TAG: "Alzheimer’s"

UC Irvine MIND redesignated as Alzheimer’s Disease Research Center


Prestigious $11M renewal grant continues highly impactful programs.

By Tom Vasich, UC Irvine

UC Irvine’s Institute for Memory Impairments and Neurological Disorders has received a five-year, $11 million grant from the National Institute on Aging to renew its status as one of only 27 Alzheimer’s Disease Research Centers in the nation — a list that includes all five UC medical centers.

The prestigious award, which supports a major component of UCI MIND, will allow the center to continue its highly impactful clinical and basic research programs, as well as community and caregiver education programs.

“With its ADRC designation, UCI MIND is part of an elite network of researchers with a broad scope of expertise, spanning many different disciplines,” said Frank LaFerla, the Hana & Francisco J. Ayala Dean of the Francisco J. Ayala School of Biological Sciences and the ADRC leader. “This opportunity for collaboration allows researchers around the country to share cutting-edge ideas and research results.”

Involving more than 100 investigators, the ADRC has directed its research efforts at discovering the cellular, molecular and clinical risk factors that trigger neuronal dysfunction and neuropathological changes in the aging brain and that can result in Alzheimer’s disease or other forms of dementia. In particular, the ADRC studies three distinct groups: people with Down syndrome and Alzheimer’s disease, those with mild cognitive problems at risk for dementia, and nonagenarian subjects in the 90+ Study.

The center’s multidisciplinary team takes a comprehensive approach to research and care through mandated core components: clinical evaluation, neuropathology, community outreach and education, and data management and statistics.

UCI’s ADRC hosts three major research projects. One focuses on state-of-the-art, high-resolution neuroimaging of older adults with and without mild cognitive impairment to test a neurocognitive model of age-related memory deficits. Another project seeks to understand the molecular mechanisms associated with the Down syndrome brain. And the third investigates the long-term benefit of neural stem cell transplantation as a potential Alzheimer’s treatment. As part of that effort, LaFerla and colleague Mathew Blurton-Jones established the nation’s first Core facility to develop induced pluripotent stem cells to facilitate Alzheimer’s disease research.

“ADRC activities are at the heart of our mission with UCI MIND,” said Andrea Tenner, professor of molecular biology & biochemistry and UCI MIND director. “By fostering multidisciplinary basic, clinical and behavioral research in Alzheimer’s disease and translating these findings into practice, we plan to make a real difference in the lives of the millions of afflicted Americans.”

To learn more about UCI’s ADRC or participate in a clinical evaluation, call (949) 824-2382 or go to www.alz.uci.edu.

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Related link:
UC Davis Alzheimer’s Disease Center opens new clinic in Walnut Creek

 

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Genetics overlap found between Alzheimer’s, cardiovascular risk factors


Inflammation, high blood lipids may play role in dementia risk, also offer therapeutic targets.

By Scott LaFee, UC San Diego

An international team of scientists, led by researchers at the UC San Diego School of Medicine, have found genetic overlap between Alzheimer’s disease (AD) and two significant cardiovascular disease risk factors: high levels of inflammatory C-reactive protein (CRP) and plasma lipids or fats. The findings, based upon genome-wide association studies involving hundreds of thousands of individuals, suggest the two cardiovascular phenotypes play a role in AD risk – and perhaps offer a new avenue for potentially delaying disease progression.

The findings are published in current online issue of Circulation.

“For many years we have known that high levels of cholesterol and high levels of inflammation are associated with increased risks for Alzheimer’s disease,” said study co-author Paul M. Ridker, M.D., M.P.H., the Eugene Braunwald Professor of Medicine at Harvard Medical School and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital. “The current work finds that specific genetic signals explain a part of these relationships. We now need to characterize the function of these genetic signals and see whether they can help us to design better trials evaluating inflammation inhibition as a possible method for Alzheimer’s treatment.”

The researchers used summary statistics from genome-wide association studies of more than 200,000 individuals, looking for overlap in single nucleotide polymorphisms (SNPs) associated with clinically diagnosed AD and CRP and the three components of total cholesterol: high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides (TG). SNPs are fragments of DNA sequence that commonly vary among individuals within a population.

They found up to a 50-fold enrichment of AD SNPs for different levels of association with CRP, LDL, HDL and TG, which then lead to identification of 55 loci – specific locations on a gene, DNA sequence or chromosome – linked to increased AD risk. The researchers next conducted a meta-analysis of these 55 variants across four independent AD study cohorts, encompassing almost 145,000 persons with AD and healthy controls, revealing two genome-wide significant variants on chromosomes 4 and 10. The two identified genes – HS3ST1 and ECHDC3 – were not previously associated with AD risk.

“Our findings indicate that a subset of genes involved with elevated plasma lipid levels and inflammation may also increase the risk for developing AD. Elevated levels of plasma lipids and inflammation can be modified with treatment, which means it could be possible to identify and therapeutically target individuals at increased risk for developing cardiovascular disease who are also at risk for developing Alzheimer’s disease,” said Rahul S. Desikan, M.D., Ph.D., research fellow and radiology resident at the UC San Diego School of Medicine and the study’s first author.

If so, the research may have significant ramifications. Late-onset AD is the most common form of dementia, affecting an estimated 30 million persons worldwide – a number that is expected to quadruple over the next 40 years. The societal costs, from medical to lost productivity, are staggering. The 2010 World Alzheimer Report estimated total annual costs at $606 billion.

“Currently, there are no disease modifying therapies and much attention has been focused upon prevention and early diagnosis,” said Ole A. Andreassen, M.D., Ph.D., a senior co-author and professor of biological psychiatry at the University of Oslo in Norway. “Delaying dementia onset by even just two years could potentially lower the worldwide prevalence of AD by more than 22 million cases over the next four decades, resulting in significant societal savings.”

