Benzodiazepine and related drug use increases hip fractures in persons with Alzheimer's disease

The use of benzodiazepines and related drugs increases the risk of hip fracture by 43% in persons with Alzheimer's disease, according to a new study from the University of Eastern Finland. The hip fracture risk was investigated in community-dwelling Finnish persons with Alzheimer's disease. The results of the study were published in the Journal of the American Medical Directors Association.

In total, 21% of persons with Alzheimer's disease initiated benzodiazepine and related drug use during the study. During benzodiazepine and related drug use, 2.5 hip fractures occurred per 100 person-years whereas without drug use, the incidence was 1.4 hip fractures per 100 person-years. The use of benzodiazepines and related drugs increased the hip fracture risk especially during the first six months of drug use. There was no difference within the drug group, as benzodiazepines increased the hip fracture risk as much as benzodiazepine-related drugs.

Additionally, long-term hospital stays exceeding four months after hip fracture were more common in persons with Alzheimer's disease who used benzodiazepines and related drugs at the time of hip fracture than in persons who did not use such drugs.

Treatment guidelines in different countries recommend that behavioral and psychological symptoms of dementia should be treated with nonpharmacological options. Benzodiazepines and related drugs can be used in infrequent or short-term treatment of symptoms. The results of this study highlight the importance of the guidelines to avoid adverse events associated with benzodiazepine and related drug use.

The study was based on the MEDALZ (MEDication use and ALZheimer's disease) cohort, including all Finnish persons diagnosed with Alzheimer's disease between 2005 and 2011, amounting to 70,718 persons. This study involved 46,373 persons who had no history of hip fractures and who had not used benzodiazepines and related drugs during the year preceding the study. The follow-up time in the study was up to five years.

Article: Risk of Hip Fracture in Benzodiazepine Users With and Without __alzheimer Disease, Saarelainen L, Tolppanen A-M, Koponen M, Tanskanen A, Sund R, Tiihonen J, Hartikainen S, Taipale H, Journal of the American Medical Directors Association, doi: 10.1016/j.jamda.2016.09.019, published online 12 November 2016.

Macular degeneration: Study sheds light on Alzheimer's proteins in retina

Previous studies have shown that the bet-amyloid proteins found in Alzheimer's disease also accumulate in the retinas of people with age-related macular degeneration. Now, a new study reveals insights that help to better understand how the retina becomes damaged in this way.

The retinas of people with AMD show deposits of the type of proteins that accumulate in the brains of people with Alzheimer's disease.

The researchers - from Southampton University in the United Kingdom - report their findings in the journal Experimental Eye Research.

Age-related macular degeneration (AMD) is a progressive eye disease that kills the light-sensitive cells (retinal photoreceptors) of the retina - the layer of tissue at the back of the eye.

AMD is a leading cause of vision loss in people aged 50 and older and affects some 50 million people worldwide.

Most of the damage in AMD occurs in the macula - an area near the center of the retina needed for seeing objects directly in front of us clearly and sharply. As AMD progresses, it gets harder to do everyday things like drive, read, do close work, use a computer, and recognize faces.

One change that occurs in the retina of people with AMD as the disease progresses is an increase in the number and size of fatty deposits called drusen.

In their study paper, the researchers explain that the causes of AMD are understood to be complex, with both genetic as well as environmental risks factors, and share similarities with Alzheimer's disease.

They note how recent studies have shed a lot of light on the genetic causes of AMD - although this is not matched by insights into the molecular mechanisms involved.

However, they also note that other studies have found aged and AMD retinas also show accumulation of the types of beta-amyloid proteins that are found in toxic plaques in the brains of people with Alzheimer's disease, and "for which there appears to be no clear genetic basis."

Amyloid proteins took less than 24 hours to enter retinal cells

Deposits of Alzheimer's-related beta-amyloid have been found in various parts of the retinas of people with AMD - including inside drusen and the light-sensitive cells.

Fast facts about macular degeneration

• AMD has few symptoms in the early stages, so it is important to get your eyes checked regularly
• Not everyone with early AMD will develop late AMD
• AMD arises less often in people who take regular exercise, do not smoke, and have healthy diets that include green leafy vegetables and fish.

Learn more about macular degeneration

For their study, Dr. Arjuna Ratnayaka, a lecturer in vision sciences at Southampton, and colleagues used cell cultures and mouse models of AMD to investigate mechanisms of Alzheimer's beta-amyloid accumulation inside retinal cells.

They were particularly interested in the speed with which the proteins find their way inside the retinal cells.

The researchers found the retinal cells internalized the amyloid proteins within 24 hours of being exposed to them.

They also discovered that the amyloid proteins are retained inside the retinal cells, where they gradually impair a molecular mechanism reliant on the protein encoded by the MAP-2 gene. Among other things, MAP-2 mechanisms help to maintain important structures inside cells called microtubules.

Dr. Ratnayaka says they were surprised at the speed with which the amyloid proteins entered the cells, and he suggests the finding may help explain how a healthy retina can switch to a diseased, AMD retina.

The team is now planning to evaluate how the beta-amyloid proteins actually enter the retinal cells and set about causing internal damage. The hope is the continuing work will lead to measures to prevent or treat AMD.

"We know that AMD is caused by a combination of genetic, environmental and lifestyle risk factors, but this novel discovery could open up new possibilities to understand how the aging retina becomes damaged. Such advances are important if we are to develop better AMD treatments in the future."

Dr. Arjuna Ratnayaka

Discover how gut microbes influence the development of wet AMD.

Written by Catharine Paddock PhD

Alzheimer's disease proteins could be at fault for leading cause of vision loss among older people

Research from the University of Southampton gives new insight into possible causes of Age-related Macular Degeneration (AMD), a leading cause of vision loss among people aged 50 and older.

The study, published in the journal Experimental Eye Research, discovered that a group of proteins, which are linked to Alzheimer's disease, are able to accumulate in the retina and damage it.

The researchers hope that the discovery could lead to better treatments for patients.

AMD is a progressive disease that causes the death of the retinal photoreceptors, the light-sensitive cells at the back of the eye. The most severe damage occurs in the macula, a small area of the retina that is needed for sharp, central vision necessary for reading, driving and other daily tasks.

There are two different types of AMD - 'wet' and 'dry'. In wet AMD, the growth of leaky blood vessels which damage the retina can be stopped. However, this does not work for everyone, and is a way to manage rather than cure wet AMD. By contrast, dry AMD has no approved treatment as yet.

Dr Arjuna Ratnayaka, a Lecturer in Vision Sciences at the University of Southampton, who led the study, said: "We know that AMD is caused by a combination of genetic, environmental and lifestyle risk factors, but this novel discovery could open up new possibilities to understand how the ageing retina becomes damaged. Such advances are important if we are to develop better AMD treatments in the future.

"AMD currently affects more than 600,000 people in the UK and 50 million individuals worldwide. This figure is expected rise significantly as our society grows older. We urgently need new treatments to stop people spending their twilight years in blindness."

The study, which used both cell cultures and mouse models, analysed how quickly Amyloid beta proteins, which are thought to be a likely cause of Alzheimer's disease, entered the retina and how they damaged it.

The team found that the Amyloid beta proteins entered the cells of the retina within 24 hours of exposure and then began to break the cell's scaffold structure.

Dr Ratnayaka added: "The speed in which these proteins entered the retinal cells was unexpected. These findings have given some insights into how a normal healthy retina can switch to a diseased AMD retina. We hope that this could lead to designing better treatments for patients in the future."

The research team's next step will be to evaluate how the Amyloid beta proteins get into retinal cells and study more closely how damage occurs, with a view of establishing preventative measures or treatment options.

The study was funded by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3R), the Macular Society UK, Fight for Sight, the Gift of Sight Appeal and the Hampshire and Isle of Wight Community Foundation.

Article: The Alzheimer's-related amyloid beta peptide is internalised by R28 neuroretinal cells and disrupts the microtubule associated protein 2 (MAP-2), Arjuna Ratnayaka et al., Experimental Eye Research, doi: 10.1016/j.exer.2016.10.013, published online 15 October 2016.

Brain volume may help diagnose dementia with Lewy bodies

Dementia with Lewy bodies is not an easy condition to diagnose, making it difficult to treat in a timely fashion. New research measuring brain volume may be the key to recognizing this disease early on and starting medication earlier.

Dementia with Lewy bodies affects more than 1 million Americans.

Dementia with Lewy bodies (DLB) is a relatively common type of dementia, affecting an estimated 1.3 million Americans.

DLB accounts for around 10-15 percent of all dementia cases.

Common DLB symptoms include movement disorders, hallucinations, cognitive problems, sleep difficulties, depression, and attention deficits.

Some of these symptoms are shared with Alzheimer's and Parkinson's diseases; however, the treatments for DLB and Alzheimer's differ, and the earlier a diagnosis is reached, the more effective the treatment will be.

Identifying patients with mild cognitive impairments who are at risk of developing DLB is vital for effective early interventions.

Difficulties diagnosing dementia with Lewy bodies

DLB is characterized by a buildup of Lewy bodies - protein deposits - in the brain. Lewy bodies also appear in other diseases, including Parkinson's disease. Depending on where the Lewy bodies appear, symptoms vary.

If they arise in the base of the brain, they can create motor symptoms similar to Parkinson's. When they appear in the outer layers of the brain, they produce cognitive symptoms, similar to Alzheimer's. Diagnosing DLB is primarily a case of watching symptoms develop and gradually ruling out other, similar conditions; there are no reliable diagnostic tests.

Researchers from the Mayo Clinic in Rochester, MN, set out to investigate whether brain volume could be useful in diagnosing DLB at an earlier stage. Their findings are published this week in the journal Neurology.

"Being able to identify people who are at risk for dementia with Lewy bodies is important so they can receive the correct treatments early on. Early diagnosis also helps doctors know what drugs to avoid - up to 50 percent of people with dementia with Lewy bodies have severe reactions to antipsychotic drugs."

