Existing drugs point to first treatment for strokes linked to dementia

by University of Edinburgh

Micrograph showing cortical pseudolaminar necrosis, a finding seen in strokes on medical imaging and at autopsy. H&E-LFB stain. Credit: Nephron/Wikipedia

People who experience a type of stroke linked with nearly half of all dementias could be treated for the first time by repurposing two cheap and common drugs, a trial shows.

08 Jun 2023--Researchers found that isosorbide mononitrate and cilostazol, which are already used to treat other heart and circulatory diseases, can safely improve the debilitating outcomes people experience after lacunar stroke.

The two drugs, which were found to be even more effective when used in combination, could be available as a treatment for lacunar strokes within five years, if the results are confirmed in further trials, experts say.

Lacunar strokes affect at least 35,000 people in the UK each year. They are caused by cerebral small vessel disease, where small blood vessels deep within the brain become damaged and stop working properly. Small vessel disease is also a common cause of cognitive impairment and dementia.

The strokes can be distressing as people may develop problems with their thinking and memory, movement, and even dementia. There are currently no specific effective treatments.

The trial, led by the Universities of Edinburgh and Nottingham and the UK Dementia Research Institute, involved 363 people who had experienced a lacunar stroke.

As well as their standard stroke prevention treatment, for one year participants took either isosorbide mononitrate or cilostazol individually, both drugs together, or neither.

The trial, funded by the British Heart Foundation, investigated cilostazol and isosorbide mononitrate as they possibly improve the function of the inner lining of blood vessels, which researchers believe play a role in small vessel disease.

Participants that took both drugs were nearly 20 percent less likely to have problems with their thinking and memory compared to the group that did not take either drug. They were also more independent and reported a better quality of life.

In addition, those who took isosorbide mononitrate were less likely to have had further strokes at one year than those who did not take the drug.

Taken on their own, isosorbide mononitrate also improved thinking and memory skills, and quality of life, while cilostazol improved independence and mood. These effects were strengthened when the two drugs were taken together, researchers say.

The team is now planning to test these drugs in a larger four-year clinical trial, which they hope to start by the end of 2023. They are also looking to test whether the drugs are effective in different conditions linked to small vessel disease, such as vascular cognitive impairment and dementia.

The findings are published in the journal JAMA Neurology. This work was also supported by the Alzheimer's Society and Stroke Association.

Professor Joanna Wardlaw, Chair of Applied Neuroimaging at the University of Edinburgh and Foundation Chair at the UK Dementia Research Institute, said, "Now we understand more about what is triggering these small vessel strokes to attack the brain, we've been able to focus our efforts on treatments that can put a halt to this damage. We need to confirm these results in larger trials before either drug can be recommended as a treatment. However, as these drugs are already widely available for other circulatory disorders, and inexpensive, it shouldn't take too long to move our findings from research into everyday clinical practice."

Professor Sir Nilesh Samani, Medical Director at the British Heart Foundation, said, "These promising findings provide a long-awaited positive step towards the first treatments becoming available for lacunar strokes, offering much needed hope for thousands of people. Lacunar strokes are not the only way that cerebral small vessel disease can affect someone. These findings also open new avenues of research into other conditions related to small vessel disease, such as vascular dementia."

More information: Isosorbide Mononitrate and Cilostazol Treatment in Patients With Symptomatic Cerebral Small Vessel Disease, JAMA (2023). DOI: 10.1001/jamaneurol.2023.1526 , jamanetwork.com/journals/jaman … /fullarticle/2805321

Provided by University of Edinburgh 

Dementia study lists everyday factors that may influence risk

Experts have created a shortlist of environmental factors that may contribute to our risk of developing dementia.

The list includes exposure to air pollution and a lack of vitamin D but researchers caution that the evidence is not yet sufficient to draw solid conclusions.