Senior author Anders M. Dale, Ph.D., professor of neurosciences and radiology and director of the Center for Translational Imaging and Precision Medicine at UC San Diego, said further research will be needed: “Careful and considerable effort will be required to further characterize the novel candidate genes detected in this study and to detect the functional variants responsible for the association of these loci with Alzheimer’s risk. It will also be important to understand whether these genes, in combination with other known markers such as brain imaging, cerebrospinal fluid measurements and APOE E4 status, can improve the prediction of disease risk in AD.”

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Retired NFL players who suffered concussions show pattern of protein deposits


New test may lead to better identification of brain disorders like CTE.

PET scan of a brain with suspected CTE. More red and yellow indicates more abnormal brain proteins.

By Rachel Champeau, UCLA

A new UCLA study takes another step toward the early understanding of a degenerative brain condition called chronic traumatic encephalopathy, or CTE, which affects athletes in contact sports who are exposed to repetitive brain injuries. Using a new imaging tool, researchers found a strikingly similar pattern of abnormal protein deposits in the brains of retired NFL players who suffered from concussions.

The innovative imaging technique uses a chemical marker combined with positron emission tomography, or PET scan, and was initially tested in five retired NFL players and described in an article published in 2013. Now, building on their previous work, the UCLA researchers found the same characteristic pattern in a larger number of retired players who had sustained concussions.

The latest study also shows that the brain imaging pattern of people who have suffered concussions is markedly different from the scans of healthy people and from those with Alzheimer’s disease. Researchers say the findings could help lead to better identification of brain disorders in athletes and would allow doctors and scientists to test treatments that might help delay the progression of the disease before significant brain damage and symptoms emerge.

The study appears in today’s (April 6) online edition of the Proceedings of the National Academy of Science.

CTE is thought to cause memory loss, confusion, progressive dementia, depression, suicidal behavior, personality changes and abnormal gaits and tremor.

Common factor in CTE and Alzheimer’s

Currently, CTE can only be diagnosed definitively following autopsy. To help identify the disease, doctors look for an accumulation of a protein called tau in the regions of the brain that control mood, cognition and motor function. Tau is also one of the abnormal protein deposits found in the brains of people with Alzheimer’s, although in a distribution pattern that is different from that found in CTE.

“The distribution pattern of the abnormal brain proteins, primarily tau, observed in these PET scans, presents a ‘fingerprint’ characteristic of CTE,” said Dr. Jorge Barrio, senior author of the study and a professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA.

The team identified four stages of deposits that could signify early to advanced levels of CTE.

“These different stages reflected by the brain marker may give us more insight into how CTE develops and allow us to track the disease over time,” said Dr. Vladimir Kepe, an author of the study and a research pharmacologist in molecular and medical pharmacology at the Geffen School of Medicine.

The new, larger study included 14 retired NFL players (including the five subjects from the earlier study), all of whom had sustained at least one concussion. Their results were compared with those of 19 men and nine women with healthy brains and 12 men and 12 women with Alzheimer’s disease of similar ages.

Participants received a scan using the UCLA-developed technique, which previously was used for assessing neurological changes associated with Alzheimer’s disease. The test involves injecting a chemical marker called FDDNP, which binds to deposits of neurofibrillary tau “tangles” and amyloid beta “plaques” — the hallmarks of Alzheimer’s. Then, using PET scans, the researchers were able to pinpoint where in the brain these abnormal proteins accumulated.

Participants also underwent MRI scans, neuropsychological testing, and neurological and physical exams to determine whether they had symptoms consistent with CTE, Alzheimer’s dementia or normal aging.

“We found that the imaging pattern in people with suspected CTE differs significantly from healthy volunteers and those with Alzheimer’s dementia,” said Dr. Julian Bailes, an author of the study and director of the Brain Injury Research Institute and the Bennett Tarkington Chairman of the Department of Neurosurgery at NorthShore University HealthSystem in Evanston, Illinois. “These results suggest that this brain scan may also be helpful as a test to differentiate trauma-related cognitive issues from those caused by Alzheimer’s disease.”

Tau and CTE

The PET scans revealed that the imaging patterns of the retired football players showed tau deposit patterns consistent with those that have been observed in autopsy studies of people with CTE.

In addition, the areas in the brain where the patterns occurred were also consistent with the types of symptoms experienced by some of the study participants.

Compared with healthy people and those with Alzheimer’s, the former athletes had higher levels of FDDNP in the amygdala and subcortical regions of the brain, which are areas that control learning, memory, behavior, emotions, and other mental and physical functions.

People with Alzheimer’s, on the other hand, had higher levels of FDDNP in areas of the cerebral cortex that control memory, thinking, attention and other cognitive abilities. And the athletes who had experienced more concussions also had higher FDDNP levels.

The next stage of the research will include multisite studies and will follow subjects over time to determine how effectively FDDNP can detect possible CTE and predict future symptoms. Researchers also will expand the studies to include other groups of people affected by brain injury, such as military personnel.

Previous brain autopsy studies have shown that amyloid plaques are present in less than 45 percent of retired football players, most typically in those with advanced CTE. Most of the retired players in the new study did not have advanced CTE, which suggests that their FDDNP signal represents mostly tau deposits in the brain.

The scans of people with the highest levels of FDDNP binding in areas where tau accumulates in CTE, also show binding in areas of the brain affected by amyloid plaques, which is consistent with autopsy findings indicating that this abnormal protein also plays a role in more serious cases of CTE.

