Archived: An Online Chat Discussing The Past And Future Of Alzheimers Research
We had to design a very conservative study that takes these participants out, said Ophir Keret, a neurologist at the University of California, San Francisco who was a researcher on both studies, because we wanted to isolate the effect that epilepsy would have.
Michela Gallagher, a professor of psychology and neuroscience at Johns Hopkins University, said the researchers used good criteria for defining unprovoked seizures independent of things that could be causing , and pointed to the large sample size and long time period for tracking each veterans health trajectory as two of the studys strengths. One weakness she noted is that the Veterans Affairs health data used in the study did not allow researchers to differentiate between Alzheimers or other types of dementia. Neither the veterans study or the smaller one has been published yet in a peer-reviewed journal.
Why Do People With Dementia Develop Seizures
Ultimately, anything that changes the structure of the brain can cause seizures.
This happens for some people after a stroke, a head injury, or with a brain infection like meningitis. A similar problem is happening in the brain in dementia. As cells in the brain die and the brain shrinks this can lead to epilepsy.
In addition, we know that two proteins that build up in the brain of people with Alzheimers disease amyloid and tau affect how the brains nerve cells communicate with each other.
Sometimes these nerve cells can become ‘hyper-excitable’, meaning they can behave uncontrollably, causing epileptic seizures.
The Role Of Seizures In Dementia
While studying seizures and dementia, scientists were also triggered on the topic of the role seizures in the illness.
A study was conducted towards this end. Researchers observed 55 patients aged 50-69 years.
They were all admitted to an Israeli medical center with their first known seizure. A quarter of the participants developed dementia later on.
Another study that was done in the US looking at almost 300,000 veterans who were all over 55 years uncovered that seizures increased the risk of people developing dementia over a period of one to nine years.
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New Clues On Why Womens Alzheimers Risk Differs From Mens
Research with mouse models supports the hypothesis that seizures or other epileptic events may sometimes be an early feature of Alzheimers disease. Scientists have recorded such abnormal electrical activity in the brains of mice before they went on to accumulate amyloid plaques or tau tangles, both hallmarks of Alzheimers. Many of these events had no outward manifestation, suggesting again that the prevalence of epileptic activity may be going unrecognized and therefore underestimated.
Seizures are an extreme example of an imbalance in brain function. Normally, a class of cells called inhibitory neurons, which have received scant attention until recently, act much like the bouncers at a night club. Their job is to manage the timing and flow of brain signals and keep excitatory neurons under control. As we age, inhibitory neurons appear to become less effective, resulting in chronic hyperactivity. Low-level hyperactivity has been detected in the hippocampus a brain region critical to memory of both rodents and older people with mild cognitive impairment.
Researchers once assumed that hyperactivity was a compensatory mechanism to make up for a brain that couldnt keep up with cognitive demands. Now many believe the reverse is true that hyperactivity is pathological and interferes with memory and that this imbalance is a core feature of Alzheimers disease.
‘silent’ Seizures Tied To Alzheimer’s Symptoms
Researchers suggest they’re a potential target for treating the disease
TUESDAY, May 2, 2017 — Undetected or “silent” seizures may contribute to some symptoms associated with Alzheimer’s disease, such as confusion, a small study suggests.
The seizures occur in the hippocampus — a part of the brain involved in the consolidation of memories. Researchers suspect that treating these seizures could help manage Alzheimer’s or possibly slow it down.
“While it is not surprising to find dysfunction in brain networks in Alzheimer’s disease, our novel finding that networks involved in memory function can become silently epileptic could lead to opportunities to target that dysfunction with new or existing drugs to reduce symptoms or potentially alter the course of the disease,” said study senior author Dr. Andrew Cole.
Cole directs the Massachusetts General Hospital Epilepsy Service.
“We now have to study more individuals to validate this finding and understand how prevalent it is in Alzheimer’s patients, whether it occurs in other neurodegenerative disorders and how it responds to treatment,” he said in a hospital news release.
