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Friday, July 24, 2015

Low-dose lithium reduces side effects from most common treatment for Parkinson's disease

Buck Institute research provides further validation that low-dose lithium could be repurposed as a therapy for the incurable neurodegenerative disorder  
Lithium

July 24, 2015/Novato, CA. 
Low-dose lithium reduced involuntary motor movements – the troubling side effect of the medication most commonly used to treat Parkinson’s disease (PD) – in a mouse model of the condition that is diagnosed in about 60,000 Americans each year.  The third in a series of studies from the Andersen lab involving PD and low-dose lithium, the results add to mounting evidence that low-doses of the psychotropic drug could benefit patients suffering from the incurable, degenerative condition.
This study, published online in Brain Research, involved Parkinsonian mice that were given Carbidopa/Levodopa (sold as Sinemet®), a drug used to boost levels of the neurotransmitter dopamine, which is lost in PD. While the medication remains the single most effective agent in the management of PD symptoms, long-term use causes its own side effects, among them abnormal involuntary movements or AIMS.  Buck professor and senior scientist Julie Andersen, PhD, says AIMS become problematic for 30 percent of patients after four to six years of treatment with Sinemet, with 90 percent of patients suffering from the complication after nine years of chronic use.  “For patients these side effects are just as devastating as the freezing that is associated with PD.”  “In our mice we saw significant behavioral improvement.”  
In this study, Andersen and her team dosed the mice with an amount of lithium equivalent to about a quarter of what humans receive for the treatment of psychiatric diseases. Researchers found that lithium boosted the expression of tyrosine hydroxylase which increases dopamine synthesis via the inhibition of calpain-1, an enzyme that normally reduces dopamine synthesis.
In earlier studies, Andersen’s team found that low-dose lithium was protective in two different mouse models of PD. Treatment in mice with a human mutation for PD began when the animals reached late middle-age, the human equivalent of about 60, which is the average age of onset of Parkinson’s in humans. “We clearly saw a prevention of the motor difficulties we would expect to see in the animals,” said Andersen. “The treatment also protected the area of the brain that is normally damaged by Parkinson’s.”   
Plans for a clinical trial of low-dose lithium for PD patients are in early stages. “This study suggests potential therapeutic benefit in PD,” said David K. Simon, MD, PhD, Associate Professor of Neurology at Harvard Medical School in Boston.  Simon chairs the Scientific Review Committee for the Parkinson’s Study Group, a not-for-profit network of Parkinson’s Centers.
“One caveat is that other agents that have shown clear efficacy in this model of PD have subsequently failed to show benefit in clinical studies in PD (e.g. CoQ10, creatine, and pioglitazone). However, this study provides additional evidence on top of prior work from Dr. Andersen’s lab and others that lithium may have therapeutic potential in PD, which is a hypothesis that should be tested in clinical trials,” he said.
Lithium is a naturally occurring element, not a ‘developed’ molecule like most medications. It was approved by the FDA for the treatment of bipolar disorder in 1970 and has shown to be effective for treating mood disorders and suicidal thoughts.  Previous studies suggest that at low doses lithium has a protective effect in other neurodegenerative diseases including Alzheimer’s and Huntington’s.
Citation: The combination of lithium and L-Dopa/Carbidopa reduces MPTP-induced abnormal involuntary movements (AIMs) via calpain-1 inhibition in a mouse model: relevance for Parkinson’s disease therapy. 
This work was supported by grants from National Institutes of Health 5P20GM103653-02; RL1 NS062415
Other Buck Institute contributors include: Rebecca R. Riley and Anand Rane. Corresponding author Y. Hwan Kim, a former member of the Andersen lab, is now in the Department of Biological Sciences, Delaware State University, Carol A. Lazzara, from Delaware State University also contributed to the work.
About the Buck Institute for Research on Aging

The Buck Institute is the U.S.’s first independent research organization devoted to Geroscience – focused on the connection between normal aging and chronic disease. Based in Novato, CA, The Buck is dedicated to extending “Healthspan”, the healthy years of human life and does so utilizing a unique interdisciplinary approach involving laboratories studying the mechanisms of aging and those focused on specific diseases. Buck scientists strive to discover new ways of detecting, preventing and treating age-related diseases such as Alzheimer’s and Parkinson’s, cancer, cardiovascular disease, macular degeneration, osteoporosis, diabetes and stroke.  In their collaborative research, they are supported by the most recent developments in genomics, proteomics, bioinformatics and stem cell technologies. For more information: www.thebuck.org

http://www.buckinstitute.org/buck-news/low-dose-lithium-reduces-side-effects-most-common-treatment-parkinsons-disease#.VbK2OkEGStM.facebook

