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The PSN neurology and neurosurgery hub contains articles on stroke, multiple sclerosis, Parkinson’s disease, and seizures.

Alzheimer’s Researchers Cast a Broader Net to Find a Cure

With the demographic shift toward an increasingly elderly population, it has been predicted that the number of people afflicted with dementia will triple by 2050, with the cost to the healthcare system estimated to be $1.1 trillion.

The complex neuropathology underlying Alzheimer’s disease (AD) is only beginning to be understood, and we have only scratched the surface in investigating the role that each underlying biology plays in propagating disease.

This complexity can be used as a weapon against disease by combining drugs of different biologies with the hope that a multipronged therapeutic attack will add up to a cure.

To consider the players in such combinations, let us review what we know today.

When Alois Alzheimer first described amyloid plaques and neurofibrillary tangles as cardinal features of the disease, it brought about a revolution in perception; dementia went from being a social stigma or sign of weak character to a physical disease of the brain that might someday be cured through development of new medicines.

It took nearly 80 years for scientists to “take apart” amyloid plaques and neurofibrillary tangles and discover compositions principally of beta-amyloid peptide (βAP or Aβ) and the microtubule-associated protein tau, respectively.

Coincident with these key discoveries, a curious schism emerged: The research community began dividing into camps that favored βAP or tau as principal causal agents in AD.

This schism became so pronounced in the 1990s that it was whimsically dubbed the “βAPtist/Tauist war.”

While science thrives on the pursuit of competing hypotheses, the βAPtist/Tauist war had an unfortunate consequence: Research seeking a more integrated understanding of AD pathophysiology was discouraged, and clinical approaches to treatment became narrowly focused.

Large-effect genes focused attention on βAP

The proponents of βAP hypothesized that a generation of βAP from a longer protein called the amyloid precursor protein (APP) is a seminal event in the development of AD.

This view was strongly boosted by the discovery that a sizable number of genetic mutations in APP and in γ-secretase – one of the enzymes that liberates βAP from APP – invariably led to an early-onset form of AD.

Enthusiasm built for the idea that slowing the rate at which βAP was liberated from APP or preventing βAP from forming aggregates believed to be toxic in the brain would prevent or delay AD from developing, and likely mitigate symptoms in AD patients.

The “amyloid hypothesis” has now been pursued in the clinic over the past 2 decades through the design of inhibitors for the APP cleaving enzymes β-secretase and γ-secretase, which are responsible for βAP generation.

Another therapeutic approach has been to design antibodies that bind to βAP or aggregates of βAP to accelerate their removal from the brain or decrease their toxicity.

The clinical trial results to date for treatments aimed at the amyloid hypothesis are disappointing at best.

First generation γ-secretase inhibitors were amenable to design, but they were plagued by safety issues. Centrally penetrant β-secretase inhibitors have been much more difficult to design and are only now entering advanced clinical trials.

Multiple antibodies against βAP have failed to meet their primary clinical endpoints. Whether they were tested too late in the disease or they just didn’t work is not clear.

So while it is premature to write an epitaph for the “amyloid hypothesis,” the clinical record to date suggests we need to be casting a wider net in the battle against AD.

Smaller-effect genes reveal the complexity of Alzheimer’s

Genes affecting the generation of βAP from APP are rare, but they increase one’s chances of getting early-onset AD to near certainty.

Over the years, other genes and gene families impacting the risk of AD have emerged. These gene variants tend to have a much broader distribution in the general population, but their impact on increasing one’s lifetime risk of developing AD is lower than for the so-called familial genes.

Consequently, it has often been necessary to study large populations – as opposed to individual families – to identify these genetic risk factors.

The oldest and best known of these “smaller-effect” genes is a specific variant of apolipoprotein E, known as ApoE4. Possessing a single ApoE4 gene increases one’s lifetime risk of developing AD by three-fold in Caucasians.

While apoE studies by AD researchers have focused on its potential role as a βAP transport protein, this emphasis likely reflects the “βAPtist bias.”

ApoE has been studied more broadly for its causal role in vascular/metabolic disease. Viewed from this perspective, one needs to look no further than the APP gene that sparked the βAPtist movement to find AD’s vascular connections: Mutations within βAP lead to vascular diseases of the brain, and the best established function for one variant of APP is as a regulator of the blood coagulation cascade.

