Low Levels Of “Memory Protein” Linked to Cognitive Decline in Alzheimer’s Disease

(Johns Hopkins Medicine) Working with human brain tissue samples and genetically engineered mice, Johns Hopkins Medicine researchers together with colleagues at the National Institutes of Health, the University of California San Diego Shiley-Marcos Alzheimer’s Disease Research Center, Columbia University, and the Institute for Basic Research in Staten Island say that consequences of low levels of the protein NPTX2 in the brains of people with Alzheimer’s disease (AD) may change the pattern of neural activity in ways that lead to the learning and memory loss that are hallmarks of the disease.

This discovery, described online in the April 25 edition of eLife, will lead to important research and may one day help experts develop new and better therapies for Alzheimer’s and other forms of cognitive decline.

AD currently affects more than five million Americans.

Clumps of proteins called amyloid plaques, long seen in the brains of people with AD, are often blamed for the mental decline associated with the disease. But autopsies and brain imaging studies reveal that people can have high levels of amyloid without displaying symptoms of AD, calling into question a direct link between amyloid and dementia.

This new study shows that when the protein NPTX2 is “turned down” at the same time that amyloid is accumulating in the brain, circuit adaptations that are essential for neurons to “speak in unison” are disrupted, resulting in a failure of memory.

“These findings represent something extraordinarily interesting about how cognition fails in human Alzheimer’s disease,” says Paul Worley, M.D., a neuroscientist at the Johns Hopkins University School of Medicine and the paper’s senior author.

“The key point here is that it’s the combination of amyloid and low NPTX2 that leads to cognitive failure.”

Since the 1990s, Worley’s group has been studying a set of genes known as “immediate early genes,” so called because they’re activated almost instantly in brain cells when people and other animals have an experience that results in a new memory.

The gene NPTX2 is one of these immediate early genes that gets activated and makes a protein that neurons use to strengthen “circuits” in the brain.

“Those connections are essential for the brain to establish synchronized groups of ‘circuits’ in response to experiences,” says Worley, who is also a member of the Institute for Basic Biomedical Sciences.

“Without them, neuronal activation cannot be effectively synchronized and the brain cannot process information.”

Worley says he was intrigued by previous studies indicating altered patterns of activity in brains of individuals with Alzheimer’s. Worley’s group wondered whether altered activity was linked to changes in immediate early gene function.

To get answers, the researchers first turned to a library of 144 archived human brain tissue samples to measure levels of the protein encoded by the NPTX2 gene. NPTX2 protein levels, they discovered, were reduced by as much as 90 percent in brain samples from people with AD compared with age-matched brain samples without AD. By contrast, people with amyloid plaques who had never shown signs of AD had normal levels of NPTX2. This was an initial suggestion of a link between NPTX2 and cognition.

Prior studies had shown NPTX2 to play an essential role for developmental brain wiring and for resistance to experimental epilepsy. To study how lower-than-normal levels of NPTX2 might be related to the cognitive dysfunction of AD, Worley and his collaborators examined mice bred without the rodent equivalent of the NPTX2 gene.

Tests showed that a lack of NPTX2 alone wasn’t enough to affect cell function as tested in brain slices. But then the researchers added to mice a gene that increases amyloid generation in their brain. In brain slices from mice with both amyloid and no NPTX2, fast-spiking interneurons could not control brain “rhythms” important for making new memories. Moreover, a glutamate receptor that is normally expressed in interneurons and essential for interneuron function was down-regulated as a consequence of amyloid and NPTX2 deletion in mouse and similarly reduced in human AD brain.

Worley says that results suggest that the increased activity seen in the brains of AD patients is due to low NPTX2, combined with amyloid plaques, with consequent disruption of interneuron function. And if the effect of NPTX2 and amyloid is synergistic — one depending on the other for the effect — it would explain why not all people with high levels of brain amyloid show signs of AD.

The team then examined NPTX2 protein in the cerebrospinal fluid (CSF) of 60 living AD patients and 72 people without AD. Lower scores of memory and cognition on standard AD tests, they found, were associated with lower levels of NPTX2 in the CSF. Moreover, NPTX2 correlated with measures of the size of the hippocampus, a brain region essential for memory that shrinks in AD.

In this patient population, NPTX2 levels were more closely correlated with cognitive performance than current best biomarkers  — including tau, a biomarker of neurodegenerative diseases, and a biomarker known as A-beta-42, which has long been associated with AD. Overall, NPTX2 levels in the CSF of AD patients were 36 to 70 percent lower than in people without AD.

“Perhaps the most important aspect of the discovery is that NPTX2 reduction appears to be independent of the mechanism that generates amyloid plaques. This means that NPTX2 represents a new mechanism, which is strongly founded in basic science research, and that has not previously been studied in animal models or in the context of human disease.  This creates many new opportunities,” says Worley.

“One immediate application may be to determine whether measures of NPTX2 can be helpful as a way of sorting patients and identifying a subset that are most responsive to emerging therapies.” Worley says. For instance, drugs that disrupt amyloid may be more effective in patients with relatively high NPTX2. His group is now providing reagents to companies to assess development of a commercial test that measures NPTX2 levels.

More work is needed, Worley adds, to understand why NPTX2 levels become low in AD and how that process could be prevented or slowed.

Funding for the studies described in the eLife article was provided by the National Institutes of Health under grant numbers MH100024, R35 NS-097966, P50 AG005146, and AG05131, Alzheimer’s Disease Discovery Foundation and Lumind.