Pioglitazone 'Unlikely' to Slow Parkinson's


July 23, 2015
The diabetes drug pioglitazone is unlikely to modify progression in early Parkinson's disease (PD), new results from a phase 2 study suggest.
The authors, the NINDS Exploratory Trials in Parkinson Disease investigators, led by Tanya Simuni, MD, Northwestern University, Chicago, Illinois, conclude, "Further study of pioglitazone in a larger trial in patients with Parkinson's disease is not recommended."
The FS-ZONE study, published in the August issue of The Lancet Neurology, was a futility study, which the authors describe as "phase 2 clinical trials designed to identify and eliminate compounds that have low likelihood of being efficacious in definitive efficacy studies by comparing the primary outcome measure in the treatment group versus placebo to a prespecified threshold value."
For the study, 210 patients with early PD were randomly assigned to one of three groups: pioglitazone 15 mg/day, pioglitazone 45 mg/day, or placebo. The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score between baseline and 44 weeks.
The primary analysis showed that pioglitazone at 45 mg/day showed a mean difference in UPDRS score of –1.12, which was deemed to be futile. The pioglitazone dose of 15 mg/day showed a –1.83 difference in UPDRS score, which was not futile in the primary analysis, but sensitivity analyses and secondary outcome measures suggested that this dose was also futile.
The authors note that pioglitazone was chosen for testing because it had shown neuroprotective effects in tissue culture and animal models.
"Unfortunately, this is another study in which animal models were not predictive of efficacy in human beings," they write, adding that toxin animal models may not reflect Parkinson's disease pathogenesis.
Is UPDRS Best Endpoint? 
In an accompanying editorial, Fabrizio Stocchi, Institute for Research and Medical Care, Rome, Italy, points out that there are some concerns about the sensitivity of the UPDRS in patients with mild disease.
But Dr Simuni and coauthors argue that the UPDRS "is the best validated measure and the one that has extensive data showing its sensitivity to change in early Parkinson's disease."
They add, "Consistent findings for all secondary outcomes, which included a spectrum of validated measures of quality of life, disability, and cognitive impairment, support an absence of biological effect rather than a failure to capture and measure an effect."
Serum and urine biomarkers also failed to show a separation of the active treatment groups from placebo.
"The finding that both clinical and biological markers failed to move is disappointing, but solidifies the conclusion that pioglitazone is not promising for further testing in early Parkinson's disease," the authors conclude.
They note that 12 other possible neuroprotectant agents have been recommended by an expert committee for clinical testing. Most have entered phase 2 studies and 4 have completed phase 3 studies, but all studies have been negative so far.
Given these disappointing results, the researchers suggest that "neuroprotection might not be feasible unless we intervene at the premotor stage of the disease."
The study was funded by the National Institute of Neurological Disorders and Stroke. Dr Simuni reports that he received personal fees from Acadia, Abbvie, Allergan, Eli Lilly, Harbor, Ibsen, Merz, UCB Pharma, and US World Meds; received grants, personal fees, honorarium, consulting fees, and educational grant support from and was a speaker for GE Medical and TEVA; received consulting fees from and was an advisory board member and speaker for IMPAX; received personal fees and consulting fees from and was a speaker for Lundbeck; and received research funding from Auspex, Biotie, Civitas, National Institutes of Health, and Michael J. Fox Foundation during the conduct of the study. Dr Stocchi reports he has received honoraria and research grants from Novartis, Teva, UCB, GlaxoSmithKline, Boehringer Ingelheim, IMPAX, Lundbeck, Merck, and Britannia.
Lancet Neurol. 2015;14:795-803, 780-781. Abstract Editorial
http://www.medscape.com/viewarticle/848572?src=wnl_edit_tpal

Thursday, July 23, 2015

Teeth reveal lifetime exposures to metals, toxin

Published: 







