Oops! Memantine’s actions really aren’t all that and a bag of chips

Memantine is the most recent weapon in the fight against Alzheimer’s. There’s been a lot of hype surrounding the drug because….

The first-generation of compounds aimed to boost the brain’s acetylcholine levels led to the development of drugs such as Aricept™ (donepezil) and Excelon™ (rivastigmine). Attempts to develop drugs that block the action of glutamate by a considerable number of pharmaceutical companies and researchers were not successful for a long time, since these receptors are also required for normal brain function, learning and memory in particular. It was therefore considered a major breakthrough when a drug called memantine was discovered to have beneficial effects in Alzheimer’s disease, which did not affect the normal function of glutamate signalling, but only the excessive actions leading to cell death.

Sounds awesome, right? Well, things aren’t always what they seem.

In the present study, researchers report that memantine has a much more complex pharmacological profile than originally described. It does in fact work rather similar to the originally introduced drugs that affect acetylcholine-related signalling, in addition to weak actions on glutamate, and has negative effects on neuronal communication at high concentrations. At lower concentrations, memantine was able to enhance signalling between neurones of the hippocampus (the main brain area affected in Alzheimer’s disease) and was indeed able to reverse learning and memory deficits. However, a pharmacological analysis showed that this was not due to its ability to block glutamate signalling, but rather to an additional and more potent action on the acetylcholine system.

The press release mentions that there’s a lot of hope that memantine can be applied to other brain disorders that involve exessive glutamate release, such as following stroke or trauma.
This isn’t to say that memantine doesn’t work. But we do need to be judicious in how we apply these drugs as they have a presumed mechanism of action, but the targeted mechanism may not be the primary one affected in humans.

Alzheimer’s Disease and risky sexual behavior: not quite a false alarm?

Abel over at Terra Sigillata got is writ in a tinger over bad grammar and was concerned that Alzheimer’s Disease had been tied to risky sexual behavior. His conclusion was that he got a poorly worded email notice about two separate problems that were linked inappropriately by a semicolon. So everything’s fine, all clear, right? He’s free to engage in risky sexual behavior without fear of getting Alzheimer’s Disease (AD) later in life!
That’s not entirely true.
We’ve known that inflammation plays a huge role in the Alzheimer’s disease process. Unfortunately, inflammation is caused by a number of sexually transmitted diseases, such as those of the herpes family. What’s more, herpes viruses have a proclivity for neural tissue. Multiple herpes viruses have been found in the brains of AD patients; indeed (note the proper use of a semicolon, Abel), herpes simplex 1 (HSV-1) is a known risk factor for AD. Additionally, other herpes viruses have been studied and it appears that human herpes virus 6 (HHV-6) type B (but not type A) may be another with a strong link to incidence of AD. Cytomegalovirus (CMV) and HSV-2 seems to lack a relationship, and very few control or AD brains are infected with them.
Now now now, I know what you’re thinking. You’re saying “Aha Evil! HSV-2 is the simplex virus commonly associated with sexual activity!” While this is true, HSV-1 infection can and does result from sexual activity, just as HSV-2 is not only transferred via genitogenital contact. CMV is also transmitted sexually.
As I said, thankfully, HSV-2 rates seem to be quite low in AD brain and in elderly control brain. However, that could change in the future. As Tara at Aetiology mentions, the elderly are a population that is at an increasingly high risk for STD transfer, as the geriatric population is largely ignored by educational efforts, and they are less likely to practice safe sex or use condoms . An increase in the incidence of HSV-2 in the elderly could conceivably change that.
To make matters worse, those at risk for AD due to the presence of the apoE4 gene get a double whammy: HSV-1 is present at higher levels in the brains of those with the apoE4 allele, and HSV-1 shifts processing of amyloid precursor protein into Abeta (1-40) and (1-42) overdrive, which is unfortunate since Abeta protein fragments are what aggregate and form one of the pathological hallmarks of AD; the amyloid plaque. Fibrillar Abeta is thought to “gum up” synapses and contribute to neuronal dysfunction and cell death.
On a related note, CMV may also cause problems for the aging noggin– it is transmitted sexually and also increase the risk of vascular dementia.
It is thought that merely having, say, HSV-1 isn’t causative (obviously it isn’t because 85% of people have HSV-1 from a young age and not that many people develop AD), but that HSV-1 “flareups” in the brain, over time, increase the inflammatory processes that contribute to AD, so that the effect is cumulative.
So Abel, you’re sorta right and unfortunately sorta not. We don’t have rock solid evidence that sex=Alzheimer’s by a long shot, but there’s definitely some cause for concern that STDs (or at least viruses that target the brain and can be transmitted sexually) may be contributing to the incidence of AD, and quite possibly to other neurodegenerative diseases.