19 oct 2016--The team say that future research should focus on their shortlist, which points to the factors that show at least moderate evidence of a link.
Dementia is known to be associated with lifestyle factors such as high blood pressure in mid-life, smoking, diabetes, obesity, depression and low educational attainment, as well as genetic factors.
These risk factors however, leave around a third of dementia risk unexplained. Researchers led by the University of Edinburgh sought to determine whether other issues are at play, including the environment in which we live.
The team from the University's Alzheimer Scotland Dementia Research Centre reviewed dozens of previous studies that have considered environmental risk factors linked to dementia.
They found that a lack of vitamin D - produced by the body through exposure to sunlight - and exposure to air pollution were implicated, along with occupational exposure to some types of pesticide.
Excessive levels of minerals found in drinking water may be linked to the disease, the research suggested, but the evidence was mixed.
Dementia is a major global public health crisis that is expected to grow as people live longer. Almost 47 million people live with dementia worldwide and this is predicted to increase to more than 131 million by 2050.
Estimates indicate the disease costs the UK more than £26 billion annually and worldwide dementia care costs exceed the market value of Google or Apple each year.
There is a growing consensus among doctors that a significant proportion of cases could be prevented or delayed by addressing environmental factors linked to the disease.
The team behind the latest research says future studies should focus on the shortlist of environmental risk factors flagged up in their study.
The research, published in the journal BMC Geriatrics, was funded by Alzheimer Scotland and Dr Russ was supported by Alzheimer Scotland through the Marjorie MacBeath fellowship.
Dr Tom Russ, of the Alzheimer Scotland Dementia Research Centre at the University of Edinburgh, said: "Our ultimate goal is to prevent or delay the onset of dementia. Environmental risk factors are an important new area to consider here, particularly since we might be able to do something about them.
"We found that the evidence is particularly strong for air pollution and vitamin D deficiency. But we really need more research to find out whether these factors are actually causing dementia and how, and if so, what we can do to prevent this."
Jim Pearson, Director of Policy and Researcher at Alzheimer Scotland, said: "We welcome the findings of this important area of research from our colleagues at the Alzheimer Scotland Dementia Research Centre at the University of Edinburgh. The research study substantially improves our knowledge and understanding of environmental factors which may increase the risk of developing dementia and provides a basis for further, and more focussed, research in this area.
"Dementia is a global public health priority. There are 90,000 people living with dementia in Scotland and the number is on the rise. We need much more research into the causes of dementia, treatments and supports that allow people to live well with dementia as well as the prevention and cure of dementia."

More information: Lewis O. J. Killin et al, Environmental risk factors for dementia: a systematic review, BMC Geriatrics (2016). DOI: 10.1186/s12877-016-0342-y


Provided by University of Edinburgh

Link between vitamin D and dementia risk confirmed

Vitamin D deficiency is associated with a substantially increased risk of dementia and Alzheimer's disease in older people, according to the most robust study of its kind ever conducted.

08 aug 2014--An international team, led by Dr David Llewellyn at the University of Exeter Medical School, found that study participants who were severely Vitamin D deficient were more than twice as likely to develop dementia and Alzheimer's disease.

The team studied elderly Americans who took part in the Cardiovascular Health Study. They discovered that adults in the study who were moderately deficient in vitamin D had a 53 per cent increased risk of developing dementia of any kind, and the risk increased to 125 per cent in those who were severely deficient.

Similar results were recorded for Alzheimer's disease, with the moderately deficient group 69 per cent more likely to develop this type of dementia, jumping to a 122 per cent increased risk for those severely deficient.

The study was part-funded by the Alzheimer's Association, and is published in August 6 2014 online issue of Neurology, the medical journal of the American Academy of Neurology. It looked at 1,658 adults aged 65 and over, who were able to walk unaided and were free from dementia, cardiovascular disease and stroke at the start of the study. The participants were then followed for six years to investigate who went on to develop Alzheimer's disease and other forms of dementia.

Dr Llewellyn said: "We expected to find an association between low Vitamin D levels and the risk of dementia and Alzheimer's disease, but the results were surprising – we actually found that the association was twice as strong as we anticipated.

"Clinical trials are now needed to establish whether eating foods such as oily fish or taking vitamin D supplements can delay or even prevent the onset of Alzheimer's disease and dementia. We need to be cautious at this early stage and our latest results do not demonstrate that low vitamin D levels cause dementia. That said, our findings are very encouraging, and even if a small number of people could benefit, this would have enormous public health implications given the devastating and costly nature of dementia."

Research collaborators included experts from Angers University Hospital, Florida International University, Columbia University, the University of Washington, the University of Pittsburg and the University of Michigan. The study was supported by the Alzheimer's Association, the Mary Kinross Charitable Trust, the James Tudor Foundation, the Halpin Trust, the Age Related Diseases and Health Trust, the Norman Family Charitable Trust, and the National Institute for Health Research Collaboration for Leadership in Applied Research and Care South West Peninsula (NIHR PenCLAHRC).

Dementia is one of the greatest challenges of our time, with 44 million cases worldwide – a number expected to triple by 2050 as a result of rapid population ageing. A billion people worldwide are thought to have low vitamin D levels and many older adults may experience poorer health as a result.

The research is the first large study to investigate the relationship between vitamin D and dementia risk where the diagnosis was made by an expert multidisciplinary team, using a wide range of information including neuroimaging. Previous research established that people with low vitamin D levels are more likely to go on to experience cognitive problems, but this study confirms that this translates into a substantial increase in the risk of Alzheimer's disease and dementia.

Vitamin D comes from three main sources – exposure of skin to sunlight, foods such as oily fish, and supplements. Older people's skin can be less efficient at converting sunlight into Vitamin D, making them more likely to be deficient and reliant on other sources. In many countries the amount of UVB radiation in winter is too low to allow vitamin D production.

