For a study appearing in the August edition of Learning & Memory, Michael Yassa, associate professor of neurobiology and behavior and neurology, and colleagues designed and employed a test that uses participants’ recall of stories with differing emotional content to identify memory deficits and decline, particularly in the context of aging and Alzheimer’s disease.

Thirty-two older adults (21 females and 11 males with a mean age of 74.8) took part in the study. After each story was read aloud, they were asked to recite all the details they could remember. The task was repeated after 20 minutes and one week later. This allowed the neurobiologists to observe how story recall varied as time passed.

The study team included Stephanie Leal, who recently earned a doctorate at UCI, and Jessica Noche, a clinical research specialist in the Yassa lab.

“We were interested in seeing how emotional memory changes over time, so we developed a test to detect the subtle changes that occur with different types of emotional memory in older adults,” Noche said. “We specifically compared responses to positive, negative and neutral stories to learn whether emotional valence had a role in the way stories were remembered over time.”

Study subjects also took a verbal learning exam to gauge general memory performance. This served to distinguish between individuals who were high performers and those who were low performers (i.e., showing subtle memory deficits). Importantly, none of them suffered from overt memory problems severe enough for a clinical diagnosis.

Analyzing the results, researchers found that low-performing older adults exhibited a large “positivity effect,” or propensity to remember positive information. However, this came at the expense of retaining neutral material. On the other hand, high-performing older adults could recall more from neutral stories at the expense of retaining positive details.

“We suggest that this bias toward positive retention may be a compensatory mechanism that masks the effects of memory loss in the elderly, although this remains speculative,” Yassa said. “It’s possible that selectively remembering positive information may be related to changes in the brain networks supporting memory, emotional valence and reward value. Future studies using brain imaging techniques will be essential in understanding the mechanisms underlying this effect.”

Since all study participants at the time of testing had no memory complaints, researchers believe that the exam they created, called the Emotional Logical Memory Test, may tap into subtle changes in emotional memory abilities prior to obvious symptoms of cognitive decline. Further work will be necessary to establish whether subjects expressing the positivity effect are more likely to develop Alzheimer’s disease. If so, the test could prove to be a valuable tool in the early detection of Alzheimer’s susceptibility.

The study was reported in Restorative Neurology and Neuroscience.

Investigators at the University of Texas at Dallas proposed that only tasks that involved sustained mental effort and challenge would facilitate cognitive function. Senior author Denise Park and lead author Ian McDonough compared changes in brain activity in 39 older adults that resulted from the performance of high-challenge activities that required new learning and sustained mental effort compared to low-challenge activities that did not require active learning. All of the participants underwent a battery of cognitive tests and brain scans using functional magnetic resonance imaging (fMRI), an MRI technology that measures brain activity by detecting changes associated with blood flow.

Participants were randomly assigned to the high-challenge, low-challenge, or placebo groups. The high-challenge group spent at least 15 hours per week for 14 weeks learning progressively more difficult skills in digital photography, quilting, or a combination of both. The low-challenge group met for 15 hours per week to socialize and engage in activities related to subjects such as travel and cooking with no active learning component. The placebo group engaged in low-demand cognitive tasks such as listening to music, playing simple games, or watching classic movies. All participants were tested before and after the 14-week period and a subset was retested a year later.

The high-challenge group demonstrated better memory performance after the intervention, and an increased ability to modulate brain activity more efficiently to challenging judgments of word meaning in the medial frontal, lateral temporal, and parietal cortex regions of the brain. These are brain areas associated with attention and semantic processing. Some of this enhanced brain activity was maintained a year later. This increased neural efficiency in judging words was demonstrated by participants showing lowered brain activity when word judgments were easy and increasing activity when they became hard. This is a pattern of response typical of young adults. Before participating in the high-challenge intervention, the older adults were processing every item, both easy and hard, with maximum brain activity. After participation, they were able to modulate their brain activity to the demands of the task, thus showing a more efficient use of neural resources. This change in modulation was not observed in the low-challenge group.

