What Is Fisetin? And Does It Slow Dementia?

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This is the Medscape Neurology Minute. I am Dr. Alan Jacobs. Researchers at the Salk Institute for Biological Studies have published a series of studies evaluating a flavonol called fisetin, found in many fruits and vegetables, that has been shown to protect neurons in the brain from the effects of aging. The compound is known to have both antioxidant and anti-inflammatory effects on brain cells. They have now investigated the memory-protecting effects of fisetin in a strain of double-transgenic Alzheimer’s disease (AD) mice. Three-month-old mice had fisetin added to their food. By 9 months of age, mice that had not received fisetin began performing more poorly in water mazes, a standard test of animal learning and memory. Mice fed fisetin daily performed as well as control mice without the Alzheimer’s transgene at both 9 months and 1 year old. The researchers next found that in AD mice with memory impairment, pathways involved in cellular inflammation were activated. In fisetin-fed AD mice, those pathways were dampened, and anti-inflammatory molecules were activated. The researchers plan to further probe the molecular details of how fisetin protects memory and study how the timing of fisetin doses affect its influence on AD and whether fisetin can reverse declines in memory once they have already appeared. This has been the Medscape Neurology Minute. I’m Dr. Alan Jacobs.

Watch the video here: http://bit.ly/1ilnGnR

By Alan R. Jacobs, MD – http://www.medscape.com/

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BrainBriefs: The Alcoholic Brain, Autoimmune Epilepsy

Molecular analysis of brain tissue from alcoholics revealed numerous differences from normal controls, potentially providing a key link connecting the brain to behavior in chronic alcoholism. Also, another study connects autoimmunity to at least some cases of epilepsy, and a novel antipsychotic drug targets negative symptoms in schizophrenia.

BrainBriefs: The Alcoholic Brain, Autoimmune Epilepsy

This Is Your Brain on Alcohol for Years

Brain autopsies in 20 alcoholic individuals versus 20 matched controls revealed a spectrum of differences in protein types and concentrations that may “provide a molecular basis for some of the neuronal and behavioral abnormalities attributed to alcoholics,” according to a British-Spanish research group.

Led by Amaia Erdozain, PhD, and Wayne Carter, PhD, of the University of Nottingham in England, the researchers examined the prefrontal cortex (Brodmann area 9) in exquisite detail, using gel electrophoresis, two types of mass spectrometry, and other assays to identify and quantify proteins present in the postmortem tissue.

Key findings in the alcoholic specimens compared with controls included:

  • Thinner cytoskeletons around cell nuclei in cortical and subcortical neurons
  • Disrupted subcortical neuron patterning
  • “Dramatic” reductions in spectrin-beta II and in alpha- and beta-tubulins
  • Greater alpha-tubulin acetylation
  • Reduced proteasome activity

Not only might these molecular changes reflect or cause the clinical effects of chronic alcoholism, they may also contribute to the overall brain atrophy seen in the condition, the researchers suggested in their report, appearing online in PLoS ONE.

Limitations to the study included less-than-perfect assays for some proteins and variations among the alcoholic subjects in age, duration of alcoholism, and cumulative alcohol intake; these subjects may not be representative of alcoholics in the general population.

Autoimmune Basis for Epilepsy

Another study supports the notion that at least some cases of epilepsy have their roots in autoimmunity, and this one comes at the question from a new angle.

Analysis of U.S. insurance claims data on some 2.5 million people found that a diagnosis of epilepsy was nearly four-fold more common among those with autoimmune disorders, according to a report in JAMA Neurology.

Kenneth D. Mandl, MD, MPH, of Harvard Medical School in Boston, and colleagues, compared the presence of an epilepsy diagnosis in insurance plan members who had any of 12 autoimmune disorders listed in their records — such as psoriasis, rheumatoid arthritis, or celiac disease — versus other plan members

After adjusting for other factors, they found an odds ratio of 3.8 for an epilepsy diagnosis (95% CI 3.6-4.0) associated with any of these conditions. No one type of autoimmunity stood out as a special risk factor, the authors indicated.