The study also found evidence that there is a threshold level of Vitamin D circulating in the bloodstream below which the risk of developing dementia and Alzheimer's disease increases. The team had previously hypothesized that this might lie in the region of 25-50 nmol/L, and their new findings confirm that vitamin D levels above 50 nmol/L are most strongly associated with good brain health.

Commenting on the study, Dr Doug Brown, Director of Research and Development at Alzheimer's Society said: "Shedding light on risk factors for dementia is one of the most important tasks facing today's health researchers. While earlier studies have suggested that a lack of the sunshine vitamin is linked to an increased risk of Alzheimer's disease, this study found that people with very low vitamin D levels were more than twice as likely to develop any kind of dementia.

"During this hottest of summers, hitting the beach for just 15 minutes of sunshine is enough to boost your vitamin D levels. However, we're not quite ready to say that sunlight or vitamin D supplements will reduce your risk of dementia. Large scale clinical trials are needed to determine whether increasing vitamin D levels in those with deficiencies can help prevent the dementia from developing."

Provided by University of Exeter

Regular physical activity reduces risk of dementia in older people

Regular physical activity may help older people reduce their chances of getting dementia.

03 nov 2012--In a new study published in the American Heart Association journal Stroke, older, non-disabled people who regularly engaged in physical activity reduced their risk of vascular-related dementia by 40 percent and cognitive impairment of any etiology by 60 percent.

The protective effect of regular physical activity remained regardless of age, education, changes in the brain's white matter and even previous history of stroke or diabetes, researchers said. The findings are based on a prospective multinational European study that included yearly comprehensive cognitive assessments for three years. The results are part of increasing evidence that regular physical activity promotes brain health, researchers said.

"We strongly suggest physical activity of moderate intensity at least 30 minutes three times a week to prevent cognitive impairment," said Ana Verdelho, M.D., lead author of the study and a neuroscience researcher at the University of Lisbon, Santa Maria Hospital in Portugal. "This is particularly important for people with vascular risk factors such as hypertension, stroke or diabetes."

The analysis included 639 people in their 60s and 70s; 55 percent were women and almost 64 percent said they were active at least 30 minutes a day three times a week. The activity included gym classes, walking and biking.

The American Heart Association recommends at least 150 minutes of moderate exercise every week or 75 minutes of vigorous exercise for optimal health.

Researchers performed magnetic resonance imaging (MRI) tests at the beginning and end of the study to gauge white matter changes in the brain, an indicator of possible cognitive decline.

"Damage of the cerebral white matter is implicated in cognitive problems including depression, walking difficulties and urinary complaints," Verdelho said. "White matter changes are very common in older people and mainly associated with vascular risk factors like hypertension and stroke."

Throughout the study, researchers asked participants in phone interviews and clinical visits about depression, quality of life and performing everyday activities.

At the end of the follow-up, 90 patients had dementia, including 54 with vascular dementia in which impaired blood flow to the brain causes cognitive decline, and 34 patients met criteria for Alzheimer's disease. Another 147 patients developed cognitive impairment, but not dementia.

Provided by American Heart Association

Heavy NSAID Use Linked to Dementia in Elderly

Study differs from previous studies; possibly due to delayed onset

24 april 2009- Contrary to earlier studies suggesting that users of nonsteroidal anti-inflammatory drugs (NSAIDs) have a reduced risk of developing dementia, heavy NSAID use in the elderly is associated with a higher risk of developing dementia, according to a study published online April 22 in Neurology.

John C. S. Breitner, M.D., from the Department of Veterans Affairs Medical Center in Seattle, and colleagues examined the association between the use of NSAIDs and dementia in 2,736 elderly (65 years and older) dementia-free individuals.

Based on computerized pharmacy records, the researchers found that 351 individuals (12.8 percent) were heavy NSAID users (more than 500 standard daily doses) at baseline, while an additional 107 became heavy users during the follow-up period. After up to 12 years of follow up, 476 individuals developed dementia, of which 356 was Alzheimer dementia. Heavy NSAID use was associated with a higher risk of developing dementia (adjusted hazard ratios of 1.66 for dementia and 1.57 for Alzheimer dementia).

"These findings differ from those of other studies with younger cohorts," Breitner and colleagues conclude. "The results observed elsewhere may reflect delayed onset of Alzheimer dementia in NSAID users."

Abstract
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Does universal health care affect attitude toward dementia?

Britons perceive greater societal stigma from diagnosis than do Americans

INDIANAPOLIS, 15 jan 2009 – A new study has found that in spite of their universal health care system which facilitates access to free dementia care, older adults in the United Kingdom are less willing to undergo dementia screening than their counterparts in the U.S. because the Britons perceive greater societal stigma from diagnosis of the disease than do Americans.

