1. Study suggests declining sense of smell may help identify patients with mild cognitive impairment

    November 21, 2017 by Ashley

    From the Columbia University Medical Center press release:

    Researchers at Columbia University Medical Center (CUMC) and the New York State Psychiatric Institute (NYSPI) may have discovered a way to use a patient’s sense of smell to treat Alzheimer’s disease before it ever develops. Having an impaired sense of smell is recognized as one of the early signs of cognitive decline, before the clinical onset of Alzheimer’s disease. The researchers at CUMC and NYSPI have found a way to use that effect to determine if patients with mild cognitive impairment may respond to cholinesterase inhibitor drugs to treat Alzheimer’s disease.

    The findings were published online this week in the Journal of Alzheimer’s Disease.

    Cholinesterase inhibitors, such as donepezil, enhance cholinergic function by increasing the transmission of the neurotransmitter acetylcholine in the brain. Cholinergic function is impaired in individuals with Alzheimer’s disease. Cholinesterase inhibitors, which block an enzyme that breaks down acetylcholine, have shown some effectiveness in improving the cognitive symptoms of Alzheimer’s disease. However, they have not been proven effective as a treatment for individuals with mild cognitive impairment (MCI), a condition that markedly increases the risk of Alzheimer’s disease.

    “We know that cholinesterase inhibitors can make a difference for Alzheimer’s patients, so we wanted to find out if we could identify patients at risk for Alzheimer’s who might also benefit from this treatment,” said D.P. Devanand, MBBS, MD, professor of psychiatry, scientist in the Gertrude H. Sergievsky Center at CUMC, and co-director of the Memory Disorders Clinic and the Late Life Depression Clinic at NYSPI. “Since odor identification tests have been shown to predict progression to Alzheimer’s, we hypothesized that these tests would also allow us to discover which patients with MCI would be more likely to improve with donepezil treatment.”

    In this year-long study, 37 participants with MCI underwent odor identification testing with the University of Pennsylvania Smell Identification Test (UPSIT). The test was administered before and after using an atropine nasal spray that blocks cholinergic transmission.

    The patients were then treated with donepezil for 52 weeks, and were periodically reevaluated with the UPSIT and with memory and cognitive function tests. Those who had a greater decline in UPSIT scores, indicating greater cholinergic deficits in the brain, after using the anticholinergic nasal spray test saw greater cognitive improvement with donepezil.

    In addition, short-term improvement in odor identification from baseline to eight weeks tended to predict longer-term cognitive improvement with donepezil treatment over one year.

    “These results, particularly if replicated in larger populations, suggest that these simple inexpensive strategies have the potential to improve the selection of patients with mild cognitive impairment who are likely to benefit from treatment with cholinesterase inhibitors like donepezil,” said Dr. Devanand.


  2. Study examines prevalence of Subjective Cognitive Decline (SCD)

    November 20, 2017 by Ashley

    From the IOS Press press release:

    A memory complaint, also called Subjective Cognitive Decline (SCD), is a subjective disorder that appears to be relatively common, especially in elderly persons. The reports of its prevalence in various populations range from approximately 10% to as high as 88%, although it is generally thought that the prevalence of everyday memory problems lie within the range of 25% to 50%. It has been suggested that SCD may be an indication of cognitive decline at a very early stage of a neurodegenerative disease (i.e. preclinical stage of Alzheimer’s disease) that is undetectable by standard testing instruments. SCD may represent the first symptomatic manifestation of Alzheimer’s disease in individuals with unimpaired performance on cognitive tests.

    The McNair and Kahn Scale or Cognitive Difficulties Scale was employed to define and characterize cognitive complaints in the GuidAge study, involving a population of more than 2800 individuals aged 70 years or older having voluntarily complained of memory problems to their general practitioner (GPs). It contains items that are related to difficulties in attention, concentration, orientation, memory, praxis, domestic activities and errands, facial recognition, task efficiency, and name finding.

    The results of the GuidAge study suggest that the assessment of cognitive complaint voluntarily reported to primary-care physicians, by the McNair and Kahn scale can predict a decline in cognitive performance, as 5 items out of 20 were statistically significant.