© The Johns Hopkins University, The Johns Hopkins Hospital, and Johns Hopkins Health System. All rights reserved.


Diet Drinks Linked to Increased Stroke and Dementia Risk

(MedScape.com) New question marks over the safety of diet soda have arisen following a study linking intake of artificially sweetened beverages to both stroke and dementia.

The study, published online in Stroke on April 20, showed that consumption of one can of diet soda or more each day was associated with a three times increased risk for stroke and dementia over a 10-year follow-up period compared with individuals who drank no artificially sweetened beverages.

“There are many studies now suggesting detrimental effects of sugary beverages, but I think we also need to consider the possibility that diet drinks may not be healthy alternatives,” lead author, Matthew P. Pase, PhD, Boston University School of Medicine, Massachusetts, told Medscape Medical News.

“We can’t show cause and effect in this study as it is observational in design, but given the popularity of diet drinks we desperately need more research on this question.”

He is not yet recommending against diet beverages based on this study, he added,

“but I would urge caution — especially to those individuals who consume multiple diet drinks daily. I believe we need to rethink the place of these drinks.”

It is possible that the observation could be due to reverse causality, he noted.

“It is not clear whether the diet sodas are causing stroke and dementia or whether unhealthy people gravitate more towards these drinks than healthier people.

“If you already have cardiovascular risk factors, you are likely to have been advised to lower your sugar intake and so may move away from sugary beverages to diet drinks,” Dr Pase said.

“We did find that a higher intake of diet soda was linked to diabetes at baseline, but again we don’t know which came first. Did the diet drinks increase the risk of developing diabetes, or did diabetic patients choose diet drinks as they have to limit their sugar intake?”

The link between diet drinks and dementia became nonsignificant when adjusted for vascular risk factors. Dr Pase suggested this could be because the association may be mediated through vascular risk factors — artificial sweeteners could be increasing vascular risk factors.

“Or it could just be that people with vascular risk factors drink more diet sodas, which is perfectly possible as they could have been advised to cut down on sugar.”

The link with ischemic stroke was still there in all models after adjustment for all other risk factors.

Sugar-sweetened beverages were not associated with stroke or dementia risk, but the authors say this should not be taken as evidence that sugary drinks are safe.

“There are many other studies suggesting harmful effects of sugar-sweetened drinks, and we did not have large enough numbers of people consuming sugary drinks in our current study for reliable information on this,” Dr Pase said.

“We had much larger numbers of individuals reporting intake of artificially sweetened drinks.”

Another study by the same group, published online in Alzheimer’s and Dementia on March 5, shows a link between consumption of both sugar-sweetened and artificially sweetened beverages and reduction in brain volume in a middle-aged cohort. In the cross-sectional study, the sugary drinks, which included both soda and fruit juice, were also associated with worse episodic memory.

“Greater intake of total sugary beverages, fruit juice, and soft drinks were all associated with characteristics of preclinical Alzheimer’s disease,” the authors concluded.

“Additional studies are warranted to confirm our findings and evaluate if sugary beverages are associated longitudinally with worsening of subclinical Alzheimer’s disease and with incident Alzheimer’s disease.”

Commenting on these studies for Medscape Medical News, Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer’s Association, said,

“Both studies are difficult to interpret — the conclusions are a bit different to one another — but epidemiological data is messy.”

Still, he added, “These two papers should certainly sound warning bells, but neither are suggesting we can take just one simple step of cutting out sodas and or juice to reduce our risk of stroke or dementia. We must look at the whole picture of diet and exercise, of which this is just one very small piece.”

“Of the two papers, it is easier to grasp that high sugar intake is not doing good things to the brain, but there is growing evidence in the literature that diet drinks are not necessarily the panacea that some once might have believed them to be,” Dr Fargo noted.

“We can’t say from this data that that someone who drinks a few diet [beverages] will have a significantly higher risk of dementia. It’s all just speculation. The best thing we can do is conduct further studies to find out more. The health recommendations are unlikely to be simple, but perhaps it may not be the best idea to replace a sugary beverage with an artificially sweetened drink. It’s a better idea to skip both and just drink water.”

In the study published in Stroke, researchers analyzed data from the Framingham Heart Study Offspring cohort on intake of sugar sweetened and artificially sweetened beverages and the incidence of a first stroke or diagnosis of dementia.

The stroke cohort included 2888 participants older than age 45 years (average age, 62 years) and the dementia cohort included 1484 participants older than age 60 years (average age, 69 years).

All participants had completed regular food intake questionnaires. For the current study, researchers focused on beverage intake from 1991 to 2001 and the occurrence of stroke or dementia in the following 10 years.

There were 97 cases of incident stroke (82 ischemic) and 81 cases of incident dementia (63 consistent with Alzheimer’s disease).

Results showed that after adjustments for age, sex, education (for analysis of dementia), caloric intake, diet quality, physical activity, and smoking, higher recent and higher cumulative intake of artificially sweetened soft drinks were associated with an increased risk for ischemic stroke, all-cause dementia, and Alzheimer’s disease dementia.

When the researchers compared daily cumulative intake to 0 beverages per week (reference), the hazard ratios were 2.96 (95% confidence interval [CI], 1.26 – 6.97) for ischemic stroke and 2.89 (95% CI, 1.18 – 7.07) for Alzheimer’s disease.