Researchers surveyed 125 older adults in Indianapolis and 120 older adults in Kent, England, on their opinions on the perceived harms and benefits of dementia screening. None of those surveyed had been diagnosed with dementia, however significantly more of the U.K. participants (48 percent) had close friends or relatives who have or had Alzheimer's disease compared to U.S. participants (27 percent).

The study of public attitudes toward early detection of dementia across different health-care systems was conducted by researchers from Indiana University in the United States and the universities of Kent and London in the United Kingdom. The research was funded in part by the U.S. National Institute on Aging, and appears in an advance online publication of the International Journal of Geriatric Psychiatry.

"From my prospective, it was a genuine surprise that having a universal health care system, which provides services and support to all those who need it, didn't protect from perceived stigma and negativity," said the study's corresponding author, Malaz Boustani, M.D., assistant professor of medicine at the IU School of Medicine and a Regenstrief Institute research scientist.

Even when taking into account education and race differences, Britons indicated greater concern with the stigma of diagnosis, with potential loss of independence, and with emotional suffering than their American counterparts.

"This study, which investigates the acceptance and societal stigma associated with dementia – something very difficult to track – provides us with a unique insight as Americans debate the pros and cons of universal health care," said study first author, Michael Justiss, Ph.D., assistant professor of occupational therapy, School of Health and Rehabilitation Sciences, Indiana University-Purdue University Indianapolis.

Dementia is a growing global public health problem in both countries leading to a high burden of suffering for society with an annual cost of $100 billion in the U.S. and $10 billion in the U.K.

"In spite of the fact that new strategies for both treatment and prevention of dementia are currently being developed, this study gives us an initial awareness so that we can develop improved care pathways for dementia. We hope the United Kingdom's Dementia Strategy published in the next few months will consider some of this study's findings," said Chris Fox, MB, BS of the University of Kent, who led the British researchers.

"This pilot study is the beginning, not the end. We need to do further exploration with a bigger sample, with different types of individuals. But this study which found deep concern about dementia screening despite access to health care services in U.K., clearly tells us that there are many issues we must explore as we attempt to retool the American health care system. We have to be careful not to put the horse before the cart as we debate national health care in the U.S.," said Dr. Boustani, who is also an IU Center for Aging Research center scientist. Dr. Boustani has written extensively on the dementia screening.

###

Co-authors of the study include Christopher Callahan, M.D., Sui Hui, Ph.D., Greg Sachs, M.D., and Hugh Hendrie, MB, ChB of the IU School of Medicine, the Regenstrief Institute and the IU Center for Aging Research; Patrick Healey, M.D., at St. Vincent Hospital, Institute on Aging, Indianapolis; Cornelius Katona, M.D., of University College London and researchers at the University of Kent.

New study supports statin's anti-dementia effects

NEW YORK, 09 jan 2009– In the largest cohort study to date, treatment with a cholesterol-lowering statin drug was found to reduce new cases of Alzheimer's disease, regardless of the specific type of statin used or a person's genetic risk for the disease.

Numerous studies have looked at the relationship between statin use and the development of Alzheimer's disease, with conflicting results. One explanation for the inconsistencies is that only the fat soluble or "lipophilic" statins, which could get into the brain more easily than water soluble or "hydrophilic" statins, were included in the studies.

To explore these issues, Dr. M. M. B. Breteler and colleagues at the Erasmus Medical Center in Rotterdam, the Netherlands, analyzed data from the prospective, population-based Rotterdam Study. The analysis included 6992 subjects, 55 years old or older, who were free of dementia when examined between 1990 and 1993.

During follow-up until 2005 (an average of 9.2 years), 582 subjects were diagnosed with Alzheimer's. After controlling for social, demographic and clinical factors that might raise a person's risk of getting the disease, statin users had a significant 43 percent reduced risk of Alzheimer's disease compared with those who never used statins.

The protective effect was similar for fat soluble and water soluble statins. Examples of fat soluble statins are atorvastatin (Lipitor), simvastatin (Zocor), lovastatin (Mevacor), or fluvastatin (Lescol). An example of a water soluble statin is pravastatin (Pravachol).

The protective effect of statin use against Alzheimer's disease was also similar for persons with and without the major gene mutation associated with an increased risk of Alzheimer's disease (i.e., the apolipoprotein E-epsilon-4 allele).

On the other hand, the use of other cholesterol-lowering drugs such as fibrates or nicotinic acid failed to exhibit similar benefit, Breteler's team reports.

The findings appear in this month's issue of the Journal of Neurology, Neurosurgery and Psychiatry.

In a commentary published with the study, Dr. Larry Sparks at the Sun Health Research Institute in Sun City, Arizona, states: "All in all, it is clear that somewhere between normal cognitive performance and profound dementia of Alzheimer's disease, statin therapy exerts a beneficial effect."