Is it possible that too much iron in infant formula may potentially increase risk for neurodegenerative diseases like Parkinson's in adulthood -- and are teeth the window into the past that can help us tell? This and related theories were described in a "Perspectives" article authored by researchers from the Icahn School of Medicine at Mount Sinai and the University of Technology Sydney and Florey Institute of Neuroscience and Mental Health in Australia, and published online recently in Nature Reviews Neurology.
"Teeth are of particular interest to us for the measurement of chemical exposure in fetal and childhood development: they provide a chronological record of exposure from their microchemical composition in relation to defined growth lines, much like the rings in a tree trunk," said Manish Arora, BDS, MPH, PhD, Director of Exposure Biology at the Senator Frank Lautenberg Environmental Health Sciences Laboratory at Mount Sinai and Associate Professor in Preventive Medicine and Dentistry at the Icahn School of Medicine. "Our analysis of iron deposits in teeth as a method for retrospective determination of exposure is just one application: we believe teeth have the potential to help track the impact of pollution on health globally."
Dr. Arora, along with Dominic Hare, PhD, used the dental biomarker technology to distinguish breast-fed babies from formula fed babies. Now this technology can be applied to study the link between early iron exposure and late-life brain diseases like Parkinson's and Alzheimer's, which are associated with the abnormal processing of iron. While not all formula fed babies will experience neurodegeneration in adulthood, the combination of increased iron intake during infancy with a predisposition to impaired metal metabolism such as the inability of brain cells to remove excessive metals may damage those cells over time.
Dr. Hare, a Chancellor's Research Fellow in the Elemental Bio-imaging Facility at the University of Technology Sydney, says "Only now do we have the technology available to use to look back in time at someone's diet as a child, more than 60 years after they stopped wearing diapers. State-of-the-art imaging technology is a chemical time machine that can tell us about decades-old chemical exposures that are equivalent to a drop of ink in a swimming pool."
In the case of baby formula, the need to better understand human iron metabolism has become more urgent with the global popularity of formula and fortified cereals. Adding iron to formula has been an industry standard for decades, in part because about two billion people worldwide - mostly in developing nations - are thought to have chronic anemia and iron deficiency. Evidence, however, that children in the United States or Europe, for instance, get too little iron is insufficient, according to the authors, and the reported developmental and nutritional benefits of iron are modest. The European Society for Paediatric Gastroenterology, Hepatology, and Nutrition have since stated that there's no evidence that babies of normal birthweight need iron supplementation, yet in the U.S. it's still commonplace. Dr. Hare continues: "While it might seem like drawing a long bow linking what happens in childhood to diseases we think of as associated with growing old, the increasing rates of these diseases mean we need to do everything we can to find out what might play a role in how the disease starts. Knowing this gives us something to target when designing new treatments."
Beyond the wide-reaching hypothesis that iron supplementation may increase risk of neurodegeneration, the authors think a priority in pediatric research should be the rigorous determination of iron supplementation needs of infants according to their individual iron status. Formula manufacturers have a responsibility to replicate the chemical composition of breast milk, particularly with regard to iron content. The current 'one size fits all' approach to iron supplementation may be both clinically unnecessary and introduce an unacceptable risk later in life. Whether this hypothesis proves to be true or not, it calls into question decades of treatment dogma that deserves to be revisited with the most cutting-edge technology available.