    These 5 items are:

    • item 1, “I hardly remember usual phone numbers”,
    • item 5, “I forget appointment, dates, where I store things”,
    • item 6, “I forget to call people back when they called me”,
    • item 10, “I forget the day of the week”,
    • item 13, “I need to have people repeat instructions several times.”

    Thanks to this short scale GPs, in clinical practice, can identify which patients with memory complaints should be referred to a memory center to assess cognitive functions.


  3. Study suggests biomarker may predict early Alzheimer’s disease

    by Ashley

    From the Sanford-Burnham Prebys Medical Discovery Institute press release:

    Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a peptide that could lead to the early detection of Alzheimer’s disease (AD). The discovery, published in Nature Communications, may also provide a means of homing drugs to diseased areas of the brain to treat AD, Parkinson’s disease, as well as glioblastoma, brain injuries and stroke.

    “Our goal was to find a new biomarker for AD,” says Aman Mann, Ph.D., research assistant professor at SBP who shares the lead authorship of the study with Pablo Scodeller, Ph.D., a postdoctoral researcher at SBP. “We have identified a peptide (DAG) that recognizes a protein that is elevated in the brain blood vessels of AD mice and human patients. The DAG target, connective tissue growth factor (CTGF) appears in the AD brain before amyloid plaques, the pathological hallmark of AD.”

    “CTGF is a protein that is made in the brain in response to inflammation and tissue repair,” explains Mann. “Our finding that connects elevated levels of CTGF with AD is consistent with the growing body of evidence suggesting that inflammation plays an important role in the development of AD.”

    The research team identified the DAG peptide using in vivo phage display screening at different stages of AD development in a mouse model. In young AD mice, DAG detected the earliest stage of the disease. If the early appearance of the DAG target holds true in humans, it would mean that DAG could be used as a tool to identify patients at early, pre-symptomatic stages of the disease when treatments already available may still be effective.

    “Importantly, we showed that DAG binds to cells and brain from AD human patients in a CTGF-dependent manner” says Mann. “This is consistent with an earlier report of high CTGF expression in the brains of AD patients.”

    “Our findings show that endothelial cells, the cells that form the inner lining of blood vessels, bind our DAG peptide in the parts of the mouse brain affected by the disease,” says Erkki Ruoslahti, M.D., Ph.D., distinguished professor at SBP and senior author of the paper. “This is very significant because the endothelial cells are readily accessible for probes injected into the blood stream, whereas other types of cells in the brain are behind a protective wall called the blood-brain barrier. The change in AD blood vessels gives us an opportunity to create a diagnostic method that can detect AD at the earliest stage possible.

    “But first we need to develop an imaging platform for the technology, using MRI or PET scans to differentiate live AD mice from normal mice. Once that’s done successfully, we can focus on humans,” adds Ruoslahti.

    “As our research progresses we also foresee CTGF as a potential therapeutic target that is unrelated to amyloid beta (Aß), the toxic protein that creates brain plaques,” says Ruoslahti. “Given the number of failed clinical studies that have sought to treat AD patients by targeting Aß, it’s clear that treatments will need to be given earlier — before amyloid plaques appear — or have to target entirely different pathways.

    DAG has the potential to fill both roles — identifying at risk individuals prior to overt signs of AD and targeted delivery of drugs to diseased areas of the brain. Perhaps CTGF itself can be a drug target in AD and other brain disorders linked to inflammation. We’ll just have to learn more about its role in these diseases.”


  4. Study suggests sleep apnea may increase risk of developing Alzheimer’s disease

    November 19, 2017 by Ashley

    From the American Thoracic Society press release:

    Obstructive sleep apnea (OSA) may put elderly people at greater risk of developing Alzheimer’s disease (AD), according to new research published online in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

    In “Obstructive Sleep Apnea Severity Affects Amyloid Burden in Cognitively Normal Elderly: A Longitudinal Study,” researchers report that biomarkers for amyloid beta (Aß), the plaque-building peptides associated with Alzheimer’s disease, increase over time in elderly adults with OSA in proportion to OSA severity. Thus, individuals with more apneas per hour had greater accumulation of brain amyloid over time.

    According to the authors, AD is a neurodegenerative disorder that afflicts approximately five million older Americans. OSA is even more common, afflicting from 30 to 80 percent of the elderly, depending on how OSA is defined.