Study author Dr. Kejal Kantarci

The research utilized 160 participants from the Mayo Clinic Alzheimer's Disease Research Center. All of the individuals had mild cognitive impairments - a slight but measurable reduction in cognitive abilities. People with mild cognitive impairments are known to be at a greater risk of developing Alzheimer's or other types of dementia.

Individuals with other neurological conditions, epilepsy, brain tumors, and substance abuse were excluded.

Charting changes in hippocampus volume

Each participant received an MRI scan at the start of the study and an average of two more annual scans. During the trial, 61 participants (38 percent) developed Alzheimer's disease and 20 people (13 percent) progressed to probable DLB. It is referred to as "probable" because DLB can only be definitively diagnosed by an autopsy.

Specifically, the team examined the volume of the hippocampus, an area known to shrink in the lead up to Alzheimer's.

Once the data were analyzed, patients with no measurable shrinkage were 5.8 times more likely to develop DLB when compared with those who did display hippocampal shrinkage.

Seventeen out of the 20 participants (85 percent) who developed DLB had normal hippocampus volumes. Conversely, 37 out of the 61 individuals (61 percent) who went on to develop Alzheimer's disease did show shrinkage.

DLB does not always affect memory, so when the researchers only looked at the data from those whose cognitive deficits did not include memory problems, the results were even more pronounced. As the authors explain, "we demonstrated that those with preserved hippocampal volumes are at an increased risk for probable DLB."

Although the study is on a relatively small scale, the results are encouraging. Dr. Kantarci hopes that the research will be duplicated and followed up with studies that include a postmortem autopsy to confirm DLB diagnoses.

Learn more about the difficulty in diagnosing dementia with Lewy bodies.

Written by Tim Newman

Occupational therapy fails to aid functioning in Alzheimer's patients

Alzheimer's disease currently affect over 5 million American seniors. Given that the majority of dementia disorders cannot be cured, caregiving and support are highly significant. Most patients with Alzheimer's live with the illness at home and are cared for by members of their family. New research, however, suggests home-based occupational therapy may not be very effective in slowing down mental decline.

Research shows occupational therapy may be less effective than we think.

Alzheimer's disease is the sixth leading cause of death in the United States. It is currently estimated to affect 5.4 million Americans, or 1 in 9 adults aged 65 and over.

Given that Alzheimer's and most dementia-related conditions do not have a cure or a disease-modifying treatment, most patients live with the disease and are cared for in their home by a family member.

In fact, 70 percent of patients with Alzheimer's live at home, and they receive 75 percent of their care from an informal caregiver.

Over 15 million people in the U.S. work as unpaid caregivers, their efforts amounting to hundreds of billions of dollars each year.

Additionally, caregivers for people with dementia bear a heavier burden compared with other caregivers, as a quarter of them work at least 40 hours each week.

Most of the care provided involves assisting with daily activities, such as household chores, shopping, cooking, or providing transportation.

Helping patients do their day-to-day activities, with the aim of recovering physical or mental abilities and regaining a sense of independence, is commonly referred to as occupational therapy.

New research - published in the journal Annals of Internal Medicine - examines whether occupational therapy actually helps slow down cognitive and functional decline in patients with Alzheimer's.

Assessing the effect of occupational therapy on Alzheimer's patients

A team of researchers from the Indiana Center for Aging Research and the Regenstrief Institute in Indianapolis, IN, wanted to see if collaborative care combined with 2 years of home-based occupational therapy delays functional decline.

The team was led by Dr. Cristopher M. Callahan, the Cornelius and Yvonne Pettinga professor of medicine at Indiana University's School of Medicine, and the founding director of the Indiana University Center for Aging Research.

Fast facts about Alzheimer's

• In the U.S., someone develops Alzheimer's every 66 seconds
• Family caregivers spend more than $5,000 annually caring for a relative with Alzheimer's
• This year, Alzheimer's and other dementias with cost the U.S. around $236 billion.

Learn more about Alzheimer's

Researchers designed a randomized, controlled clinical trial involving 180 patients with Alzheimer's disease and their informal caregivers.

Participants were divided into two groups. All 180 participants received collaborative care for dementia from the Healthy Aging Brain Center, in collaboration with the primary care practices from the Eskenazi Health Center.

The researchers at Indiana University and the Regenstrief Institute had previously shown that their primary care practices reduced caregiver stress and improved behavioral symptoms for patients. However, their practices were not shown to stop functional decline.

In this new study, one of the two groups also received occupational therapy for 24 months, in addition to collaborative care. The intervention group had 91 participants.

Over the 2 years, an occupational therapist traveled to the home of the patient and family caregiver.

The occupational therapy was tailored to the needs of each patient and focused on issues identified by the caregiver, such as bathing safely or getting in and out of cars. Therapists also helped patients resume activities they used to enjoy before the disease, such as gardening.

Participants remained seated for the majority of the sessions.

At the end of the 24 months, researchers measured the ability to function in daily living for both groups.

Occupational therapy did not reduce functional decline

Both groups showed a similar decline in functional living scores, the researchers found.

"Persons with dementia face a steady decline in function that we found is not slowed by home-based occupational therapy," says Dr. Callahan.

The tailored therapy did not delay the loss of everyday functions, such as walking, eating, bathing, and toileting.

"The participants in the study declined both mentally and functionally as the neurodegeneration of the brain continued. This is a disappointing outcome because previously published, but shorter-term studies had suggested these interventions might be able to slow the physical decline that leads to nursing home placement."

Dr. Cristopher M. Callahan

Given the imminent and irreversible cognitive decline in dementia and the lack of drug-based therapies, treatment options are limited. As Dr. Callahan points out, this makes caregiving extremely important, as well as the decisions we make regarding our use of resources.

"There is a limited amount of money that we - families and society - have available for these patients and their caregivers and we should spend that money on things that patients and families find the most helpful," Dr. Callahan says. He also emphasizes the importance of making a wider range of options available to support family caregivers.

Dr. Callahan suggests that making home adjustments, such as removing risks for falls, making bathrooms more easily accessible, and making kitchens safer, may keep Alzheimer's patients out of an institution and help them enjoy the comfort of their home for longer.

As the authors of the study conclude:

"Given the burden of caring for persons with dementia, which largely is shouldered by family members, research must focus on identifying strategies to support caregivers in the home to provide care to persons with dementia.

If the gradual functional decline attributable to Alzheimer's disease is irreversible, a new generation of assistive devices, home modifications, community services, and technologies is needed to make longer-term support in the home a practical reality for patients and families."

Read about how dementia rates are on the decrease in the U.S.

Written by Ana Sandoiu

Morning Break: Brexit's Drug Shortage; Addyi a Bust? Borrowing for Cancer Care

A government-backed report from Britain says the country may face delays in receiving new drugs as a result of "Brexit" -- because drugmakers will apply first for approvals in bigger markets such as the EU and U.S. (Reuters)

Remember Addyi, the much ballyhooed drug for "hypoactive sexual desire disorder" in women, which hardly anyone has taken or prescribed? Now there's a lawsuit by the drug's former owners against current owner Valeant, arguing that the latter's marketing missteps have cost them millions in royalties. (Bloomberg)

Thrombotic events in trial participants could sink Roche's Factor VIII mimetic drug emicizumab, also known as ACE910, for hemophilia. (Reuters)

Merck's investigational BACE1 Inhibitor for Alzheimer's treatment moves on to phase III clinical trials. (Scientific American)

About a third of cancer patients borrow money from friends and family to afford treatment, according to new statistics that also show cancer patients are 260% more likely to file for bankruptcy. (STAT)

Here's a short list: 4 ways to boost productivity in healthcare, according to healthcare futurist Joe Flower. (Fierce Healthcare)

Exposure to western cultures linked to higher drinking rates among Chinese university students, according to new research. (PLOS ONE)

Christian doctors warned of "ever-increasing serious threats," by Catholic archbishop. (Catholic News Agency)

Cardiologists still don't know why women and minorities experience worse stenting outcomes compared to white, male counterparts. Nicole Lou reports the details from the TCT meeting. (MedPage Today)

A bit of anxiety and ADHD makes a normal brain, according to a review of nearly 200 neuroscience studies. (Futurity)

Investing more resources in primary care, mental health, and diabetes prevention will pay itself off and lead to "a healthier Medicare," according to government officials. (Press release)

Morning Break is a daily guide to what's new and interesting on the Web for healthcare professionals, powered by the MedPage Today community. Got a tip? Send it to us: MPT_editorial@everydayhealthinc.com.

2016-11-03T09:02:09-0400

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Eli Lilly Alzheimer's drug fails to show benefits in final stage clinical trial

Eli Lilly and Company has announced that their drug solanezumab has failed to meet its primary endpoint of slowing cognitive decline in people with mild Alzheimer's disease.

The phase III trial, called EXPEDITION 3, was started in 2013 after the same drug failed to meet its primary endpoints in two earlier clinical trials in mild to moderate Alzheimer's. However, further analysis of the earlier trials showed a slowing of cognitive decline in only those volunteers with mild Alzheimer's. The findings at that time were encouraging enough to support the drug going back into another phase III trial in people only in the mild stages of the disease. Unlike previous trials with the drug, EXPEDITION 3 used amyloid PET brain scans or spinal fluid tests to select only those patients with high levels amyloid who were most likely to respond to the drug.

Solanezumab is one of several drugs in development that are designed to target amyloid - a key protein that builds up into 'plaques' early in the brain in Alzheimer's disease. The drug is a monoclonal antibody designed to tag single amyloid molecules circulating in the blood and the brain, mopping them up to prevent more plaques forming.

EXPEDITION 3 was a multinational, 18-month placebo-controlled trial in over 2,100 people with mild Alzheimer's disease.