The team also reported initial results of scans of two military veterans. Researchers note that more expanded studies will help them better understand how different causes of head injury may contribute to chronic brain disorders.

In the paper, the researchers note that the FDDNP PET scan is one of several methods — including blood-based biomarkers, diffusion tensor imaging MRI and resting state functional MRI — that are being studied by scientists across the country to help diagnose CTE early.

With more than 500 neuroscientists throughout campus, UCLA is a leader in research to understand the human brain, including efforts to treat, cure and prevent traumatic brain injury and brain disorders such as Alzheimer’s disease.

This study was supported by grants from the NIH (P01-AG025831 and M01-RR00865) and gifts to UCLA from the Toulmin Foundation and Robert and Marion Wilson. No company provided research funding for this study.

The FDDNP marker used with brain PET scans to identify abnormal proteins is intellectual property owned by UCLA and licensed to TauMark, LLC. UCLA authors Dr. Jorge Barrio, Dr. Gary Small and Dr. Sung-Cheng Huang are co-inventors of the PET marker. Barrio and Small have a financial interest in the company. Other disclosures are available in the manuscript.

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UC Davis: Study finds characteristic pattern of protein deposits in retired NFL players’ brains

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‘Gold standard’ method created for measuring key early sign of Alzheimer’s


UCLA helps validate first standardized protocol for measuring an early sign of Alzheimer’s.

Liana Apostolova, UCLA

By Mark Wheeler, UCLA

After six years of painstaking research, a UCLA-led team has validated the first standardized protocol for measuring one of the earliest signs of Alzheimer’s disease — the atrophy of the part of the brain known as the hippocampus.

The finding marks the final step in an international consortium’s successful effort to develop a unified and reliable approach to assessing signs of Alzheimer’s-related neurodegeneration through structural imaging tests, a staple in the diagnosis and monitoring of the disease. The study is published in the journal Alzheimer’s and Dementia.

Using brain tissue of deceased Alzheimer’s disease patients, a group headed by Dr. Liana Apostolova, director of the neuroimaging laboratory at the Mary S. Easton Center for Alzheimer’s Disease Research at UCLA, confirmed that the newly agreed-upon method for measuring hippocampal atrophy in structural MRI tests correlates with the pathologic changes that are known to be hallmarks of the disease — the progressive development of amyloid plaques and neurofibrillary tangles in the brain.

“This hippocampal protocol will now become the gold standard in the field, adopted by many if not all research groups across the globe in their study of Alzheimer’s disease,” said Apostolova, who was invited to play a key role in the consortium because of her reputation as one of the world’s leading experts in hippocampal structural anatomy and atrophy. “It will serve as a powerful tool in clinical trials for measuring the efficacy of new drugs in slowing or halting disease progression.”

The brain is the least accessible and most challenging organ to study in the human body; as a result, Alzheimer’s disease can be diagnosed definitively only by examining brain tissue after death. In living patients, physicians diagnose Alzheimer’s by evaluating other health factors, known as biomarkers, in combination with memory loss and other cognitive symptoms.

The hippocampus is a small region of the brain that is associated with memory formation, and memory loss is the earliest clinical feature of Alzheimer’s disease. Its shrinkage or atrophy, as determined by a structural MRI exam, is a well-established biomarker for the disease and is commonly used in both clinical and research settings to diagnose the disease and monitor its progression.

But until now, the effectiveness of structural MRI has been limited because of the widely different approaches being used to identify the hippocampus and measure its volume — which has called into question the validity of this approach. A typical hippocampus is about 3,000 to 4,000 cubic millimeters in volume. But, Apostolova notes, two scientists analyzing the same structure can come up with a difference of as much as 2,000 cubic millimeters.

In addition, no previous study had verified whether estimates for the volume of the hippocampus using MRI corresponded to actual tissue loss.

To address these deficiencies, the European Alzheimer’s Disease Consortium–Alzheimer’s Disease Neuroimaging Initiative was established to develop a Harmonized Protocol for Hippocampal Segmentation, or HarP — an effort to establish a definitive method for measuring hippocampal shrinkage through structural MRI in a way that best corresponds to the Alzheimer’s disease process.

Once the HarP was established, Apostolova and four other experts were invited to develop the gold standard for measuring the hippocampus to be used by anyone employing the HarP protocol. The UCLA-led team then validated the technique and ensured the changes in the hippocampus corresponded to the hallmark pathologic changes associated with Alzheimer’s disease.

“The technique is meant to be used on scans of living human subjects, so it’s important that we are absolutely certain that this methodology measures what it is supposed to and captures disease presence accurately,” Apostolova said.

To do that, her group used a powerful 7 Tesla MRI scanner to take images of the brain specimens of 16 deceased individuals — nine who had Alzheimer’s disease and seven who were cognitively normal — each for 60 hours. This provided unprecedented visualization of the hippocampal tissue, Apostolova said.

After applying the protocol to measure the hippocampal structures, the researchers analyzed the tissues for two changes that signify the disease: a buildup of amyloid tau protein and loss of neurons. The team found a significant correlation between hippocampal volume and the Alzheimer’s disease indicators.

“As a result of the years of scientifically rigorous work of this consortium, hippocampal atrophy can finally be reliably and reproducibly established from structural MRI scans,” Apostolova said.

Although the technique can be used immediately in research settings such as clinical trials, the next step, Apostolova noted, will be to use the standardized protocol to validate automated techniques available for measuring the hippocampus so the approach could be used more widely — including for the diagnosis of the disease in doctor’s offices and other patient care settings.