But children in the sample appeared to be more susceptible than adults to epilepsy in conjunction with autoimmunity, with an odds ratio of 5.2 (95% CI 4.1-6.5).

Other studies have also suggested that epilepsy may have an autoimmune component, especially in cases that don’t respond to conventional anti-seizure medications.

For example, Italian researchers reported last year that they had found neural autoantigens in 14 of 72 patients with drug-resistant epilepsy.

And Mayo Clinic researchers said last fall that immunotherapies such as intravenous immunoglobulin or steroids may be tried in patients with treatment-refractory epilepsy, after achieving success in 18 out of 29 patients.

Mandl and colleagues noted that their study was based on claims data, which may be flawed and/or incomplete. Nevertheless, they wrote, “The potential role of autoimmunity must be given due consideration in epilepsy so that we are not overlooking a treatable cause.”

Novel Antipsychotic Targets Negative Symptoms

An investigational drug called bitopertin showed promise for addressing the negative symptoms of schizophrenia in a phase II trial, researchers reported, although they haven’t been matched in later studies.

In an 8-week, 323-patient trial, those receiving the oral drug according to the study protocol showed significantly greater reductions in negative symptoms than the placebo group, according to Luca Santarelli, MD, of F. Hoffmann-La Roche in Basel, Switzerland, and colleagues writing online in JAMA Psychiatry.

Roche is developing the drug and funded the trial.

Other antipsychotic drugs have proven effective in treating hallucinations and other types of disturbed thinking that define schizophrenia. But negative symptoms — such as apathy and social withdrawal — have been a tougher nut to crack with pharmacotherapies. Old-line antipsychotics such as chlorpromazine did little to improve the negative symptoms; newer “atypical” agents were billed as doing a better job, but have still fallen far short of optimal.

As Santarelli and colleagues explained in their journal report, this lack of effect on negative symptoms “may explain why as few as 30% of patients treated with second-generation antipsychotics achieve functional or symptomatic remission and even fewer attain full recovery.”

Bitopertin has a novel mechanism of action. It inhibits the reuptake of glycine, which is intended to boost activity of so-called NMDA receptors. Impaired NMDA activity is believed to be at the root of schizophrenia’s negative symptoms as well as a contributor to the positive symptoms.

In Roche’s phase II study, patients were randomized in groups of about 80 to three doses of bitopertin (10, 30, or 60 mg/day orally) or placebo.

Inclusion criteria were designed to enroll patients whose symptoms were predominantly on the negative side. Hence, patients with scores of more than 28 on the eight positive symptoms evaluated in the Positive and Negative Syndrome Scale (PANSS) were excluded, as were those with especially high scores on certain positive symptoms. Patients were allowed to remain on conventional antipsychotics that they were taking at recruitment, except for clozapine.

For the primary outcome in a per-protocol analysis that excluded 92 participants, change from baseline in PANSS negative symptom scores, results were as follows:

  • 10 mg/day: -6.50 (95% CI minus 7.66-minus 5.34)
  • 30 mg/day: -6.65 (95% CI minus 7.84-minus 5.46)
  • 60 mg/day: -5.21 (95% CI minus 6.44-minus 3.98)
  • Placebo: -4.86 (95% CI minus 6.01-minus 3.71)

The declines were significantly larger for the 10- and 30-mg/day group than in the placebo group (both P<0.05) but not for the 60-mg/day group (P=0.68).

A responder analysis showed a similar pattern. Using a 20% decrease in total PANSS negative symptom score as the threshold for response, this was achieved by 65% and 60% of the 10- and 30-mg/day group compared with 43% for both the placebo and 60-mg/day groups. For only the lowest dosage group was the difference from placebo statistically significant, however (P=0.01).