The headline results shows that the drug did not cause a statistically significant slowing in memory and thinking decline compared to a placebo treatment, as measured by a cognitive test called ADAS-Cog14. While Lilly reports that several of the secondary measurements being taken in the trial showed a signal in the right direction, these were much smaller than hoped for.

As a result, Lilly will not be submitting the drug for regulatory approval for the treatment of mild Alzheimer's. However, the drug is currently planned to enter another phase III trial in people at an even earlier stage of the disease called 'prodromal Alzheimer's'. This term describes people with early memory and thinking problems not severe enough to be classed as dementia, but who have signs of amyloid on PET scans and in spinal fluid. If it continues, this trial is expected to report results in 2021.

Dr David Reynolds, Chief Scientific Officer at Alzheimer's Research UK, said: "Our 15-year wait for a new Alzheimer's drug does not end today, but we shouldn't view this setback as the end of the line - the journey towards a new treatment can and will continue. It's very disappointing that solanezumab has not shown benefit for people with mild Alzheimer's and will no doubt trigger important debate within the research community. We only have headline information today, so we'll need to see the full data to understand why solanezumab didn't show benefits and what researchers must learn from the findings.

"Solanezumab is designed to mop up amyloid protein - a key hallmark of Alzheimer's - and is the result of years of development based on the concept that this protein is a central driver of the disease. While today's results are a setback for the amyloid hypothesis, there are several other anti-amyloid drugs still in clinical trials that work in different ways, some of which are being tested even earlier in the disease process than solanezumab. We can't disregard these ongoing trials and their findings will now be more important than ever in shaping the search for disease-modifying treatments for Alzheimer's.

"Today is undoubtedly a set-back for people with Alzheimer's and their families, and highlight the ongoing importance of drug discovery efforts into other aspects of the biology of Alzheimer's. Our understanding of the biology of Alzheimer's is expanding and with it are our approaches for improving the lives of those with the disease. Alzheimer's Research UK is already supporting millions of pounds of treatment research taking place in labs around the country today, including our pioneering Drug Discovery Alliances, to ensure that this hard work continues."

Highlights from SfN 2016

This year's Society for Neuroscience drew more than 30,000 neuroscientists to the San Diego Convention Center. Highlights included a brain-computer interface that helped an ALS patient communicate; results of a 25-year evaluation of fetal neuron transplant for Parkinson's; and NINDS Chief Walter Koroshetz's hopeful outlook for a new type of Huntington's therapy.

Brain Implant Helps Locked-In Patient Communicate

End of the Road for Fetal Neuron Transplant in Parkinson's?

NINDS Chief Sees Hope for Huntington's Treatment

MS Induction Tx May Actually Work in Immune System

Is There a Center for Cognitive Reserve in MS Brains?

2016-11-25T12:00:00-0500

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Stages of Dementia: How Does the Disease Change Over Time?

Dementia is not a specific illness or disease. It involves a variety of symptoms associated with impaired thinking, memory, and communication.

To have a diagnosis of dementia, the decline in functioning must affect a person's ability to perform everyday activities.

This article will look at several types of dementia, and how they change as the condition progresses.

Contents of this article:

1. Types of dementia
2. How do symptoms of dementia change over time?
3. How do treatment options change over time?
4. Diagnosis and outcome
5. Living with dementia in the later stages

Types of dementia

Beta-amyloid plaques may be found in the brain of people with Alzheimer's disease.

Dementia may have different causes. Changes to the brain depend on the type of dementia a person has. Common types of dementia include Alzheimer's disease, vascular dementia, dementia with Lewy bodies, and mixed dementia.

Alzheimer's disease

The most common cause of dementia is Alzheimer's disease. According to the Alzheimer's Association, between 60 and 80 percent of dementia is caused by Alzheimer's.

It is not entirely clear what causes Alzheimer's, but clumps of a protein called beta-amyloid are found in the brain of people with this type of dementia.

Vascular dementia

Vascular dementia may occur when there is reduced circulation to the brain due to a stroke or other conditions, resulting in damage to the blood vessels in the brain.

Dementia with Lewy bodies

Dementia with Lewy bodies happens when abnormal proteins develop in the brain, called Lewy bodies. The protein deposits may be found throughout the brain, including the cerebral cortex, the area involved in language and thinking.

Mixed dementia

Mixed dementia involves more than one cause. Blood vessel problems may be present along with abnormal proteins in the brain, for example.

How do symptoms of dementia change over time?

Regardless of the cause, symptoms of dementia tend to worsen over time.

The rate of progression varies from person to person. Genetics, age, and overall health may play a role in how fast the disease progresses.

Early symptoms

Dementia often, but not always, starts with a mild decline in the ability to think. For example, someone may forget a recent conversation or the name of a familiar object.

At this point, the decrease in memory may not greatly affect a person's ability to function daily.

Early symptoms may also include a decreased ability to perform certain tasks, such as paying bills or following a recipe. Subtle changes in personality may also be noticed by people close to an individual with dementia.

At this stage, a person with dementia may start to realize something is not right, but they may choose to hide their symptoms.

Moderate dementia symptoms

Dementia may start with a decrease in memory.

As dementia progresses, symptoms become harder to hide. More noticeable symptoms may develop. Help with self-care or everyday activities may be needed.

Personality changes may become more noticeable. The person may experience paranoia or fear. Symptoms may include increased confusion and memory loss.

People with moderate dementia commonly forget their address or other personal information, including their phone number. Sleep patterns and mood may change.

Late-stage or severe dementia symptoms

Gradually, dementia can progress and become severe. Memory is often significantly affected. Someone with dementia may not recognize family members.

During late-stage dementia, symptoms may include an inability to communicate, walk, and control bowel and bladder function.

A person with late-stage dementia may have muscle rigidity and abnormal reflexes. Full-time personal care is usually needed for eating, bathing, and dressing. People with severe dementia are vulnerable to infections, including pneumonia and bed sores.

How do treatment options change over time?

Currently, there is no cure for dementia, including Alzheimer's disease, but there are treatments. Treatment usually aims to decrease symptoms and manage behavioral changes.

Treatment may also change over time. Different classifications of medication may be prescribed, based on the stage of the disease.

Medications may reduce symptoms by affecting chemicals that carry messages to the brain cells.

These drugs are called cholinesterase inhibitors. They are often prescribed for people with mild to moderate symptoms. Cholinesterase inhibitors treat symptoms associated with confusion, communication, and memory.

In people with moderate-to-severe dementia, treatment may also include memantine. Memantine is a drug that may help improve language, thinking, and memory.

Memantine works by regulating glutamate, a chemical in the brain that is involved in memory and learning. Memantine may delay the progression of symptoms temporarily for some people.

Treatment options may include medications that reduce behavioral changes, such as anxiety and sleep problems.

In later stages, different medications may be needed, as symptoms develop. Particular drugs may be recommended to treat specific symptoms, such as fear, restlessness, and hallucinations.

As dementia progresses, treatment may also focus on improving the quality of life. For example, occupational therapy may be useful to teach people with dementia how to use adaptive equipment or to improve fine motor skills.

Diagnosis and outcome

A person with an early diagnosis of dementia may want to communicate their wishes for future care as soon as they can.

No single test can determine if a person has dementia. Tests will focus on the ability to think and neurological evaluation.

Tests evaluate skills such as reasoning, language, and memory. Movement, balance, and visual perception are also examined.

A medical history and blood tests can help to rule out other causes of symptoms.

Imaging studies, such as a CT or PET scan, can determine if a specific protein is deposited in the brain, or if there is any interruption to the blood flow to the brain.

Dementia scales can help to decide if dementia is present, and how far it has progressed.

The Global Deterioration Scale may be used to determine the severity of overall dementia.

Ratings range from one to seven, where seven indicates the most severe stage. A combination of tests may be used to make an assessment.

The outlook for people with dementia varies. Age at diagnosis and response to treatment affect how the condition progresses.

People with Alzheimer's dementia often live for about 10 years after diagnosis, according to the Mayo Clinic.

However, everyone is different. Some people with dementia survive 20 years or more after diagnosis.

Living with dementia in the later stages

It may be helpful for a person with dementia to be involved in decisions about their care before they become unable to communicate their wishes.

Advanced care planning allows an individual with dementia to state what they want and do not want, such as living in a nursing home or being cared for at home.

Living with late-stage dementia can often be challenging for patients and caregivers. As symptoms progress, more care is required.

Strategies that may help someone with late-stage dementia include techniques to jog memory, such as visual clues or notes.

Assistive technology devices include communications aids, automatic shutoff devices, and computerized recall devices.

Caregivers should create an environment that is calm and safe. It is important to identify and correct safety concerns. This includes removing tripping hazards and making sure rooms are easy to get around.

Caregivers should also ensure that medication is taken correctly, and that nutritional needs are met. Late-stage dementia can also be a difficult time for caregivers. Having a strong support system and allowing time to recharge is essential.

Written by MaryAnn de Pietro

Antibiotic restores cell communication in brain areas damaged by Alzheimer's disease

New research from the Djavad Mowafaghian Centre for Brain Health at UBC has found a way to partially restore brain cell communication around areas damaged by plaques associated with Alzheimer's disease.

The findings, published in Nature Communications, demonstrate a possible target and a potential drug treatment to reduce damage to the brain that occurs in the early stages of Alzheimer's disease. Using Ceftriaxone, an FDA-approved antibiotic used to treat bacterial infections, researchers were able to reduce synaptic disruption and clear the lines of neuronal communication in mice.

Amyloid plaques of -amyloid deposits develop in brain regions of patients with Alzheimer's disease, These plaques are linked to the damage found in Alzheimer's disease because they prevent cell communication and are toxic to nerve cells. The researchers found that the brain areas around these plaques show high levels of glutamate, a signaling molecule essential to communication between brain cells, accompanying high levels of hyperactivity in glia, the brain's support cells. It's in this glutamate-rich environment that communication between neurons is changed or disrupted, causing neurons to die in the later stages of the disease.