These and other findings in recent years have led AD to be viewed as a vascular/metabolic disease, even prompting AD to be referred to as “type 3 diabetes.”

The role of innate immune system genes in AD

Genome-wide association studies approach the genetics of AD from the opposite end of the spectrum as single family studies. These studies explore the full genome of very large numbers of individuals to look for genes contributing to risk of disease.

Such studies have identified novel genes and gene families that underlie the pathophysiology of AD. Among the more prominent of these players are genes of the innate immune system.

Studies that explore changes in transcriptional activity across the entire genome also implicate the innate immune system in AD.

One interesting example of note is TREM2, an innate immune gene that – similar to ApoE4 – increases lifetime risk of developing AD by three-fold in certain populations. TREM2 genetics extend the curious vascular connection of AD in a way similar to APP: While certain mutations increase risk of AD, other mutations lead to Nasu-Hakola disease – a vascular dementia.

Circling back to tau, there is still no identified tau genetic mutation leading to AD. While this fact has given tau a decided disadvantage in the βAPtist/Tauist war, other properties of tau pathology clearly implicate tau in dementia.

First, there are genetic mutations in tau known to lead to non-AD dementia. As we’ve seen with the TREM2 and APP examples, such mutations offer important clues about AD biology even if they do not specifically lead to AD.

Second, pathologic changes in tau are associated with a wide variety of central nervous system(CNS) disorders, collectively called tauopathies.

Third, the appearance of tau-related pathology in AD correlates much better with the onset of dementia than does the appearance of amyloid plaques (which can precede clinical AD by decades). Thus, the absence of a direct genetic link between tau and AD is a poor argument for de-emphasizing the potential role of tau in the pathogenesis of AD.

An integrated approach to AD is emerging

The recent string of clinical trial failures in AD will teach us little if they are used only to resurrect old βAPtist/Tauist rivalries. Rather, the emerging science reminds us that AD is a complicated disease with multiple stages of development.

Researchers are likely to learn much more about the biology of AD by investigating the common links among pathologies implicated in AD rather than studying those pathologies in isolation.

Four biologies ripe for investigating these common links in AD are βAP/amyloid pathology, tau/neurofibrillary tangle pathology, vascular/metabolic dysregulation, and innate immune dysregulation/neuroinflammation. Just a few of the many known intersection points for these biologies are mentioned here.

Putting all the biological puzzle pieces together will take time. Unfortunately, the AD epidemic facing the aging baby boomer generation is fast approaching with no time to spare.

In the absence of an integrated understanding of how AD develops and what treatments may work best at different disease stages, it is important, like in other complex diseases, to consider strategies such as combination therapy sooner than we might traditionally pursue these.

Apart from the many βAP-focused treatments in later stage clinical development for AD, TRx-0237 is a tau-focused compound in development.

A large number of tau-directed monoclonal antibodies are also in preclinical development. Agents having a vascular/metabolic disease focus include intranasal insulin, the PPARγ agonist pioglitazone, and the calcium channel blocker nilvadipine.

Treatments targeting the immune system include intravenous immunoglobulin and the RAGE antagonist TTP-488.

These agents and others that are more comprehensively reviewed elsewhere, together with symptomatic approaches such as the 5HT6 antagonist idalopirdine – an investigational compound designed to improve neurocognitive function – are possible contenders for combinations.

To make combination therapy in AD a reality, it will – to borrow a phrase – “take a village” to make it happen.

Leaders from industry, the Food and Drug Administration (FDA), the National Institutes of Health (NIH), academia, and patient groups will need to come together to enable funding, trial design, and solve a host of complex issues associated with delivering combination therapy.

But there is hope. Such public-private partnerships like the Global Alzheimer’s Platform and others have already begun to take up this important challenge.

Mapping the Circuit of Our Internal Clock

What’s that old saying about Mussolini? Say what you will but he made the trains run on time. Well, the suprachiasmatic nucleus – SCN for short – makes everything in the body run on time. The SCN is the control center for our internal genetic clock, the circadian rhythms which regulate everything from sleep to hunger, insulin sensitivity, hormone levels, body temperature, cell cycles and more.