    “Several studies have suggested that sleep disturbances might contribute to amyloid deposits and accelerate cognitive decline in those at risk for AD,” said Ricardo S. Osorio, MD, senior study author and assistant professor of psychiatry at New York University School of Medicine.

    “However, so far it has been challenging to verify causality for these associations because OSA and AD share risk factors and commonly coexist.”

    He added that the purpose of this study was to investigate the associations between OSA severity and changes in AD biomarkers longitudinally, specifically whether amyloid deposits increase over time in healthy elderly participants with OSA.

    The study included 208 participants, age 55 to 90, with normal cognition as measured by standardized tests and clinical evaluations. None of the participants was referred by a sleep center, used continuous positive airway pressure (CPAP) to treat sleep apnea, was depressed, or had a medical condition that might affect their brain function. The researchers performed lumbar punctures (LPs) to obtain participants’ cerebrospinal fluid (CSF) soluble Aß levels, and then used positron emission tomography, or PET, to measure Aß deposits directly in the brain in a subset of participants.

    The study found that more than half the participants had OSA, including 36.5 percent with mild OSA and 16.8 percent with moderate to severe OSA. From the total study sample, 104 participated in a two-year longitudinal study that found a correlation between OSA severity and a decrease in CSF Aß42 levels over time. The authors said this finding is compatible with an increase in amyloid deposits in the brain; the finding was confirmed in the subset of participants who underwent amyloid PET, which showed an increase in amyloid burden in those with OSA.

    Surprisingly, the study did not find that OSA severity predicted cognitive deterioration in these healthy elderly adults. Andrew Varga, MD, PhD, study coauthor and a physician specializing in sleep medicine and neurology at the Icahn School of Medicine at Mount Sinai in New York, said this finding suggests that these changes were occurring in the preclinical stages of AD.

    “The relationship between amyloid burden and cognition is probably nonlinear and dependent on additional factors,” he added. This study finding may also be attributable to the study’s relatively short duration, highly educated participants and use of tests that fail to discern changes in cognitive abilities that are subtle or sleep-dependent, the authors wrote.

    The high prevalence of OSA the study found in these cognitively normal elderly participants and the link between OSA and amyloid burden in these very early stages of AD pathology, the researchers believe, suggest the CPAP, dental appliances, positional therapy and other treatments for sleep apnea could delay cognitive impairment and dementia in many older adults.

    “Results from this study, and the growing literature suggesting that OSA, cognitive decline and AD are related, may mean that age tips the known consequences of OSA from sleepiness, cardiovascular, and metabolic dysfunction to brain impairment,” Dr. Osorio said. “If this is the case, then the potential benefit of developing better screening tools to diagnose OSA in the elderly who are often asymptomatic is enormous.”


  5. Study investigates patterns of degeneration in Alzheimer’s disease

    November 18, 2017 by Ashley

    From the Brigham and Women’s Hospital press release:

    Alzheimer’s disease (AD) is known to cause memory loss and cognitive decline, but other functions of the brain can remain intact. The reasons cells in some brain regions degenerate while others are protected is largely unknown. In a paper to be published in Stem Cell Reports, researchers from Brigham and Women’s Hospital have found that factors encoded in the DNA of brain cells contribute to the patterns of degeneration, or vulnerability, in AD.

    AD is characterized by plaques composed of amyloid ?-protein (A?) and tangles composed of Tau protein; accumulation of A? protein leads to disruption of Tau and, eventually, neurodegeneration which affects brain regions in a variety of ways. The front, rostral, portion of the brain is generally more damaged by plaque build-up while the back, caudal, portion is generally spared.

    Though there are several mechanisms that could cause these differences, the team focused on the potential contributions of cell-autonomous factors among neuronal subtypes that could affect both the generation of and the responses to A?. In a novel application of human induced-pluripotent stem cell (iPSC) technology, the team generated powerful culture systems that represent different areas of the brain. The systems were developed by taking skin cells from patients with a familial Alzheimer’s disease mutation and turning these skin cells into stem cells. Stem cells divide to make more stem cells, providing an unlimited supply of cells. Stem cells also can be turned into any type of cell in the body, including brain cells. In this study, the authors showed that vulnerable brain cells made more toxic A? protein compared to brain cells from more protected regions of the brain.