Depression is all in your head….

…but for those who suffer from it, “in your head” can be more debilitating than other chronic, painful illnesses. A massive WHO survey study of 60 countries reported that 3.2% of people had depression over the course of a year. Interestingly, though…

This was a bit lower than for asthma (3.3 percent), arthritis (4.1 percent), and angina (4.5 percent), and higher than for diabetes (2.0 percent.)
But the results of a quality-of-life index called the “global mean health score” showed that depression was, by a significant margin, the most difficult to bear.

The most difficult to bear, and also quite prevalent.

The study, published in the British journal The Lancet, says that depression accounts for the greatest share of non-fatal disease burden, accounting for almost 12 percent of total years lived with disability worldwide.
The researchers called on doctors around the world to be more alert in the diagnosis and treatment of the condition, noting that it is fairly easy to recognize and treat.
They also note that even if the prevalence of depression is similar to the four other chronic physical diseases, the lifetime risk — the number of people who cycle in and out of depression — is five to 10 times greater.

As the article says, depression is pretty easy to identify. Educating doctors and the public about the warning signs is a simple thing, but getting people to stop looking away isn’t.
I think it’s pretty obvious that we, as a society, need to step up and remove the stigma associated with mental health issues. Not only are they as prevalent as so-called “real” diseases and disorders, more people will experience them at some point in their lives. Every facet of life is affected too, from rearing children to personal health to productivity at work, which may not necessarily be the case with a physical disorder. National health care system, I’m looking at you….

Promising Effects of Statins on Alzheimer’s Pathology

Finally we get some data on changes in AD pathology with statin use! Statins are taken for lowering cholesterol, but they have other beneficial effects such as modulating inflammatory responses. Thus, they could prove beneficial in the treatment of AD given the disease has a significant inflammatory component.
According to the press release

The two changes in the brain that are considered the most definitive hallmarks of Alzheimer’s are brain “plaques” and “tangles.” After controlling for variables including age at death, gender, and strokes in the brain, the researchers found significantly fewer tangles in the brains of people who had taken statins than in those who had not. “These results are exciting, novel, and have important implications for prevention strategies,” said senior co-author Eric Larson, MD, MPH, the leader of the ACT study and executive director of Group Health Center for Health Studies. “But they need to be confirmed, because ACT is not a randomized controlled trial.”

As the press release rightly points out

A randomized controlled trial of statin treatment and brain autopsy findings would be problematic for ethical and practical reasons, said Dr. Larson. But the ACT setting made the study more rigorous than previous observational epidemiological studies, because it uses reliable automated pharmacy records, is based in a community population, and includes autopsies in people both with and without dementia.

so don’t expect any prospective comparisons anytime soon. Or, ever. However, this study appears promising as it backs up the epidemiological data. I’ll have to see if I can get my hands on the actual paper and post about it.

Eat chana masala to prevent Alzheimer’s!

Yes, that title is a bit ostentatious. But the foods we eat contain many compounds that can be beneficial to brain health. One strategy for optimizing our brains for long-term peak performance is to identify these compounds and discover how they are beneficial. Head-healthy chemicals have previously been isolated from curries and spices before, and it looks like we’ve found another curcuminoid, bisdemethoxycurcumin, which may be useful in combating Alzheimer’s Disease:

Researchers have isolated bisdemethoxycurcumin, the active ingredient of curcuminoids — a natural substance found in turmeric root — that may help boost the immune system in clearing amyloid beta, a peptide that forms the plaques found in Alzheimer’s disease. Using blood samples from Alzheimer’s disease patients, researchers found that bisdemethoxycurcumin boosted immune cells called macrophages to clear amyloid beta.