Now, researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), the University of California Santa Barbara, and Washington University in St. Louis have shown for the first time how neurons in the SCN are connected to each other, shedding light on this vital area of the brain. Understanding this structure – and how it responds to disruption – is important for tackling illnesses like diabetes and posttraumatic stress disorder. The scientists have also found that disruption to these rhythms such as shifts in work schedules or blue light exposure at night can negatively impact overall health.

The research was recently published in the Proceedings of the National Academy of Sciences (PNAS).

“The SCN has been so challenging to understand because the cells within it are incredibly noisy,” said John Abel, first author of the paper and graduate student at SEAS. “There are more than 20,000 neurons in the SCN, each of which not only generates their own autonomous circadian oscillations but also communicates with other neurons to maintain stable phase lengths and relationships. We were able to cut through that noise and figure out which cells share information with each other.”

The SCN looks like a miniature brain, with two hemispheres, inside the hypothalamus. It receives light cues from the retina to help it keep track of time and reset when necessary. When functioning probably, the neurons inside both hemispheres oscillate in a synchronized pattern.

In order to understand the structure of the network, Abel and the team had to disrupt that pattern. The researchers used a potent neurotoxin commonly found in pufferfish to desynchronize the neurons in each hemisphere, turning the steady, rhythmic pulse of oscillations into a cacophony of disconnected beats. The team then removed the toxin and observed the network as it reestablished communication, using information theory to figure out which cells had to communicate to resynchronize the whole network.

“It’s like trying to figure out if a group of people are friends without being able to look at their phone calls or their text messages,” Abel said. “In a large group of other people, you might not be able to tell who is in contact with each other, but if a certain group shows up together at a party, you can probably assume they’re friends because they show similar behavior.”

By observing the SCN at single-cell resolution, Abel and the team identified a core group of very friendly neurons in the center of each hemisphere that share a lot of information during resynchronization. They also observed dense connections between the hubs of each hemisphere. The neurons outside these central hubs, in the area called the shell, behaved more like acquaintances than friends, sharing little information amongst themselves.

“We were surprised to find that the shell lacked a functionally connected cluster of neurons,” said Abel. “We’ve known that exposure to an artificially long day can split the SCN into core and shell phase clusters which oscillate out of sync with each other. We’ve assumed that the neurons in the shell communicated to synchronize that rhythm but our research suggests that phase clustering in the shell is actually mediated by the core neurons.”

Previous research also assumed that the core SCN was dominant only due to its role in receiving light cues from the eyes. By using the neurotoxin to disrupt circadian rhythms, Abel and the team demonstrated that the core is the key to resynchronization even without light cues.

“For the last 15 years our group has been studying the complex control mechanisms that are responsible for the generation of robust circadian rhythms in the brain,” said Frank Doyle, the John A. Paulson Dean and John A. & Elizabeth S. Armstrong Professor of Engineering & Applied Sciences, who co-authored the paper. “This work brings us one step closer to reverse engineering those paradigms by elucidating the topology of communication amongst neurons, thus demonstrating the importance of a systems perspective to link genes to cells to the SCN tissue.”

The research was coauthored by Kirsten Meeker, Peter St. John, Benjamin Bales and Linda Petzold of UC Santa Barbara and Thomas Wang, Daniel Granados-Fuentes and Eric Herzog, of Washington University. It was funded by the National Institute of Health and the US Army Research Office.

Telemedicine to Ensure 24/7 Access in Rural Germany

Using telecommunications to connect stroke experts to stroke patients in rural areas continued to improve and sustain stroke care, according to new research in the American Heart Association’s journal Stroke.

This is the largest and longest evaluation of telemedicine for stroke and took place in rural Bavaria, Germany.

With the tele-medical linked Stroke Units, patients in regional hospitals had around-the-clock access to consultations with vascular neurologists at stroke centers, including evaluation of brain imaging and patient examination via videoconferencing when needed.

Researchers reviewed the use of telemedicine for 10 years and found:

  • The number of patients receiving the clot-busting drug tissue plasminogen activator  for ischemic (clot-caused) stroke rose from 2.6 percent to 15.5 percent.
  • The median time between a patient’s arrival at a regional hospital until tPA was administered fell from 80 minutes to 40 minutes; exceeding American Heart Association/American Stroke Association’s “Target: Stroke” goal of treating at least 50 percent of patients within 60 minutes.
  • The median time between onset of stroke symptoms and receiving tPA fell from 150 minutes to 120 minutes.