    In addition, the researchers found that brain cells in the protected, caudal portion of the brain have a less toxic response to A? than their rostral counterparts. Though early-onset, familial Alzheimer’s disease (fAD) accounts for a small number of AD cases, the study of fAD patients, or samples in this case, can reveal important aspects of the cell and molecular mechanisms underlying all types of AD. The team is currently using this information to investigate exactly why caudal neurons are protected and what differences in cell type cause neurons to be protected from AD.

    “These findings illuminate our understanding of why some neurons are spared and why others are not spared in AD,” said Christina Muratore, PhD, of the Department of Neurology. “If we can find out more information about why these subtypes of cells are protected, we may be able to use this information to tailor therapies to protect the vulnerable cells.”


  6. Researchers identify new protective function for a brain protein genetically linked to Alzheimer’s

    November 16, 2017 by Ashley

    From the Sanford-Burnham Prebys Medical Discovery Institute press release:

    Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) have identified a new protective function for a brain protein genetically linked to Alzheimer’s. The findings, published in the Journal of Experimental Medicine, could inform novel treatment strategies.

    “We found that a protein called SORLA directly limits the ability of amyloid beta, the toxic protein that causes Alzheimer’s, to trigger the destruction of neuronal connections,” says Huaxi Xu, Ph.D., professor and the Jeanne and Gary Herberger Leadership Chair of SBP’s Neuroscience and Aging Research Center. (SORLA stands for sortilin-related receptor with LDLR class A repeats.) “This is actually the third way that SORLA has been shown to defend against neurodegeneration.”

    “It’s becoming increasingly clear that the SORLA gene has a major influence on Alzheimer’s development — more and more Alzheimer’s-associated mutations in the SORLA gene are being discovered,” Xu adds. “Our findings help explain why they are so important.”

    SORLA is one of many genes in which mutations are associated with increased risk of Alzheimer’s, which affects 5.5 million people in the U.S. The biggest risk factor is age — as the average life expectancy increases, the number of people with Alzheimer’s is expected to almost triple by 2050.

    Alzheimer’s begins when amyloid beta aggregates into small clusters outside neurons. Those clusters, called oligomers, induce toxic signaling that damages the connections between synapses so that neurons can no longer talk to one another. Synapse loss is the reason Alzheimer’s patients develop memory problems.

    Xu and his collaborators suspected that SORLA — a trafficking protein that shuttles molecules between cellular compartments — might help protect against amyloid beta induced toxic signaling based on their prior observations. SORLA has already been shown to counteract production of amyloid beta and eliminate it from the space around neurons.

    Xu’s team recently reported that SORLA physically interacts with EphA4, one of the receptors through which amyloid beta provokes synaptic dysfunction. (EphA4 exists primarily to control the wiring of neuronal networks as the brain develops and regulate the behavior of synapses in the adult brain.)

    In this study, Xu’s team established that SORLA could mitigate the toxic EphA4 signaling caused by amyloid beta. They also showed that increasing levels of SORLA in mice reduced cognitive impairments caused by amyloid beta.

    “These observations suggest that early-stage Alzheimer’s could be treated with drugs that increase levels of SORLA, or that enhance its interaction with EphA4,” comments Xu. “We’re currently searching for drugs that have either of these effects.

    “The researchers also found that EphA4 is over-activated in brain tissue from Alzheimer’s patients, and that over-activation correlates with decreased binding to SORLA, demonstrating the relevance of this discovery to human disease.

    “Our study also provides support to explore EphA4 inhibitors as Alzheimer’s therapeutics,” Xu notes. “There’s preclinical data from disease models suggesting they have some efficacy.”

    “SORLA is becoming a hot topic in Alzheimer’s research. No other protein has yet been found to influence Alzheimer’s pathogenesis in so many ways. And it may do even more — we plan to explore whether it modulates other cell surface amyloid beta receptors such as the cellular prion protein and the NMDA receptor.”

     


  7. Study suggests maintaining strong social networks linked to slower cognitive decline

    November 12, 2017 by Ashley

    From the Northwestern University press release:

    Maintaining positive, warm and trusting friendships might be the key to a slower decline in memory and cognitive functioning, according to a new Northwestern Medicine study.