Is it possible that too much iron in infant formula may potentially increase risk for neurodegenerative diseases like Parkinson's in adulthood -- and are teeth the window into the past that can help us tell? This and related theories were described in a "Perspectives" article authored by researchers from the Icahn School of Medicine at Mount Sinai and the University of Technology Sydney and Florey Institute of Neuroscience and Mental Health in Australia, and published online recently in Nature Reviews Neurology.
"Teeth are of particular interest to us for the measurement of chemical exposure in fetal and childhood development: they provide a chronological record of exposure from their microchemical composition in relation to defined growth lines, much like the rings in a tree trunk," said Manish Arora, BDS, MPH, PhD, Director of Exposure Biology at the Senator Frank Lautenberg Environmental Health Sciences Laboratory at Mount Sinai and Associate Professor in Preventive Medicine and Dentistry at the Icahn School of Medicine. "Our analysis of iron deposits in teeth as a method for retrospective determination of exposure is just one application: we believe teeth have the potential to help track the impact of pollution on health globally."
Dr. Arora, along with Dominic Hare, PhD, used the dental biomarker technology to distinguish breast-fed babies from formula fed babies. Now this technology can be applied to study the link between early iron exposure and late-life brain diseases like Parkinson's and Alzheimer's, which are associated with the abnormal processing of iron. While not all formula fed babies will experience neurodegeneration in adulthood, the combination of increased iron intake during infancy with a predisposition to impaired metal metabolism such as the inability of brain cells to remove excessive metals may damage those cells over time.
Dr. Hare, a Chancellor's Research Fellow in the Elemental Bio-imaging Facility at the University of Technology Sydney, says "Only now do we have the technology available to use to look back in time at someone's diet as a child, more than 60 years after they stopped wearing diapers. State-of-the-art imaging technology is a chemical time machine that can tell us about decades-old chemical exposures that are equivalent to a drop of ink in a swimming pool."
In the case of baby formula, the need to better understand human iron metabolism has become more urgent with the global popularity of formula and fortified cereals. Adding iron to formula has been an industry standard for decades, in part because about two billion people worldwide - mostly in developing nations - are thought to have chronic anemia and iron deficiency. Evidence, however, that children in the United States or Europe, for instance, get too little iron is insufficient, according to the authors, and the reported developmental and nutritional benefits of iron are modest. The European Society for Paediatric Gastroenterology, Hepatology, and Nutrition have since stated that there's no evidence that babies of normal birthweight need iron supplementation, yet in the U.S. it's still commonplace. Dr. Hare continues: "While it might seem like drawing a long bow linking what happens in childhood to diseases we think of as associated with growing old, the increasing rates of these diseases mean we need to do everything we can to find out what might play a role in how the disease starts. Knowing this gives us something to target when designing new treatments."
Beyond the wide-reaching hypothesis that iron supplementation may increase risk of neurodegeneration, the authors think a priority in pediatric research should be the rigorous determination of iron supplementation needs of infants according to their individual iron status. Formula manufacturers have a responsibility to replicate the chemical composition of breast milk, particularly with regard to iron content. The current 'one size fits all' approach to iron supplementation may be both clinically unnecessary and introduce an unacceptable risk later in life. Whether this hypothesis proves to be true or not, it calls into question decades of treatment dogma that deserves to be revisited with the most cutting-edge technology available.
Is it possible that too much iron in infant formula may potentially increase risk for neurodegenerative diseases like Parkinson's in adulthood -- and are teeth the window into the past that can help us tell? This and related theories were described in a "Perspectives" article authored by researchers from the Icahn School of Medicine at Mount Sinai and the University of Technology Sydney and Florey Institute of Neuroscience and Mental Health in Australia, and published online recently in Nature Reviews Neurology.
"Teeth are of particular interest to us for the measurement of chemical exposure in fetal and childhood development: they provide a chronological record of exposure from their microchemical composition in relation to defined growth lines, much like the rings in a tree trunk," said Manish Arora, BDS, MPH, PhD, Director of Exposure Biology at the Senator Frank Lautenberg Environmental Health Sciences Laboratory at Mount Sinai and Associate Professor in Preventive Medicine and Dentistry at the Icahn School of Medicine. "Our analysis of iron deposits in teeth as a method for retrospective determination of exposure is just one application: we believe teeth have the potential to help track the impact of pollution on health globally."
Dr. Arora, along with Dominic Hare, PhD, used the dental biomarker technology to distinguish breast-fed babies from formula fed babies. Now this technology can be applied to study the link between early iron exposure and late-life brain diseases like Parkinson's and Alzheimer's, which are associated with the abnormal processing of iron. While not all formula fed babies will experience neurodegeneration in adulthood, the combination of increased iron intake during infancy with a predisposition to impaired metal metabolism such as the inability of brain cells to remove excessive metals may damage those cells over time.
Dr. Hare, a Chancellor's Research Fellow in the Elemental Bio-imaging Facility at the University of Technology Sydney, says "Only now do we have the technology available to use to look back in time at someone's diet as a child, more than 60 years after they stopped wearing diapers. State-of-the-art imaging technology is a chemical time machine that can tell us about decades-old chemical exposures that are equivalent to a drop of ink in a swimming pool."
In the case of baby formula, the need to better understand human iron metabolism has become more urgent with the global popularity of formula and fortified cereals. Adding iron to formula has been an industry standard for decades, in part because about two billion people worldwide - mostly in developing nations - are thought to have chronic anemia and iron deficiency. Evidence, however, that children in the United States or Europe, for instance, get too little iron is insufficient, according to the authors, and the reported developmental and nutritional benefits of iron are modest. The European Society for Paediatric Gastroenterology, Hepatology, and Nutrition have since stated that there's no evidence that babies of normal birthweight need iron supplementation, yet in the U.S. it's still commonplace. Dr. Hare continues: "While it might seem like drawing a long bow linking what happens in childhood to diseases we think of as associated with growing old, the increasing rates of these diseases mean we need to do everything we can to find out what might play a role in how the disease starts. Knowing this gives us something to target when designing new treatments."
Beyond the wide-reaching hypothesis that iron supplementation may increase risk of neurodegeneration, the authors think a priority in pediatric research should be the rigorous determination of iron supplementation needs of infants according to their individual iron status. Formula manufacturers have a responsibility to replicate the chemical composition of breast milk, particularly with regard to iron content. The current 'one size fits all' approach to iron supplementation may be both clinically unnecessary and introduce an unacceptable risk later in life. Whether this hypothesis proves to be true or not, it calls into question decades of treatment dogma that deserves to be revisited with the most cutting-edge technology available.