He points out that nearly 20 previous studies have assessed the effect of statin use on later risk of Alzheimer's disease in older people, and the majority found substantial benefit.

Sparks concludes that "it is our task to identify at what point in time statin therapy might be of the greatest benefit in order to effectively target which patients to treat with cholesterol-lowering statins."

SOURCE: Journal of Neurology, Neurosurgery and Psychiatry, January 2009.

Florida Adopts ‘Silver Alerts’ for Mentally Impaired Elderly Who Wander Off

By CARMEN GENTILE

MIAMI, 19 dec 2008 — Charlie Brownlee, who is 76 and suffers from dementia, staggered out of his sister’s Miami home barefoot one day last month and got behind the wheel of a car.

Mr. Brownlee’s condition is generally manageable with medication, but on that day the family was dealing with the death of a relative, and no one had remembered to give him his pills. “And just like that,” said his sister, Mary Agnes Jones, “no one knew where he was.”

Frantic, the family reported Mr. Brownlee’s disappearance to the police, who immediately issued a bulletin under Florida’s newly created Silver Alert program.

Similar to the Amber Alert, declared when a child is abducted, a Silver Alert is circulated when a person 60 or older who suffers from dementia or another cognitive impairment like Alzheimer’s disease goes missing. About a dozen other states, including neighboring Georgia, have adopted similar programs, and legislation creating a national program is pending in Congress.

In Florida, where the elderly are so large a share of the population and, according to state government estimates, account for half a million cases of Alzheimer’s, the Silver Alert has had an immediate impact, officials say.

Indeed, all of the 19 people for whom the state has issued bulletins since adopting its program in November have been found, said E. Douglas Beach, Florida’s secretary of elder affairs. That includes Mr. Brownlee, who, having been missing for two days, was discovered by a police officer parked in a roadside ditch some 30 miles north of his sister’s house.

One feature of the Florida program sends an automated phone call to every residence within a one-mile radius of the missing person’s home, providing pertinent information like a physical description and the vehicle being driven, if any. In Mr. Brownlee’s case, said Detective Jose Rojas of the Miami Police Department’s missing persons unit, “we put out about 5,000 calls describing what he looked like, the car he was driving and which way we thought he was traveling.”

In another feature, for cases like Mr. Brownlee’s in which the missing person is thought to be behind the wheel, the Florida Department of Transportation’s “dynamic message signs,” which normally alert drivers to traffic conditions and detours, flash a physical description of the person, the kind of vehicle, its license plate number and possible direction traveled.

Mr. Brownlee was apparently trying to return to his own home, in Tuscaloosa, Ala., when he was found. Some who suffer from dementia think they can quickly get back to their former homes, however distant, said Christa Ksiezopolski of the Alzheimer and Parkinson Association of Indian River County, up the coast just north of Fort Pierce.

“They aren’t like you or I,” Ms. Ksiezopolski said. “They don’t understand how far they are from home.”

That can be all the more serious in a state to which so many of the elderly move.

“You see how many seniors we have here,” Gov. Charlie Crist said the other day at the groundbreaking of a new home for the elderly in South Miami. “It’s important that we take care of the seniors that are vulnerable.”

Hebrew SeniorLife study on under-reported dementia deaths questions accuracy of mortality statistics

Boston, Mass. 11 dec 2008– Deaths due to dementia and Alzheimer's disease are underreported on death certificates, according to a study conducted by Hebrew SeniorLife's Institute for Aging Research (IFAR), raising concerns about the accuracy of mortality statistics based on these documents.

According to the National Center for Health Statistics (NCHS), which derives its data from death certificates, Alzheimer's disease, the most common form of dementia, is the fifth leading cause of death among Americans over age 65. Dementia is the loss of mental capacities—thinking, memory, reasoning and decision making, among others—that interferes with a person's daily functioning.

The IFAR researchers used data collected between 2003 and 2007 from the Choices, Attitudes, and Strategies for Care of Advanced Dementia at the End-of-Life, or CASCADE, study of 323 residents from 22 Boston-area nursing homes with advanced dementia. Of the 323 participants, 165 died during follow up. Thirty-seven percent of all decedents had no mention of dementia anywhere on their death certificates. Among the subset of 114 decedents diagnosed with Alzheimer's disease prior to death, documentation of dementia anywhere on their death certificate was none (33.3%), Alzheimer's disease (27.2%), dementia without further specification (37.7%), and vascular dementia (0.9%).

"Despite the terminal stage of dementia in our cohort," says lead author Susan L. Mitchell, M.D., M.P.H., a senior scientist at IFAR, "dementia was not recorded on 37 percent of death certificates. The absence of Alzheimer's disease on three-quarters of death certificates of decedents with this premortem diagnosis is a particular problem because, among the causes of dementia, NCHS ranks only Alzheimer's disease among its leading causes of death."

The study was published in the December 10 issue of the Journal of the American Medical Association.