    SuperAgers — who are 80 years of age and older who have cognitive ability at least as good as people in their 50s or 60s — reported having more satisfying, high-quality relationships compared to their cognitively average, same-age peers, the study reports.

    Previous SuperAger research at the Cognitive Neurology and Alzheimer’s Disease Center (CNADC) at Northwestern University Feinberg School of Medicine has focused on the biological differences in SuperAgers, such as discovering that the cortex in their brain is actually larger than their cognitively average, same-age peers. This study, published Oct. 23 in the journal PLOS ONE, was the first to examine the social side of SuperAgers.

    “You don’t have the be the life of the party, but this study supports the theory that maintaining strong social networks seems to be linked to slower cognitive decline,” said senior author Emily Rogalski, associate professor at Northwestern’s CNADC.

    Participants answered a 42-item questionnaire called the Ryff Psychological Well-Being Scale, which is a widely used measure of psychological well-being. The scale examines six aspects of psychological well-being: autonomy, positive relations with others, environmental mastery, personal growth, purpose in life and self-acceptance. SuperAgers scored a median overall score of 40 in positive relations with others while the control group scored 36 — a significant difference, Rogalski said.

    “This finding is particularly exciting as a step toward understanding what factors underlie the preservation of cognitive ability in advanced age, particularly those that may be modifiable,” said first author Amanda Cook, a clinical neuropsychology doctoral student in the laboratory of Rogalski and Sandra Weintraub.

    Other research studies have reported a decline in social networks in people with Alzheimer’s disease and Mild Cognitive Impairment (MCI), and previous literature has shown psychological well-being in older age to be associated with reduced risk of developing Alzheimer’s dementia.

    “It’s not as simple as saying if you have a strong social network, you’ll never get Alzheimer’s disease,” Rogalski said. “But if there is a list of healthy choices one can make, such as eating a certain diet and not smoking, maintaining strong social networks may be an important one on that list. None of these things by themself guarantees you don’t get the disease, but they may still have health benefits.


  8. Study suggests risk of oversharing in conversation increases with age

    November 10, 2017 by Ashley

    From the University of Edinburgh press release:

    The risk of oversharing in conversation — or providing a listener with too much irrelevant detail — increases as we age, research suggests.

    Tests carried out on a group of 100 people show the thinking skills that influence how we respond to people’s points of view deteriorate with age.

    Linguists used a series of computerised listening and visual tests to assess thinking skills in the group, whose ages ranged from 17 to 84 years old.

    The team tested how participants’ attention skills — the ability to concentrate on one thing and ignore another — influenced their ability to consider a partner’s perspective in conversation.

    The researchers, from The University of Edinburgh and Northwestern University in Illinois, completed two listening tests to assess two types of attention skills.

    Firstly, they tracked inhibition — the ability to focus and ignore distracting information.

    Then they monitored switching — the ability to shift focus between two different sounds and filter relevant information.

    Researchers asked participants to describe one of four objects to a partner who could only see three of the objects. The researchers found older participants were more likely to mention details about the hidden object, revealing irrelevant information to their partner.

    The team found an age-related decline in attention switching skills, and that this ability determined how older adults responded to their partner’s perspective.

    For younger adults, their ability to filter distracting information was what determined their ability to consider others’ perspectives more effectively.

    Lead researcher Madeleine Long, of the University of Edinburgh’s School of Philosophy, Psychology and Language Sciences, said: “The study identified two attentional functions that influence whether we consider another’s point of view and how that changes as we age. This is particularly important for older adults who are more susceptible to revealing private information.

    “We hope these findings can be used to design targeted training that helps older adults improve these skills and avoid embarrassing and potential risky communicative errors.”


  9. New research shows where in the brain the earliest signs of Alzheimer’s occur

    November 8, 2017 by Ashley

    From the Lund University press release:

    Researchers at Lund University in Sweden have for the first time convincingly shown where in the brain the earliest signs of Alzheimer’s occur. The discovery could potentially become significant to future Alzheimer’s research while contributing to improved diagnostics.

    In Alzheimer’s, the initial changes in the brain occur through retention of the protein, ?-amyloid (beta-amyloid). The process begins 10-20 years before the first symptoms become noticeable in the patient.

    In Nature Communications, a research team headed by Professor Oskar Hansson at Lund University has now presented results showing where in the brain the initial accumulation of ?-amyloid occurs. It is in the inner parts of the brain, within one of the brain’s most important functional networks — known as the default mode network.