"By imaging the glial cells and glutamate itself around the plaques, we were able to see that the cells were not able to 'remove' the glutamate accumulating in these brain areas. By using Ceftriaxone, we were able to up-regulate glutamate transport," explains Dr. MacVicar, principal investigator and professor of psychiatry. "By restoring glutamate levels, we were able to mostly restore neuronal activity."

The team's findings have implications for treatment of early symptoms of Alzheimer's disease.

"This dysfunction in cell communication occurs at a very early stage in the disease, before memory impairment is detectable," says Dr. Jasmin Hefendehl, a former Postdoctoral Fellow in Dr. MacVicar's lab and the lead author on the paper. "This makes our discovery particularly interesting, as it opens a window for an early intervention strategy to possibly prevent or delay neuron and memory loss."

Ceftriaxone is an antibiotic that is commonly administered before some types of surgery to prevent infections. Although a recent clinical trial failed to see improvements for treating amyotrophic lateral sclerosis (ALS), the researchers are hopeful about its potential for early intervention in treating Alzheimer's disease.

Article: Mapping synaptic glutamate transporter dysfunction in vivo to regions surrounding Aβ plaques by iGluSnFR two-photon imaging, J. K. Hefendehl, J. LeDue, R. W. Y. Ko, J. Mahler, T. H. Murphy & B. A. MacVicar, Nature Communications, doi:10.1038/ncomms13441, published online 11 November 2016.

Could loneliness be a sign of Alzheimer's?

Previous research has suggested loneliness may be associated with Alzheimer's disease among older adults. A new study supports this link, after identifying a marker of early Alzheimer's in the brains of seniors with greater self-reported loneliness.

Researchers suggest loneliness in older age might represent brain changes related to Alzheimer's.

Study co-author Nancy J. Donovan, of Brigham and Women's Hospital and Harvard Medical School in Boston, MA, and colleagues report their findings in JAMA Psychiatry.

According to a 2010 survey from the American Association of Retired Persons (AARP), around 32 percent of adults aged 60-69 and 25 percent of adults aged 70 and older in the United States report feeling lonely.

As well as increased risk of depression, heart disease, and stroke, loneliness in older adults has been associated with greater risk of cognitive decline and Alzheimer's disease.

For their study, Donovan and team set out to determine whether loneliness is associated with pathological brain changes that might be a marker of Alzheimer's.

Specifically, they looked at whether loneliness might be associated with levels of amyloid proteins in the brain. These proteins can form clumps called plaques, which are considered a hallmark of Alzheimer's.

Loneliness 7.5 times more likely in adults with high amyloid levels

The research included 79 adults - 43 women and 36 men - of an average age of 76 years with normal cognitive functioning.

The team used the UCLA Loneliness Scale to assess how lonely each participant felt. This tool asks three questions: "How often do you feel left out?," "How often do you feel isolated from others?," and "How often do you feel you lack companionship?"

The answer to each question is scored on a 4-point scale, with 1 representing "never" and 4 representing "often." In total, participants' average loneliness score was 5.3 out of 12.

Using brain imaging, the researchers measured amyloid protein levels in cortical areas of the participants' brains, including the frontal, lateral temporal and lateral, and medial parietal regions.

Compared with participants with low cortical amyloid levels, subjects with high amyloid levels were 7.5 times more likely to report feeling lonely, the researchers found.

This association was stronger for participants who were carriers of APOEε4 - a gene that is associated with increased risk of Alzheimer's.

The results remained after accounting for a number of potential confounding factors, including age, sex, anxiety, depression, and socioeconomic status.

Donovan and colleagues say their results point to loneliness as a sign of early Alzheimer's, after showing loneliness can be reflected in pathological brain changes related to the disease.

Commenting on their findings, the authors write:

"We report a novel association of loneliness and cortical amyloid burden in cognitively normal older adults and present evidence for loneliness as a neuropsychiatric symptom relevant to preclinical AD [Alzheimer's disease].

This work will inform new research into the neurobiology of loneliness and other socioemotional changes in late life and may enhance early detection and intervention research in AD."

Future implications for Alzheimer's disease

Alzheimer's is the most common form of dementia, affecting around 5.4 million people in the U.S. This number is expected to reach 13.8 million by 2050, unless new prevention and treatment strategies are discovered.

In an editorial linked to the study, Dr. Paul B. Rosenberg, of the Department of Psychiatry and Behavioral Sciences at Johns Hopkins Bayview Medical Center in Baltimore, MD, says the results from Donovan and team may advance the development of early screening methods for Alzheimer's.

"One can imagine a future landscape of treatment in which older persons are screened for AD risk with a mix of self-report measures (mood and memory concerns), cognitive screens performed on a tablet or smartphone, and genetics including APOEε4 and future studies with whole-genome sequencing; the genetics is still costly but in a decade should become inexpensive," says Dr. Rosenberg.

"We might calculate a risk index and use this to stratify older persons for biomarker assessment and interventions," he adds. "This approach would be beneficial not only for public health in developing countries but also for low- and middle-income countries where the majority of the world's persons with AD already live and where the at-risk populations are huge."

"In this endeavor, measures such as loneliness and mood symptoms yet to be identified may loom large, and Donovan et al. have contributed a significant advance in this regard," concludes Dr. Rosenberg.

Read about how loneliness might alter the immune system to cause illness.

Written by Honor Whiteman

Workout May Mitigate Cognitive Impairment

Action Points

• Note that this randomized trial of aerobic exercise among a population of individuals with vascular cognitive impairment showed mixed results with regards to improvement at 6 months.
• Importantly, any benefits seen were lost in longer-term follow-up.

Aerobic exercise led to a modest short-term improvement in memory and thinking skills in older people with vascular cognitive impairment, but it didn't hold long-term, researchers found.

In a proof-of-concept study, patients with mild vascular cognitive impairment who had 3 hour-long sessions of aerobic exercise training weekly for 6 months had a greater improvement in cognition than those randomized to usual care (-1.71 point difference on the ADAS-Cog, P=0.02), Teresa Liu-Ambrose, PT, PhD, of the University of British Columbia in Vancouver, and colleagues reported online in Neurology.

But this benefit wasn't maintained at 6-month follow-up (-0.63 point difference, P=0.46), they reported.

"This [ADAS-Cog] result, while modest, was similar to [the 1-2 point improvement] seen in previous studies testing the use of drugs for people with vascular cognitive impairment," Liu-Ambrose said in a statement. "However, the difference was less than what is considered to be the minimal clinically important difference of 3 points."

For the study, they randomized 70 adults, mean age 74, to aerobic exercise training or to usual care for a 6-month period, and assessed them at the end of the trial and again 6 months later.

Controls received education on vascular cognitive impairment. The exercise group was given a pedometer to serve as both an incentive and a monitoring tool, and participants kept daily logs of the number of steps taken outside of classes. Liu-Ambrose said a pedometer can be an incentive tool as it provides feedback, but is limited in that it doesn't provide any indication of exercise intensity.

In addition to the ADAS-Cog findings, the researchers saw small but non-significant improvements in executive function and activities of daily living for those in the exercise group.

They also found that aerobic exercise significantly improved general cardiovascular capacity (30.35 meter difference on the 6-minute walk test, P=0.02), and reduced resting diastolic blood pressure (-6.89 mm Hg difference, P=0.02), but these cardiovascular benefits didn't persist at the 6-month follow-up.

During the 6-month intervention period, improvements in ADAS-Cog correlated with reduced resting diastolic blood pressure (P=0.01) but not with improvements in distance walked in 6 minutes (P=0.22), they reported.

These findings are important, the researchers said, given that high blood pressure is a risk factor for developing vascular cognitive impairment: "Notably, we observed that aerobic exercise reduced diastolic blood pressure from approximately 80 to 75 mm Hg, which might confer protection against future stroke," they wrote.

Although there remains much to learn about the relationship between late-life blood pressure and cognitive function, "our correlational finding also suggests that reduced blood pressure may be a pathway by which aerobic exercise promotes cognitive health among those with mild vascular cognitive impairment."

The researchers noted that strategies to increase the sustainability of the observed effects are needed, such as a longer intervention period (e.g., 12 months) or the inclusion of behavioral components (e.g., self-monitoring or incentive schemes).

In an accompanying editorial, Alexandra Foubert-Samier, MD, PhD, of Bordeaux University Hospital in France, and Leon Flicker, MBBS, PhD, of Royal Perth Hospital in Australia, noted that strengths of the study are its randomized design, and that it met its predefined feasibility criteria with a recruitment rate of 17%, a withdrawal rate of less than 15%, and an average exercise adherence of 68%.

They noted limitations including the small mean between-group difference on the ADAS-Cog, the fact that only 1 of the 3 outcome measures was positive, and the "surprising" lack of impact exercise had on executive function, given the positive effect seen in prior observational studies.

The study time frame may have been insufficient to improve executive function, which may be related to reductions in diastolic blood pressure, they suggested.

Liu-Ambrose concluded that while the current results may not apply to individuals with more severe vascular cognitive impairment, "our data suggest identification and recruitment of this population is feasible and a thrice-weekly aerobic exercise training can be delivered to this target population with an acceptable level of compliance."

This work was supported by the Canadian Stroke Network and the Heart and Stroke Foundation of Canada.

The authors and the editorialists report no disclosures relevant to the manuscript.

• Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

2016-10-21T13:00:00-0400

• Primary Source

  Neurology

  Source Reference: Liu-Ambrose T, et al "Aerobic exercise and vascular cognitive impairment: A randomized controlled trial" Neurology 2016; DOI: 10.1212/WNL.0000000000003332.