The findings show that mentally demanding activities may be neuroprotective and an important element for maintaining a healthy brain into late adulthood.

“The present findings provide some of the first experimental evidence that mentally-challenging leisure activities can actually change brain function and that it is possible that such interventions can restore levels of brain activity to a more youth-like state. However, we would like to conduct much larger studies to determine the universality of this effect and understand who will benefit the most from such an intervention,” explained senior author Denise C. Park, PhD, of the Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas.

McDonough, who is now an assistant professor of Psychology at the University of Alabama and was first author on the study, said: “The study clearly illustrates that the enhanced neural efficiency was a direct consequence of participation in a demanding learning environment. The findings superficially confirm the familiar adage regarding cognitive aging of ‘Use it or lose it.’”

Park added, “Although there is much more to be learned, we are cautiously optimistic that age-related cognitive declines can be slowed or even partially restored if individuals are exposed to sustained, mentally challenging experiences.”

Now, thanks to investigators from the Perelman School of Medicine at the University of Pennsylvania, researchers in this field know better. Erle S. Robertson, PhD, a professor of Microbiology and Otorhinolaryngology and Director of the Tumor Virology Training Program at the Abramson Cancer Center, and colleagues published in mBio that EBV and a related virus, Kaposi’s sarcoma-associated herpesvirus (KSHV), can infect and replicate in both cultured and primary neurons.

Though by no means proving causality, those data do suggest viral infection could underlie at least some of the symptoms of those brain disorders, as well as the potential utility of antiviral drugs as a novel therapeutic strategy.

According to Robertson, several lines of evidence suggested the possibility that gammaherpesviruses could infect brain tissue. First, the viruses are enriched in the cerebrospinal fluid and brain tissue of individuals with such conditions as multiple sclerosis (MS) and Alzheimer’s disease. In addition, individuals with a history of infectious mononucleosis caused by EBV are more likely to develop MS, while those who have never been infected with EBV are less likely to do so. Particularly tellingly, the drug acyclovir, which can inhibit EBV and related viruses, has been examined as a potential treatment for MS, with some positive, albeit inconclusive, results.

Still, says Robertson, the ability of gammaherpesviruses to infect neurons has been “controversial.” Devan Mehta, a student in Robertson’s lab, working with postdoctoral fellow Hem C. Jha, PhD, and Dennis Kolson, MD, PhD, a professor of Neurology, tested the link directly. Using genetically modified viruses that express green fluorescent protein (GFP), Mehta infected human neuroblastoma cells (neurons differentiated from cancer cells) and primary human fetal neurons, monitoring the infection over time by microscopy and protein expression.

In both cell types, infection with either EBV or KSHV resulted in the appearance of a fluorescent signal in the infected cells, as well as the appearance of key viral proteins. The media in which infected cells were grown also contained functional virus particles capable of infecting other cells, indicating a mode of infection that tears open host cells. On the other hand, treatment of infected cells with acyclovir reduced the production of virus particles.

“I couldn’t believe it,” Robertson said. “After 50 years of studying EBV, nobody had ever seen the virus in nerve cells. But maybe they just never looked.”

According to Robertson, these data suggest that viral infection of neurons could be associated with neuropathology, though he emphasizes that it is not the same as establishing causality. Such proof, if it ever comes, could be years away.

“There’s likely to be association of this virus with neurons,” he stated. “But more studies will be necessary to know whether it is actually associated with disease pathology.”

The Genetics of Disease

Some diseases are caused by a genetic mutation, or permanent change in one or more specific genes. If a person inherits from a parent a genetic mutation that causes a certain disease, then he or she will usually get the disease. Sickle cell anemia, cystic fibrosis, and early-onset familial Alzheimer’s disease are examples of inherited genetic disorders.

In other diseases, a genetic variant may occur. A single gene can have many variants. Sometimes, this difference in a gene can cause a disease directly. More often, a variant plays a role in increasing or decreasing a person’s risk of developing a disease or condition. When a genetic variant increases disease risk but does not directly cause a disease, it is called a genetic risk factor.