None of the differences in outcomes were statistically significant in an intent-to-treat analysis, which included the 92 patients who failed to complete the 8-week study, failed drug screens, were rated by an evaluator who had lost certification, or otherwise deviated from the study protocol.

Drug-related adverse effects were more numerous with increasing dosage, the investigators reported. Most common were somnolence, dizziness, and headache. No lab or cardiac abnormalities were noted in any patient.

Santarelli and colleagues did not appear concerned about the lack of efficacy in the high-dose group. This result was consistent with findings in animal models, they indicated. One explanation is that overloading NMDA receptors with glycine causes the receptors to withdraw inside cell membranes, resulting in diminution of receptor activity. Another possibility is that overexcitement of NMDA alters activity in other neurotransmitter pathways that ultimately counteracts the intended effect.

Roche has commenced six phase III trials of bitopertin with longer treatment intervals and omitting the higher dosage. Initial results in two of these trials failed to match the phase II findings, according to Roche, but the firm said it would await completion of the others before deciding on whether to pursue marketing approvals.

The bitopertin study was funded by Roche. Most authors including Santarelli were Roche employees.

The alcohol study was funded by the Wellcome Trust and government and university sources in Spain. All authors declared they had no relevant financial interests.

The epilepsy study was funded by U.S. and Australian government grants. All authors declared they had no relevant financial interests.

By John Gever, Deputy Managing Editor, MedPage Today

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Alzheimers: Where do biomarkers fit in diagnosis?

Where do biomarkers fit into the diagnosis of Alzheimer’s disease? That’s the question we asked of three eminent Alzheimer’s disease researchers and clinicians: Constantine Lyketsos, MD, MHS, of Johns Hopkins University; Marc Gordon, MD, of Zucker Hillside Hospital in Glen Oaks, N.Y.; andWilliam Klunk, MD, PhD, of the University of Pittsburgh Medical Center. Their answers ranged from the here-and-now of PET scans to future possibilities such as blood tests.

ImageWatch the video here! http://www.medpagetoday.com/HOTTOPICSNeurology/Neurology-Videos/442

By Constantine Lyketsos, MD, MHS – www.medpagetoda.com

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Traumatic Brain Injury and Accelerated Alzheimer’s

This is the Medscape Neurology Minute. I am Dr. Alan Jacobs. There are thought to be epidemiologic and pathophysiologic links between traumatic brain injury (TBI) and Alzheimer disease. Amyloid plaques have been found in the brains of up to 30% of patients who died at any age in the acute phase of a TBI. Now, researchers from the University of Cambridge, England, have published a study in JAMA Neurology [1] in which they performed PET using Pittsburgh Compound B (PiB), a marker of brain amyloid deposition in 15 patients with TBI and 11 healthy control individuals. The patients with TBI were recruited after a maximum of 1 year after injury. They validated their findings using autopsy-acquired brain tissue from 16 TBI victims and 17 patients with nonneurologic causes of death. The results showed that compared with the controls, the patients with TBI showed significantly increased PiB binding throughout the cortical gray matter and the striatum. In the autopsy tissue samples, they found PiB binding in the neocortical gray matter in the same regions where amyloid deposition was demonstrated by immunohistochemistry, thus validating the specificity of the PiB signal to amyloid. The investigators concluded that the use of PiB PET for amyloid imaging following TBI provides the potential for understanding the pathophysiology of TBI, for characterizing the mechanistic drivers of disease progression or suboptimal recovery in the subacute phase of TBI, and for identifying patients at high risk for accelerated Alzheimer disease and for evaluating the potential of antiamyloid therapy. This has been the Medscape Neurology Minute. I’m Dr. Alan Jacobs.

Watch the video here!: http://bit.ly/1egGzgG

By Dr. Alan Jacobs – www.medscape.com

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Alzheimer’s Is Expensive, Deadly and Growing. So Where’s the Research Money?

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Sitting before a mostly absent Senate committee in February, actor Seth Rogen sought to draw attention to an as yet incurable disease that is quietly killing millions of Americans and, perhaps worse, reducing their final years to a harrowing ordeal for both them and their families. He had come to Washington, D.C., to talk about Alzheimer’s.