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Treatment approach used in cancer holds promise for Alzheimer's disease

New Alzheimer's treatment could be delivered as nasal spray.

Researchers have developed a novel treatment that could block the development of Alzheimer's disease using microscopic droplets of fat to carry drugs into the brain. This treatment approach, which is used to target drugs to cancer cells, has been successfully applied to Alzheimer's disease for the first time, restoring memory loss in mice.

The study, which was led by researchers at Lancaster University and funded by Alzheimer's Society, is published in the journal Nanomedicine: Nanotechnology, Biology and Medicine.

The treatment uses tiny droplets of fat, called nanoliposomes, which are coated in protein fragments that are able to stop amyloid protein accumulating into plaques, even at low concentrations. Amyloid plaques are the toxic clumps of protein that cause damage to cells in the brains of people with Alzheimer's disease.

Mice that were genetically altered to develop Alzheimer's disease were injected with the nanoliposomes for three weeks. Those which received the drug recovered their long-term memory and could recognise familiar objects after a 24-hour period. In comparison, mice which received a placebo injection had no memory of objects seen the day before.

Lead researcher, Professor David Allsop, commented: "Following results this summer, there is renewed optimism for antibody drugs - treatments that harness the body's immune system to target amyloid plaques. However if these prove successful, treatments will have to be administered in a clinic by an IV drip and could have some potentially harmful side effects.

"Using nanoliposomes offers an alternative way to inhibit the toxic build-up of amyloid plaques without activating an immune response in the brain. Our hope is that this could one day be administered by something as simple and non-invasive as a nasal spray, which patients could use in the comfort of their own home."

Nanoliposomes are already used to better target toxic chemotherapy drugs to cancer cells. Recent studies have also shown that the fat droplets can pass directly into the brain through the nose, opening up the possibility of using a nasal spray to administer treatments for brain diseases, such as Alzheimer's.

Commenting on the need for innovative approaches to dementia treatments, Dr Doug Brown, Director of Research and Development at Alzheimer's Society, said: "With no new dementia drugs in nearly 15 years, we're at a critical time for dementia research. It's absolutely vital we continue to sniff-out new approaches to getting drugs into the brain. While we wait in anticipation for the results of ongoing clinical trials, Alzheimer's Society will continue to fund innovative research to tackle dementia head-on."

"Nanotechnology is promising great benefits to people with many different types of cancer, and it's exciting that it could one day offer the same hope to people with the most common form of dementia."

There are 850,000 people in the UK living with dementia, and currently available drugs are only able to treat the symptoms of dementia, rather than slowing its progression. The research team at Lancaster University are now seeking investment from industry to take their novel treatment forward to be tested in people.

Article: Retro-inverso peptide inhibitor nanoparticles as potent inhibitors of aggregation of the Alzheimer's Aβ peptide, Maria Gregori, Mark Taylor, Elisa Salvati, Francesca Re, Simona Mancini, Claudia Balducci, Gianluigi Forloni, Vanessa Zambelli, Silvia Sesana, Maria Michael, Christos Michail, Claire Tinker-Mill, Oleg Kolosov, Michael Scherer, Stephen Harris, Nigel J. Fullwood, Massimo Masserini, David Allsop, Nanomedicine: Nanotechnology, Biology and Medicine, doi: 10.1016/j.nano.2016.10.006, published online 19 October 2016.

Understanding psychological dimensions of dementia can improve care, says new British Psychological Society report

To help people live well with dementia we need a better understanding of its psychological impact, according to a new British Psychological Society report (BPS).

The report stresses that dementia affects a person's sense of identity, how they think and behave, their mood and their personal relationships.

So improving people's experience of dementia means improving the support they receive to process how they feel and how they understand the condition, their future and their relationships.

Dr Linda Clare, Chair of the BPS Dementia Advisory Group, said: "Maintaining a sense of control, identity and connection is a key focus as dementia progresses. Without it there is a risk that the person will experience a sense of isolation and dislocation at a time when the resources to protect against this threat are lacking.

"That's why we say putting the person at the centre of care is vital to help people to live well with dementia."

The BPS report 'Psychological Dimensions of Dementia: Putting the person at the centre of care'highlights a number of areas where action is needed to improve understanding and care, and makes recommendations for commissioning services.

The recommendations include:

• People with dementia should be supported in making their own decisions as far as possible.
• Care and treatment should be individually tailored to each person's needs and circumstances.
• Dementia care plans must cover all the person's needs, including equal access to the right healthcare for other mental or physical health needs.
• Families and carers should be included in care planning at all times and have access to psychological support.

Dr Clare continued: "The rights of people with dementia must be respected. We need to ensure their active and meaningful involvement in decisions about their own lives and in planning and evaluating the services they receive.."

Dementia risk increased with use of blood-thinning drugs

A new study reviewing medical data from 6,000 patients reports that individuals with atrial fibrillation who take anticoagulants are at higher risk of dementia than patients who take the blood-thinning drugs for other reasons.

Researchers have linked warfarin to increased dementia risk, particularly for patients with AF.

Atrial fibrillation (AF) is the most common irregular heartbeat condition. The incidence rate in the population of adults aged 65 and older is 10 percent, as reported by the Atrial Fibrillation Association (AFA). AF is not life-threatening in most cases, but it is known to be a leading cause of stroke.

Researchers from the Intermountain Medical Center Heart Institute in Salt Lake City, UT, compared the medical notes of patients who regularly took anticoagulants. They found that dementia cases were higher among AF patients.

The team presented their work at the American Heart Association Scientific Sessions 2016, held in New Orleans, LA.

Anticoagulant therapy is used to thin the blood of AF patients. The most commonly used anticoagulant is warfarin.

AF patients are prone to developing blood clots because their irregular heartbeat prevents the blood from being pumped through the chambers of the heart efficiently. This can lead of pooling of the blood and subsequent formation of blood clots.

Blood clots can travel to the brain and cause stroke. The AFA report that 3 million people worldwide are affected by AF-related stroke each year.

Dementia occurs more often in AF patients

Dementia is a broad term for a number of diseases that affect the brain and cause progressive intellectual decline. Alzheimer's disease is the most common form of dementia, but there are many others.

According to the National Institutes of Health, there are approximately 5 million individuals in the United States who have Alzheimer's disease. Dementia is now the leading the cause of death in England and Wales, as reported by the United Kingdom Office for National Statistics.

Age is thought to be the main risk factor for dementia. The number of people living with dementia is expected to increase, as life expectancy is getting longer.

Patients with AF have previously been reported to have a higher risk of developing all types of dementia.

Greater dementia risk for warfarin users with AF

In a retrospective study of medical notes, the team found that patients with AF who took warfarin were two to three times more likely to have dementia than those without AF who took warfarin.

The authors conclude that taking warfarin is associated with an increased risk of dementia in all patients, but more so in AF patients.

Lead author Dr. Jared Bunch, director of electrophysiology at the Intermountain Medical Center Heart Institute in Salt Lake City, explains:

"Atrial fibrillation patients are at higher risk of developing all forms of dementia compared to patients without atrial fibrillation."

"Warfarin is used to lower risk of stroke in patients with atrial fibrillation, but when the blood levels of the drug are erratic it contributes to the dementia risk," he adds. "This dementia risk is observed in people with and without atrial fibrillation that are exposed to long-term warfarin treatment."

Study limitations

In the study, the authors discuss the limitations of their work. They explain that a retrospective study such as this makes use of commonly used medical codes in patient notes in a database to assign patients to different groups, such as those who take warfarin and those with AF or other conditions.

Although this type of study can use the medical records of thousands of individuals, it is designed to look at how different conditions relate to each other, but not at cause and effect.

They suggest designing a prospective study, which recruits patients and follows them over many years. This type of study can specifically examine the mechanism by which warfarin therapy may cause dementia and how this is different in AF patients.

"Further research is needed to identify the many complex mechanisms that link atrial fibrillation to dementia. We are initiating a series of new studies that are aimed to understand what treatments may reduce the risk of developing dementia in atrial fibrillation patients," concludes Dr. Bunch.

Read about a study that suggests loneliness may be an early sign of Alzheimer's.

Written by Yella Hewings-Martin

AHA: No Cognitive Benefit from Heart Drugs in HOPE-3

NEW ORLEANS -- A large substudy of the HOPE-3 trial found no benefit relating to cognitive function in patients who took cholesterol or blood pressure-lowering drugs.

In recent years cognitive decline and dementia have emerged as a concern equal if not even greater than cardiovascular disease in aging people. Hypertension has been linked to cognitive decline while some have suggested that statins may lead to memory problems.

The main HOPE-3 study, reported in April at the American College of Cardiology meeting and published in the New England Journal of Medicine, found that in a primary prevention setting statin therapy with rosuvastatin lowered cardiovascular events significantly but antihypertensive therapy did not have a significant effect.

A HOPE-3 substudy, presented by Jackie Bosch, PhD, of McMaster University, at the American Heart Association meeting in New Orleans, examined the effect of the study drugs on cognitive and functional decline in 1,626 patients over more than 5 years of followup.

There were no significant differences in any of cognitive and functional outcome measures in the study. However, there was a trend toward improvement in a post hoc analysis that looked at the small number of patients (n=93) who at baseline were in the highest tertile of blood pressure (over 145 mm Hg) and LDL (over 140 mg dL).

One potentially important finding of the study is that there was no evidence of any sort for cognitive decline in patients taking rosuvastatin. This, Bosch said in an interview, helps refute earlier anecdotal and observational studies that raised concerns about the cognitive effects of statins. She said she supported removing the black box warning about cognitive effects on statin labels.

Sverre Kjeldsen, MD, PhD, of Oslo University Hospital, said that this study does not end all "hope" that blood pressure reduction may help prevent cognitive decline. He pointed out that baseline blood pressure levels in HOPE-3 were not very high to begin with (138/82 mm Hg). "If we want to prevent cognitive decline by treating high blood pressure, blood pressure must be clearly elevated. It is great that the HOPE-3 investigators are trying, but HOPE-3 is not really a hypertension study. People may need to have higher blood pressure and maybe long-lasting hypertension, and the trial intervention may need to continue for a longer period of time."