Identifying genetic variants may help researchers find the most effective ways to treat or prevent diseases such as Alzheimer’s in an individual. This approach, called precision medicine, takes into account individual variability in genes, environment, and lifestyle for each person.

Alzheimer’s Disease Genetics

Alzheimer’s disease is an irreversible, progressive brain disease. It is characterized by the development of amyloid plaques and neurofibrillary, or tau, tangles; the loss of connections between nerve cells (neurons) in the brain; and the death of these nerve cells. There are two types of Alzheimer’s—early-onset and late-onset. Both types have a genetic component.

Early-Onset Alzheimer’s Disease

Early-onset Alzheimer’s disease occurs in people age 30 to 60 and represents less than 5 percent of all people with Alzheimer’s. Most cases are caused by an inherited change in one of three genes, resulting in a typle known as early-onset familial Alzheimer’s disease, or FAD. For others, the disease appears to develop without any specific, known cause.

A child whose biological mother or father carries a genetic mutation for early-onset FAD has a 50/50 chance of inheriting that mutation. If the mutation is in fact inherited, the child has a very strong probability of developing early-onset FAD.

Early-onset FAD is caused by any one of a number of different single-gene mutations on chromosomes 21, 14, and 1. Each of these mutations causes abnormal proteins to be formed. Mutations on chromosome 21 cause the formation of abnormal amyloid precursor protein (APP). A mutation on chromosome 14 causes abnormal presenilin 1 to be made, and a mutation on chromosome 1 leads to abnormal presenilin 2.

Each of these mutations plays a role in the breakdown of APP, a protein whose precise function is not yet fully understood. This breakdown is part of a process that generates harmful forms of amyloid plaques, a hallmark of the disease.

Critical research findings about early-onset Alzheimer’s have helped identify key steps in the formation of brain abnormalities typical of the more common late-onset form of Alzheimer’s. Genetics studies have helped explain why the disease develops in people at various ages.

NIA-supported scientists are continuing research into early-onset disease through the Dominantly Inherited Alzheimer Network (DIAN), an international partnership to study families with early-onset FAD. By observing the Alzheimer’s-related brain changes that occur in these families long before symptoms of memory loss or cognitive issues appear, scientists hope to gain insight into how and why the disease develops in both its early- and late-onset forms.

In addition, an NIA-supported clinical trial in Colombia, South America, is testing the effectiveness of an amyloid-clearing drug in symptom-free volunteers at high risk of developing early-onset FAD.

Late-Onset Alzheimer’s Disease

Most people with Alzheimer’s have the late-onset form of the disease, in which symptoms become apparent in the mid-60s and later. The causes of late-onset Alzheimer’s are not yet completely understood, but they likely include a combination of genetic, environmental, and lifestyle factors that affect a person’s risk for developing the disease.

Researchers have not found a specific gene that directly causes the late-onset form of the disease. However, one genetic risk factor—having one form of the apolipoprotein E (APOE) gene on chromosome 19—does increase a person’s risk. APOE comes in several different forms, or alleles:

APOE ε2 is relatively rare and may provide some protection against the disease. If Alzheimer’s disease occurs in a person with this allele, it usually develops later in life than it would in someone with the APOE ε4 gene.

APOE ε3, the most common allele, is believed to play a neutral role in the disease—neither decreasing nor increasing risk.

APOE ε4 increases risk for Alzheimer’s disease and is also associated with an earlier age of disease onset. A person has zero, one, or two APOE ε4 alleles. Having more APOE ε4 alleles increases the risk of developing Alzheimer’s.

APOE ε4 is called a risk-factor gene because it increases a person’s risk of developing the disease. However, inheriting an APOE ε4 allele does not mean that a person will definitely develop Alzheimer’s. Some people with an APOE ε4 allele never get the disease, and others who develop Alzheimer’s do not have any APOE ε4 alleles.

Using a relatively new approach called genome-wide association study (GWAS), researchers have identified a number of regions of interest in the genome (an organism’s complete set of DNA, including all of its genes) that may increase a person’s risk for late-onset Alzheimer’s to varying degrees. By 2015, they had confirmed 33 regions of interest in the Alzheimer’s genome.