“Cooperation within medical networks can be a huge benefit for patients. Telemedicine is a wonderful option to support the close cooperation of physicians from regional hospitals and tertiary stroke centers,” said Peter Müller-Barna, M.D., lead author and consultant in the department of neurology at the Agatharied Hospital in Hausham, Germany.

In 2003, TeleStroke Units were introduced to 12 regional hospitals lacking neurology and neurosurgery departments in Bavaria, Germany. Telemedicine linked them with two neurological stroke centers with vascular neurologists and other neurological experts. By 2012, there were 15 TeleStroke Units that had provided 31,864 consultations.

Between the first year of implementation and the end of 2012, the percentage of patients with stroke or mini-stroke who were treated at hospitals with telemedicine units rose from 19 percent to 78 percent.

“This illustrates the growing acceptance of the TeleStroke Units by emergency services personnel and general physicians, and also by the population and their political representatives. Still, the goal should be closer to 100 percent and we are now setting up further units in administrative districts that lack one,” Müller-Barna said.

“In my opinion, the improving thrombolysis rate and door-to-needle times can mostly be attributed to growing experience, practice and continuous quality management. The extended time window for thrombolysis also had an influence,” Müller-Barna said.

The researchers also found from 2003 to 2012, the proportion of patients transferred to stroke centers from regional hospitals fell from 11.5 percent to 7 percent.

“Telemedicine can accelerate the emergency transfer of patients in need of neurosurgery. At the same time, it helps avoid unnecessary transfers because expert vascular neurologists are involved in remote patient assessment by video examination and the interpretation of CT scans,” Müller-Barna said.

The benefits of TeleStroke Units should also be applicable in the United States in any region without direct access to a stroke unit or local stroke expertise, researchers said.

The use of telemedicine to ensure 24/7 access to consultation and care in rural areas is one of the major recommendations of the AHA/ASA in the organization’s  2013 policy statement on systems of care.

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Life’s Imprint On DNA Now Mappable In Single Cell

New technique maps life’s effects on our DNA: Powerful single-cell technique to study environmental effects on DNA

Researchers in the UK have developed a powerful new technique that uses a single cell to map the epigenetic marks that life leaves on our DNA. The development is considered a breakthrough because it will allow scientists to better understand the effect of environment on DNA, such as during the early life of the embryo, and in the development of diseases like cancer.

‘Epigenetic marks’ are chemical tags or proteins that mark DNA and act as a kind of cellular memory. They do not change the DNA sequence but record a cell’s experiences onto the DNA, which allows cells to remember an experience long after it has faded. Placing these tags is part of normal development; they tell genes whether to be switched on or off and so can determine how the cell develops. Different sets of active genes make a skin cell different from a brain cell, for example. However, environmental cues such as diet can also alter where epigenetic tags are laid down on DNA and influence an organism’s long-term health.

Dr Gavin Kelsey, from the Babraham Institute, said: “The ability to capture the full map of these epigenetic marks from individual cells will be critical for a full understanding of early embryonic development, cancer progression and aid the development of stem cell therapies.

“Epigenetics research has mostly been reliant on using the mouse as a model organism to study early development. Our new single-cell method gives us an unprecedented ability to study epigenetic processes in human early embryonic development, which has been restricted by the very limited amount of tissue available for analysis.”

Effects on our DNA

The research, published in Nature Methods, offers a new single-cell technique capable of analysing DNA methylation — one of the key epigenetic marks — across the whole genome. The method treats the cellular DNA with a chemical called bisulphite. Treated DNA is then amplified and read on high-throughput sequencing machines to show up the location of methylation marks and the genes being affected.

These analyses will help to define how epigenetic changes in individual cells during early development drive cell fate. Current methods observe epigenetic marks in multiple, pooled cells. This can obscure modifications taking place in individual cells at a time in development when each cell has the potential to form in a unique way. The new method has already revealed that many of the methylation marks that differ between individual cells are precisely located in sites that control gene activity.