Kjeldsen also said that he "deeply regrets that we never investigated cognitive function in all the hypertension trials that we did over the years, but when we planned and initiated these trials in the early and late 1990's we were not aware of the situation, although we should have been."

Franz Messerli, MD, of Mount Sinai, said that there have been several studies that "have documented cognition to improve following the use of renin angiotensin inhibitors and calcium channel blockers in the hypertensive elderly. That blood pressure lowering did not affect cognition in HOPE-3 is disappointing but not entirely unexpected since the majority of patients were normotensive at baseline. In normotensive patients reduction in blood pressure not only has no effect on cardiovascular events (as shown) but also may actually worsen cerebral perfusion and even cause a J-curve phenomenon. The good news in HOPE-3 is that rosuvastatin had no negative effect on cognition, while being highly effective in reducing cardiovascular outcomes."

Ralph Sacco, MD, of University of Miami, agreed at an American Heart Association press conference that an important finding was the absence of any signal for harm with statin treatment. He said that it was difficult to detect a difference in a population that was somewhat healthier than expected. He held out hope that significant benefits might be found by treating, on the one hand, higher risk populations or, on the other hand, younger patients for a longer period of time. Bosch agreed that earlier intervention may be the best way to achieve a beneficial effect.

2016-11-13T16:45:00-0500

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Alzheimer's disease: New analyses from Phase 3 studies showing clinical benefit of Tramiprosate

Results published in The Journal of the Prevention of Alzheimer's Disease (JPAD) describe analyses of Phase 3 data for the investigational amyloid-targeted drug, tramiprosate, in patients with Mild to Moderate Alzheimer's disease (AD). These efficacy analyses evaluated patient subgroups based on the number of e4 alleles of apolipoprotein E (APOE4), a major genetic risk factor in up to 65 percent of patients with AD.^1,2 The published results showed a gene-dose effect at the high dose of tramiprosate (150 mg, twice daily), with patients with two APOE4 alleles (APOE4/4 homozygotes) showing the largest clinical benefit, those with one APOE4 allele (APOE4 heterozygotes) showing an intermediate benefit, while APOE4 non-carriers showed no benefit from tramiprosate. The results published in JPAD are the first evidence from a large clinical trial to associate efficacy of an amyloid-targeted agent with APOE4 status in AD patients.

The manuscript, titled "Clinical Benefits of Tramiprosate in Alzheimer's Disease Are Associated with Higher Number of APOE4 Alleles: The 'APOE4 Gene-Dose Effect'," is featured in the advanced online publication of The Journal of the Prevention of Alzheimer's Disease (JPAD)³ with lead authors from Alzheon, Inc., a biopharmaceutical company focused on treatments for neurodegenerative and neuropsychiatric disorders. Based on the analyses in the publication, Alzheon is developing ALZ-801, an optimized oral prodrug of tramiprosate, and has refined the design of the pivotal clinical trial to evaluate ALZ-801 as a potential disease-modifying agent in symptomatic AD patients who are APOE4/4 homozygotes.

Anton P. Porsteinsson, MD, Professor of Psychiatry at the University of Rochester School of Medicine and Dentistry and Director of the Alzheimer's Disease Care, Research and Education Program at the University of Rochester in Rochester, NY, and an investigator in the North American Phase 3 clinical trial, commented: "The genetically‐defined population of APOE4 carriers has an 8‐12 fold increased risk of developing AD and has more rapidly progressive disease, usually becoming symptomatic a decade earlier than non‐carriers of the APOE4 genotype. These analyses with tramiprosate in the APOE4 subgroups are compelling, and suggest a meaningful clinical benefit, on top of the existing symptomatic AD treatments, in Alzheimer's patients who are in great need of new treatments. We can apply these insights about the therapeutic response of APOE4 carriers to refine patient selection and potentially improve the success rate of new Alzheimer's medicines."

The efficacy and safety analyses with tramiprosate published in JPAD reveal a therapeutic effect in patients who are carriers of APOE4 after segmenting them from the larger, non-genetically-defined study population in the Phase 3 clinical program, involving more than 2,000 AD patients in North America and Europe. In the overall Mild and Moderate AD study population with baseline MMSE of 16-26 (and any APOE genotype), the North American study did not demonstrate a significant benefit with either of two tramiprosate doses (100 mg BID and 150 mg BID), compared to placebo, during the 78-week study period.⁴ As a result, the European study was terminated before completion, and the results were not previously published.

"To our knowledge, this is the first time that the clinical benefits of an amyloid-targeted agent have been associated with the number of APOE4 alleles in Alzheimer's patients. This new insight shows how we can apply a precision medicine approach in AD and develop this drug for the right patients, namely patients with the APOE4 genotype, which carries the highest risk as well as the earliest onset and faster disease progression," said Martin Tolar, MD, PhD, Founder, President and CEO of Alzheon. "These newly-published findings form the basis for the design of our Phase 3 program, and further support our company's commitment to advance ALZ-801 into pivotal studies in APOE4/4 homozygous AD patients who represent up to 15% of AD patients¹. We are preparing to advance ALZ-801, a promising new treatment for Alzheimer's disease, into confirmatory clinical studies in 2017."

The observed gene-dose effects of tramiprosate in APOE4 carriers are consistent with the prevalence of amyloid pathology in AD patients. Amyloid imaging in AD clinical trials has shown the highest prevalence of positive amyloid scans in APOE4/4 homozygotes, and the lowest prevalence in APOE4 non-carriers.⁵ As one of the few orally-administered amyloid-targeted agents, tramiprosate blocks the aggregation of beta amyloid monomers into toxic oligomers, and was developed to show efficacy in patients with amyloid pathology and an accurate diagnosis of AD.

Efficacy Results in APOE4/4 Homozygous Patients from the JPAD Phase 3 Analyses

The published results showed the largest clinical benefit in the Alzheimer's APOE4/4 homozygous AD patients, who represent approximately 15 percent of patients in the study.³ APOE4/4 homozygous patients who received the high dose of tramiprosate showed efficacy benefit compared to placebo on both cognitive and functional measures in the Phase 3 analyses. The effects on the ADAS-cog cognitive outcome were significant at Week 65 (LS means difference from placebo: 3.47, nominal p = 0.007) and Week 78 (2.60, nominal p = 0.043), and corresponded to 66 percent and 40 percent benefit from tramiprosate compared to placebo. These effects were supported by functional benefits on the CDR-SB that showed a positive trend at Week 65 (LS means difference from placebo: 0.79, nominal p = 0.063) and were numerically in favor of tramiprosate at Week 78 (0.54, nominal p = 0.21).

"APOE4/4 homozygous AD patients are especially challenging since they are known to have the highest burden of amyloid pathology in cerebral cortex and blood vessels, which explains their susceptibility to ARIA-E with some amyloid-targeted treatments. In these new subgroup analyses, the high dose of tramiprosate showed promising clinical effects in APOE4/4 homozygous AD patients already receiving maximal standard of care, and this dose was not associated with any events of vasogenic edema," said Susan Abushakra, MD, Chief Medical Officer of Alzheon and lead author on the JPAD publication. "Replication of these findings in Alzheon's planned Phase 3 study would provide a meaningful therapeutic advance for AD patients with the APOE4/4 genotype, and we are now preparing to carry forward these results into the development of ALZ-801."

Safety Results from the JPAD Phase 3 Analyses

The safety profile of tramiprosate in 2,025 AD patients across the two studies was favorable and similar in the APOE4 carriers and non‐carriers. The main adverse events were gastrointestinal (nausea, vomiting and weight loss), which were mild or moderate in severity.

New ARIA-E safety analyses were reported in the JPAD publication. Brain magnetic resonance imaging (MRI) evaluations in 426 patients were conducted during the Phase 3 studies and did not reveal any events of vasogenic brain edema (ARIA-E or amyloid-related imaging abnormalities-edema) on either dose of tramiprosate. Vasogenic edema (or brain swelling) is a side effect observed in clinical studies with some injectable anti-amyloid antibodies, which requires MRI monitoring and can occasionally be serious.⁶

Article: Clinical Benefits of Tramiprosate in Alzheimer's Disease Are Associated with Higher Number of APOE4 Alleles: The 'APOE4 Gene-Dose Effect, S. Abushakra, A. Porsteinsson, B.Vellas, J. Cummings, S. Gauthier, J.A. Hey, A. Power, S. Hendrix, P. Wang, L. Shen, J. Sampalis, M. Tolar, The Journal of the Prevention of Alzheimer's Disease, doi: 10.14283/jpad.2016.115, published online 24 October 2016.

Tweaking the immune response might be a key to combat neurodegeneration

Study suggests zebrafish might teach us how to tackle Alzheimer's disease: Patients with Alzheimer's or other neurodegenerative diseases progressively loose neurons yet cannot build new ones. However, modulating the immune response might help the human brain to better cope with such conditions and regenerate. The research group led by Caghan Kizil at the German Center for Neurodegenerative Diseases (DZNE) in Dresden report on these findings in the journal Cell Reports. Their conclusions are based on studying zebrafish, an organism well-known for its ability to counteract neuronal damage by regenerating lost cells.

Zebrafish and humans are obviously quite different species. However, they share an evolutionary past that translates into various similarities on the cellular and molecular scale. "The regenerative skills apparent in zebrafish might lie dormant in humans and might somehow be activated by pulling the right strings", Dr. Kizil explains. "This is why we study if and how zebrafish cope with neurodegeneration. We want to understand the basic molecular mechanisms of such a regenerative aptitude in order to design better clinical therapies."