Rogen, known more for his vulgar comedy and stoner persona than his activism, had a personal reason for testifying. In 2006, his mother-in-law was diagnosed with early-onset Alzheimer’s at 55. At first he thought this meant a future of lost keys and mismatched shoes. A few years later, the family faced “the real, ugly truth of the disease,” Rogen testified. “After forgetting who she and her loved ones were, my mother-in-law, a teacher for 35 years, then forgot how to speak, feed herself, dress herself and go to the bathroom herself—all by the age of 60.”

An estimated 5.2 million Americans have Alzheimer’s, and there is no treatment that prevents, slows, stops or reverses it. If doctors don’t find a cure, the future is grim: By 2025, the number of people age 65 and older with Alzheimer’s is expected to grow by 40 percent to 7.1 million Americans, according to the Alzheimer’s Association‘s 2014 Alzheimer’s Disease Facts and Figures report. Americans are living longer than ever before, many well into their 80s and 90s. With advanced age the number one risk factor for Alzheimer’s, there could be as many as 16 million Americans with Alzheimer’s in 2050, costing $1.2 trillion in health care, long-term care and hospice care.

“The situation is so dire that it caused me, a lazy, self-involved, generally self-medicated man-child, to start an entire charity organization,” Rogen told the few senators who had bothered to show up, referring to Hilarity for Charity, which raises money to support Alzheimer’s research and help families.

“Americans whisper the word Alzheimer’s because their government whispers the word Alzheimer’s,” he added. Later, Rogen blasted the absent senators,tweeting, “Not sure why only two senators were at the hearing. Very symbolic of how the government views Alzheimer’s. Seems to be a low priority.”

WHERE’S THE MONEY?

“The epidemic is upon us,” says Dr. John Trojanowski, co-director of the Center for Neurodegenerative Disease Research and director of the Institute on Aging, both at the University of Pennsylvania School of Medicine. “It’s a very difficult thing to say to a patient that there’s nothing we have for you, but that is the honest response. There are no disease-modifying therapies for Alzheimer’s.”

Alzheimer’s is one of the costliest chronic diseases to the country. Total costs of caring for Americans with Alzheimer’s and other dementias is expected to reach $214 billion this year, with Medicare and Medicaid covering $150 billion and out-of-pocket expenses reaching $36 billion.

Read the full article here: http://bit.ly/1ee19hP

By Abigail Jones – www.newsweek.com

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Anesthesia, Surgery May Double Dementia Risk

Anesthesia and surgery significantly increase the risk for dementia, new research suggests.

A large population-based study conducted by investigators at the Neurological Institute in Taipei Veterans General Hospital, in Taipei City, Republic of China, showed that the risk of developing dementia nearly doubled within 3 to 7 years of anesthesia and surgery. In addition, the average time to dementia diagnosis was shorter in patients who had anesthesia and surgery compared with their counterparts who did not undergo these procedures.

The study adds to “growing concerns that anesthetic agents may have neurodegenerative complications,” study investigator Jong-Ling Fuh, MD, of the Neurological Institute, told Medscape Medical News.

“In vitro and animal studies showed that inhaled anesthetic drugs can promote amyloid beta oligomerization and impair memory. However, it remains controversial whether anesthesia and surgery contribute to the development of dementia in human studies,” she said.

“This population-based study provides statistically sound evidence for the association of dementia with anesthesia and surgery. Our findings support the view that patients who undergo anesthesia and surgery may be at increased risk of dementia.”

“Although we do not know how to mitigate the risk of dementia after anesthesia and surgery at this point, physicians and surgeons should be more vigilant about the possible development of long-term cognitive decline postoperatively in patients who have undergone anesthesia and surgery,” Dr. Fuh added.

The study was published in the March issue of the British Journal of Psychiatry.