The study involved only two women. They were both in their 60s with symptoms associated with Alzheimer’s disease. The women had bouts of confusion or asked the same questions repeatedly.
Brain images and cerebrospinal fluid tests suggested they had Alzheimer’s, but swings in the women’s symptoms were much more dramatic than usual.
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People With Dementia Are At Risk Of Seizures
Alzheimer described this way back in 1911. What is not clear yet is how common the seizures are.
This is because some seizures can be quite complex.
Many people are familiar with the generalized tonic-clonic seizures that make people fall to the ground, become stiff and unresponsive and their bodies shake with convulsions.
However, there is another type of seizure that mainly affects individuals with dementia.
These are known as focal onset seizures.
They generally involve short periods of increased unresponsiveness or amnesia.
The person going through this can showcase involuntary repeating movements of the arms, hands, face like swallowing, lip-smacking, or chewing.
Because it does not go on for long, it can easily be missed.
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Gallagher has been putting this theory to the test in clinical trials. A short phase 2 trial completed in 2017 used a common anti-seizure drug called levetiracetam and measured reduced activity in the hippocampus of test subjects coupled with improved performance on memory tests.
Gallagher started a company, AgeneBio, that is now recruiting 830 subjects for a phase 3 clinical trial using a specially formulated low-dose version of the drug. Patients with the type of mild cognitive impairment that precedes Alzheimers will take the drug for a year and a half to crank down the neural activity, said Gallagher, and see whether the disease progresses more slowly. Three smaller phase 2 trials using a similar strategy are also underway, sponsored by the Medical College of Wisconsin, University of Minnesota, University of San Francisco, and Oxford University Hospitals.
Mucke, like Gallagher and many other neuroscientists, believes that the phenomenon of hyperactivity is ripe for the discovery of additional therapeutic entry points that might not only be symptomatically beneficial but also have the potential to be disease-modifying. He points out that brain rhythms have a strong impact on immune system function in the brain, which is increasingly implicated in the pathogenesis of Alzheimers disease.
So, if we do establish that this is an early sign, one thing that I would be very interested in evaluating, said Keret, is whether interventions at this stage are successful.
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Tau: Agent Or Bystander
Tangles of an abnormal form of tau protein are characteristic of Alzheimers brain tissue, as well as chronic traumatic encephalopathy. Now theres evidence that tau may be associated with some cases of epilepsy, too.
Tau is a key protein thats normally involved in the cytoskeletona complex network in the cytoplasm that helps manage many functions, including maintaining a cells shape and the process of cell division. In humans, tau is found mainly in neurons, and helps to stabilize axon microtubules.
Tau has more than 70 sites that can potentially hold a phosphate group . Partial phosphorylation is par for the course, but a fully phosphorylated tau protein detaches from microtubules and congregates in the cell, clinging to other p-taus and forming tangles that are associated with neuronal damage and cell death.
In a study of 33 people with temporal lobe epilepsy who underwent epilepsy surgery, researchers analyzed the resected tissue and gave it a p-tau burden score. Higher burden scores predicted cognitive decline in the year after surgery and were associated with the presence of secondary generalized seizures before surgery. The researchers did not find levels of amyloid-beta, another key protein associated with Alzheimers disease. They suggest that any underlying tau-related neurodegeneration in people with TLE is not a typical Alzheimers disease process, but that perhaps certain types of epilepsy have a unique tau deposition pattern.
It Quickly Became Clear That Most People Dont Know That Having Dementia Particularly Alzheimers Disease Can Increase Your Risk Of Seizures
In our group, around 1 in 8 patients with dementia described episodes which we believe could have been epileptic seizures.
We interviewed our participants one year later and found that those who had described having had epileptic seizures previously performed less well on memory tests than those who showed no evidence of epilepsy.
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Repetitive Lip Smacking Hand Movements Or Jerking
“One of my patients would pick at the left side of her collar repeatedly. It could be the person is fidgeting with a collar or buttons, fumbling with their hands, making kneading movements or rubbing their fingers together,” O’Dwyer explains. “We call these automatisms, because they look like automatic, natural movements.”