Funding for the study was provided by the National Institute on Aging (P50 AG16570), the Jim Easton Consortium for Alzheimer’s Drug Discovery and Biomarker Development, the National Institutes of Health (R01 AG040770), and the Alzheimer’s Association (IIRG 10-174022). Please see the paper for a complete list of the study’s authors.

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Control switch for unfolded protein response may be key to multiple diseases


Discovery opens new drug development avenues for treating variety of diseases.

By Bonnie Ward, UC San Diego

Researchers at the UC San Diego School of Medicine have discovered a control switch for the unfolded protein response (UPR), a cellular stress relief mechanism drawing major scientific interest because of its role in cancer, diabetes, inflammatory disorders and several neural degenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS), otherwise known as Lou Gehrig’s disease.

The normal function of the UPR pathway is to protect cells from stress but it can also trigger their death if the stress is not resolved. The researchers’ discovery of a control switch that acts on the UPR pathway, published today (March 25) in the online edition of EMBO Reports, opens new drug development avenues for treating a wide variety of diseases by modulating the UPR pathway to prevent excessive cell death.

“Our paper reports that two highly conserved pathways – the UPR and the nonsense-mediated RNA decay pathway – intersect with each other at a pivotal point in cell stress,” said Miles Wilkinson, Ph.D., senior author and professor in the Department of Reproductive Medicine and a member of the UC San Diego Institute for Genomic Medicine. “In essence, we’ve shown that the nonsense-mediated RNA decay pathway, typically referred to as ‘NMD,’ keeps the UPR in check to avoid the potentially dangerous consequences if the UPR pathway were allowed to mount an inadvertent response to innocuous stress.”

In cells, like people, too much stress can cause bad things to happen. In the case of cells, one such bad consequence is the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER), the cell’s protein-making factory. To carry out their many biological functions, proteins must be precisely folded in the correct shape. The body’s answer to excessive cell stress and accompanying misshapen proteins is the unfolded protein response. The UPR kicks in and restores normal ER-folding capacity by adjusting certain cellular processes. If this fails, the UPR instructs the cell to self-destruct, a process known as programmed cell death or apoptosis.

Wilkinson describes the UPR pathway as a double-edged sword. “In a large number of diseases, ranging from cancer to ALS, major stress occurs in the affected cells, leading the UPR pathway to be triggered,” he said. “And that’s meant to be helpful. But if the stress isn’t relieved in a timely fashion, it triggers cell death.  A limited amount of cell death is normal, but if too many cells die, especially critical cells, then it’s a problem. Chronic UPR activation and excessive cell death has been implicated in brain disorders like Alzheimer’s and Parkinson’s disease.”

In their study, Wilkinson, with first author Rachid Karam, Ph.D., and colleagues found that the NMD pathway plays a critical role in shaping the activities of UPR. Specifically, they discovered that NMD prevents inappropriate activation of the UPR and also promotes its timely termination to protect cells from prolonged ER stress.

“Because of the important role of UPR in regulating cell life/death decisions, it is critical that mechanisms are in place to prevent unnecessary UPR activation in response to innocuous or low-level stimuli,” said Wilkinson. “In this report we demonstrate that the NMD pathway serves in this capacity by raising the threshold for triggering UPR and also promoting its shut off at the appropriate time.”

He added that NMD doesn’t deter the UPR if an important stress comes along where more action is needed.

“Although NMD normally represses the UPR, our paper and previous work have shown that it gets out of the way if there’s a real problem,” Wilkinson noted.

Previous studies from the Wilkinson group and others have established that NMD has two broad roles. First, it is a quality control mechanism used by cells to eliminate faulty messenger RNA (mRNA) – molecules that are essential for transcribing genetic information into the construction of proteins critical for life. Second, NMD degrades a specific group of normal mRNAs.

The latest study shows that NMD suppresses inappropriate UPR activities by driving the rapid decay of several normal mRNAs encoding proteins critical for the UPR.

“We demonstrate that NMD directly targets the mRNAs encoding several UPR components, including the highly conserved UPR sensor, IRE1-alpha, whose NMD-dependent degradation partly underpins this process,” said Wilkinson.  “Our work not only sheds light on UPR regulation, but demonstrates the physiological relevance of NMD’s ability to regulate normal mRNAs.”

Co-authors include Chih-Hong Lou, Heike Kroeger, Jonathan H. Lin, all at UC San Diego; Lulu Huang, formerly of UC San Diego and now at ISIS Pharmaceuticals.

Funding for this research came, in part, from NIH grant (RO1 GM111838).

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UCSF team finds key to making neurors from stem cells


Pnky, noncoding RNA found in brain stem cells, may have range of clinical applications.

In this cluster of neurons, the greens cells have been infected with a virus to reduce levels of the RNA molecule called Pnky, resulting in increased production of neurons. Someday this finding could be important for regenerative medicine and cancer treatment.

By Steve Tokar

A research team at UC San Francisco has discovered an RNA molecule called Pnky that can be manipulated to increase the production of neurons from neural stem cells.

The research, led by neurosurgeon Daniel A. Lim, M.D., Ph.D., and published today (March 19) in Cell Stem Cell, has possible applications in regenerative medicine, including treatments of such disorders as Alzheimer’s disease, Parkinson’s disease and traumatic brain injury, and in cancer treatment.

Pnky is one of a number of newly discovered long noncoding RNAs (lncRNAs), which are stretches of 200 or more nucleotides in the human genome that do not code for proteins, yet seem to have a biological function.

The name, pronounced “Pinky,” was inspired by the popular American cartoon series Pinky and the Brain. “Pnky is encoded near a gene called ‘Brain,’ so it sort of suggested itself to the students in my laboratory,” said Lim. Pnky also appears only to be found in the brain, he noted.