On the diet drink results, he said, “We found that people who drank at least one can of diet soda each day had a 3 times increased risk of stroke and dementia than those not drinking any such beverages.”

He noted that lower intakes (between 1 and 6 drinks a week) were still associated with stroke but not dementia.

Sugar-sweetened beverages were not associated with stroke or dementia.

In addition to the smaller numbers on sugary beverages, there was also the possibility that more of those who drank sugar-sweetened beverages may have died of heart disease during the study period and would therefore not be included in the stroke and dementia endpoints, he said.

Dr Pase said it is not known how diet soda could be causing harm, but there some data suggest that artificial sweeteners may predispose toward weight gain.

“Animal studies have shown that rats given artificial sweeteners gain weight more than rats given an identical diet without artificial sweeteners,” he said.

“These artificial sweeteners have also been linked to a change in the composition of gut bacteria and the development of glucose intolerance. There is some data on this in humans too, but it is much more difficult in humans to show cause and effect.”

He added: “There is the possibility that the association of sweetness and calories becomes uncoupled in the brain when we consume artificial sweeteners. The brain is conditioned to expect calories when it senses a sweet taste, but if this doesn’t happen maybe people tend to overcompensate with other sweet food.”

Markers of Preclinical Alzheimer’s

In the study published in Alzheimer’s and Dementia, the researchers, again led by Dr Pase, used Framingham data to look at possible links between sugar-sweetened and artificially sweetened beverage intake and results of neuropsychological (n = 4276) and MRI (n = 3846) markers of preclinical Alzheimer’s disease.

They found that greater consumption of total sugary beverages was associated with lower total brain volume and lower memory scores. Relative to no intake, the difference in total brain volume associated with consuming 1 to 2 or more than 2 sugary beverages per day was equivalent to 1.6 and 2.0 years of brain aging, respectively, and the difference in memory scores was equivalent to 5.8 and 11.0 years of brain aging, respectively.

Higher diet soft drink intake was associated with smaller total brain volume and poorer performance on one of the neuropsychological tests.

In an editorial accompanying the study published in Stroke, and addressing the results with the diet drinks, Heike Wersching, MD, University of Munster, Germany, and Hannah Gardener, ScD, and Ralph L. Sacco, MD, University of Miami Miller School of Medicine, Florida, reiterate that whether the observed associations between artificially sweetened beverages and stroke and dementia are causal or reflect reverse causation bias is difficult to elucidate, and further studies are needed.

They suggest that future epidemiologic studies could include requirements for data on previous weight fluctuations, dieting behavior, changes in sweetened/artificially sweetened beverage consumption over time, and reasons for choosing artificially sweetened beverages.

“The work by Pase et al highly encourages further discussion and more research into this question, for even small causal effects would have tremendous effects on public health due to the popularity of both artificially sweetened and sugar sweetened beverage consumption,” they conclude.

They add that the current body of literature is inconclusive about the causal nature of the associations between artificially sweetened beverage consumption and risk for stroke, dementia, diabetes mellitus, and the metabolic syndrome.

The growing number of epidemiologic studies showing strong associations between frequent consumption of artificially sweetened beverages and vascular outcomes, however, suggests that it may not be reasonable to substitute or promote these drinks as healthier alternatives to sugary drinks.

“Both sugar-sweetened and artificially sweetened soft drinks may be hard on the brain,” they conclude.

 Stroke. Published online April 20, 2017. Abstract, Editorial

Alzheimer’s & Dementia. Published online March 5, 2017.  Abstract


By Sue Hughes

Copyright © 1994-2017 by WebMD LLC.


‘Everybody Knows Somebody’: This State is a Laboratory for the Future of Alzheimer’s in America

(PBS.org) North Dakota’s sparse geography has long made it a natural frontier: Pioneers here pushed the boundaries of westward expansion, then agriculture, and recently domestic oil drilling. Now the state finds itself on the leading edge of a new boom that it never would have chosen: Alzheimer’s disease.

Cases are climbing across the United States, and especially in North Dakota, which has the country’s second highest death rate from the disease. While Alzheimer’s is the sixth leading cause of death nationally, it already ranks third here.

“Everybody knows somebody” affected by the disease, said Kendra Binger, a program manager with the Alzheimer’s Association of Minnesota and North Dakota. As public awareness rises along with the numbers of cases, “it’s hard to ignore anymore.”

This makes the state an ideal laboratory to glimpse at the future of Alzheimer’s in America, and to identify strategies that could help the rest of the country cope. The devastating disease has strained families and the state budget. So North Dakota — a place that prides itself on personal independence and financial parsimony — has found new ways to support its residents and a new consensus to spend money on prevention.

The state’s primary strategy is to assist family caregivers — the estimated 30,000 North Dakota spouses, siblings, sons, and daughters looking after loved ones with dementia. A half-dozen consultants roam the state to evaluate families’ needs, train caregivers, connect them to services, and offer advice. Studies show the program has helped families keep their loved ones out of nursing homes and save the state money.

“We are not well-prepared, to put it mildly,” to respond to the growing Alzheimer’s crisis across the country, said Marc Cohen, clinical professor of gerontology and director of the Center for Long-Term Services and Supports at the University of Massachusetts, Boston. Since the burden of caring for dementia patients falls heavily on family members, he added, strategies like North Dakota’s are “exactly what is needed.”