These behaviors don’t typically last long, often less than a minute, and can easily be perceived as nervous tics. In fact, they may be tics. But if you notice them happening regularly, over a period of at least a few months, talk to a doctor to rule out or confirm seizures as the cause.
“We got really lucky with this woman who was plucking at her collar,” O’Dwyer says. “Her daughter thought it was just something her mom did. She’d actually been doing it for years. It wasn’t until we had her hooked up to an EEG monitor while she was doing it, and she had a focal seizure, that we realized it was epilepsy.”
Another red flag: sudden, brief jerking movements.
“You know how sometimes when you’re falling asleep and in your mind you step off a cliff, your body jerks? It’s the same phenomenon. In a person who’s awake, that kind of involuntary spasm is called a myoclonic jerk,” O’Dwyer says, “and it’s a sign of seizure activity.”
Myoclonic jerks are extremely common in people with dementia especially later-stage Alzheimer’s disease but if you see them in a healthy adult while they’re awake, consult a neurologist.
Potential Unknown Causes Of New
Although some of new-onset epilepsies in the elderly show identified etiology, one-third to one-half of geriatric epilepsies still have undetected causes, to date, despite the current advances in technology.
Paraneoplastic limbic encephalitis and posterior reversible leukoencephalopathy syndrome are probably the most rare of the unknown causes of new-onset epilepsy in the elderly. Therefore, these rare factors should be taken into account when no identified causes can explain the reason for geriatric epilepsy.
Immune factors may be potential causes in patients with undetected causes. A recent study conducted in the US of adult patients in several intensive care units, highlights the immune origin of the novo new-onset refractory SE. In this case, immunomodulatory treatment is more effective than antiepileptic drugs.
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What Is The Link Between Seizures And Dementiablog
There are some symptoms of dementia that are more commonly known, such as memory loss. Seizures are a less common symptom of dementia that are not as understood. Hear from one of our dementia researchers who has been studying seizures in people with the condition.
How common are epileptic seizures in dementia? Who is most at risk of having them? What do these seizures look like? What effect do they have on how someones memory changes over time?
These are the questions that I have been researching since starting my PhD in 2016. I’m a student funded by Alzheimers Society as part of the University of Exeter doctoral training centre.
Episodic Confusion Memory Loss Or Word
The period after a seizure, called the post-ictal period, tends to last longer in older adults than in younger people many hours, or even days. During this period, people are dazed or confused, and afterward they often have no memory of anything that occurred.
If you notice that a loved one is missing chunks of time, talk to their doctor especially if these episodes occur over a period of several months or are becoming more frequent.
“I had a patient who didn’t remember his granddaughters wedding,” O’Dwyer says. “That’s what initially brought him to a neurologist. He was distraught. He saw pictures of himself at the wedding, so he knows he attended, but he had absolutely no memory of being there.”
Since memory loss, confusion and searching for words are also common symptoms of dementia, epilepsy may be misdiagnosed as Alzheimer’s disease. Look for a diagnosis of “atypical dementia,” or when the symptoms suggest dementia but testing shows the person doesn’t have it. In these cases, an electroencephalogram can help determine if epilepsy is the real culprit.
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The Connection Between Alzheimer’s Disease And Silent Seizures
Researchers at Baylor College of Medicine found that people had increased levels of a protein called deltaFosB in their hippocampus for about two weeks after a silent seizure. This protein is responsible for regulating other proteins, and researchers found that it suppressed the creation of another protein called calbindin.
Calbindin is necessary for the creation of new memories, which is one of the things people with Alzheimers disease struggle with the most. The low level of calbindin means that people will have a harder time making and keeping memories. Researchers looked into supplementing calbindin levels in mice who had silent seizures and found that this practice can improve memory in animal models.
In A Phase 2 Clinical Trial Patients With Epileptic Activity Benefitted From The Medication
- University of California – Los Angeles Health Sciences
- An inexpensive anti-seizure medication markedly improves learning and memory and other cognitive functions in Alzheimer’s patients who have epileptic activity in their brains, according to a new study.