Co-first authors Alex Ramos, Ph.D., and Rebecca Andersen, who are students in Lim’s laboratory, first studied Pnky in neural stem cells found in mouse brains, and also identified the molecule in neural stem cells of the developing human brain. They found that when Pnky was removed from stem cells in a process called knockdown, neuron production increased three to four times.

“It is remarkable that when you take Pnky away, the stem cells produce many more neurons,” said Lim, an assistant professor of neurological surgery and director of restorative surgery at UCSF. “These findings suggest that Pnky, and perhaps lncRNAs in general, could eventually have important applications in regenerative medicine and cancer treatment.”

Lim observed that Pnky has an intriguing possible connection with brain tumors.

Using an analytical technique called mass spectrometry, Ramos found that Pnky binds the protein PTBP1, which is also found in brain tumors and is known to be a driver of brain tumor growth. In neural stem cells, Pnky and PTBP1 appear to function together to suppress the production of neurons. “Take away one or the other and the stem cells differentiate, making more neurons,” said Lim. “It is also possible that Pnky can regulate brain tumor growth, which means we may have identified a target for the treatment of brain tumors.”

Lim said that the larger significance of the research is that it adds to a growing store of knowledge about lncRNAs, previously unknown sections of the genome that some biologists have referred to as the “dark matter” of the human genome.

“Recently, over 50,000 human lncRNAs have been discovered. Thus, there may be more human lncRNAs than there are genes that code for proteins,” said Lim. “It is possible that not all lncRNAs have important biological functions, but we are making a start toward learning which ones do, and if so, how they function. It’s a new world of experimental biology, and the students in my lab are right there on the frontier.”

Lim had particular praise for Ramos, an M.D.-Ph.D. student in the UCSF Medical Scientist Training Program, and Andersen, who has a fellowship from the prestigious National Science Foundation (NSF) Graduate Research Fellowship Program. “They have been a great collaborative team and an inspiration to others in my lab,” said Lim. “I think they represent the pioneering, investigative spirit of the UCSF student body.”

Co-authors of the study are Siyuan John Liu, Tomasz Jan Nowakowski, Sung Jun Hong, Caitlin Gertz, Ryan D. Salinas, Hosniya Zarabi and Arnold Kriegstein, M.D., Ph.D., all of UCSF.

The study was supported by funds from the National Institutes of Health, U.S. Department of Veterans Affairs, NSF, UCSF, San Francisco State University and the Howard Hughes Medical Institute.

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Commentary: Study affirms varied factors contribute to cognitive decline


Editorial: ‘A call for new thoughts about what might influence brain aging.’

Charles DeCarli, UC Davis

By Phyllis Brown, UC Davis

A study published online today (March 16) in JAMA Neurology that finds associations between reduced hippocampal volume (HVa) and being male, but not the gene APOE ɛ4, suggests that there are multiple factors contributing to cognitive decline throughout adulthood, according to an accompanying commentary by UC Davis Alzheimer’s Disease Center Director Charles DeCarli.

The research, by Clifford R. Jack and colleagues at the Mayo Clinic and Foundation, compared age, sex and apolipoprotein E ɛ4 (APOE ɛ4) genotype effects on memory, brain structure and the amyloid brain plaques associated with Alzheimer’s disease, using positron emission tomography (PET) in 1,246 cognitively normal individuals between the ages of 30 and 95.

The study found:

  • Overall memory worsened from age 30 through the 90s.
  • HVa worsened gradually from age 30 to the mid-60s and more steeply after that with advancing age.
  • Median amyloid accumulation seen on PET scans was low until age 70 but increased after that.
  • Memory was worse in men than women overall, especially after 40.
  • The HVa was lower in men than women overall, especially after 60.
  • For both males and females, memory performance and HVa were not different by APOE ɛ4 carrier status at any age.

“If one ascribes religiously to the concept that a large proportion of cognitive differences with age are driven by incipient disease, then one might expect that memory performance — a cognitive ability that changes most dramatically with age and is common to Alzheimer’s disease — would follow increasing levels of associated cerebral amyloid and be strongly associated with hippocampal atrophy. In their article Jack et al present new information that challenges the notion that amyloid accumulation explains memory performance across the entire age range,” DeCarli says in his editorial.

“Importantly, this work does not only address the likely highly significant impact of cerebral amyloid accumulation on dementia risk, but also extends current knowledge relating to the impact of the aging process across the spectrum of ages 30 to 95 years to brain structure, amyloid accumulation and memory performance among cognitively normal individuals.”

DeCarli notes that “If one tenaciously holds to the notion that the insidious consequences of other diseases may be contributing to these earlier differences, vascular brain injury is an obvious candidate. Vascular risk factors, such as diabetes mellitus, are associated with subtle cognitive impairment among individuals aged 47 to 57 years and hypertension is associated with significantly greater cerebral atrophy among individuals 40 years on average.”

Other contributing factors include genetic influences, which include sex differences and the “major effects” of APOE ɛ4 genotype on amyloid retention beyond age 70 years.

“Understanding the basic biology of these early processes is likely to substantially inform us about ways in which we can maintain cognitive health and optimize resistance to late-life dementia. However, such work requires the necessary motivation found by seminal work, such as that of Jack et al, which tell us where and when to investigate these processes. Establishing what is normal creates avenues for new research, increasing the likelihood of discovering novel therapeutics for late-life disease states, which is a laudable goal indeed,” DeCarli says.

For more information, visit alzheimer.ucdavis.edu.

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Boosting a natural protection against Alzheimer’s


Combining investigational therapy with gene variant may reduce dangers from brain plaques.