Dr Gavin Kelsey, said: “Our work provides a proof-of-principle that large-scale, single-cell epigenetic analysis is achievable to help us understand how epigenetic changes control embryonic development. The application of single-cell approaches to epigenetic understanding goes far beyond basic biological research. Future clinical applications could include the analysis of individual cancer cells to provide clinicians with the information to tailor treatments, and improvements in fertility treatment by understanding the potential for epigenetic errors in assisted reproduction technologies.”

Prof Wolf Reik, a founder of the Wellcome Trust Sanger Institute Single Cell Genomics Centre, added: “This exciting new method has already given some remarkable insights into how much variation there is in the epigenetic information in embryonic stem cells. This may underlie the enormous plasticity these cells have to develop into many different cell types in the body.”

Motorized Device Helps People Walk

The U.S. Food and Drug Administration today allowed marketing of the first motorized device intended to act as an exoskeleton for people with lower body paralysis (paraplegia) due to a spinal cord injury. ReWalk is a motorized device worn over the legs and part of the upper body that helps an individual sit, stand, and walk with assistance from a trained companion, such as a spouse or home health aide.

According to the U.S. Centers for Disease Control and Prevention there are about 200,000 people in the United States living with a spinal cord injury, many of whom have complete or partial paraplegia.

“Innovative devices such as ReWalk go a long way towards helping individuals with spinal cord injuries gain some mobility,” said Christy Foreman, director of the Office of Device Evaluation, at the FDA’s Center for Devices and Radiological Health. “Along with physical therapy, training and assistance from a caregiver, these individuals may be able to use these devices to walk again in their homes and in their communities.”

ReWalk consists of a fitted, metal brace that supports the legs and part of the upper body; motors that supply movement at the hips, knees, and ankles; a tilt sensor; and a backpack that contains the computer and power supply. Crutches provide the user with additional stability when walking, standing, and rising up from a chair. Using a wireless remote control worn on the wrist, the user commands ReWalk to stand up, sit down or walk.

ReWalk is for people with paraplegia due to spinal cord injuries at levels T7 (seventh thoracic vertebra) to L5 (fifth lumbar vertebra) when accompanied by a specially trained caregiver. It is also for people with spinal cord injuries at levels T4 (fourth thoracic vertebra) to T6 (sixth thoracic vertebra) where the device is limited to use in rehabilitation institutions. The device is not intended for sports or climbing stairs.

Prior to being trained to use ReWalk, patients should be able to stand using an assistive standing device (e.g., standing frame), and their hands and shoulders should be able to support crutches or a walker. Patients should not use the device if they have a history of severe neurological injuries other than spinal cord injury, or have severe spasticity, significant contractures, unstable spine, unhealed limb fractures or pelvic fractures. Patients should also not use the device if they have severe concurrent medical diseases such as infection, circulatory conditions, heart or lung conditions, or pressure sores.

Patients and their caregivers must undergo training developed by the manufacturer to learn and demonstrate proper use of the device.

To assess safety and effectiveness of ReWalk, the FDA reviewed testing done to assess ReWalk’s durability, its hardware, software and battery systems, and other safety systems that help minimize risk of injury should the device lose balance or power.

The FDA also reviewed clinical data based on 30 study participants. The clinical tests assessed the participants’ ability to walk various distances, the amount of time needed to walk various distances, performance on various walking surfaces and slight slopes, and performance walking in areas where jostling might occur. Studies also assessed the risk of certain physical effects on the user. Additionally, observational data from 16 patients were also provided to support use of the device on various walking surfaces in the home and community with various levels of assistance from a trained companion. Risks associated with ReWalk include pressure sores, bruising or abrasions, falls and associated injuries, and diastolic hypertension during use.

The FDA reviewed the ReWalk through its de novo classification process, a regulatory pathway for novel, first-of-its-kind medical devices that are generally low-to moderate-risk. The FDA is requiring Argo Medical Technologies, Inc., the manufacturer of ReWalk, to complete a post-market clinical study that will consist of a registry to collect data on adverse events related to the use of the ReWalk device and prospectively and systematically assess the adequacy of its training program.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Eye Test May Be Able To Detect Alzheimer’s

Eye Test May Be Able To Detect Alzheimer’s Decades Before Onset

More than 5 million Americans currently have Alzheimer’s disease. That number is expected to increase dramatically in the decades ahead.

On Sunday, researchers announced the promising results of a study on a new test to pick up on the disease years – if not decades – in advance. And they’re looking for signs in an unusual place: the eye.