The results also suggest a new drug development approach for the disease that differs from the amyloid-beta vaccine. The new approach relies on the innate immune system, which is present at birth rather than on antibodies produced by B cells, which is a later developed part of the active immune system.

I like these strategies. Chemicals that occur naturally in the diet and which have anti-inflammatory properties can be consumed in low levels, chronically, and provide health benefits on the cheap. Combining these dietary benefits with drug-based strategies may in fact boost performance of the drugs, and if nothing else we have a new chemical structure to tinker with and hopefully provide more effective therapeutic agents in the future. Additionally, anti-inflammatory dietary factors can protect other organ systems from a myriad of inflammation-related issues that occur with aging.

The Basics of Menopause and Hormone Therapy III: Cognitive Consequences

This is the third part in an overview of menopause and hormone therapy. Parts one and two are here and here. This time around I describe changes in cognitive and behavioral profiles for women and animal models of menopause. I may decide to expand on a handful of studies at a later date, but for now I wanted to provide a very brief overview of human studies, problems inherent to human studies, and animal studies. I think the next part of this series will focus on the quality of our animal models and what they have to tell us. But for now, anyone who is interested in these issues knows where to start digging!
Granted, some of the info in this series is a bit dated, but I’ll do future posts to expand on recent findings. I also posted a follow-up on factors to consider when evaluating hormone therapy use and comparing new findings to “common wisdom”.

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Status Epilepticus, TLE, and GABA-A Receptor Gene Therapy

Temporal lobe epilepsy (TLE) refers to a condition where recurrent seizures arise in the temporal lobe of the brain. This condition is seen in humans and animals. Often, TLE arises following a neural insult such as head trauma or tumor, but can also be triggered by infection. These febrile seizures are often seen in children under the age of five, and subsequent scans can show atrophy of temporal lobe structures such as the hippocampus. The hippocampus is highly interconnected with other temporal lobe structures, so a seizure that originates from or propagates through the hippocampus is likely to result in widespread seizure activity.
While febrile convulsions of short duration (on the order of a few minutes) are somewhat normal in infants, convulsions lasting more than one hour indicate a high risk for developing TLE in the future. TLE resulting in status epilepticus (SE) is of particular concern, as SE is a life-threatening condition where the brain enters a state of persistent seizure, either from one long episode or a series of recurring episodes. Medication may not be effective at controlling SE, and complications are almost inevitable. If SE is the result of TLE, resection of the entire temporal lobe can be successful at eliminating seizure activity. While the brain is very “plastic” in younger children who can recover from this sort of surgery and go on to live almost completely normal lives, such drastic surgery is not desirable as age increases because the brain’s ability to compensate for the surgery is diminished.
With this in mind, I turn your attention to a recent publication.

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The Importance of Biodiversity, or Yet Another Interesting Toxin

Looks like yet another interesting toxin was found, this time in a venomous snail. This discovery comes from the lab of an old player in the field, who apparently discovered the conotoxin that is used in Prialt.

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Antisense Oligonucleotide Therapy for ALS patients?

Amyotrophic Lateral Sclerosis is a devastating disease that claims the upper and lower motor neurons, and ultimately the lives of most patients within 3-5 years of diagnosis, usually from respiratory failure. Patients lose control of voluntary muscles as the pathways that innervate them degenerate. Lou Gehrig and Stephen Hawking are two famous ALS patients.
Now a group suggests that antisense oligonucleotide therapy may be used to effectively treat some forms of the disease.

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Everybody Post About Mirror Neurons!!!

Mixing Memory brings up some excellent points regarding mirror neurons in primates, and Frontal Cortex follows up with his thoughts. To both of them I say “bravo, but your skepticism probably doesn’t go far enough”.
We give Rizzolatti et al too much credit with their conclusions. After all, they’ve only demonstrated the existence of mirror neurons in monkeys. Due to the obvious inherent difficulties associated with recording from human neurons in vivo, no one has yet (to my knowledge) published anything that demonstrates the existence of mirror neurons in people. Instead, we stick people in scanners and infer that they have mirror regions, or mirror neural systems, that are at least in part composed of mirror neurons. These regions are associated with language and imitation, but any evidence that mirror neurons are involved with either behavior in humans is circumstantial at best.

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