Posts tagged cognitive decline

Similarities found between HIV-associated brain damage and impairment from genetic fat-storage disease

Johns Hopkins scientists have found that levels of certain fats found in cerebral spinal fluid can predict which patients with HIV are more likely to become intellectually impaired.

The researchers believe that these fat markers reflect disease-associated changes in how the brain metabolizes these fat molecules. These changes disrupt the brain cells’ ability to regulate the activity of cells’ “garbage disposals” meant to degrade and flush the brain of molecular debris. In this case, too much cholesterol and a fat known as sphingomyelin build up in the lysosomes — the garbage disposals — backing up waste and leading to often debilitating cognitive declines. 

As many as half of patients infected with HIV will develop some form of cognitive impairment, ranging from mild (trouble counting change or driving a car) to frank dementia (an inability to manage activities of every day life), but no tests have been available to predict which people were more likely to suffer cognitive losses.

 “Every researcher of neurodegenerative disease is chasing biomarkers for the same reason: It’s better to identify problems before they strike,” says Norman J. Haughey, Ph.D., an associate professor in the departments of neurology and psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. He led the current study described online in the journal Neurology.

“It’s very hard to reverse brain damage after it starts,” he says. “Instead, we want to figure out who is likely to lose cognitive function and stop the damage before it happens.”

Haughey and his team analyzed 321 cerebral spinal fluid samples collected from seven test sites across the continental United States, Hawaii and Puerto Rico. The samples came from 291 HIV-positive participants and 30 HIV-negative subjects. The investigators found that early accumulations of a small number of these fat molecules could predict the probability of cognitive decline. As cognitive function declined in these patients, the number of different types of fat molecules that accumulated increased. The types of accumulating fat molecules in HIV were very similar to those that accumulate in inherited forms of a class of diseases called lysosomal storage disorders. This suggests that in some HIV-infected patients, the brain is retaining more of these fats, and this may disrupt the function of lysosomes.

Haughey says he believes some of these impairments in the metabolism of these fats found in people with HIV stems from the infection itself, while others may be linked to the lifesaving antiretroviral therapy taken by most people with HIV. The medications have been associated with elevated blood cholesterol and triglycerides, along with a host of other side effects. Those with HIV are now taking these drugs for decades and the complications from long-term use have not been well studied, he says.

The similarities between the metabolic disturbances in HIV-infected individuals and those apparent in lysosomal storage disorders are enabling Haughey and his team to collaborate with researchers who study genetic lysosomal storage diseases, and who are developing experimental treatments to clear the fat buildup. They are currently exploring dietary and pharmacological interventions designed to restore balance that could potentially restore brain metabolism in HIV-infected individuals, and in doing so could promote good brain health by ensuring the lysosomes function properly.

(Source: hopkinsmedicine.org)

The degeneration of a small, wishbone-shaped structure deep inside the brain may provide the earliest clues to future cognitive decline, long before healthy older people exhibit clinical symptoms of memory loss or dementia, a study by researchers with the UC Davis Alzheimer’s Disease Center has found.

The longitudinal study found that the only discernible brain differences between normal people who later developed cognitive impairment and those who did not were changes in their fornix, an organ that carries messages to and from the hippocampus, and that has long been known to play a role in memory.

“This could be a very early and useful marker for future incipient decline,” said Evan Fletcher, the study’s lead author and a project scientist with the UC Davis Alzheimer’s Disease Center.

“Our results suggest that fornix variables are measurable brain factors that precede the earliest clinically relevant deterioration of cognitive function among cognitively normal elderly individuals,” Fletcher said.

The research is published online today in JAMA Neurology.

Hippocampal atrophy occurs in the later stages of cognitive decline and is one of the most studied changes associated with the Alzheimer’s disease process. However, changes to the fornix and other regions of the brain structurally connected to the hippocampus have not been as closely examined. The study found that degeneration of the fornix in relation to cognition was detectable even earlier than changes in the hippocampus.

“Although hippocampal measures have been studied much more deeply in relation to cognitive decline, our direct comparison between fornix and hippocampus measures suggests that fornix properties have a superior ability to identify incipient cognitive decline among healthy individuals,” Fletcher said.

The study was conducted over five years in a group of 102 diverse, cognitively normal people with an average age of 73 who were recruited through community outreach at the Alzheimer’s Disease Center. The researchers conducted magnetic resonance imaging (MRI) studies of the participants’ brains that described their volumes and integrity. A different type of MRI was used to determine the integrity of the myelin, the fatty coating that sheaths and protects the axons. The axons are analogous to the copper wiring of the brain’s circuitry and the myelin is like the wiring’s plastic insulation.

Either one of those things being lost will “degrade the signal transmission” in the brain, Fletcher said.

The researchers also conducted psychological tests and cognitive evaluations of the study participants to gauge their level of cognitive functioning. The participants returned for updated MRIs and cognitive testing at approximately one-year intervals. At the outset, none of the study participants exhibited symptoms of cognitive decline. Over time about 20 percent began to show symptoms that led to diagnoses with either mild cognitive impairment (MCI) and, in a minority of cases, Alzheimer’s disease.