These bright dots are proteins called beta amyloids visible in the retina of a patient diagnosed with Alzheimer’s diseases.

Beta amyloids are typically found in the brain and have been known to be linked to Alzheimer’s.

Dr. James Galvin is a neurologist at New York University Langone Medical Center.

“What makes it unique is that the retina is actually an extension of the brain and so we think that a lot of the pathology that is occurring in the brain may also be occurring in the retina,” he said.

Eye Test for Alzheimer's

Australian researcher Shaun Frost tested 40 people using a liquid form of curcumin, the natural substance that makes curry yellow. Curcumin sticks to beta amyloids, allowing doctors to spot the proteins with a simple eye test.

Frost found that the test positively identified 100 percent of the participants who had Alzheimer’s.

Alzheimer’s so far is incurable, so why is it important to be able to detect it?

“Well, for several reasons. So we have medicines today that treat the symptoms of the disease, so you’d like to be able to pick up the disease as soon as possible, so you can start someone on an available medicine. But more importantly, in order to develop new therapies, we need to be able to identify people at the earliest stages,” said Galvin.

Currently, the disease is detected through spinal taps or PET scans, which are invasive, expensive and not readily available.

The developers of the eye test say it can predict the onset of Alzheimer’s 15 to 20 years before clinical diagnosis. The full study, involving 200 subjects, is expected to be completed earlier this year.

Dose Of Measles Virus Destroys Woman’s Incurable Cancer

Dose Of Measles Virus Destroys Woman’s Incurable Cancer

In what they describe as a proof of principle study, doctors in the US were able to keep a woman with deadly multiple myeloma – an incurable bone marrow cancer – free of all signs of living cancer cells for over 6 months by giving her just one high dose of measles virus.

Two patients received a single intravenous dose of measles virus that was engineered to kill myeloma plasma cells and not harm other cells.

The team, from the Mayo Clinic in Rochester, MN, says both patients responded to the treatment, showing reduced bone marrow cancer and levels of myeloma protein.

But one patient, a 49-year-old woman, experienced complete remission and remained disease-free for over 6 months.

A report on this first study to establish the feasibility of the treatment appears in the journal Mayo Clinic Proceedings.

Proof virotherapy works for disseminated cancer

First author Dr. Stephen Russell, hematologist and co-developer of the therapy, says:

This is the first study to establish the feasibility of systemic oncolytic virotherapy for disseminated cancer. These patients were not responsive to other therapies and had experienced several recurrences of their disease.”

The treatment is an example of oncolytic virotherapy – using engineered viruses to fight cancer – an approach that dates back to the 1950s. Thousands of patients have received this type of therapy, using oncolytic viruses from various families, including common cold viruses, herpes viruses and pox viruses.

But the authors say this is the first well-documented case of a patient with cancer that has spread experiencing complete remission at all disease sites after receiving oncolytic virus therapy.

The video below details the patient’s treatment and remission:

Myeloma is a cancer that develops in plasma cells – a type of blood cell made in the bone marrow. According to the American Cancer Society, the disease is relatively uncommon, and in the US, there is a 1 in 149 risk of developing it.

Myeloma can arise in any part of the body where there is bone marrow, including the spine, rib cage and pelvis. Multiple myeloma means it is occurring in more than one place.

The disease, which also causes skeletal or soft tissue tumors, usually responds to drugs that stimulate the immune system, but it eventually overcomes them and is rarely cured.

First use of highest possible dose of engineered measles virus

Dr. Russell and colleagues explain in their article that they chose to report these two cases in particular because they were the first patients they had studied who had received the highest possible dose, and with limited previous exposure to measles, so their immune systems did not have many antibodies to the virus. They had also exhausted other treatment options.

Senior author Dr. Angela Dispenzieri, an expert in multiple myeloma, says in very simple terms, the measles virus makes the cancer cells join together and explode. The treatment also appears to trigger another lasting benefit:

There’s some suggestion that it may be stimulating the patient’s immune system to further recognize the cancer cells or the myeloma cells and help mop that up more effectively than otherwise.”

Having effectively completed a phase I clinical trial – to prove the concept that the measles virus can fight cancer – the team is now moving quickly into a phase II trial involving more patients.