Betty Mahlke, a retired bookkeeper, discovered the impact of North Dakota’s approach two years ago, when her husband, Larry, started forgetting everyday details — a troubling symptom of the Alzheimer’s diagnosis he’d received years before. It’s lonely enough caring for a loved one with dementia in the heart of a city, surrounded by service organizations and care options. But like Betty, many of North Dakota’s growing ranks of family caregivers are doing it in far lonelier places: on isolated farms or in small towns across 350 miles of the Great Plains.

The Mahlkes lived in Jamestown, a city of 15,000 halfway between Fargo and Bismarck, a hundred miles from each. Jamestown is hardly the state’s most remote community; it is home to the National Buffalo Museum, a stock car racetrack, and high school football games that Larry Mahlke loved to frequent. But it has limited support services compared to a big city. So when a visiting consultant, Beth Olson, came to give a presentation on dementia at the local senior center in March 2015, Betty seized the chance.

“Every little hint” about how to care for Larry resonated, Betty recalled.

“I was just grasping for anything that could help.”

Soon after, Olson visited the Mahlkes at home, and that began a relationship that would carry Betty through the deepening challenges to come. At first, Olson suggested puzzles and games that could help Larry, a retired furnace installer and insurance salesman, keep his mind active. When he later stopped recognizing his own home, she coached Betty on the best response. Instead of arguing, Betty would invite him into the car, drive a few blocks, drive back, and say they were home. Sometimes the gambit worked, Betty said.

“Other times he’d say, ‘This is not my house,’ and we’d have to drive around some more.”

Olson’s personalized support of the Mahlkes is North Dakota’s model for easing the burden of Alzheimer’s and other forms of dementia. Olson is a care consultant with the state’s Dementia Care Services Program, established in 2009. Republican state Senator Dick Dever proposed the program after discovering personally the difficulty of caring for a family member with Alzheimer’s. The state Legislature approved it with overwhelming support in both houses. Michigan is now piloting a similar program in three counties and working to expand it statewide.

What makes North Dakota such an Alzheimer’s hot spot? Like much of the rest of the Midwest, it’s graying. Rural counties are emptying out as young people depart for better job prospects elsewhere, leaving an earlier, aging generation behind. This is a familiar story for Betty Mahlke, whose four grown sons all settled out of state (in Minnesota, Nevada, and Idaho) for the sake of work.

The youth exodus has been countered in North Dakota by a flood of young arrivals coming to work the oil fields — but only in a fraction of the state’s counties, and not enough to divert the overall trend. The state still has a high ratio of elderly residents. Especially large is the group called the “oldest old,” those age 85 and over, who are dramatically more likely to die from Alzheimer’s than the group age 65 and over. In the latest US Census, only Rhode Island had a larger portion of its populace in the “oldest old” range.

Still, that explanation doesn’t satisfy Dr. Donald Jurivich, chair of geriatrics at the University of North Dakota School of Medicine and Health Sciences, who believes there’s more at play than migration patterns. When he shows his colleagues North Dakota’s high dementia numbers, he said,

“People have pretty much been stupefied.” Why wouldn’t Rhode Island, with its higher ratio of “oldest old,” match North Dakota in dementia deaths?

And why not Iowa, whose population of “oldest old” is nearly as high? The only state with a comparable ratio of the very elderly whose dementia death rate surpasses North Dakota is neighboring South Dakota.

Jurivich and his colleagues have speculated on a host of possible causes, none yet proven: Perhaps North Dakota’s high Alzheimer’s death rates could be explained by radon exposure, a meat-heavy diet, genetic predispositions among the northern Europeans who settled this part of the Midwest, or simply state-by-state differences in record keeping. He’s applying for grants to fund further study to solve the mystery.

The Dementia Care Services Program, meanwhile, has to cope with the realities on the ground. The program, run by the regional Alzheimer’s Association, substantially expanded the shoestring work that the association was doing before 2009. Previously, two consultants had covered the entire state, counseling families one-on-one (including Dever’s family) and raising their own funds. Thus stretched, they couldn’t range far beyond Fargo and Bismarck, the two largest cities.

Now, six care consultants do the job, dividing the state into eight zones. As Olson did with the Mahlkes, the consultants assess patients’ needs, teach caregivers what to expect and how to respond, refer them to services, lead support groups, and answer questions by phone and in person. Importantly, they often visit patients’ homes, even those in the remotest corners of the state. Between January 2015 and this February, nearly three-quarters of the 2,602 consultations were done in person.

Deaths from Alzheimer’s have jumped 74 percent since 2000 in North Dakota, and the program’s caseload has similarly exploded. The number of families served has risen steadily since 2011, from about 500 in every two-year period to a current pace that could double that. The program costs the state $600,000 a year.

The program’s main purpose is to help families keep loved ones with dementia at home, rather than in a nursing facility, for longer. With average nursing home costs running over $8,000 a month per patient, and the state’s share of Medicaid paying half the price, even a few weeks’ delay can make a dent. For families, having the knowledge and support to keep a loved one at home can also make a big emotional impact, relieving the bewilderment and burnout that often afflicts caregivers and preventing costly, avoidable medical care for patients and caregivers alike.

That’s what it did for Betty Mahlke. Though the caregiving exhausted her, she couldn’t stomach the idea of moving her husband into a care facility. When Larry eventually couldn’t recognize even her, Olson had already prepared her for how to respond.

