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  • richardmitnick 6:32 pm on December 17, 2017 Permalink | Reply
    Tags: , Dementia, Gas chromatography mass spectrometry, , The build-up of urea in the brain to toxic levels can cause brain damage – and eventually dementia,   

    From University of Manchester: “Major cause of dementia discovered” 

    U Manchester bloc

    University of Manchester

    12 December 2017
    Michael Addelman
    Media Relations Officer: Biology, Medicine, and Health
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    A montage of three images of single striatal neurons transfected with a disease-associated version of huntingtin, the protein that causes Huntington’s disease. Nuclei of untransfected neurons are seen in the background (blue). The neuron in the center (yellow) contains an abnormal intracellular accumulation of huntingtin called an inclusion body (orange). Credit: Wikipedia/ Creative Commons Attribution 3.0 Unported license. MedicalXpress.com

    An international team of scientists have confirmed the discovery of a major cause of dementia, with important implications for possible treatment and diagnosis.
    Professor Garth Cooper from The University of Manchester, who leads the Manchester team, says the build-up of urea in the brain to toxic levels can cause brain damage – and eventually dementia.
    The work follows on from Professor Cooper’s earlier studies, which identified metabolic linkages between Huntington’s, other neurodegenerative diseases and type-2 diabetes.
    The team consists of scientists from The University of Manchester, the University of Auckland, AgResearch New Zealand, the South Australian Research and Development Institute, Massachusetts General Hospital and Harvard University.

    The latest paper by the scientists, published today in the PNAS, shows that Huntington’s Disease – one of seven major types of age-related dementia – is directly linked to brain urea levels and metabolic processes.

    Their 2016 study revealing that urea is similarly linked to Alzheimer’s, shows, according to Professor Cooper, that the discovery could be relevant to all types of age-related dementias.

    The Huntington’s study also showed that the high urea levels occurred before dementia sets in, which could help doctors to one day diagnose and even treat dementia, well in advance of its onset.
    Urea and ammonia in the brain are metabolic breakdown products of protein. Urea is more commonly known as a compound which is excreted from the body in urine. If urea and ammonia build up in the body because the kidneys are unable to eliminate them, for example, serious symptoms can result.

    Professor Cooper, who is based at The University of Manchester’s Division of Cardiovascular Sciences, said: “This study on Huntington’s Disease is the final piece of the jigsaw which leads us to conclude that high brain urea plays a pivotal role in dementia.

    “Alzheimer’s and Huntington’s are at opposite ends of the dementia spectrum – so if this holds true for these types, then I believe it is highly likely it will hold true for all the major age-related dementias.

    “More research, however, is needed to discover the source of the elevated urea in HD, particularly concerning the potential involvement of ammonia and a systemic metabolic defect.
    “This could have profound implications for our fundamental understanding of the molecular basis of dementia, and its treatability, including the potential use of therapies already in use for disorders with systemic urea phenotypes.”

    Dementia results in a progressive and irreversible loss of nerve cells and brain functioning, causing loss of memory and cognitive impairments affecting the ability to learn. Currently, there is no cure. The team used human brains, donated by families for medical research, as well as transgenic sheep in Australia.

    Manchester members of the team used cutting-edge gas chromatography mass spectrometry to measure brain urea levels. For levels to be toxic urea must rise 4-fold or higher than in the normal brain says Professor Cooper.

    He added: “We already know Huntington’s Disease is an illness caused by a faulty gene in our DNA – but until now we didn’t understand how that causes brain damage – so we feel this is an important milestone.

    “Doctors already use medicines to tackle high levels of ammonia in other parts of the body Lactulose – a commonly used laxative, for example, traps ammonia in the gut. So it is conceivable that one day, a commonly used drug may be able to stop dementia from progressing. It might even be shown that treating this metabolic state in the brain may help in the regeneration of tissue, thus giving a tantalising hint that reversal of dementia may one day be possible.”

    Professor Cooper expresses his thanks to all the families of patients with Huntington’s disease in New Zealand who so generously supported this research through the donation of brain tissue to the Neurological Foundation of New Zealand Douglas Human Brain Bank in the Centre for Brain Research.