    “A big piece of the puzzle in Alzheimer’s research is now falling into place. We previously did not know where in the brain the earliest stages of the disease could be detected. We now know which parts of the brain are to be studied to eventually explain why the disease occurs,” says Sebastian Palmqvist, associate professor at Lund University and physician at Skåne University Hospital.

    The default mode network is one of several networks, each of which has a different function in the brain. It is most active when we are in an awake quiescent state without interacting with the outside world, for example, when daydreaming. The network belongs to the more advanced part of the brain. Among other things, it processes and links information from lower systems.

    The study, conducted in collaboration with Michael Schöll, associate senior lecturer at the University of Gothenburg, and William Jagust, professor at the University of California, is based on data from more than 400 people in the United States who have an increased risk of developing Alzheimer’s, and about as many participants from the Swedish research project, BioFINDER. The brain status of all the participants was monitored for two years, and compared to a control group without any signs of Alzheimer’s.

    The difficulty of determining which individuals are at risk of developing dementia later in life, in order to subsequently monitor them in research studies, has been an obstacle in the research world. The research team at Lund University has therefore developed a unique method to identify, at an early stage, which individuals begin to accumulate ?-amyloid and are at risk.

    The method combines cerebrospinal fluid test results with PET scan brain imaging. This provides valuable information about the brain’s tendency to accumulate ?-amyloid.

    In addition to serving as a roadmap for future research studies of Alzheimer’s disease, the new results also have a clinical benefit:

    “Now that we know where Alzheimer’s disease begins, we can improve the diagnostics by focusing more clearly on these parts of the brain, for example in medical imaging examinations with a PET camera,” says Oskar Hansson, professor at Lund University, and medical consultant at Skåne University Hospital.

    Although the first symptoms of Alzheimer’s become noticeable to others much later, the current study shows that the brain’s communication activity changes in connection with the early retention of ?-amyloid. How, and with what consequences, will be examined by the research team in further studies.


  10. Inflammation in middle age may be tied to brain shrinkage decades later

    November 5, 2017 by Ashley

    From the American Academy of Neurology press release:

    People who have biomarkers tied to inflammation in their blood in their 40s and 50s may have more brain shrinkage decades later than people without the biomarkers, according to a study published in the November 1, 2017, online issue of Neurology®, the medical journal of the American Academy of Neurology. The brain cell loss was found especially in areas of the brain that are affected by Alzheimer’s disease.

    “These results suggest that inflammation in mid-life may be an early contributor to the brain changes that are associated with Alzheimer’s disease and other forms of dementia,” said study author Keenan Walker, PhD, of Johns Hopkins University School of Medicine in Baltimore, Md. “Because the processes that lead to brain cell loss begin decades before people start showing any symptoms, it is vital that we figure out how these processes that happen in middle age affect people many years later.”

    People with the inflammation markers and brain shrinkage also had lower scores on average on a memory test.

    For the study, researchers tested the levels of five markers of inflammation in the blood, including the white blood cell count, in 1,633 people with an average age of 53. An average of 24 years later, the participants took a memory test and had brain scans to measure the volume of several areas of the brain.

    The participants were divided into three groups based on how many elevated levels of inflammation they had among the five biomarkers.

    Compared to the people with no elevated levels, people with elevated levels on three or more biomarkers had on average 5 percent lower volume in the hippocampus and other areas of the brain associated with Alzheimer’s disease.

    Walker said that the effect of one standard deviation increase in the overall inflammation score in mid-life on brain volume decades later was similar to the effect associated with having one copy of the apolipoprotein E (APOE) e4 gene that increases the risk of Alzheimer’s disease.

    Every standard deviation increase in the inflammation score was also associated with a hippocampus volume that was 110 cubic millimeters smaller and the volume of other areas affected by Alzheimer’s disease was 532 cubic millimeters smaller.

    On the memory test, where people were asked to remember a list of 10 words, the people with no elevated markers remembered an average of about 5.5 words, while those with three or more elevated markers remembered an average of about five words.

    Limitations of the study include that the biomarkers were measured only once. Walker said it’s not clear whether a single measurement can adequately determine that people have chronic inflammation.