“We found that if you looked at various brain factors there was one — and only one — that seemed to be predictive of whether a person would have cognitive decline, and that was the degradation of the fornix,” Fletcher said.

The study measured two relevant fornix characteristics predicting future cognitive impairment — low fornix white matter volume and reduced axonal integrity. Each of these was stronger than any other brain factor in models predicting cognitive loss, Fletcher said. 

He said that routine MRI examination of the fornix could conceivably be used clinically in the future as a predictor of abnormal cognitive decline.

“Our findings suggest that if your fornix volume or integrity is within a certain range you’re at an increased risk of cognitive impairment down the road. But developing the use of the fornix as a predictor in a clinical setting will take some time, in the same way that it took time for evaluation of cholesterol levels to be used to predict future heart disease,” he said.

Fletcher also said that the finding may mark a paradigm shift toward evaluation of the brain’s white matter, rather than its gray matter, as among the very earliest indicators of developing cognitive loss. There is currently a strong research focus on understanding brain processes that lead eventually to Alzheimer’s disease. He said the current finding could fill in one piece of the picture and motivate new directions in research to understand why and how fornix and other white matter change is such an important harbinger of cognitive impairment. 

“The key importance of this finding is that it suggests that white matter tract measures may prove to be promising candidate biomarkers for predicting incipient cognitive decline among cognitively normal individuals in a clinical setting, possibly more so than gray matter measures,” he said.

(Source: ucdmc.ucdavis.edu)

If you forget where you put your car keys and you can’t seem to remember things as well as you used to, the problem may well be with the GluN2B subunits in your NMDA receptors.

And don’t be surprised if by tomorrow you can’t remember the name of those darned subunits.

They help you remember things, but you’ve been losing them almost since the day you were born, and it’s only going to get worse. An old adult may have only half as many of them as a younger person.

Research on these biochemical processes in the Linus Pauling Institute at Oregon State University is making it clear that cognitive decline with age is a natural part of life, and scientists are tracking the problem down to highly specific components of the brain. Separate from some more serious problems like dementia and Alzheimer’s disease, virtually everyone loses memory-making and cognitive abilities as they age. The process is well under way by the age of 40 and picks up speed after that.

But of considerable interest: It may not have to be that way.

“These are biological processes, and once we fully understand what is going on, we may be able to slow or prevent it,” said Kathy Magnusson, a neuroscientist in the OSU Department of Biomedical Sciences, College of Veterinary Medicine, and professor in the Linus Pauling Institute. “There may be ways to influence it with diet, health habits, continued mental activity or even drugs.”

The processes are complex. In a study just published in the Journal of Neuroscience, researchers found that one protein that stabilizes receptors in a young animal – a good thing conducive to learning and memory – can have just the opposite effect if there’s too much of it in an older animal.

But complexity aside, progress is being made. In recent research, supported by the National Institutes of Health, OSU scientists used a genetic therapy in laboratory mice, in which a virus helped carry complementary DNA into appropriate cells and restored some GluN2B subunits. Tests showed that it helped mice improve their memory and cognitive ability.

The NMDA receptor has been known of for decades, Magnusson said. It plays a role in memory and learning but isn’t active all the time – it takes a fairly strong stimulus of some type to turn it on and allow you to remember something. The routine of getting dressed in the morning is ignored and quickly lost to the fog of time, but the day you had an auto accident earns a permanent etching in your memory.

Within the NMDA receptor are various subunits, and Magnusson said that research keeps pointing back to the GluN2B subunit as one of the most important. Infants and children have lots of them, and as a result are like a sponge in soaking up memories and learning new things. But they gradually dwindle in number with age, and it also appears the ones that are left work less efficiently.

“You can still learn new things and make new memories when you are older, but it’s not as easy,” Magnusson said. “Fewer messages get through, fewer connections get made, and your brain has to work harder.”

Until more specific help is available, she said, some of the best advice for maintaining cognitive function is to keep using your brain. Break old habits, do things different ways. Get physical exercise, maintain a good diet and ensure social interaction. Such activities help keep these “subunits” active and functioning.

Gene therapy such as that already used in mice would probably be a last choice for humans, rather than a first option, Magnusson said. Dietary or drug options would be explored first.

“The one thing that does seem fairly clear is that cognitive decline is not inevitable,” she said. “It’s biological, we’re finding out why it happens, and it appears there are ways we might be able to slow or stop it, perhaps repair the NMDA receptors. If we can determine how to do that without harm, we will.”

(Source: oregonstate.edu)

A class of drug, called ACE inhibitors, which are used to lower blood pressure, slow the rate of cognitive decline typical of dementia, suggests research published in the online journal BMJ Open.

Furthermore, these drugs may even boost brain power, the research indicates.

The researchers compared the rates of cognitive decline in 361 patients who had either been diagnosed with Alzheimer’s disease, vascular dementia, or a mix of both. 

Eighty five of the patients were already taking ACE inhibitors; the rest were not.

The researchers also assessed the impact of ACE inhibitors on the brain power of 30 patients newly prescribed these drugs, during their first six months of treatment. The average age of all the participants was 77.