“We’d be sitting in the living room and he would look at me strangely, and you could see that fear in his eyes, that this lady is not anybody he knows,” Betty recalled.

“There were times when we’d go to bed at night and he’d lay on the edge of the bed, stiff as a board.”

When Larry said, “Where’s Betty?” she knew to reassure him: “I’ll go try and find her.” Then she’d leave the room, change her shirt, and come back in.

Without that preparation, Betty said, she wouldn’t have known how to handle Larry’s confusion. And if she’d had to travel to a bigger city to attend the presentation that first introduced her to Olson, she’d never have gone. All told, without the Dementia Care Services Program, she said, she could never have kept Larry at home for so long.

A formal evaluation of the program backed up stories like Betty’s with statistics. The study, conducted at the University of North Dakota Center for Rural Health, looked at the first 3 1/2 years of the program. Caregivers reported that it helped them feel more empowered, less likely to need emergency room visits and hospitalizations for their loved ones, and less likely to place their loved ones in long-term care. The researchers estimated the resulting cost savings at $800,000 for medical and hospital services avoided and $39 million for long-term care.

Michigan, too, studied its similar, small pilot program and found that it reduced nursing home placements by more than 9 percent and saved the state over $500,000 in a single year.

The bottom line, said Brad Gibbens, deputy director of the UND Center for Rural Health:

“If you can provide some support services for the family caregiver, you can improve the lives of those with dementia and the family caregiver, and likely save the public taxpayer some money.”

Even so, the North Dakota program lost over 10 percent of its funding in a budget crunch last year and could face further cutbacks as the state grapples with a continued shortfall. This comes as Republican congressional leaders in Washington have proposed capping Medicaid money sent to states as part of the Affordable Care Act repeal, which could make such dementia care programs all the more important.

Over the past quarter-century, the balance of Medicaid money spent on long-term care has shifted away from nursing homes and toward more home- and community-based care. UMass Boston’s Cohen warns that the proposed caps could reverse that trend, resulting in cuts for optional support programs and thus sending more patients into nursing homes.

“If there is less money available to pay for home and community-based care,” he said, “families will have to pick up the slack — or people will have greater unmet need — and training to make them more effective will become more important.”

As the number of Alzheimer’s patients grows and federal dollars potentially dwindle, other states are likely to need to develop similar supports for families, for reasons both humane and pragmatic.

“We know people do better at home, and people want to care for their loved ones at home,” said Gretchen Dobervich, a one-time field director for the regional Alzheimer’s Association who now represents Fargo as a Democratic member of the state Assembly.

Plus, “with the large numbers of people we’re going to see with this disease, there’s no way we’re going to be able to have enough care facilities to treat the number of diagnoses we’re going to see.”

The North Dakota program ultimately enabled Betty Mahlke to care for Larry at home until just three weeks before his death. One day in March 2016, a year after entering the Dementia Care Services Program and six years after his initial diagnosis, Betty went out for a few hours and left Larry in the care of a health aide from a company Olson had helped her find. Larry, disoriented and distressed, shoved the unfamiliar woman and walked out of the house, searching for Betty. He walked a block in the late-winter cold without a coat or shoes on. Betty told Olson, who happened to be in town for an event, and the two of them brought him home.

The next night, his last night at home, Betty and Larry had a picnic dinner in the living room and danced waltzes like they had as younger sweethearts. The following day, Betty brought him to a nursing home, where hospice helped pay part of the staggering $1,860-per-week cost. Larry died less than three weeks later, at age 74. The Mahlkes had been married for 51 years.

“I don’t think that he suffered” during those few weeks in the nursing home, “so that was a blessing,” Betty said.

“I did it for my husband, and I know he would have done it for me.”

This article is reproduced with permission from STAT. It was first published on April 12, 2017. Find the original story here.



BY Grace Rubenstein, STAT

© 1996 – 2017 NewsHour Productions LLC. All Rights Reserved.


Two Existing Drugs Halt Neurodegeneration In Mice

(MedicalNewsToday.com) Researchers have made a major leap forward in the treatment of Alzheimer’s and Parkinson’s, after identifying two existing drugs that prevented brain cell death in mouse models of neurodegenerative disease.

In a new study, researchers from the Medical Research Council (MRC) in the United Kingdom reveal how a licensed antidepressant and a compound currently being trialled as a cancer drug blocked brain cell death, reduced brain shrinkage, and restored memory in mouse models of prion disease and frontotemporal dementia (FTD).

Study leader Prof. Giovanna Mallucci, of the MRC’s Toxicology Unit and the University of Cambridge in the U.K., and colleagues believe that their findings could lead to much-needed treatments for Alzheimer’s disease and other neurodegenerative diseases in as little as 2 to 3 years.

Clinical trials are needed to determine the safety and efficacy of the compounds for neurodegenerative disease in humans, but the fact that one of the compounds is already used for the treatment of depression could speed up the process.

Prof. Mallucci and her team recently reported their findings in the journal Brain.

Restoring Protein Production in Brain Cells

Neurodegenerative disease is an umbrella term for numerous conditions that involve the damage and loss of brain cells. Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis are all examples of neurodegenerative disease.

In a study published in 2013, Prof. Mallucci and her team uncovered a specific pathway that contributes to brain cell death.

The researchers found that misfolded proteins in the brain – which are abundant in the brains of patients with Alzheimer’s and other neurodegenerative disorders – over-activate an unfolded protein response, which hampers the production of new proteins in brain cells. This “starves” the brain cells and kills them.