Dr. Mitchell and her colleagues say an "appreciation that patients die from and with dementia is necessary to inform end-of-life decision making." They add that the underreporting of deaths from dementia may hamper the planning of much-needed health services for people dying from this condition.

Scientists at HSL's Institute for Aging Research conduct rigorous medical and social studies, leading the way in developing strategies for maximizing individuals' strength, vigor and physical well-being, as well as their cognitive and functional independence, in late life.

Sharp-witted elderly shed insight on dementia

CHICAGO, 17 nov 2008– People who manage to keep a razor-sharp memory well into their 80s appear to have fewer fiber-like tangles of a protein linked with Alzheimer's than those who age normally, U.S. researchers said on Sunday.

Lower levels of this protein, known as tau, appear to be a critical factor in maintaining memory skills, they said.

"It was always assumed that the accumulation of these tangles is a progressive phenomenon through the aging process," Changiz Geula of Northwestern University's Feinberg School of Medicine in Chicago, said in a statement.

"But we are seeing that some individuals are immune to tangle formation and that the presence of these tangles seems to influence cognitive performance," said Geula, who is presenting his findings at a Society for Neuroscience meeting in Washington.

While most studies of memory and aging involve people with some form of cognitive decline, Geula studied the so-called "super-aged," or those who maintain sharp cognitive skills in advanced age.

The researchers studied the brains of five deceased people considered super-aged because of their high scores on memory tests at age 80, and compared them to the brains of elderly individuals who had no signs of dementia.

They found far fewer tau tangles in those who had sharp memories than those with normal memories for their age.

Curiously, the number of sticky plaques made of beta amyloid-- considered a hallmark of Alzheimer's disease -- was about the same in both groups.

While tau protein accumulates inside brain cells, forming fibrous tangles that eventually cause the cell to burst, beta-amyloid plaques accumulate outside the brain cell, disrupting cell-to-cell communication.

People with Alzheimer's disease have abnormal levels of both plaques and tangles. There is no cure for Alzheimer's, and current drugs merely delay symptoms.

Many drug companies have been working on therapies to remove clumps of beta amyloid from the brains of people with Alzheimer's in the hope of slowing or reversing the course of the disease, but have met with limited success.

Recently, however, some companies have begun to focus on therapies directed at toxic tangles caused by an abnormal buildup of the tau protein.

One, a nasal spray made by Allon Therapeutics Inc, improved some measures of memory in an early-stage study of patients with mild cognitive impairment, a precursor to Alzheimer's.

Rember, made by TauRX Therapeutics in Singapore, improved key measures of thinking and memory in some people with moderate Alzheimer's disease.

Geula said new research will focus on what makes cells in super-aged brains more resistant to tangle formation.

"We want to see what protects the brains of these individuals against the ravages that cause memory loss," he said.

Alzheimer's is the most common form of dementia, affecting 5.2 million people in the United States and 26 million globally, according to the Alzheimer's Association