Between 1999 and 2010, the cognitive decline of each patient was assessed using either the Standardised Mini Mental State Examination (SMMSE) or the Quick Mild Cognitive Impairment (Qmci) screen on two separate occasions, six months apart.

Compared with those not taking ACE inhibitors, those on these drugs experienced marginally slower rates of cognitive decline. 

In those whose brain power had been assessed by Qmci, which is a more sensitive screen than the SMMSE, the difference was small, but significant.

And the brain power of those patients newly prescribed ACE inhibitors actually improved over the six month period, compared with those already taking them, and those not taking them at all.

This might be because these patients stuck to their medication regimen better, or it might be a by-product of better blood pressure control, or improved blood flow to the brain, suggest the authors.

But it is the first time that there has been any evidence to suggest that blood pressure lowering drugs may not only halt cognitive decline, but may actually improve brain power.

“This [study] supports the growing body of evidence for the use of ACE inhibitors and other [blood pressure lowering] agents in the management of dementia,” write the authors. 

“Although the differences were small and of uncertain clinical significance, if sustained over years, the compounding effects may well have significant clinical benefits,” they add.

They caution, however, that recent evidence indicates that ACE inhibitors may be harmful in some cases, so if larger studies confirm that they work well in dementia, it may be only certain groups of patients with the condition who stand to benefit.

(Source: group.bmj.com)

The trajectory of amyloid plaque buildup—clumps of abnormal proteins in the brain linked to Alzheimer’s disease—may serve as a more powerful biomarker for early detection of cognitive decline rather than using the total amount to gauge risk, researchers from Penn Medicine’s Department of Radiology suggest in a new study published online July 15 in the Journal of Neurobiology of Aging.

Amyloid plaque that starts to accumulate relatively early in the temporal lobe, compared to other areas and in particular to the frontal lobe, was associated with cognitively declining participants, the study found. “Knowing that certain brain abnormality patterns are associated with cognitive performance could have pivotal importance for the early detection and management of Alzheimer’s,” said senior author Christos Davatzikos, PhD, professor in the Department of Radiology, the Center for Biomedical Image Computing and Analytics, at the Perelman School of Medicine at the University of Pennsylvania.

Today, memory decline and Alzheimer’s—which 5.4 million Americans live with today—is often assessed with a variety of tools, including physical and bio fluid tests and neuroimaging of total amyloid plaque in the brain. Past studies have linked higher amounts of the plaque in dementia-free people with greater risk for developing the disorder. However, it’s more recently been shown that nearly a third of people with plaque on their brains never showed signs of cognitive decline, raising questions about its specific role in the disease.

Now, Dr. Davatzikos and his Penn colleagues, in collaboration with a team led by Susan M. Resnick, PhD, Chief, Laboratory of Behavioral Neuroscience at the National Institute on Aging (NIA), used Pittsburgh compound B (PiB) brain scans from the Baltimore Longitudinal Study of Aging’s Imaging Study and discovered a stronger association between memory decline and spatial patterns of amyloid plaque progression than the total amyloid burden.

“It appears to be more about the spatial pattern of this plaque progression, and not so much about the total amount found in brains. We saw a difference in the spatial distribution of plaques among cognitive declining and stable patients whose cognitive function had been measured over a 12-year period. They had similar amounts of amyloid plaque, just in different spots,” Dr. Davatzikos said. “This is important because it potentially answers questions about the variability seen in clinical research among patients presenting plaque. It accumulates in different spatial patterns for different patients, and it’s that pattern growth that may determine whether your memory declines.”

The team, including first author Rachel A. Yotter, PhD, a postdoctoral researcher in the Section for Biomedical Image Analysis, retrospectively analyzed the PET PiB scans of 64 patients from the NIA’s Baltimore Longitudinal Study of Aging whose average age was 76 years old. For the study, researchers created a unique picture of patients’ brains by combining and analyzing PET images measuring the density and volume of amyloid plaque and their spatial distribution within the brain. The radiotracer PiB allowed investigators to see amyloid temporal changes in deposition.

Those images were then compared to California Verbal Learning Test (CLVT) scores, among other tests, from the participants to determine the longitudinal cognitive decline. The group was then broken up into two subgroups: the most stable and the most declining individuals (26 participants).

Despite lack of significant difference in the total amount of amyloid in the brain, the spatial patterns between the two groups (stable and declining) were different, with the former showing relatively early accumulation in the frontal lobes and the latter in the temporal lobes.   

A particular area of the brain may be affected early or later depending on the amyloid trajectory, according to the authors, which in turn would affect cognitive impairment. Areas affected early with the plaque include the lateral temporal and parietal regions, with sparing of the occipital lobe and motor cortices until later in disease progression.

“This finding has broad implications for our understanding of the relationship between cognitive decline and resistance and amyloid plaque location, as well as the use of amyloid imaging as a biomarker in research and the clinic,” said Dr Davatzikos. “The next step is to investigate more individuals with mild cognitive impairment, and to further investigate the follow-up scans of these individuals via the BLSA study, which might shed further light on its relevance for early detection of Alzheimer’s.”

(Source: uphs.upenn.edu)