A method called whole genome sequencing determines the complete DNA sequence of a person’s genome at a single time. Another method called whole exome sequencing looks at the parts of the genome that directly code for the proteins. Using these two approaches, researchers can identify new genes that contribute to or protect against disease risk. Recent discoveries have led to new insights about biological pathways involved in Alzheimer’s and may one day lead to effective interventions.

Genetic Testing

A blood test can identify which APOE alleles a person has, but results cannot predict who will or will not develop Alzheimer’s disease. It is unlikely that genetic testing will ever be able to predict the disease with 100 percent accuracy, researchers believe, because too many other factors may influence its development and progression.

Currently, APOE testing is used in research settings to identify study participants who may have an increased risk of developing Alzheimer’s. This knowledge helps scientists look for early brain changes in participants and compare the effectiveness of treatments for people with different APOE profiles. Most researchers believe that APOE testing is useful for studying Alzheimer’s disease risk in large groups of people but not for determining any one person’s risk.

Genetic testing is used by researchers conducting clinical trials and by physicians to help diagnose early-onset Alzheimer’s disease. However, genetic testing is not otherwise recommended.

Research Questions

Discovering all that we can about the role of Alzheimer’s disease genetic risk and protective factors is an important area of research. Understanding more about the genetic basis of the disease will help researchers to:

Answer a number of basic questions—What makes the disease process begin? Why do some people with memory and other thinking problems develop Alzheimer’s while others do not?

Determine how genetic risk and protective factors may interact with other genes and lifestyle or environmental factors to affect Alzheimer’s risk in any one person.

Identify people who are at high risk for developing Alzheimer’s so they can benefit from new interventions and treatments as soon as possible.

Focus on new prevention and treatment approaches.

This glossary may be helpful to you in reading more about Alzheimer’s and genetics:

Allele—A form of a gene. Each person receives two alleles of a gene, one from each biological parent. This combination is one factor among many that influence a variety of processes in the body. On chromosome 19, the apolipoprotein E (APOE) gene has three common alleles: ε2, ε3, and ε4.

Apolipoprotein E (APOE) gene—A gene on chromosome 19 involved in making a protein that helps carry cholesterol and other types of fat in the bloodstream. The APOE ε4 allele is the major known risk-factor gene for late-onset Alzheimer’s disease.

Chromosome — A compact structure containing DNA and proteins present in nearly all cells of the body. Chromosomes carry genes, which direct the cell to make proteins and direct a cell’s construction, operation, and repair. Normally, each cell has 46 chromosomes in 23 pairs. Each biological parent contributes one of each pair of chromosomes.

DNA (deoxyribonucleic acid)—The hereditary material in humans and almost all other organisms. Almost all cells in a person’s body have the same DNA. Most DNA is located in the cell nucleus.

Gene—A basic unit of heredity. Genes direct a cell to make proteins and guide almost every aspect of a cell’s construction, operation, and repair.

Genetic mutation—A permanent change in a gene that can be passed on to children. The rare, early-onset familial form of Alzheimer’s disease is associated with mutations in genes on chromosomes 21, 14, and 1.

Genetic risk factor—A change in a gene that increases a person’s risk of developing a disease.

Genetic variant—A change in a gene that may increase or decrease a person’s risk of developing a disease or condition.

Genome—An organism’s complete set of DNA, including all of its genes. Each genome contains all of the information needed to build and maintain that organism.

Genome-wide association study (GWAS)—A study approach that involves rapidly scanning the genomes of many individuals to find genetic variations associated with a particular disease.

Protein—A substance that determines the physical and chemical characteristics of a cell and therefore of an organism. Proteins are essential to all cell functions and are created using genetic information.

Reprinted with permission of the National Institute on Aging. For more information from the NIA on Alzheimer’s, click here.