By Christina Johnson and Scott LaFee, UC San Diego

Researchers at the UC San Diego School of Medicine have identified a gene variant that may be used to predict people most likely to respond to an investigational therapy under development for Alzheimer’s disease (AD). The study, published today (March 12) in Cell Stem Cell, is based on experiments with cultured neurons derived from adult stem cells.

“Our results suggest that certain gene variants allow us to reduce the amount of beta amyloid produced by neurons,” said senior author Lawrence Goldstein, Ph.D., director of UC San Diego Sanford Stem Cell Clinical Center and UC San Diego Stem Cell Program. “This is potentially significant for slowing the progression of Alzheimer’s disease.” AD is the most common cause of dementia in the United States, afflicting one in nine people age 65 and older.

The genetic risk factor investigated are variants of the SORL1 gene. The gene codes for a protein that affects the processing and subsequent accumulation of beta amyloid peptides, small bits of sticky protein that build up in the spaces between neurons. These plaques are linked to neuronal death and related dementia.

Previous studies have shown that certain variants of the SORL1 gene confer some protection from AD, while other variants are associated with about a 30 percent higher likelihood of developing the disease. Approximately one-third of the U.S. adult population is believed to carry the non-protective gene variants.

The study’s primary finding is that variants in the SORL1 gene may also be associated with how neurons respond to a natural compound in the brain that normally acts to protect nerve cell health. The protective compound, called BDNF, short for brain-derived neurotrophic factor, is currently being investigated as a potential therapy for a number of neurological diseases, including AD, because of its role in promoting neuronal survival.

For the study, UC San Diego researchers took skin cells from 13 people, seven of whom had AD and six of whom were healthy control subjects, and reprogrammed the skin cells into stem cells. These stem cells were coaxed to differentiate into neurons, and the neurons were cultured and then treated with BDNF.

The experiments revealed that neurons that carried disease-protective SORL1 variants responded to the therapy by reducing their baseline rate of beta amyloid peptide production by, on average, 20 percent. In contrast, the neurons carrying the risk variants of the gene, showed no change in baseline beta amyloid production.

“BDNF is found in everyone’s brain,” said first author Jessica Young, Ph.D., a postdoctoral fellow in the Goldstein laboratory. “What we found is that if you add more BDNF to neurons that carry a genetic risk factor for the disease, the neurons don’t respond. Those with the protective genetic profile do.”

“The value of this kind of stem cell study is that it lets us probe the uniquely human aspects of disease and identify how a person’s DNA might determine their drug response, in this case to a potential treatment for Alzheimer’s,” Young said. “Future clinical trials on BDNF should consider stratifying patients based on their SORL1 risk factor and likelihood of benefiting from the therapy.”

Co-authors include Jonathan Boulanger-Weill, Daniel A. Williams, Grace Woodruff, Floyd Buen, Arra C. Revilla, Cheryl Herrera, Mason A. Israel, Shauna H. Yuan, and Steven D. Edland, all at UC San Diego.

Funding for the study was provided, in part, by the California Institute of Regenerative Medicine, A.P. Gianinni Foundation for Medical Research, BrightFocus Foundation and the National Institutes of Health (grant 2P50AG005131-31).

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Study shows feasibility of blood-based test for diagnosing Alzheimer’s


An effective blood test would be safe, affordable and easy to administer.

Liana Apostolova, UCLA

By Mark Wheeler, UCLA

UCLA researchers have provided the first evidence that a simple blood test could be developed to confirm the presence of beta amyloid proteins in the brain, which is a hallmark of Alzheimer’s disease.

Although approximately 5 million Americans are living with Alzheimer’s, no reliable blood-based test currently exists for the neurodegenerative disorder that is the sixth-leading cause of death in the United States. Using blood-based biomarkers — a signature of proteins in the blood that indicate the presence of a disease — to diagnose Alzheimer’s could be a key advance.

“Blood-based biomarkers would have the important advantage of being safe, affordable and easy to administer in large groups or in rural areas, and therefore could have an enormous impact on clinical care and clinical trials alike,” said Dr. Liana Apostolova, director of the neuroimaging laboratory at the Mary S. Easton Center for Alzheimer’s Disease Research at UCLA and head of the research team. Results of the study appeared in the journal Neurology.

Alzheimer’s disease can be diagnosed definitively only by examining brain tissue after death. While people are alive, physicians must rely on proxy measures, or biomarkers, along with cognitive symptoms such as memory loss.

Two current methods for determining the beta-amyloid formation characteristic of Alzheimer’s disease both have drawbacks. Cerebrospinal fluid can be obtained from patients, but that requires a spinal tap, an invasive procedure that carries the risk of nerve damage and other serious side effects. Another method, the amyloid PET scan, while effective, exposes subjects to radiation. The PET scan is also expensive and is not typically covered by insurance as a diagnostic test. Also, few medical centers have the technology.

For their study, the UCLA researchers developed a simple signature for predicting the presence of brain amyloidosis — the build-up of amyloid in the brain — including several blood proteins known to be associated with Alzheimer’s disease, along with information routinely obtained in the course of a clinical work-up for patients suspected to have the disease, such as results of memory testing and structural magnetic resonance imaging.

Using blood samples and other data from patients with mild cognitive impairment from the Alzheimer’s Disease Neuroimaging Initiative – a large public-private partnership that began in 2004 – the UCLA researchers found that their method could be used to predict the presence of amyloid in the brain with modest accuracy.

“Our study suggests that blood protein panels can be used to establish the presence of Alzheimer’s-type pathology of the brain in a safe and minimally invasive manner,” Apostolova said. “We need to further refine and improve on the power of this signature by introducing new disease-related metrics, but this indicates that such a test is feasible and could be on the market before long.”