In their 2013 study, the team used an experimental drug to reactivate protein production in brain cells. While it was successful in halting brain cell death, the compound was toxic to the pancreas and unsafe for human testing.

Now, the researchers have identified two new compounds that have not only proven effective for preventing brain cell death in mice, but they also had minimal side effects.

Neurodegeneration Prevented in Mice

For the new study, Prof. Mallucci and colleagues tested more than 1,000 compounds on roundworms, or Caenorhabditis elegans. The team notes that roundworms have a functioning nervous system and are commonly used to screen drugs that might be effective in mammals.

The researchers identified a number of compounds that showed promise for restoring protein production in the brain cells of neurodegenerative disease mouse models.

The team then tested these compounds on mouse models of prion disease – a group of neurodegenerative diseases caused by proteins called prions, which prompt the misfolding of healthy proteins – and a familial form of FTD.

FTD is a type of dementia caused by the loss of brain cells in the frontal lobes of the brain.

Two compounds were found to be effective: trazodone and dibenzoylmethane (DBM). Trazodone is a medication used for the treatment of depression, while DBM is a licorice-derived compound currently undergoing testing as an anti-cancer drug.

In most of the mouse models of prion disease, both drugs prevented signs of brain cell death by recovering protein production, and in FTD mouse models, the drugs restored memory.

Additionally, the researchers found that the drugs led to a decrease in brain shrinkage in both mouse models. Brain shrinkage is a hallmark of neurodegenerative disease.

The team notes that the side effects of both drugs were minimal.

An ‘Exciting First Step’ for the Treatment of Neurodegenerative Disease

The next step for the researchers is to conduct clinical trials to determine the safety and efficacy of trazodone and DBM for the treatment of neurodegenerative disease in humans.

Trazodone is the most promising candidate, since its safety has already been established in humans.

“We know that trazodone is safe to use in humans, so a clinical trial is now possible to test whether the protective effects of the drug we see on brain cells in mice with neurodegeneration also applies to people in the early stages of Alzheimer’s disease and other dementias.

We could know in 2 to 3 years whether this approach can slow down disease progression, which would be a very exciting first step in treating these disorders.” Prof. Giovanna Mallucci

Dr. Doug Brown, director of research and development at the Alzheimer’s Society in the U.K., says that he is “excited by the potential of these findings.”

“They show that a treatment approach originally discovered while researching prion disease might also work to prevent the death of brain cells in some forms of dementia,” he adds.

“This research is at a very early stage and has not yet been tested in people – but as one of the drugs is already available as a treatment for depression, the time taken to get from the lab to the pharmacy could be dramatically reduced.”



Written by Honor Whiteman

Healthline Media UK Ltd, Brighton, UK.

© 2004-2017 All rights reserved. MNT is the registered trademark of Healthline Media.


The High Cost of Caring for Loved Ones With Alzheimer’s

(USNews.com) A diagnosis of Alzheimer’s disease can be overwhelming for an individual with the progressive and presently incurable condition, as well as for family.

The most common cause of dementia can wrench away a loved one in stages of cognitive decline and memory problems; it eventually disrupts all facets of daily function and is a leading cause of death. What’s more, the cost to care for a person with Alzheimer’s can be staggering, experts say, placing even more stress on caregivers.

In a recent report, the Alzheimer’s Association projected the nation will spend $259 billion in 2017 to care for people with the disease and other forms of dementia. Various reports list Alzheimer’s as one of the costliest diseases to treat in America – if not the costliest, alongside diabetes, heart disease and cancer.

A separate 2016 Alzheimer’s Association report found that nearly half – or 48 percent – of caregivers cut back on their own expenses, including basic necessities, such as food, transportation and medical care, notes Ruth Drew, director of family and information services at the association.

“For one family that’s waiting to buy a new car or not going on a fancy vacation,” she says.

“But for others it hits a lot harder, and it may mean just not really having enough food and not having enough of the basic necessities.”

Paying the Bill

Though some with early-onset Alzheimer’s are under 65, most with Alzheimer’s are older adults on Medicare. Experts worry whether the federal insurance program will be able to handle the snowballing bill, but for now, it covers the lion’s share of health costs – including medications for those with prescription drug plans. However, in addition to some out-of-pocket medical costs, long-term care costs can be crippling for families.

The average annual bill for a private room in a nursing home can top $90,000; it runs more than $40,000 for assisted living, according to a 2016 Genworth Financial cost of care survey. Specialized round-the-clock memory care offered by some nursing care facilities for those with Alzheimer’s and dementia can further drive up costs.

“Even adult day services, which often are the most cost-effective way to get care for someone who needs that level of care, can be about $24,000 a year,” Drew says. Experts recommend asking about sliding fee scales, based on income, which are sometimes used to price adult day care.

“You can see even if a person has a sizable nest egg, they could run through it very quickly,” she says.

Given that, Drew says it’s worth considering purchasing long-term care insurance, to help cover costs for nursing home care, or depending on the plan, in-home health services.

“That is typically not available after there’s a diagnosis of Alzheimer’s,” she says.

While noting there’s no one-size-fits all recommendation, Drew suggests people who have some assets and wouldn’t immediately qualify for Medicaid take a look at long-term care insurance to see if it that would be a good fit. She adds that it’s also worth considering family health history, including risk for developing Alzheimer’s and other debilitating diseases, when deciding whether to purchase long-term care insurance. Each policy is different; so it’s important to read stipulations and limitations regarding what the plans do and don’t cover.