    This work was supported by the CHDI Foundation (A-8247) and Brain Research New Zealand.
    The paper ‘Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases’ is available on request
    Other Manchester-based scientists who made important contributions are Dr Stefano Patassini and Dr Jingshu Xu.

    Relevant papers include:
    Graded perturbations of metabolism in multiple regions of human brain in Alzheimer’s disease: Snapshot of a pervasive metabolic disorder. Biochimica et Biophysica Acta (2016)
    Identification of elevated urea as a severe, ubiquitous metabolic defect in the brain of patients with Huntington’s disease. Biochemical and Biophysical Research Communications (2015)
    Metabolite mapping reveals severe widespread perturbation of multiple metabolic processes in Huntington’s disease human brain. Biochimica et Biophysica Acta (2016)
    Elevation of brain glucose and polyol-pathway intermediates with accompanying brain-copper deficiency in patients with Alzheimer’s disease: metabolic basis for dementia. Scientific Reports (2016)
    Evidence for widespread, severe brain copper deficiency in Alzheimer’s dementia. Metallomics. (2017)
    Proteomic Analysis of the Human Brain in Huntington’s Disease Indicates Pathogenesis by Molecular Processes Linked to other Neurodegenerative Diseases and to Type-2 Diabetes. Journal of Huntington’s Disease (2013)
    Proteomic analysis of the brain in Alzheimer’s disease: Molecular Phenotype of a complex disease process. Proteomics (2001)

    See the full article here .

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    U Manchester campus

    The University of Manchester (UoM) is a public research university in the city of Manchester, England, formed in 2004 by the merger of the University of Manchester Institute of Science and Technology (renamed in 1966, est. 1956 as Manchester College of Science and Technology) which had its ultimate origins in the Mechanics’ Institute established in the city in 1824 and the Victoria University of Manchester founded by charter in 1904 after the dissolution of the federal Victoria University (which also had members in Leeds and Liverpool), but originating in Owens College, founded in Manchester in 1851. The University of Manchester is regarded as a red brick university, and was a product of the civic university movement of the late 19th century. It formed a constituent part of the federal Victoria University between 1880, when it received its royal charter, and 1903–1904, when it was dissolved.

    The University of Manchester is ranked 33rd in the world by QS World University Rankings 2015-16. In the 2015 Academic Ranking of World Universities, Manchester is ranked 41st in the world and 5th in the UK. In an employability ranking published by Emerging in 2015, where CEOs and chairmen were asked to select the top universities which they recruited from, Manchester placed 24th in the world and 5th nationally. The Global Employability University Ranking conducted by THE places Manchester at 27th world-wide and 10th in Europe, ahead of academic powerhouses such as Cornell, UPenn and LSE. It is ranked joint 56th in the world and 18th in Europe in the 2015-16 Times Higher Education World University Rankings. In the 2014 Research Excellence Framework, Manchester came fifth in terms of research power and seventeenth for grade point average quality when including specialist institutions. More students try to gain entry to the University of Manchester than to any other university in the country, with more than 55,000 applications for undergraduate courses in 2014 resulting in 6.5 applicants for every place available. According to the 2015 High Fliers Report, Manchester is the most targeted university by the largest number of leading graduate employers in the UK.

    The university owns and operates major cultural assets such as the Manchester Museum, Whitworth Art Gallery, John Rylands Library and Jodrell Bank Observatory which includes the Grade I listed Lovell Telescope.

  • richardmitnick 12:26 pm on August 28, 2017 Permalink | Reply
    Tags: , , , Dementia,   

    From Brown: “Researchers seek to catch Alzheimer’s early by peeking into the eyes” 

    Brown University
    Brown University

    August 28, 2017
    David Orenstein

    Research spanning the academic-medical partnership among Brown University, Rhode Island Hospital and Butler Hospital is advancing the possibility that the retinas will give doctors a way to identify Alzheimer’s disease risk long before symptoms begin.