Although there is no treatment that can halt or reverse the progression of Alzheimer’s disease, a non-invasive, inexpensive and reliable test for diagnosing the disease could spare people with dementia and their families the anxiety associated with uncertainty, direct them to support services earlier, and improve their likelihood of benefiting from current and future advances in treatment.

Such a test would also have a major impact on research. “With the advent of the amyloid PET scan we are learning that as many as 25-30 percent of subjects who enroll in Alzheimer’s disease clinical trials turn out not to have the disease,” said Apostolova. “That makes it difficult to measure the effects of the treatment being tested.”

Other authors of the study include Kristy Hwang, David Avila, Omid Kohannim, David Elashoff and Sophie Sokolow, all of UCLA; Edmond Teng from UCLA and Veterans Affairs Greater Los Angeles Healthcare System; Paul Thompson from the University of Southern California; Clifford Jack from the Mayo Clinic; William Jagust from the UC Berkeley; Leslie Shaw and Dr. John Trojanowski from the University of Pennsylvania School of Medicine; and Dr. Michael Weiner from the University of Pittsburgh and Department of Veterans Affairs Medical Center in San Francisco.

There were multiple funders for the study including the UCLA Easton Consortium for Alzheimer’s Drug Discovery and Biomarker Development, the National Institute of Mental Health (U01 AG024904), and the Alzheimer’s Disease Neuroimaging Initiative. Please see paper for complete list.

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Tau-associated MAPT gene increases risk for Alzheimer’s


UC San Diego-led findings could improve dementia diagnosis and treatment.

Microscopic image depicting plaques and tangles characteristic of Alzheimer’s disease. (Image courtesy of Tom Deerinck, UC San Diego)

By Scott LaFee, UC San Diego

An international team of scientists, led by researchers at the UC San Diego School of Medicine, has identified the microtubule-associated protein tau (MAPT) gene as increasing the risk for developing Alzheimer’s disease (AD). The MAPT gene encodes the tau protein, which is involved with a number of neurodegenerative disorders, including Parkinson’s disease (PD) and AD. These findings provide novel insight into Alzheimer’s neurodegeneration, possibly opening the door for improved clinical diagnosis and treatment.

The findings are published in the Feb. 18 online issue of Molecular Psychiatry.

Alzheimer’s disease, which afflicts an estimated 5 million Americans, is typically characterized by progressive decline in cognitive skills, such as memory and language and behavioral changes. While some recent AD genome-wide association studies (GWAS), which search the entire human genome for small variations, have suggested that MAPT is associated with increased risk for AD, other studies have found no association. In comparison, a number of studies have found a strong association between MAPT and other neurodegenerative disorders, such as PD.

“Though a tremendous amount of work has been conducted showing the involvement of the tau protein in Alzheimer’s disease, the role of the tau-associated MAPT gene is still unclear,” said Rahul S. Desikan, M.D., Ph.D., research fellow and radiology resident at the UC San Diego School of Medicine and the study’s first author.

In the new Molecular Psychiatry paper, conducted with collaborators across the country and world, Desikan and colleagues narrowed their search. Rather than looking at all possible loci (specific gene locations), the authors only focused on loci associated with PD and assessed whether these loci were also associated with AD, thus increasing their statistical power for AD gene discovery.

By using this approach, they found that carriers of the deleterious MAPT allele (an alternative form of the gene) are at increased risk for developing AD and more likely to experience increased brain atrophy than non-carriers.

“This study demonstrates that tau deposits in the brains of Alzheimer’s disease subjects are not just a consequence of the disease, but actually contribute to development and progression of the disease,” said Gerard Schellenberg, Ph.D., professor of pathology and laboratory medicine at the University of Pennsylvania, principal investigator of the Alzheimer’s Disease Genetics Consortium and a study co-author.

“An important aspect was the collaborative nature of this work. Thanks to our collaborators from the Consortium, the International Parkinson’s Disease Genetics Consortium, the Genetic and Environmental Risk in Alzheimer’s Disease, the Cohorts for Heart and Aging Research in Genomic Epidemiology, deCODE Genetics and the DemGene cohort, we had tremendous access to a large number of Alzheimer’s and Parkinson’s genetic datasets that we could use to identify and replicate our MAPT finding,” said Ole A. Andreassen, M.D., Ph.D., professor of biological psychiatry at the University of Oslo and a senior co-author.

Sudha Seshadri, M.D., professor of neurology at the Boston University School of Medicine, the principal investigator of the Neurology Working Group within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and a study co-author added: “Although it has been known since Alois Alzheimer’s time that both plaques (with amyloid) and tangles (of tau) are key features of Alzheimer pathology, attempts to prevent or slow down clinical disease progression have focused on the amyloid pathway. Until this year no one had convincingly shown that the MAPT (tau) gene altered the risk of AD and this, combined with the greater ease of imaging amyloid in life, lead some researchers to postulate that tau changes were secondary to amyloid changes. The recent association of genetic variation in the MAPT gene with AD risk and the emerging availability of tau imaging are now leading to a recognition that perhaps tau changes are key in the pathophysiologic pathway of AD and this pathway should be more intensively targeted.”

These findings underscore the importance of using a multimodal and multidisciplinary approach to evaluating Alzheimer’s neurodegeneration.

“These findings suggest that the combination of genetic, molecular and neuroimaging measures may be additionally helpful for detecting and quantifying the biochemical effects of therapeutic interventions,” said Anders M. Dale, Ph.D., professor of neurosciences and radiology and director of the Center for Translational Imaging and Precision Medicine at UC San Diego and the study’s senior author.