For many, the indirect cost of caring for a person with Alzheimer’s is the most pressing – money lost taking time away from work, or quitting a job entirely to care for a family member. This economic strain disproportionately affects women in the workforce who make up the vast majority of caregivers, says Dr. Neelum Aggarwal, an associate professor of neurological sciences at Rush University Medical Center and a neurologist at the Rush Alzheimer’s Disease Center in Chicago. In speaking with caregivers, she asks them what needs to be done to keep them in the workforce, and provides resources such as lists of home health agencies and adult day care services in the area that can provide support, so caregivers can continue working.

A lack of resources can further tax caregivers of people with Alzheimer’s, who face high rates of burnout that can manifest in increased risks to their own health ranging from high blood pressure to depression. To maintain employment, check with human resources, if you work and need to take time off to provide care, regarding eligibility under the federal Family and Medical Leave Act, says Tan – who has filled out paperwork for family members of patients with Alzheimer’s.

Planning for Support

Though an Alzheimer’s diagnosis can leave families in shock, determining costs of different types of care and how those might be paid for in advance is critical. Aggarwal advises taking a team approach. Geriatric care managers, who help people navigate complex care decisions can help in planning, including assessing costs upfront, as can elder care attorneys, who may assist with everything from estate planning to advanced directives that lay out a person’s end-of-life wishes.

Dr. Zaldy Tan, medical director of UCLA Alzheimer’s and Dementia Care Program in Los Angeles, reminds caregivers to prepare themselves for a marathon, not a sprint. Those with Alzheimer’s live, on average, about eight years after symptoms become noticeable to others – and survival can range from four to 20 years, according to the Alzheimer’s Association.

Tan recommends caregivers join support groups. He notes some caregivers are reluctant to do so, thinking support groups solely provide emotional support (which experts say is also critically important).

“But in reality, it’s sort of like networking,” he says. “You have caregivers there who are taking care of people with dementia in various stages from mild, moderate to severe, so they can actually get a lot of practical tips, as well as local resources.”

Clinicians also recommend reaching out to the Alzheimer’s Association as a clearinghouse for information and to connect with various resources. The association offers a 24-hour helpline at 1-800-272-3900. “We’ve got master’s level counselors and social workers available around the clock to meet people where they are and talk about whatever they’re dealing with,” Ruth says.

Though Alzheimer’s can’t be cured, proper treatment may slow disease progression and reduce the need for care, including emergency room visits.

“Medications don’t cure or stop the disease, but they can provide some symptomatic benefits that some studies have shown delay that time to someone being placed in the nursing home,” says Dr. Jeffrey Burns, co-director of the University of Kansas Alzheimer’s Disease Center.

He also suggests considering joining a clinical trial – where care is free to patients – which could improve future treatment as well.

Even small steps – like walking – could help. Burns notes research done by the University of Kansas suggests physical exercise could possibly slow the progression of Alzheimer’s.

“If it is slowing the disease, it could reduce costs over time and keep people healthier and keep them at home longer,” he says – and keeping those with Alzheimer’s at home, where appropriate, can also reduce cost burden. Ultimately anything that may improve quality of life for those with Alzheimer’s and their caregivers and control cost is worth exploring, experts say.

“It’s an incredibly costly disease on every level – from the family to society,” Burns says.



Copyright 2017 © U.S. News & World Report L.P


Role of Vascular Disease in Development of Alzheimer’s Disease

(The JAMA Network Journals) Among adults who entered a study more than 25 years ago, an increasing number of midlife vascular risk factors, such as obesity, high blood pressure, diabetes, high cholesterol and smoking, were associated with elevated levels of brain amyloid (protein fragments linked to Alzheimer disease) later in life, according to a study published by JAMA.

Midlife vascular risk factors have been associated with late-life dementia. Whether these risk factors directly contribute to brain amyloid deposition is less well understood. Rebecca F. Gottesman, M.D., Ph.D., of the Johns Hopkins University School of Medicine, Baltimore, and colleagues examined data from 346 participants without dementia at study entry who have been evaluated for vascular risk factors and markers since 1987-1989 and with PET scans in 2011-2013 as part of the Atherosclerosis Risk in Communities (ARIC)-PET Amyloid Imaging Study. Positron emission tomography image analysis was completed in 2015.

Vascular risk factors at ARIC study entry (age 45-64 years; risk factors included body mass index 30 or greater, current smoking, hypertension, diabetes, and total cholesterol 200 mg/dL or greater) were evaluated in models that included age, sex, race, APOE genotype, and educational level.

The availability of imaging biomarkers for brain amyloid allows the study of individuals before the development of dementia and thereby allows consideration of the relative contributions of vascular disease and amyloid to cognition, as well as the contribution of vascular disease to amyloid deposition.

The researchers found that a cumulative number of midlife vascular risk factors were associated with elevated brain amyloid. Relationships between vascular risk factors and brain amyloid did not differ by race. The results were not supportive of a significant difference in association among people who were or were not carriers of an APOE 4 allele (a variant of a gene associated with increased risk for Alzheimer disease). Late-life vascular risk factors were not associated with late-life brain amyloid deposition.

“These data support the concept that midlife, but not late-life, exposure to these vascular risk factors is important for amyloid deposition,” the authors write.