    Mark Wolff prepares for a series of retinal scans for a study that may help to determine whether the eyes provide a useful window into the early development of Alzheimer’s disease. Nicholas Dentamaro.

    Mark Wolff wanted to know. To him, the thought of suffering through Alzheimer’s disease the way his father did — without knowing, and without his family knowing, what he was up against until late in its progression— is worse than learning, even while he’s still perfectly healthy, that a possible precursor of the disease has gained a toehold.

    “I’m not a worrier by nature,” Wolff said. “I just don’t want to wind up like my dad. It was just a nightmare what happened to him. He didn’t get the medical attention he needed and his quality of life could have been better.”

    So Wolff, a lighting company executive from Bristol, R.I., enrolled in a trial at Butler Hospital and found out through a positron emission tomography (PET) scan of his brain that he has early signs of amyloid plaque. The presence of plaque, a tangle of proteins that could eventually cause the neurodegeneration of Alzheimer’s disease, is a risk factor — even so, Wolff might never develop the disease. Or if he does, it might not affect him for a decade or more.

    The trial, being conducted at both Butler and Rhode Island Hospital, is led by Dr. Stephen Salloway, a professor of neurology at Brown University and director of Butler’s Memory and Aging Program. It has two goals. One is to test whether the drug solanezumab will prevent or delay memory loss and slow amyloid plaque buildup in people at increased risk for Alzheimer’s. The other, via a sub-study launched at Butler Hospital, is to test whether a retinal scan can monitor that progress as well as the much more expensive PET scans. Salloway is working on the larger trial with Dr. Brian Ott, a Brown professor of neurology and director of the Alzheimer’s Disease and Memory Disorders Center at Rhode Island Hospital.

    As part of the research, Wolff returned to Butler on a warm summer afternoon for what unfolded like an eye doctor’s appointment. Nurse practitioner Brittany Dawson dilated Wolff’s eyes with drops. From there, he stared into the same optical coherence tomography (OCT) scanner that an ophthalmologist or optometrist would use to look for macular degeneration or glaucoma. For about 20 minutes, while postdoctoral researcher Dr. Jessica Alber operated the machine and guided him through the experiment, Wolff posed his retinas for multiple close-ups that will be independently inspected for the presence of amyloid plaques.

    Inspired in large part by research led by colleague Dr. Peter Snyder, a professor of neurology and ophthalmology at Brown and senior vice president and chief research officer at Lifespan, Salloway and Ott believe that the retina may provide a reliable reflection of early but significant Alzheimer’s disease risk in the brain. If so, that could vastly expand the number of people around the world who receive an early risk assessment and could save tremendous amounts of money compared to $5,000 PET scans, Snyder said.

    The best chance for treating Alzheimer’s, Snyder said, will be to identify and treat the disease long before symptoms arise, because by then too much damage may be done. Meanwhile, the need is so widespread that it must be done inexpensively and with non-invasive equipment as common as an OCT eye scanner. PET is both too costly and not widely available enough to be the first-line screening tool.

    “We have to identify markers that are accessible to point-of-care clinicians,” Snyder said. “The number of people with Alzheimer’s disease is going to triple over the next 50 years. We have to change the impact of this disease. If we don’t get this right, the burden on society is going to be devastating.”

    Snyder expects that doctors will need to combine several biomarkers to produce an estimate of patients’ eventual Alzheimer’s risk: family history, genetics, and cognitive and memory tests will likely combine with multiple retinal indicators into a comprehensive algorithm. Those with especially high emerging risk might then go on to PET scans and early-stage treatments — perhaps solanezumab — as those are proven, he said.

    The brain in the eyes

    The retina is a part of the central nervous system that doctors can see by opening nothing more than an eyelid.

    “Potentially, the eye could be the window to the brain in the fight against Alzheimer’s,” said Salloway, who along with Ott and Snyder is affiliated with the Brown Institute for Brain Science,

    The retina has the same biochemistry and similar organization and cell types, Snyder said, so it makes sense that it, too, would be similarly susceptible to amyloid plaques. It’s no surprise given that the retina forms out of the same tissue as the brain in just the first few weeks of an embryo’s development.