Is it possible that too much iron in infant formula may potentially increase 
risk for neurodegenerative diseases like Parkinson's in adulthood -- and 
are teeth the window into the past that can help us tell? This and related
theories were described in a "Perspectives" article authored by researchers
from the Icahn School of Medicine at Mount Sinai and the University of 
Technology Sydney and Florey Institute of Neuroscience and Mental 
Health in Australia, and published online recently in Nature Reviews Neurology.
"Teeth are of particular interest to us for the measurement of chemical 
exposure in fetal and childhood development: they provide a chronological 
record of exposure from their microchemical composition in relation to 
defined growth lines, much like the rings in a tree trunk," said Manish Arora,
BDS, MPH, PhD, Director of Exposure Biology at the Senator Frank 
Lautenberg Environmental Health Sciences Laboratory at Mount Sinai and
Associate Professor in Preventive Medicine and Dentistry at the Icahn 
School of Medicine. "Our analysis of iron deposits in teeth as a 
method for retrospective determination of exposure is just one 
application: we believe teeth have the potential to help track the 
impact of pollution on health globally."
Dr. Arora, along with Dominic Hare, PhD, used the dental biomarker 
technology to distinguish breast-fed babies from formula fed babies. 
Now this technology can be applied to study the link between early iron 
exposure and late-life brain diseases like Parkinson's and Alzheimer's, 
which are associated with the abnormal processing of iron. While not all 
formula fed babies will experience neurodegeneration in adulthood 
the combination of increased iron intake during infancy with a 
predisposition to impaired metal metabolism such as the inability of brain 
cells to remove excessive metals may damage those cells over time.
Dr. Hare, a Chancellor's Research Fellow in the Elemental Bio-imaging 
Facility at the University of Technology Sydney, says "Only now do we 
have the technology available to use to look back in time at someone's diet
as a child, more than 60 years after they stopped wearing diapers. 
State-of-the-art imaging technology is a chemical time machine that can 
tell us about decades-old chemical exposures that are equivalent to a drop 
of ink in a swimming pool."
In the case of baby formula, the need to better understand human iron 
metabolism has become more urgent with the global popularity of 
formula and fortified cereals. Adding iron to formula has been an industry 
standard for decades, in part because about two billion people worldwide - 
mostly in developing nations - are thought to have chronic anemia and
iron deficiency. Evidence, however, that children in the United States or
Europe, for instance, get too little iron is insufficient, according to the authors
and the reported developmental and nutritional benefits of iron are 
modest. The European Society for Paediatric Gastroenterology, Hepatology, 
and Nutrition have since stated that there's no evidence that babies of 
normal birthweight need iron supplementation, yet in the U.S. it's
still commonplace. Dr. Hare continues: "While it might seem like drawing 
a long bow linking what happens in childhood to diseases we think of as 
associated with growing old, the increasing rates of these diseases mean 
we need to do everything we can to find out what might play a role in 
how the disease starts. Knowing this gives us something to target when 
designing new treatments."
Beyond the wide-reaching hypothesis that iron supplementation may 
increase risk of neurodegeneration, the authors think a priority in 
pediatric research should be the rigorous determination of iron 
supplementation needs of infants according to their individual iron status. 
Formula manufacturers have a responsibility to replicate the chemical 
composition of breast milk, particularly with regard to iron content. The 
current 'one size fits all' approach to iron supplementation may be both 
clinically unnecessary and introduce an unacceptable risk later in life. 
Whether this hypothesis proves to be true or not, it calls into question 
decades of treatment dogma that deserves to be revisited with the most 
cutting-edge technology available.




Adapted by MNT from original media release
http://www.medicalnewstoday.com/releases/297217.php?tw