Doctors Say Medication Is Overused in Dementia

By LAURIE TARKAN
25 june 2008--Ramona Lamascola thought she was losing her 88-year-old mother to dementia. Instead, she was losing her to overmedication.
Last fall her mother, Theresa Lamascola, of the Bronx, suffering from anxiety and confusion, was put on the antipsychotic drug Risperdal. When she had trouble walking, her daughter took her to another doctor — the younger Ms. Lamascola’s own physician — who found that she had unrecognized hypothyroidism, a disorder that can contribute to dementia.
Theresa Lamascola was moved to a nursing home to get these problems under control. But things only got worse. “My mother was screaming and out of it, drooling on herself and twitching,” said Ms. Lamascola, a pediatric nurse. The psychiatrist in the nursing home stopped the Risperdal, which can cause twitching and vocal tics, and prescribed a sedative and two other antipsychotics.
“I knew the drugs were doing this to her,” her daughter said. “I told him to stop the medications and stay away from Mom.”
Not until yet another doctor took Mrs. Lamascola off the drugs did she begin to improve.
The use of antipsychotic drugs to tamp down the agitation, combative behavior and outbursts of dementia patients has soared, especially in the elderly. Sales of newer antipsychotics like Risperdal, Seroquel and Zyprexa totaled $13.1 billion in 2007, up from $4 billion in 2000, according to IMS Health, a health care information company.
Part of this increase can be traced to prescriptions in nursing homes. Researchers estimate that about a third of all nursing home patients have been given antipsychotic drugs.
The increases continue despite a drumbeat of bad publicity. A 2006 study of Alzheimer’s patients found that for most patients, antipsychotics provided no significant improvement over placebos in treating aggression and delusions.
In 2005, the Food and Drug Administration ordered that the newer drugs carry a “black box” label warning of an increased risk of death. Last week, the F.D.A. required a similar warning on the labels of older antipsychotics.
The agency has not approved marketing of these drugs for older people with dementia, but they are commonly prescribed to these patients “off label.” Several states are suing the top sellers of antipsychotics on charges of false and misleading marketing.
Ambre Morley, a spokeswoman for Janssen, the division of Johnson & Johnson that manufactures Risperdal, would not comment on the suits, but said: “As with any medication, the prescribing of a medication is up to a physician. We only promote our products for F.D.A.-approved indications.”
Nevertheless, many doctors say misuse of the drugs is widespread. “These antipsychotics can be overused and abused,” said Dr. Johnny Matson, a professor of psychology at Louisiana State University. “And there’s a lot of abuse going on in a lot of these places.”
Dr. William D. Smucker, a member of the American Medical Directors Association, a group of health professionals who work in nursing homes, agreed. Though the group encourages doctors to conduct a thorough assessment and prescribe antipsychotics only as a last resort, he said, “Many physicians are absent without leave in the nursing home and don’t take an active role in the assessment of the patient.”
Some nursing homes are trying a different approach, so-called environmental intervention. The strategies include reducing boredom, providing intellectual and physical stimulation, exercise, calming music, bringing in pets for therapy and improving how the staff approaches and talks to dementia patients.
At the Margaret Teitz Nursing and Rehabilitation Center in Queens, social workers do life reviews of patients to understand their interests, lifestyle and former occupations.
“I had a patient who used to be in fashion,” said Nancy Goldwasser, the director of social services. “So we got her fabric samples. And she’d sit and look through the books, touch the fabric, and it would calm her.”
But such approaches are time consuming, they do not help all patients, they can be prohibitively expensive and they will be more difficult to provide as Alzheimer’s continues to increase.
“Our health care system isn’t set up to address the mental, emotional and behavioral problems of the elderly,” said Dr. Gary S. Moak, president of the American Association for Geriatric Psychiatry.
Nursing homes are short staffed, and insurers do not generally pay for the attentive medical care and hands-on psychosocial therapy that advocates recommend. It is much easier to use sedatives and antipsychotics, despite their side effects.
The first generation of antipsychotics, like Haldol, carry a significant risk of repetitive movement disorders and sedation. Second-generation antipsychotics, also called atypicals, are more commonly prescribed because the risk of movement disorders is lower. But they, too, can cause sedation, and they contribute to weight gain and diabetes.
Used correctly, the drugs do have a role in treating some seriously demented patients, who may be incapacitated by paranoia or are self-destructive or violent. Taking the edge off the behavior can keep them safe and living at home, rather than in a nursing home.
If patients are prescribed an antipsychotic, it should be a very low dose for the shortest period necessary, said Dr. Dillip V. Jeste, a professor of psychiatry and neuroscience at the University of California, San Diego.
It may take a few weeks or months to control behavior. In many cases, the patient can then be weaned off of the drugs or kept at a very low dose.
Some experts say another group of medications — antidementia drugs like Aricept, Exelon and Namenda — are underused. Research shows that 10 to 20 percent of Alzheimer’s patients had noticeable positive responses to the drugs, and 40 percent more showed some cognitive improvement, even if it was not noticeable to an observer.
“Sometimes, it’s enough to take the edge off the behavioral problems, so the family and patient can live with it and you don’t expose people to much risk,” said Dr. Gary J. Kennedy, director of geriatric psychiatry at the Montefiore Medical Center in the Bronx.
Other experts cite a lack of research backing these drugs for behavioral problems.
If patients begin showing behavioral symptoms of dementia, doctors said, they should have complete medical and psychiatric workups first, especially if symptoms develop suddenly.
“Just because someone is 95 does not mean one should not do a workup, especially if she’s been healthy,” Dr. Kennedy said.
Common causes of the symptoms include ministrokes, reparable brain hemorrhage from a mild bump on the head, hypothyroidism, dehydration, malnourishment, depression and sleep disorders.
Some doctors point out that simply paying attention to a nursing home patient can ease dementia symptoms. They note that in randomized trials of antipsychotic drugs for dementia, 30 to 60 percent of patients in the placebo groups improved.
“That’s mind boggling,” Dr. Jeste said. “These severely demented patients are not responding to the power of suggestion. They’re responding to the attention they get when they participate in a clinical trial.
“They receive both T.L.C. and good general medical and humane care, which they did not receive until now. That’s a sad commentary on the way we treat dementia patients.”
To family members looking at a nursing home for an aging parent, experts recommend seeking out homes with low staff turnover, a high ratio of staff members to patients, and programs with psychosocial components.
The Medicare Web site has basic information on individual homes at www.medicare.gov/NHcompare. The National Citizens’ Coalition for Nursing Home Reform, at www.nccnhr.org, offers a consumer guide to choosing a nursing home.
If medications are necessary, a family member should communicate with the prescribing doctor, learn the goal of each medication and be involved in making the decision.
Dr. Moak, of the psychiatry association, emphasized seeking out the doctor. Family members, he said, “often speak through the nursing staff, and that’s a huge mistake.”
Family members who are not convinced that a relative is receiving the best care should get a second opinion, as Ramona Lamascola did.
The physician she consulted, Dr. Kennedy of Montefiore, stopped her mother’s antipsychotics and sedatives and prescribed Aricept.
“It’s not clear whether it was getting her hypothyroid and other medical issues finally under control or getting rid of the offending medications,” he said. “But she had a miraculous turnaround.”
Theresa Lamascola still has dementia, but she went from confinement in a wheelchair — unable to sit still and screaming out in fear — to being able to walk with help, sit peacefully, have some memory and ability to communicate, understand subtleties of conversations and even make jokes.
Or, as her daughter put it, “I got my mother back.”