“These findings are consistent with a role of vascular disease in the development of AD.”



Journal Reference:

Rebecca F. Gottesman, Andrea L. C. Schneider, Yun Zhou, Josef Coresh, Edward Green, Naresh Gupta, David S. Knopman, Akiva Mintz, Arman Rahmim, A. Richey Sharrett, Lynne E. Wagenknecht, Dean F. Wong, Thomas H. Mosley. Association Between Midlife Vascular Risk Factors and Estimated Brain Amyloid Deposition. JAMA, 2017; 317 (14): 1443 DOI: 10.1001/jama.2017.3090

Copyright 2016 ScienceDaily or by third parties, where indicated.


Vitamin E, Selenium Supplements Did Not Prevent Dementia

(The JAMA Network) Antioxidant supplements vitamin E and selenium – taken alone or in combination – did not prevent dementia in asymptomatic older men, according to a study published online by JAMA Neurology.

Antioxidants as potential treatment for cognitive impairment or dementia have been of interest for years because oxidative stress has been implicated as a dementia pathway.

The Prevention of Alzheimer’s Disease by Vitamin E and Selenium (PREADViSE) clinical trial initially enrolled 7,540 older men who used the supplements for an average of about five years and a subset of 3,786 men who agreed to be observed longer. The men received either vitamin E, selenium, both or a placebo.

The incidence of dementia (325 of 7,338 men [4.4 percent]) was not different among the four study groups, according to the results in the article by Richard J. Kryscio, Ph.D., of the University of Kentucky, Lexington, and coauthors.

Limitations of the study include losing about half of the participants to long-term follow-up during the transition from a randomized clinical trial to a cohort study. Publicity about the negative effect of supplements also may have played a role, according to the authors.

“The supplemental use of vitamin E and selenium did not forestall dementia and are not recommended as preventive agents. This conclusion is tempered by the underpowered study, inclusion of only men, a short supplement exposure time, dosage considerations and methodologic limitations in relying on real-world reporting of incident cases,” the article concludes.



http://media.jamanetwork.com/news-item/ vitamin-e-selenium-supplements-did-not-prevent-dementia/

Copyright © 2017 American Medical Association. All Rights Reserved.


Common Sedatives Linked to Increased Risk of Pneumonia in Alzheimer’s Disease

 (Canadian Medical Association Journal) Commonly used sedatives called benzodiazepines are associated with an increased risk of pneumonia when used in people with Alzheimer disease, according to a study published in CMAJ.

“An increased risk of pneumonia is an important finding to consider in treatment of patients with Alzheimer disease,” writes Dr. Heidi Taipale, Kuopio Research Centre of Geriatric Care, University of Eastern Finland, Kuopio, Finland, with coauthors.

“Benzodiazepines and Z-drugs are frequently prescribed for this population, and long-term use is typical. Pneumonia often leads to admission to hospital, and patients with dementia are at increased risk of death related to pneumonia.”

Dementia, of which 60%-70% of cases are Alzheimer disease, is a risk factor for pneumonia, and many people with dementia are prescribed benzodiazepines and non- benzodiazepines (called Z-drugs), both of which have sedative effects.

To determine if there is a link between these drugs and pneumonia, Finnish researchers looked at data from national registries on 49 484 adults living in the community diagnosed with Alzheimer disease between 2005 and 2011 in Finland. The mean age of participants was 80 years and almost two-thirds (62.7%) were women. They matched 5232 patients taking benzodiazepines and 3269 patients taking Z-drugs with the remainder not taking either drug.

They found that benzodiazepines were linked to a 30% increased risk of pneumonia in patients with Alzheimer disease, and the risk was highest at the start of treatment (during the first 30 days).

Although the association with Z-drug use and pneumonia was not statistically significant, the authors did not conclude these drugs were safer as the study did not directly compare Z-drugs and benzodiazepines.

The authors suggest that the sedative nature of benzodiazepines may increase the risk of pneumonia by increasing the aspiration of saliva or food into the lungs.

The results are consistent with studies that have found an increased risk of pneumonia in patients of all ages taking benzodiazepines.

“Benefits and risks of the use of benzodiazepines should be carefully considered for patients with Alzheimer disease and include risk of pneumonia,” the authors conclude.

In a related commentary, Dr. Paula Rochon from Women’s College Hospital and the University of Toronto, with coauthors, writes this study “is a good reminder to clinicians to ‘first do no harm’ when prescribing these drugs for frail older women and men with dementia. Nonpharmacologic approaches should be the starting point when managing neuropsychiatric symptoms in this patient population, which should help to limit inappropriate use of these drugs.”



Journal References:

  1. Heidi Taipale, Anna-Maija Tolppanen, Marjaana Koponen, Antti Tanskanen, Piia Lavikainen, Reijo Sund, Jari Tiihonen, Sirpa Hartikainen. Risk of pneumonia associated with incident benzodiazepine use among community-dwelling adults with Alzheimer disease. Canadian Medical Association Journal, 2017; 189 (14): E519 DOI: 10.1503/cmaj.160126
  2. Paula A. Rochon, Nicholas Vozoris, Sudeep S. Gill. The harms of benzodiazepines for patients with dementia. Canadian Medical Association Journal, 2017; 189 (14): E517 DOI: 10.1503/cmaj.170193

Copyright 2017 ScienceDaily or by third parties, where indicated