They also intend to test the virus’s effectiveness as a tool to fight other cancers, such as head and neck, brain and ovarian cancers and mesothelioma. And they are engineering other viruses that may be able to kill cancer cells.

Dr. Russell says they have recently started to think along the lines of “a single shot cure for cancer, and that’s our goal with this therapy.”

He and two other authors of the study, as well as the Mayo Clinic, have declared a financial interest in the methods used in the study, which was funded by the National Cancer Institute of the National Institutes of Health, Al and Mary Agnes McQuinn, The Harold W. Siebens Foundation and The Richard M. Schulze Family Foundation.

Commonly Misdiagnosed Alzheimer’s Subtype

Alzheimer’s disease is the sixth leading cause of death in the US, affecting more than 5 million Americans. But researchers from the Mayo Clinic in Florida say they have identified a subtype of the disease that is often misdiagnosed.

The research team, led by Dr. Melissa Murray, an assistant professor of neuroscience at the Mayo Clinic, says their study suggests that around 600,000 Americans may have this variant, which they call “hippocampal sparing” Alzheimer’s disease.

To reach their findings, recently presented at the American Academy of Neurology’s Annual Meeting in Philadelphia, PA, they analyzed 1,821 brains with confirmed Alzheimer’s disease.

All subtypes of Alzheimer’s have two specific hallmarks in the brain. Amyloid beta is responsible for the formation of brain plaques, while tau produces tangles in the brain.

In order to classify each subtype, the team used tangle counts to create a mathematical algorithm. They found that while all Alzheimer’s subtypes had the same amount of amyloid beta, the hippocampal sparing variant showed tau tangles in unequal areas of the hippocampus.

Dr. Murray further explains the findings in the video below:

They discovered that in patients with this sub-type, tau specifically damages neurons in areas of the brain associated with behavior, motor recognition and awareness, and use of speech and vision.

‘Alzheimer’s disease does not necessarily equate to loss of memory’

Hippocampal sparing Alzheimer’s was identified in 11% of patients. They define the variant as a form of the disease that appears to have minimal impact on memory.

Instead, the condition appears to cause behavioral problems, such as uncontrollable and frequent outbursts of anger. The disorder may also trigger the feeling that the patient’s limbs do not belong to them and that movements are controlled by an “alien” force. Furthermore, it can cause visual interruption and language problems.

From their research, the investigators found that hippocampal sparing Alzheimer’s appears to be more common in males, with onset occurring at a much younger age than traditional Alzheimer’s. In addition, patients with this subtype seem to deteriorate more rapidly.

Lessening the Impact Of Alzheimer’s, Parkinson’s

Research Represents Novel Approach To Lessening Impact Of Alzheimer’s, Parkinson’s

A class of drugs developed to treat immune-related conditions and cancer – including one currently in clinical trials for glioblastoma and other tumors – eliminates neural inflammation associated with dementia-linked diseases and brain injuries, according to UC Irvine researchers.

In their study, assistant professor of neurobiology & behavior Kim Green and colleagues discovered that the drugs, which can be delivered orally, eradicated microglia, the primary immune cells of the brain. These cells exacerbate many neural diseases, including Alzheimer’s and Parkinson’s, as well as brain injury.

“Because microglia are implicated in most brain disorders, we feel we’ve found a novel and broadly applicable therapeutic approach,” Green said. “This study presents a new way to not just modulate inflammation in the brain but eliminate it completely, making this a breakthrough option for a range of neuroinflammatory diseases.”

The researchers focused on the impact of a class of drugs called CSF1R inhibitors on microglial function. In mouse models, they learned that inhibition led to the removal of virtually all microglia from the adult central nervous system with no ill effects or deficits in behavior or cognition. Because these cells contribute to most brain diseases – and can harm or kill neurons – the ability to eradicate them is a powerful advance in the treatment of neuroinflammation-linked disorders.

Impact Of Alzheimer’s, Parkinson’s

Green said his group tested several selective CSF1R inhibitors that are under investigation as cancer treatments and immune system modulators. Of these compounds, they found the most effective to be a drug called PLX3397, created by Plexxikon Inc., a Berkeley, Calif.-based biotechnology company and member of the Daiichi Sankyo Group. PLX3397 is currently being evaluated in phase one and two clinical trials for multiple cancers, including glioblastoma, melanoma, breast cancer and leukemia.