Short Limbs Associated with Risk of Dementias

By Todd Neale
BOSTON, 06 may 2008 -- A man with a 32-inch sleeve has a greater risk of developing Alzheimer's disease and other dementias than a man with a 35-inch sleeve.
So it seems from a prospective, longitudinal study showing that for both men and women, having shorter limbs is associated with increased risks for Alzheimer's and other dementias.
Women in the lowest quartile of arm span had a 1.42-fold greater risk of dementia and a 1.72-fold increased risk of Alzheimer's disease compared with other women, reported Tina Huang, Ph.D., of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts, and colleagues in the May 6 issue of Neurology.
Every one-inch increase in knee height in women was associated with a 16% lower risk of dementia and a 22% reduced risk of Alzheimer's disease.
For men, every one-inch increase in arm length was associated with a lowering of the risk of dementia by 6% and the risk of Alzheimer's by 7%, they said.
"Our findings with knee height and arm span are consistent with previous reports and suggest early life environment may play an important role in the determination of future dementia risk," they said.
Anthropometric measures can be used as markers of childhood environment, and may reflect nutritional or other deficits during early development, the researchers said.
Several studies have linked early environmental factors and susceptibility to disease in later life, they said, and some, including three on Korean populations, have made the connection between shorter leg and arm lengths and cognitive impairment.
For an American population, Dr. Huang and colleagues turned to the Cardiovascular Health Cognition Study, which followed 2,798 patients (mean age 72; 41% male; 89.5% white) for an average of 5.4 years.
Knee height was measured three years before the study started and arm span was measured four years after baseline.
Cerebral MRI was performed at the start of the study and at five years. Cognitive function was measured at baseline and then at each follow-up visit using the Modified Mini-Mental State Examination.
During follow-up, 480 participants developed dementia for an incidence of 31.9 cases per 1,000 person-years: 245 were possible or probable Alzheimer's disease, 213 were possible or probable vascular dementia, and 22 were other dementias.
The association of a lower risk of dementia and Alzheimer's with greater knee height was only significant in women, after controlling for age, race, and presence of the APOEe4 allele, which is known to increase the risk for dementia and Alzheimer's disease.
For women, every one-inch increase in arm length was associated with a lowering of the risk of dementia by 6% (HR 0.94, 95% CI 0.89 to 0.99) and the risk of Alzheimer's by 9% (HR 0.91, 95% CI 0.85 to 0.97).
"Differences in limb length," the researchers said, "could reflect differences in genetics, environment, or both."
Insufficient nutritional intake during childhood could cause stunted growth, which is reflected in shorter height and limb length, and impaired brain development, they said.
"Thus," they continued, "it is possible that early nutritional deficits, exposure to environmental toxins, or other unaccounted-for residual confounders could influence intelligence, cognitive functioning, level of educational attainment, or vulnerability to dementia."
The authors acknowledged that the study was limited by the measurement of arm length four years after the start of the study and the possibility of misclassification of dementia outcome.
Strengths of the study included the length of follow-up, the longitudinal, prospective design, the "state-of-the-art adjudication of incident dementia, Alzheimer's, and vascular dementias," and the high number of dementia cases.
"These reasons, plus the fact that our studies have now replicated previous findings," they concluded, "increase our confidence in concluding that the shorter a woman's knee height, or the shorter the arm span of either gender, the greater the risk of developing dementia or [Alzheimer's disease]."
They called for further studies to explore gender differences in the associations of knee height and arm span with dementia.
Dr. Huang was supported by grants from the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Charles A. King Trust, and the U.S. Department of Agriculture Agricultural Research Service. The study was supported by contracts from the National Heart, Lung, and Blood Institute and a grant from the National Institute on Aging.
The authors reported no conflicts of interest.
Primary source: NeurologySource reference:Huang T, et al "Knee height and arm span: a reflection of early life environment and risk of dementia"Neurology 2008; 70: 1818-1826.Additional Dementia Coverage