    Plaques pictured “Inclusion bodies” of amyloid plaque are visible in a subject’s retina in this scan published in Dr. Peter Snyder’s 2016 paper. Snyder et al.

    In recent years, scientists have noticed that amyloid plaques built up in the retinas. In 2016 in the journal Alzheimer’s and Dementia, Snyder and co-authors published a study of 63 cognitively normal adults with at least one parent with Alzheimer’s (just like Wolff) that compared the results of OCT scans with PET scans in the same patients. Snyder’s team found a significant relationship between amyloid levels in the cortex of the brain, as measured by PET, and the total surface area of what appear to be amyloid plaques visible in the retina.

    “Our findings support the hypothesis that retinal biomarkers could be a useful screening tool to distinguish individuals at risk for developing Alzheimer’s disease, and could be helpful in identifying ideal candidates for secondary prevention trials,” he and his co-authors wrote.

    That hypothesis is now being tested further in Salloway’s sub-study.

    In other recent work, Snyder’s research group led by Alber showed that retinal scans can also indicate other potential precursors of closely related neurodegenerative disorders, such as cerebral amyloid angiopathy.

    The group is also studying how OCT can image changes in the vasculature of the retina, because amyloid can attack and alter blood vessels as well as neurons. Finally, the researchers are measuring associations between the presence of amyloid plaque and the thickness of individual layers of the retina. In a recent presentation in London of a small study, the team reported that the retinal nerve fiber layer thins as amyloid plaque in the brain increases.

    Pushing the technology further

    As sensitive as conventional OCT has proven to be in measuring the retina, Snyder said, it could get even better through the work of Jonghwan Lee, an assistant professor of engineering at Brown.

    In his work to improve neural imaging, Lee has developed sophisticated algorithms that amplify the signal of OCT and reduce the noise. These improvements have allowed him to produce stunningly high-resolution imaging of blood flow — red blood cell by red blood cell — in even the tiniest capillaries of neural tissue. That means he might be able to very precisely observe some of the small but early changes in vasculature that Snyder is interested in.

    The two have begun to collaborate. Working in a mouse model of Alzheimer’s and with healthy controls, Lee hopes to track down the earliest vascular, neural and behavioral changes associated with the disease as the mice age.

    Brain veins. In stunning detail Brown engineer Jonghwan Lee can use retinal scanning technology to image the vasculature of neural tissue.
    Jonghwan Lee.

    “Our first hypothesis is that maybe alterations in vasculature and blood flow will appear in the brain first, so we are imaging the animal brain every month,” Lee said. “And at the same time we are testing the cognitive function of the animal and how it declines and we are looking at blood flow and vasculature in the retina.”

    “So we will make a bigger picture of which one is first, which one is earlier and how much it is earlier and significant,” Lee said.

    The goal would be to compile a predictive algorithm of the disease’s progression in the mouse from its very earliest stage using a similar combination of biomarkers — physiology, cognition and genetics — that Snyder suspects will need to be compiled for people.

    The study is very early stages, Lee said: “No one knows the exact answer yet.”

    ‘Better to know’

    In the exam room at Butler, Betty Wolff, Mark’s wife of 45 years, shared that it was initially hard for her to hear the results of the PET scan, but she agreed that it’s better to know. If the infusions he’ll begin later in the summer contain solanuzemab rather than the placebo and if the medication works, his enrollment in the trial might help to stop or slow the disease even before it even gets started. And at least if Wolff becomes symptomatic with Alzheimer’s down the road, the family will have had ample warning and will be able to manage the condition as well as possible, right from the start.

    None of those possibilities was available for Wolff’s dad, which is why he’s so eager to volunteer to advance this research. He’s no stranger to volunteering, having been a blood donor and a Big Brother for decades. Volunteering for research is a way to help society get the upper hand on Alzheimer’s disease, he said, and the huge suffering and costs that it brings.

    “We’re living longer and we understand what makes our bodies live longer,” said Wolff, who turns 70 in September. “If this is something that they don’t conquer, people are not going to have a quality of life at the end.”