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UC experts urge Congress to fund brain research


UCSF’s Bruce Miller, UC Davis’ Cameron Carter, UCLA’s Christopher Giza speak at briefing.

(From left) UC Davis' Cameron Carter, UCLA's Christopher Giza and UCSF's Bruce Miller spoke at a Jan. 29 Capitol Hill briefing discussing the current state of brain research. (Photo by Bara Vaida)

By Bara Vaida

The funding support provided by the National Institutes of Health remains crucial to finding treatments for neurodegenerative diseases, UC San Francisco’s Bruce Miller, M.D., told U.S. congressional staff last week on Capitol Hill.

The NIH’s research grants to the Department of Neurology at the UCSF School of Medicine have resulted in tremendous strides in understanding how neurodegenerative diseases, like Alzheimer’s, Parkinson’s and frontotemporal dementias develop, according to Miller, director of the UCSF Memory and Aging Center. With that understanding is the potential for treating and preventing those diseases, he added.

“The work you do here is unbelievably important to our mission,” Miller said during the Jan. 29 congressional briefing, attended by about three dozen people who work for members of Congress. The staff were invited by the University of California to learn about the latest on brain research.

NIH funding had helped foster understanding and treatment of schizophrenia, said Cameron Carter, M.D., director of UC Davis’s Center for Neuroscience and the Imaging Research Center. Christopher Giza, M.D., director of UCLA’s Steve Tisch BrainSPORT program, also spoke at the briefing. He underscored how federal research money was used to better understand and treat brain injuries.

All three physicians emphasized the need for more public money to be invested in brain disease research.

“While other diseases are declining, like heart disease, cancer and stroke, Alzheimer’s is not. We think its going to double in prevalence,” Miller told congressional staff. “The NIH is spending about $500 million a year on Alzheimer’s research. Our mantra is, this year, spend $1 billion.”

A growing risk of brain disease

Alzheimer’s is one of the most costly diseases in the U.S. – $109 billion to $240 billion a year in medical and caregiver costs, according to Rand Corp. It is also the sixth leading cause of death. About 5 million people currently live with Alzheimer’s and 500,000 of them live in California.

Miller went on to describe how NIH funding had helped scientists understand which proteins caused different types of dementias, and how those proteins aggregate and destroy brain cells. With NIH money, scientists developed molecular imaging technology that now enable researchers to see proteins accumulating in the brain before symptoms develop, offering an opportunity to potentially prevent dementia from developing.

“I am proud to say, that with NIH funding, we are starting to treat pre-symptomatic” dementia, Miller said. “Those imaging costs are huge – $3,000 to $5,000 per patient– so there are very few places in the U.S. that can do that.”

Earlier in the day, all three physicians held private discussions with staff members working for California lawmakers, including Democratic House Minority Leader Nancy Pelosi and Reps. Doris Matsui and Ted Lieu.

“I was really struck by how helpful our legislators are,” Miller said. “We reach out to them, and they reach back out to us.”

Miller provided the briefing to staff as Congress begins considering the budget for 2016, which begins on Oct. 1, 2015. The NIH’s annual budget was about $30 billion in 2015. President Barack Obama proposed increasing the NIH budget to $31.3 billion in 2016.

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Lost memories might be able to be restored


UCLA research reveals that memories may not be stored in synapses, as previously thought.

UCLA's David Glanzman with a marine snail. (Photo by Christelle Nahas, UCLA)

By Stuart Wolpert, UCLA

New UCLA research indicates that lost memories can be restored. The findings offer some hope for patients in the early stages of Alzheimer’s disease.

For decades, most neuroscientists have believed that memories are stored at the synapses — the connections between brain cells, or neurons — which are destroyed by Alzheimer’s disease. The new study provides evidence contradicting the idea that long-term memory is stored at synapses.

“Long-term memory is not stored at the synapse,” said David Glanzman, a senior author of the study, and a UCLA professor of integrative biology and physiology and of neurobiology. “That’s a radical idea, but that’s where the evidence leads. The nervous system appears to be able to regenerate lost synaptic connections. If you can restore the synaptic connections, the memory will come back. It won’t be easy, but I believe it’s possible.”

The findings were published recently in eLife, a highly regarded open-access online science journal.

Glanzman’s research team studies a type of marine snail called Aplysia to understand the animal’s learning and memory. The Aplysia displays a defensive response to protect its gill from potential harm, and the researchers are especially interested in its withdrawal reflex and the sensory and motor neurons that produce it.

They enhanced the snail’s withdrawal reflex by giving it several mild electrical shocks on its tail. The enhancement lasts for days after a series of electrical shocks, which indicates the snail’s long-term memory. Glanzman explained that the shock causes the hormone serotonin to be released in the snail’s central nervous system.

Long-term memory is a function of the growth of new synaptic connections caused by the serotonin, said Glanzman, a member of UCLA’s Brain Research Institute. As long-term memories are formed, the brain creates new proteins that are involved in making new synapses. If that process is disrupted — for example by a concussion or other injury — the proteins may not be synthesized and long-term memories cannot form.  (This is why people cannot remember what happened moments before a concussion.)

“If you train an animal on a task, inhibit its ability to produce proteins immediately after training, and then test it 24 hours later, the animal doesn’t remember the training,” Glanzman said.  “However, if you train an animal, wait 24 hours, and then inject a protein synthesis inhibitor in its brain, the animal shows perfectly good memory 24 hours later.  In other words, once memories are formed, if you temporarily disrupt protein synthesis, it doesn’t affect long-term memory. That’s true in the Aplysia and in human’s brains.”  (This explains why people’s older memories typically survive following a concussion.)

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