An inexpensive anti-seizure medication markedly improves learning and memory and other cognitive functions in Alzheimer’s patients who have epileptic activity in their brains, according to a study published in the Sept. 27th issue of JAMA Neurology.
“This is a drug that’s used for epilepsy,” says Keith Vossel, MD, MSc, director of the Mary S. Easton Center for Alzheimer’s Disease Research at UCLA, and the principal investigator on the clinical trial. “We used it in this study for Alzheimer’s patients who had evidence of silent epileptic activity, which is seizure-like brain activity without the associated physical convulsions.”
Alzheimer’s disease is the leading cause of dementia worldwide. Early symptoms include short-term memory loss, decline in problem solving, word-finding difficulties, and trouble with spatial navigation. Among Alzheimer’s patients, an estimated 10-22% develop seizures, while an additional 22-54% exhibit silent epileptic activity.
“MEG can pick up epileptic activity that EEGs miss because it’s looking at a different population of brain cells,” Dr. Vossel explained.
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What Is The Link Between Epilepsy And Dementia
For many people, the seizures occur in the late stages of the illness, say after six years of diagnosis.
Worth noting is that time matters when it comes to seizures.
Many seizures will last for about 30 seconds to 2 minutes. If one lasts for over five minutes, it is considered a medical emergency.
With this in mind check out more vital information about dementia and epilepsy below.
Don’t Ignore Potential Signs Of Epilepsy
Because many conditions can cause these symptoms in elderly people, the first step should be to see a primary care physician, geriatrician or general neurologist to rule other conditions out.
“The main difference with epilepsy is that the symptoms are episodic you’ll notice them happening multiple times over the course of several months,” O’Dwyer says. “Seizures can be quite infrequent at the beginning, though, so pay attention to how often the symptoms occur and whether they’re more frequent than the last time you saw the person.”
The key, O’Dwyer says, is to not write off the symptoms instead, write them down. “Keep a diary of everything you notice that’s out-of-the-ordinary, no matter how seemingly insignificant. And take a video with your phone and bring it to the doctor’s appointment. The more information we have, the better we can assess the situation and figure out how to help.”
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Substance Use And Withdrawal
A first-time seizure in adulthood may be related to the use of certain substances or withdrawal from them.
The most common substances associated with seizures include:
Certain substances can induce seizures by altering neurotransmitter activity. In other cases, a drug may modify electrolytes or blood flow in the brain, resulting in a seizure.
Some substances, like barbiturates, have a sedative effect on the brain. If taken regularly in high doses, suddenly stopping can cause a seizure. Stopping anti-seizure medications or taking them inconsistently can induce a seizure.
Could Targeting Tau Reduce Seizures
Given the potential links between tau and epilepsyparticularly epilepsy acquired after a brain insulttargeting the tau protein could be an opportunity to develop a true anti-epileptogenic treatment, said Terence OBrien, program director for Alfred Brain and director of neurology at The Alfred Hospital, Melbourne. Animal models suggest this possibility. Genetically modified mice that overexpress human p-tau have spontaneous seizures, while tau knockout micewhich lack tau, and therefore cannot generate p-tauare protected from seizures, both in genetic epilepsy models and in chemically induced seizure models.
The enzyme family called protein phosphatase 2A is involved in multiple types of phosphorylation and dephosphorylation within cells. There are more than 90 variants of PP2A. One, called PP2A/B, is considered to be the primary tau phosphatase. A decrease in its activity correlates with increased tau phosphorylation in vivo and in Alzheimers disease.
A study of three rat models of epileptogenesis found that each model showed a decrease in PP2A activity and an increase in p-tau in the epileptogenic brain regions. Treatment with sodium selenate a known activator of the PP2A enzyme family reduced the levels of p-tau and mitigated epileptogenesis.
Studies using animal models of traumatic brain injury show similar results: Treatment with sodium selenate increases PP2A levels, decreases p-tau, attenuates brain damage and improves behavioral outcomes.
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