In the current study, the Dresden-based neuroscientist and his co-workers succeeded in mimicking symptoms of Alzheimer's disease in zebrafish brain. Conditions were triggered by Amyloid-Beta42 (Aβ42) peptides - one of the major contributors to the disease in human brains. Similar to our brains, Amyloid molecules accumulated in the neurons of zebrafish leading to immune response, synaptic degeneration, cell death, learning deficits and other dysfunctions. "This is the first time, such conditions have been generated in adult zebrafish through Aβ42 deposits", Kizil says.

The significance of neuro-immune crosstalk

The Aβ42 deposits triggered a special inflammation-related signaling pathway that ultimately lead to enhanced neurogenesis, i.e. new neurons were built. "We found that a molecule called Interleukin-4 is very much involved in the generation of neurons. The molecule is released by the dying neurons and immune system cells. It then acts on neural stem cells, which are the progenitors of neurons, by increasing their proliferation", Kizil says. "Interleukin-4 has been known to be a player in immune response and inflammation. But to date, the direct role of IL4 on stem cell proliferation has not been shown."

A better understanding of how we could manipulate inflammatory conditions might aid to develop novel therapies against Alzheimer's, Kizil argues. "In humans inflammation does not seem to act as a positive cue for regeneration as it does in zebrafish. Possibly because other factors interfere in a complex manner. Our zebrafish model offers the opportunity to study such factors one by one in a reductionist manner. Besides, our study points to the significance of the immune response. That is to say: by tweaking the immune response, for example with drugs, and targeting the right cell types, we might unlock the potential of human neural stem cells to proliferate and build new neurons. Of course, the challenge remains as to what will happen to those new neurons. But first things first: we have to start from the stem cells."

Article: IL4/STAT6 Signaling Activates Neural Stem Cell Proliferation and Neurogenesis upon Amyloid-β42 Aggregation in Adult Zebrafish Brain, Prabesh Bhattarai, Alvin Kuriakose Thomas, Mehmet Ilyas Cosacak, Christos Papadimitriou, Violeta Mashkaryan, Cynthia Froc, Susanne Reinhardt, Thomas Kurth, Andreas Dahl, Yixin Zhang, Caghan Kizil, Cell Reports, doi: 10.1016/j.celrep.2016.09.075, published 18 October 2016.

Dementia diagnosis delayed by complex referral criteria

Complex and time-consuming memory clinic referral criteria are contributing to delays in the diagnosis of dementia, according to a paper published by the Journal of the Royal Society of Medicine. Around 850,000 people are living with dementia in the UK but the number thought to have dementia substantially exceeds those with a formal diagnosis. Early diagnosis is a priority for the government and the NHS.

Currently GPs are responsible for referring patients for assessment and diagnosis by specialists, usually in dedicated memory clinics which set referral criteria. There is considerable variation in referral criteria, with requirements set by some memory clinics that exceed national guidelines. Requirements can include different combinations of cognitive tests, laboratory blood tests, urine tests and physical examination that vary between clinics.

Lead author Dr Benedict Hayhoe, of the School of Public Health at Imperial College London, says: "GPs have difficulty assessing patients with memory problems in strict accordance with guidance within a 10-minute consultation; in our experience a significant proportion of available consultation time can be taken up by carrying out just one of the brief cognitive tests." He went on to suggest that, with current workload pressures on primary care, complex criteria involving multiple investigations are likely to provide a significant disincentive for referral.

The authors set out alternative approaches to speed up diagnosis. Dr Hayhoe said: "A primary care led process, perhaps staffed by practice nurses carrying out assessments according to protocols, may speed up diagnosis while reducing pressure on GPs and specialists." He added that it may also be appropriate to allow people with memory concerns direct access to memory clinics.

Dr Hayhoe concludes: "A system that discourages or delays referral for dementia is highly counterproductive; an urgent review of this area is necessary to establish a system that effectively supports patients and clinicians in early diagnosis, treatment and prevention."

Article: General practitioner referrals to memory clinics: are referral criteria delaying the diagnosis of dementia? Benedict Hayhoe, Azeem Majeed and Robert Perneczky, Journal of the Royal Society of Medicine, doi: 10.1177/0141076816671939, published 9 November 2016.

Elucidating sex differences in Alzheimer's disease risk

Study of memory function in early midlife period pinpoints changes linked with menopause.

Women have a two-fold higher risk of developing Alzheimer's disease than men, yet strikingly little is known about how changes in brain function promote this difference - and how early in midlife those changes can be detected. Now, in a population-based study involving more than 200 healthy women and men ages 47 to 55, a team of researchers led by the Brigham and Women's Hospital reveals specific changes in memory function that correspond to sex and menopausal stage, rather than chronological age. The work implicates key areas of the brain that are vulnerable to age-related decline and highlights the importance of ovarian hormones in maintaining memory function.

The new study appears online issue of the journal Menopause.

"For years, the dominant thinking in the field was that women were at higher risk of Alzheimer's disease simply because they tend to live longer," said senior author Jill Goldstein, PhD, Director of Research at the Connors Center for Women's Health and Gender Biology at BWH. "But that idea was perpetuated by research that looked late in life - not at middle age, when key hormonal transitions take place and when changes in memory begin to surface."

Age-related cognitive decline impacts both men and women, with people reporting forgetfulness and a lack of mental clarity (so-called "brain fog") as they age. While women in general tend to fare better than men on tests of verbal memory and men have a higher rate of mild cognitive impairment later in life, women are disproportionately affected by Alzheimer's disease. In the U.S. alone, there are roughly 5.4 million people living with Alzheimer's disease; nearly two-thirds are women.

Goldstein and her colleagues seized an opportunity to examine how and why these sex differences unfold when one of their long-studied community cohorts, known as the New England Family Study, began entering their later-40s and 50s. That allowed the researchers to carefully examine what happens to memory function in healthy, middle-age women over time as menopause unfolds - spanning the pre- , peri-, and post-menopausal periods - and to compare those findings to healthy, age-matched men.

Because the individuals studied showed no signs of dementia or obvious memory loss, standard tests of memory function were not challenging enough to detect changes. So the team turned to a series of neuropsychological tests, refined by Dorene Rentz, PsyD, a lead author on the paper, senior neuropsychologist in the Department of Neurology at BWH, and an expert on Alzheimer's disease. These tests rigorously evaluate different forms of learning and memory, offering a finer-grained view that could identify even early, age-related cognitive deficits.

The researchers found that, when compared to age-matched men, the women scored significantly higher on all categories of memory function assessed by the tests, with one notable exception: Post-menopausal women performed at roughly the same level as their male counterparts (and worse than the other women) on tests of initial learning and retrieval of information. The finding suggested changes in frontal areas of the brain, known for their roles in short-term memory and so-called "executive functions" - advanced cognitive abilities, like organizing, structuring and evaluating information. In addition, hormone measurements revealed that across all women studied, higher estradiol levels (the form of estrogen that has the greatest effects on the brain) correlated with better memory performance.

When taken together with other recent work, both from Goldstein's group and others, the Menopause paper helps paint a picture of the memory circuits in the brain that begin to change with age - in both males and females - and underscores the importance of steroid hormones, especially estradiol for women, in maintaining memory function.

"We need to develop the capability to identify early on who is at highest risk of developing Alzheimer's disease," said Goldstein. "This is critical because the treatments given after disease onset have been unsuccessful. We hope findings from our cohort will ultimately provide clues early in mid-life with regard to who is at highest risk for the disease in later mid-life, and how this may differ for men and women. "

Goldstein and her colleagues are already working toward that goal. Together with collaborator Philip de Jager, MD, PhD, who directs the Program in Translational NeuroPsychiatric Genomics at the Ann Romney Center for Neurologic Diseases at BWH, the researchers are designing a clinical risk tool that can help pinpoint patients who are most vulnerable to Alzheimer's disease. This tool - which is being developed for both men and women - will incorporate genetic risk factors as well as a host of other clinical characteristics known to affect memory decline and the sex differences therein.

"Alzheimer's disease is one of the greatest public health challenges of our time," said Goldstein. "Going forward, it is imperative that we understand how to retain memory function throughout life, and that we incorporate these sex differences into future research and therapeutic discovery strategies."

This study was supported by the National Institute of Mental Health (R01MH090291 to J. Goldstein). Additional support was provided by ORWH-NICHD BIRCWH K12 HD051959 to author E. Jacobs. The Harvard Clinical and Translational Science Center (NIH UL1RR025758) also provided support for serologic acquisition and evaluations.

Article: Sex differences in episodic memory in early midlife: impact of reproductive aging, Rentz, Dorene M. PsyD; Weiss, Blair K. BS; Jacobs, Emily G. PhD; Cherkerzian, Sara ScD; Klibanski, Anne MD; Remington, Anne MA; Aizley, Harlyn MEd; Goldstein, Jill M. PhD, Menopause, doi: 10.1097/GME.0000000000000771, published 7 November 2016.

Experimental drug shows promise in treating Alzheimer's disease

An experimental drug shows promise in treating Alzheimer's disease by preventing inflammation and removing abnormal protein clumps in the brain that are associated with the disease, suggests a study in mice presented at the ANESTHESIOLOGY® 2016 annual meeting.

A key characteristic of Alzheimer's disease is the development of abnormal protein clumps called amyloid plaques and tangled bundles of fibers in the brain. These changes cause inflammation in the brain and damage to the neurons. This progressive damage leads to memory loss, confusion and dementia. The new drug, known as NTRX-07, appears to decrease this inflammation in the brain, while preserving neurons and regenerative cells in the brain.

"This drug may reduce inflammation in the brain, which is linked to Alzheimer's disease," said lead researcher Mohamed Naguib, M.D., a physician anesthesiologist in the Department of General Anesthesiology at the Cleveland Clinic and professor of anesthesiology at the Cleveland Clinic Lerner College of Medicine. "NTRX-07 uses a different mechanism than many other Alzheimer's drugs currently available, as it targets the cause of the disease, not just the symptoms."