Crucially, microglial elimination lasted only as long as treatment continued. Withdrawal of inhibitors produced a rapid repopulation of cells that then grew into new microglia, said Green, who’s a member of UC Irvine’s Institute for Memory Impairments and Neurological Disorders.

This means that eradication of these immune cells is fully reversible, allowing researchers to bring microglia back when desired. Green added that this work is the first to describe a new progenitor/potential stem cell in the central nervous system outside of neurogenesis, a discovery that points to novel opportunities for manipulating microglial populations during disease.


Insomnia Linked To Increased Stroke

Insomnia Linked To Increased Stroke

More evidence that insomnia increases the risk for stroke comes from results of a large population-based study.

Researchers reviewed health records from the Taiwanese national population and compared stroke outcomes over a 4-year follow-up in 21,438 patients with a diagnosis of insomnia and 64,314 age- and sex-matched patients without insomnia.

Results showed that overall, insomniac patients had an 85% higher risk of developing stroke. This was reduced to 54% after adjustment for other factors. The effect seemed to be much greater in younger people, with patients with insomnia aged 18 to 34 years having an 8-fold higher risk for stroke than those of a similar age without insomnia.

“Individuals should not simply accept insomnia as a benign, although difficult, condition that carries no major health risks,” said coauthor Ya-Wen Hsu, PhD, assistant professor at Chia Nan University of Pharmacy and Science, Taiwan.

“We feel strongly that individuals with chronic insomnia, particularly younger persons, see their physician to have stroke risk factors assessed and, when indicated, treated appropriately. Our findings also highlight the clinical importance of screening for insomnia at younger ages. Treating insomnia is also very important, whether by medication or cognitive therapy,” he added.

Their findings were published online in Stroke on April 3.

“Reliable” Conclusion

Commenting on the study, Demetrius Lopes, MD, Rush University Medical Center, Chicago, Illinois, said, “I think the conclusion of the study is reliable and likely applies not only to the Taiwanese population.”

“The study brings awareness to the increased risk of stroke in young adults with chronic insomnia,” he added. “Based on this study we should investigate signs of chronic insomnia in individuals between 18 [and] 34 years old in an effort to reduce stroke. This study is in line with many other publications highlighting the importance of healthy sleeping habits.”

The study is the first to try to quantify the risk in a large population group and the first to assess whether the risk for stroke differs by insomnia subtypes, Dr. Hsu said.

During the 4-year follow-up, 583 participants with insomnia and 962 without insomnia were admitted for stroke. Results showed a higher rate of all types of strokes in those with insomnia.

Insomnia linked to Stroke

Although stroke rates increased with age, as would be expected, the association between insomnia and stroke lessened with age.

Researchers divided participants — none of whom had a previous diagnosis of stroke or sleep apnea — into different types of insomnia. In general, insomnia included difficulty initiating or maintaining sleep; chronic or persistent insomnia lasted 1 to 6 months; relapse insomnia was a return of insomnia after having been diagnosed as free of disease for more than 6 months at any assessment point during the 4-year study; and remission was defined as a change from a diagnosis of insomnia to noninsomnia at the subsequent time point.

Participants with persistent insomnia had the highest stroke risk compared with those without insomniacs (hazard ratio [HR], 2.04), followed by those with a relapse of insomnia (HR, 1.76) and those with remission of insomnia (HR, 1.55) in unadjusted analysis. But these HRs became similar among the 3 insomnia subtypes after adjustment for other relevant covariates.

Other factors associated with an increased risk for stroke were older age, diabetes mellitus, hypertension, atrial fibrillation, and lower socioeconomic status.

 The mechanism linking insomnia to stroke is not fully understood, but evidence shows that insomnia may alter cardiovascular health via systematic inflammation, impaired glucose tolerance, increased blood pressure, or sympathetic hyperactivity. Some behavioral factors (eg, physical activity, diet, alcohol use, and smoking) and psychological factors (eg, stress) might affect the observed relationship, the researchers suggest.

They conclude that intervention to improve insomnia is needed and studies should evaluate whether such intervention improves cardiovascular health. “To reduce the risk of stroke effectively, health education should be promoted to get individuals to be aware of insomnia symptoms at young age, to treat it, and to track its patterns, especially for younger adults.”