    See the full article here .

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    Located in historic Providence, Rhode Island and founded in 1764, Brown University is the seventh-oldest college in the United States. Brown is an independent, coeducational Ivy League institution comprising undergraduate and graduate programs, plus the Alpert Medical School, School of Public Health, School of Engineering, and the School of Professional Studies.

    With its talented and motivated student body and accomplished faculty, Brown is a leading research university that maintains a particular commitment to exceptional undergraduate instruction.

    Brown’s vibrant, diverse community consists of 6,000 undergraduates, 2,000 graduate students, 400 medical school students, more than 5,000 summer, visiting and online students, and nearly 700 faculty members. Brown students come from all 50 states and more than 100 countries.

    Undergraduates pursue bachelor’s degrees in more than 70 concentrations, ranging from Egyptology to cognitive neuroscience. Anything’s possible at Brown—the university’s commitment to undergraduate freedom means students must take responsibility as architects of their courses of study.

  • richardmitnick 9:22 am on August 3, 2016 Permalink | Reply
    Tags: , Dementia, Exercise, ,   

    From UCLA: “Exercise results in larger brain size and lowered dementia risk” 

    UCLA bloc


    August 02, 2016
    Enrique Rivero


    Using the landmark Framingham Heart Study to assess how physical activity affects the size of the brain and one’s risk for developing dementia, UCLA researchers found an association between low physical activity and a higher risk for dementia in older individuals. This suggests that regular physical activity for older adults could lead to higher brain volumes and a reduced risk for developing dementia.

    The researchers found that physical activity particularly affected the size of the hippocampus, which is the part of the brain controlling short-term memory. Also, the protective effect of regular physical activity against dementia was strongest in people age 75 and older.


    Though some previous studies have found an inverse relationship between levels of physical activity and cognitive decline, dementia and Alzheimer’s disease, others have failed to find such an association. The Framingham study was begun in 1948 primarily as a way to trace factors and characteristics leading to cardiovascular disease, but also examining dementia and other physiological conditions. For this study, the UCLA researchers followed an older, community-based cohort from the Framingham study for more than a decade to examine the association between physical activity and the risk for incident dementia and subclinical brain MRI markers of dementia.


    The researchers assessed the physical activity indices for both the original Framingham cohort and their offspring who were age 60 and older. They examined the association between physical activity and risk of any form of dementia (regardless of the cause) and Alzheimer’s disease for 3,700 participants from both cohorts who were cognitively intact. They also examined the association between physical activity and brain MRI in about 2,000 participants from the offspring cohort.

    What this all means: one is never too old to exercise for brain health and to stave off the risk for developing dementia.


    Zaldy Tan of UCLA; Nicole Spartano, Sanford Auerbach and Ramachandran Vasan of the Framingham Heart Study and Boston University; Charles DeCarli of UC Davis, and Sudha Seshadri of the Framingham Heart Study.


    The study appears in the Journals of Gerontology Series A: Biological Sciences and Medical Sciences.


    The research was supported by a National Institutes of Health/National Heart, Lung, and Blood Institute contract (HHSN268201500001I, N01-HC-25195, N01HV28178, R01HL093029, R01 HL131029 U01 HL096917, and 2K24HL04334) and training grant (T32-HL07224), the National Institute on Aging (R01 AG016495, AG008122, AG031287, AG047645), the National Institute of Neurological Disorders and Stroke (R01 NS017950), and the American Heart Association (11CRP4930020 and 16MCPRP30310001).

    See the full article here .

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    We doubt the critics, reject the status quo and see opportunity in dissatisfaction. Our campus, faculty and students are driven by optimism. It is not naïve; it is essential. And it has fueled every accomplishment, allowing us to redefine what’s possible, time after time.

    This can-do perspective has brought us 12 Nobel Prizes, 12 Rhodes Scholarships, more NCAA titles than any university and more Olympic medals than most nations. Our faculty and alumni helped create the Internet and pioneered reverse osmosis. And more than 100 companies have been created based on technology developed at UCLA.

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