Need for More Research

Using the Taiwan National Health Insurance Research Database, Dr. Fuh and colleagues extracted the records of 24,901 patients aged 50 years and older who underwent anesthesia for surgery between 2004 and 2007, and a control group of 110,972 randomly selected individuals matched for age and sex. They excluded anyone with a history of cancer, dementia, Parkinsonism, stroke, or brain operations.

During 3 to 7 years of follow-up, 661 patients in the anesthesia group (2.65%) and 1539 in the control group (1.39%) were diagnosed with dementia. Alzheimer’s disease accounted for the majority of these cases.

Dementia occurred sooner in the anesthesia group (mean 907 days) than in the control group (mean, 1104 days; P < .0001).

After adjusting for hypertension, hyperlipidemia, depression, and Charlson index, patients who underwent anesthesia and surgery had an estimated 1.99-fold increased risk of developing dementia (95% confidence interval [CI], 1.81 – 2.17; P < .001). The risk for dementia after anesthesia was increased similarly in men and women.

The risk was greatest with regional anesthesia (adjusted hazard ratio [HR], 1.80; 95% CI, 1.57 – 2.07), followed by intravenous/intramuscular anesthesia (HR, 1.60; 95% CI, 1.11 – 2.30) and general anesthesia (HR, 1.46; 95% CI, 1.28 – 1.68).

Of the 8 types of surgery, 5 were associated with an increased risk for dementia (dermatologic, musculoskeletal, genitourinary, digestive, and eye surgery). Ear, nose, and throat (ENT), respiratory, and cardiovascular surgery was not associated with increased dementia risk.

Dr. Fuh said “caution must be exercised in asserting causality between development of dementia and anesthesia-associated neurotoxicity. More clinical studies are needed to investigate the association and causality between anesthesia with surgery and subsequent dementia.”

Red Flags and Caveats

Commenting on the findings for Medscape Medical News, Roderic G. Eckenhoff, MD, professor and vice-chair of research, Department of Anesthesia and Critical Care, University of Pennsylvania in Philadelphia, who was not involved in the study, said that sometimes surgery is necessary, but in cases of elective surgery, patients may want to think twice.

However, he cautioned that the study has some “big red flags” and said this “is an area in need of further clarification.”

“If it’s surgery, is it the actual surgery, or the anesthesia, or is it the stress of being in the hospital? It’s probably all those things combined, but it’s probably the surgical procedure itself that causes the largest risk, at least that’s what we believe,” Dr. Eckenhoff said.

“This is a good additional study, and its real strength is its size,” Dr. Eckenhoff said.

“Even when corrected for comorbidity, they found a significant effect of having had surgery in the past and risk for dementia. The level of risk is about consistent with some of the other studies performed,” he noted.

What’s “very concerning,” he said, is that the demographics and comorbidity are “significantly different” in the surgery group and the control group, “although they did try to correct for that.”

Still, “a big red flag and qualifier with this study is that the patients needing surgery are in fact different than the patients who don’t need surgery. It may be those differences and not the fact that they had surgery itself that account for the difference in propensity for getting dementia,” Dr. Eckenhoff said.

“I think in the end we are going to find that there are small populations of people that are more vulnerable to another insult like surgery and who go downhill more quickly afterwards. The challenge is to figure out who those people are, and that’s going to require really good biomarkers,” said Dr. Eckenhoff.

The study was supported by Taipei Veterans General Hospital and other noncommercial entities. The authors have disclosed no relevant financial relationships.

Br J Psychiatry. 2014;204:188-193. Abstract

By Megan Brooks – Medscape.com

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New study ranks Alzheimer’s as third-leading cause of death, after heart disease and cancer

Alzheimer’s disease likely plays a much larger role in the deaths of older Americans than is reported, according to a new study that says the disease may be the third-leading cause of death in the United States.