Last week, the patient reported her symptoms. The doctor proceeded with the examination using the components of the classic S-O-A-P notes, which are as follows:

S=Symptoms or Chief Complaint

O=Objective Findings

A=Assessment or Analysis

P=Treatment Plan or Recommendations

The doctor recognized a potential medical emergency and transferred Chloe to the Emergency Department immediately. This week, we’ll learn what happened when Chloe first arrived in the Emergency Department.

When Chloe arrived at the Emergency Department, a neurosurgery consultant who had been alerted to her imminent arrival was already on call when she got there. He remained on standby while Chloe had a CT scan. A CT scan is sufficient and it’s usually done on an urgent basis for head trauma. It is the “gold standard”, and less costly than an MRI that may not be necessary or available as quickly or easily.

A non-contrast CT — no need for dye — showed a crescent shaped mass between the skull and surface of the cerebral hemisphere that extended beyond the suture line of the brain. There was minimal midline shift of about 5 mm consistent with mild swelling pushing brain slightly to one side.

To be continued . . .

Come back to ThirdAge.com next Thursday to find out what some people have guessed the diagnosis might be.

Getting Started

Talk with the person’s doctor about medicines to calm someone who gets upset while traveling.

Find someone to help you at the airport, train station, or bus station.

Keep important documents with you in a safe place. These include health insurance cards, passports, doctors’ names and phone numbers,  a list of medicines, and a copy of the person’s medical records.

Pack items the person enjoys looking at or holding for comfort.

Travel with another family member or friend.

Take an extra set of clothing in a carry-on bag.

People with memory problems may wander around a place they don’t know well. In case someone with Alzheimer’s disease gets lost:

•Make sure the person wears an ID bracelet or something else that tells others who he or she is.

•Carry a recent photo of the person with you on the trip.

After You Arrive

• Allow lots of time for each thing you want to do. Don’t plan too many activities.

• Plan rest periods.

• Follow a routine like the one you use at home. For example, try to have the person eat, rest, and go to bed at the same time he or she does at home.

• Keep a well-lighted path to the toilet, and leave the bathroom light on at night.

• Be prepared to cut your visit short if necessary.

Communicate with others when you’re out in public. Some caregivers carry a card that explains why the person with Alzheimer’s might say or do odd things. For example, the card could read, “My family member has Alzheimer’s disease. He or she might say or do things that are unexpected. Thank you for your understanding.”

Visiting Family and Friends

Spending time with family and friends is important to people with Alzheimer’s disease. They may not always remember who people are, but they often enjoy the company.

Here are some tips to share with people you plan to visit:

• Be calm and quiet. Don’t use a loud voice or talk to the person with Alzheimer’s as if he or she were a child.

• Respect the person’s personal space, and don’t get too close.

• Make eye contact and call the person by name to get his or her attention.

• Remind the person who you are if he or she doesn’t seem to know you.

• Don’t argue if the person is confused.

•Respond to the feelings that he or she expresses. Try to distract the person by  talking about something different.

• Remember not to take it personally if the person doesn’t recognize you, is unkind, or gets angry. He or she is acting out of confusion.

• Have ready some kind of activity, such as a familiar book or photo album to look at. This can help if the person with Alzheimer’s is bored or confused and needs to be distracted. But be prepared to skip the activity if it is not needed.

Reprinted with permission of the National Institute on Aging. For more information on age-related issues, click here to visit the agency’s website.

The team linked elevated amounts of cortisol to the gradual loss of synapses in the prefrontal cortex, the region of the brain that houses short-term memory. Previous studies have shown that cortisol negatively affects other regions of the aging brain, but this was the first study to examine its impact on the prefrontal cortex. Synapses are the connections that help us process, store, and recall information.

The release quotes corresponding author Jason Radley as saying, “Stress hormones are one mechanism that we believe leads to weathering of the brain.”

Although the findings are preliminary, they raise the possibility that short-memory decline in aging adults may be slowed or prevented with treatments that decrease levels of cortisol in susceptible individuals, Radley said. That could mean treating people who have high levels of cortisol, such as those who are depressed or those who experience traumatic life events like the death of a loved one.
According to Radley and Rachel Anderson, the paper’s lead author, short-term memory lapses related to cortisol start around age 65.