the remaining network. With this 'activity dependent degeneration' model, they could not only offer an explanation for the distribution pattern of Alzheimer pathology but also reproduce a range of phenomena encountered in actual neurophysiological data of Alzheimer patients: loss and slowing of neuronal activity, loss of communication between areas, and specific changes in brain network organization.

In upcoming projects the authors plan to verify the predictions from this study in patient data, but also to continue modeling studies. They conclude that: "the use of 'computational neurology' and network theory to unite experimental results and find plausible underlying principles in the growing bulk of human brain data seems inevitable.".

Researchers have long chronicled what goes wrong in the brains of older people with dementia. But Northwestern Medicine researcher Emily Rogalski wondered what goes right in the brains of the elderly who still have terrific memories. And, do those people — call them cognitive SuperAgers — even exist?

Rogalski's new study has for the first time identified an elite group of elderly people age 80 and older whose memories are as sharp as people 20 to 30 years younger than them. And on 3-D MRI scans, the SuperAger participants' brains appear as young — and one brain region was even bigger — than the brains of the middle-aged participants.

She was astounded by the vitality of the SuperAgers' cortex — the outer layer of the brain important for memory, attention and other thinking abilities. Theirs was much thicker than the cortex of the normal group of elderly 80 and older (whose showed significant thinning) and closely resembled the cortex size of participants ages 50 to 65, considered the middle-aged group of the study.

"These findings are remarkable given the fact that grey matter or brain cell loss is a common part of normal aging," said Rogalski, the principal investigator of the study and an assistant research professor at the Cognitive Neurology and Alzheimer's Disease Center at Northwestern University Feinberg School of Medicine.

Rogalski is senior author of the paper, which is published in the Journal of the International Neuropsychological Society.

By identifying older people who seem to be uniquely protected from the deterioration of memory and atrophy of brain cells that accompanies aging, Rogalski hopes to unlock the secrets of their youthful brains. Those discoveries may be applied to protect others from memory loss or even Alzheimer's disease.

"By looking at a really healthy older brain, we can start to deduce how SuperAgers are able to maintain their good memory," Rogalski said. "Many scientists study what's wrong with the brain, but maybe we can ultimately help Alzheimer's patients by figuring out what goes right in the brain of SuperAgers. What we learn from these healthy brains may inform our strategies for improving quality of life for the elderly and for combatting Alzheimer's disease."

By measuring the thickness of the cortex — the outer layer of the brain where neurons (brain cells) reside — Rogalski has a sense of how many brain cells are left.

"We can't actually count them, but the thickness of the outer cortex of the brain provides an indirect measure of the health of the brain," she said. "A thicker cortex, suggests a greater number of neurons."

In another region deep in the brain, the anterior cingulate of SuperAger participants' was actually thicker than in the 50 to 65 year olds.

"This is pretty incredible," Rogalski said. "This region is important for attention. Attention supports memory. Perhaps the SuperAgers have really keen attention and that supports their exceptional memories."

Only 10 percent of the people who "thought they had outstanding memories" met the criteria for the study. To be defined as a SuperAger, the participants needed to score at or above the norm of the 50 to 65 year olds on memory screenings.

"These are a special group of people," Rogalski said. They aren't growing on trees."

For the study, Rogalski viewed the MRI scans of 12 Chicago-area Superager participants' brains and screened their memory and other cognitive abilities. The study included 10 normally aging elderly participants who were an average age of 83.1 and 14 middle-aged participants who were an average age of 57.9. There were not significant differences in education among the groups.

Most of the SuperAger participants plan to donate their brains to the study. "By studying their brains we can link the attributes of the living person to the underlying cellular features," Rogalski said.

---

Journal Reference:

1. Theresa M. Harrison, Sandra Weintraub, M.-Marsel Mesulam and Emily Rogalski. Superior Memory and Higher Cortical Volumes in Unusually Successful Cognitive Aging. Journal of the International Neuropsychological Society, 2012 DOI: 10.1017/S1355617712000847