The Centers for Disease Control and Prevention lists Alzheimer’s as the sixth-leading cause of death, far below heart disease and cancer. But the new report, published Wednesday in the medical journal of the American Academy of Neurology, suggests that the current system of relying on death certificates for causes misses the complexity of dying for many older people and underestimates the impact of Alzheimer’s.

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While the CDC attributed about 84,000 deaths in 2010 to Alzheimer’s, the report estimated that number to be 503,400 among people 75 and older. That puts it in a close third place, behind heart disease and cancer, and well above chronic lung disease, stroke and accidents, which rank third, fourth and fifth.

Alzheimer’s is somewhat of a sleeping giant compared with other leading killers that have received more funding over the years. While deaths from these diseases have been going down thanks to better treatment and prevention, the number of people suffering from Alzheimer’s is quickly rising and the disease is always fatal.

More than 5 million people in the United States are estimated to have Alzheimer’s. With the aging of the baby-boom generation, this number is expected to nearly triple by 2050 if there are no significant medical breakthroughs, according to the Alzheimer’s Association.

The disease cost the nation $210 billion last year; that rate is expected to rise to $1.2 trillion by 2050.

“Scientists told us we need $2 billion a year over the coming 10 years” to see significant advancement in treatment and prevention, said Keith Fargo, director of Scientific Programs and Outreach at the Alzheimer’s Association. Funding by the National Institutes of Health for Alzheimer’s in 2012 was about $500 million, far below funding for heart disease and cancers. The estimated funding in 2013 was $484 million.

“We would like to see a response that is commensurate with the problem,” Fargo said. “Alzheimer’s disease is a serious disease and it needs to be taken seriously, and if we have the right kind of investment as a country, then we will be able to make strides similar to what we’ve made in heart disease, HIV and cancer.”

For the study, researchers at Rush Alzheimer’s Disease Center in Chicago followed 2,566 people 65 and older for an average of eight years, testing them annually for Alzheimer’s-type dementia and observing the risk of death in those who did and did not receive a clinical diagnosis of the disease.

But death certificates for many with Alzheimer’s often listed a more immediate reason for death, leading to a severe underreporting of the disease as an underlying cause, said Bryan James, the report’s lead author and an epidemiologist at the center. The study was funded by the National Institute on Aging and the Illinois Department of Public Health.

“Death certificates may not be the best way to measure how many people die from something that takes up to 10 years” to break down a person’s system, he said, adding that the disease leaves people more vulnerable to dying from infections and other problems. “We’re not saying they didn’t die of those things; we’re just saying, ‘Well, what put them in the hospital with that condition?’ ”

For example, if Alzheimer’s compromises one’s ability to swallow and results in food repeatedly going down the windpipe, that can leave a person more vulnerable to dying of pneumonia, he said.

“Trying to identify a single cause of death in elderly people is often not reflective of the real situation,” James said.

The idea that Alzheimer’s causes many more deaths is not new among experts, but the scope of the undercount is striking, said Dallas Anderson, science administrator for population studies of Alzheimer’s at the National Institute on Aging.

“Anybody who has somewhat of a knowledge of the disease registration system in the U.S. would not be surprised that there was an undercount; the surprising thing is how much of an undercount,” he said, adding that while earlier studies have had similar findings, this is the first peer-reviewed study to produce them.

“It’s shocking,” he said, “and it’ll be interesting to see how it plays out. . . . It would be nice if we could actually improve our death registration system.”

President Obama’s budget for fiscal 2015 included $100 million for an initiative to map the human brain to better understand diseases including Alzheimer’s.

But many in the field think Alzheimer’s should receive more funding.

“The disease is still very underfunded in comparison to other diseases,” James said. “Cancer has about 10 times the amount of funding, and only about three times as many people have cancer.”

Alzheimer’s is not always taken as seriously as other diseases, which may contribute to the historical lack of funding, Fargo said. “There are many people who still think of Alzheimer’s disease as just a memory problem — you forgot where you left your keys. But currently, Alzheimer’s is a universally fatal brain disease that has kind of fallen by the radar.”

By , The Washington Post

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