The authors discovered NTRX -07's memory-restoring abilities while studying the drug's potential to treat a complex, chronic pain condition called neuropathic pain. "Patients who have neuropathic pain have chronic neuroinflammation," said Dr. Naguib. "This is a compound that blunts that inflammation."

Researchers tested NTRX -07 on mice bred to have similar brain neurodegenerative issues as seen in Alzheimer's. They found that inflammation produced in response to the disease caused changes in the brain's microglia cells - immune cells that typically remove dangerous amyloid plaques (protein clumps) in the brain. As the amyloid plaques accumulated in the mice, the microglia (immune cells) were unable to remove them, leading to inflammation and damage to nerve cells, which caused decreased cognitive ability.

Microglia cells have receptors on the surface called CB2 receptors, which when activated can produce an anti-inflammatory response. NTRX -07 targets CB2 receptors, which leads to decreased inflammation and prevents damage to the brain tissue. The new drug improved removal of abnormal amyloid plaques and improved memory performance and other cognitive skills.

The drug also increased levels of a protein called SOX2, which has been shown to help new brain cells develop and protect the brain in people with Alzheimer's disease. The study found in mice treated with NTRX-07, the levels of SOX2 were restored to normal levels. In contrast, mice treated with a placebo showed decreased levels of SOX2, active inflammation in the brain, poor removal of amyloid plaques, and poor memory performance.

Joseph F. Foss, M.D., director, of clinical research for general anesthesiology at Cleveland Clinic, and Dr. Naguib are co-founders of NeuroTherapiaTM, a spin-off company created by Cleveland Clinic Innovations to develop NTRX -07. NeuroTherapiaTM recently received a $1.7 million investment from the Alzheimer's Drug Discovery Foundation to advance NTRX-07 toward human clinical trials. The company also has received $700,000 from the Alzheimer's Association to support the proposed Phase I human studies. They anticipate initiating the human clinical studies in 2017.

Regular exercise may safeguard against memory loss

More than 16 million people in the United States live with cognitive impairment. The underlying cause of vascular cognitive impairment, in particular, is caused by problems with blood supply to the brain. Scientists may have found a solution to prevent memory decline in people with this condition, in the form of regular exercise.

Regular exercise may help ward off memory decline in people with vascular cognitive impairment.

Vascular cognitive impairment (VCI) is the second leading cause of dementia - after Alzheimer's disease - accounting for around 10 percent of cases. People with VCI experience deterioration in mental abilities, such as memory, thinking, problem-solving, and language.

VCI develops as a result of reduced blood flow to the brain that damages and eventually kills brain cells. The death of brain cells causes problems with cognition - memory, thinking, and reasoning.

Blood flow can diminish due to narrowing and blockage of small blood vessels deep in the brain, through a major stroke, or many mini strokes. In many of these cases, these difficulties are linked to underlying health conditions, including high blood pressure and diabetes, and lifestyle choices such as smoking and being overweight.

While there is no specific treatment for VCI or a method to reverse the damage caused to the brain, there are ways to slow down the progression of the condition. Lifestyle changes - such as eating healthily, weight loss, quitting smoking, and regular exercise - can also tackle the underlying cause of high blood pressure.

"Studies have shown that exercise can help reduce the risk of developing memory problems, but few studies have looked at whether it can help people who already have these problems get better or keep from getting worse," says study author Teresa Liu-Ambrose, Ph.D., of the University of British Columbia in Vancouver, Canada.

Liu-Ambrose and team aimed to assess what effect an aerobic exercise-training program would have on cognitive and everyday function among 70 adults with VCI with an average age of 74 years.

The study findings were published in Neurology, a medical journal of the American Academy of Neurology.

The participants were divided into two groups. One group took part in 1-hour exercise classes three times a week for 6 months, while the other group received monthly information about VCI and a healthy diet, but no information on regular exercise.

Exercise improved thinking, blood pressure, cardiovascular capacity

Overall thinking skills, executive function skills - such as planning and organizing and how well daily tasks were completed - were assessed in participants before the study, on study completion, and then again 6 months later.

Compared with the non-exercise group, the training group experienced blood pressure improvement and improved on a test to measure overall cardiovascular capacity by logging the distance they could walk in 6 minutes. This finding is important as high blood pressure is a risk factor for developing VCI, say the researchers.

The research team discovered that the people in the exercise-training group improved on the overall thinking test by 1.7 points, compared with those who took part in zero physical activity.

"This result, while modest, was similar to that seen in previous studies testing the use of drugs for people with vascular cognitive impairment. However, the difference was less than what is considered to be the minimal clinically important difference of three points."

Teresa Liu-Ambrose, Ph.D.

When the training group was assessed after 6 months - on cessation of the exercise program - their scores were the same as those people who had not exercised. No differences were observed between the two groups, during any of the assessment stages, for tests of executive function skills and daily activities.

In an accompanying editorial, Dr. Alexandra Foubert-Samier, Ph.D., says that despite the limitations of the study, "the results of this work provide a proof of concept of the effect of physical activities on cognition in patients with VCI and encourage further studies on larger groups of people with VCI."

Future work may test further whether exercise can improve thinking skills in VCI. Larger samples may detect differences in specific thinking abilities such as a person's ability to plan and manage their finances.

Read about how high blood pressure raises the risk of cognitive decline in dementia.

Written by Hannah Nichols

Probiotics may boost learning, memory for Alzheimer's patients

A research team from Iran are the first to show how a daily dose of probiotics for 3 months could be effective for improving memory and thinking abilities in individuals with Alzheimer's disease.

Researchers found older adults with Alzheimer's who drank probiotic-enriched milk showed improvements in cognitive functioning.

The researchers found that Alzheimer's patients who consumed milk enriched with beneficial live bacteria every day for 12 weeks showed significant improvements in cognitive functioning.

Senior study author Prof. Mahmoud Salami, from Kashan University in Iran, and colleagues recently published their findings in the journal Frontiers in Aging Neuroscience.

Probiotics are defined as live microorganisms that are "helpful" to human health. These include bacterial groups such as Lactobacillus and Bifidobacterium, as well as yeasts, including Saccharomyces boulardii.

According to the National Center for Complementary and Integrative Health, probiotics can act in a number of ways. They can help create a favorable community of microbes in the gut, for example, and help stimulate immune response.

Research has shown that these friendly microorganisms - many of which are added to food products, topical medications, and dietary supplements - may help protect against numerous infections and diseases, including irritable bowel syndrome (IBS), eczema, certain allergies, colds, and tooth decay.

Previous animal studies have also shown probiotics to improve learning and memory - an association that has been attributed to beneficial alterations in the gut microbiome that affect the brain. Whether probiotics have the same effect in humans, however, has been unclear.

Cognitive functioning scores improved with probiotics

For this latest study, Prof. Salami and team set out to determine the effects of probiotics on the cognitive functioning of 52 men and women aged 60-95 who had been diagnosed with Alzheimer's disease.

Participants were randomized to one of two groups. One group was required to drink 200 milliliters of normal milk every day for 12 weeks, while the other group drank 200 milliliters of milk containing four probiotic bacteria: Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus fermentum, and Bifidobacterium bifidum.

Fast facts about Alzheimer's

• More than 5 million adults in the United States are living with Alzheimer's
• Every 66 seconds, someone in the U.S. develops the disease
• Alzheimer's kills more people than breast cancer and prostate cancer combined.

Learn more about Alzheimer's

Before and after the 12-week study period, researchers collected blood samples from the participants, and the subjects' cognitive functioning was assessed using the Mini-Mental State Examination (MMSE) scale.

As part of this examination, subjects are required to complete a number of tasks that test learning and memory, such as naming objects, counting backward, and copying a picture.

Compared with participants who consumed the untreated milk, those who received the probiotic-enriched milk demonstrated significant improvements in cognitive functioning, the team reports.

Subjects who consumed the treated milk saw average MMSE scores increase from 8.7 to 10.6 (out of a possible 30) during the 12-week study period, while scores dropped from 8.5 to 8.0 for those who drank the untreated milk.

The researchers stress that all participants remained severely cognitively impaired, but their findings are the first to show that probiotics might lead to some cognitive improvements.

"In a previous study, we showed that probiotic treatment improves the impaired spatial learning and memory in diabetic rats," notes Prof. Salami, "but this is the first time that probiotic supplementation has been shown to benefit cognition in cognitively impaired humans."

Cognitive benefits of probiotics may be down to metabolic changes

On assessing the participants' blood samples, the researchers found that subjects who consumed probiotics had lower triglycerides levels, lower levels of "bad" very low-density lipoprotein (VLDL) cholesterol, and reduced high-sensitivity C-reactive protein - a marker of inflammation.

Additionally, participants who received probiotics showed a reduction in two measures of insulin resistance and the functioning of insulin-producing beta cells in the pancreas - HOMA-IR and HOMA-B.

The team says these findings indicate the cognitive benefits of probiotics may be down to the metabolic changes they provoke. "We plan to look at these mechanisms in greater detail in our next study," notes Prof. Salami.

Walter Lukiw, a professor at Louisiana State University who was not involved in the study, hails the team's findings as "interesting and important," noting that they provide further evidence of a link between the gut microbiome and cognitive functioning.

"This is in line with some of our recent studies which indicate that the GI [gastrointestinal] tract microbiome in Alzheimer's is significantly altered in composition when compared to age-matched controls, and that both the GI tract and blood-brain barriers become significantly more leaky with aging, thus allowing GI tract microbial exudates (e.g. amyloids, lipopolysaccharides, endotoxins and small non-coding RNAs) to access central nervous system compartments," he adds.

Read how probiotics may help aid recovery from spinal cord injury.

Written by Honor Whiteman