Monday, April 1, 2019

Happy April fool's day

Thanks Katherine

Subway Car Surfaces    (April Fool's Day - 2001)

Residents of Copenhagen who visited the square in front of the town hall were greeted by a strange sight. One of the subway cars from the city's new subway, which was under construction, appeared to have burst up through the pavement. The subway car actually was a retired vehicle from the Stockholm subway. It had been cut at an angle and loose bricks were placed around it, to give the illusion that it had crashed up from below. 

The stunt was sponsored by Gevalia Coffee, whose advertisements had an ongoing theme of vehicles popping up in strange locations, with the tagline "Be ready for unexpected guests."

Saturday, March 30, 2019

Parkinson's smell test explained by science

reposted from

Parkinson's smell test explained by science

Media captionJoy Milne can smell Parkinson's disease before it is medically diagnosed
A Scottish woman who astonished doctors with her ability to detect Parkinson's disease through smell has helped scientists find what causes the odour.
Researchers in Manchester said they had identified the molecules on the skin linked to the smell and hope it could lead to early detection.
The study was inspired by Joy Milne, a 68-year-old retired nurse from Perth.
She first noticed the "musky" smell on her husband Les, who was years later diagnosed with Parkinson's disease.
Image captionJoy has worked with the University of Manchester for three years
Joy, who has worked with the University of Manchester on the research for three years, has been named in a paper being published in the journal ACS Central Science.
She has also been made an honorary lecturer at the university because of her efforts to help identify the telltale smell.
Image captionProf Perdita Barran designed experiments with a mass spectrometer to mimic what Joy does with her nose
The research revealed that a number of compounds, particularly hippuric acid, eicosane, and octadecanal, were found in higher than usual concentrations on the skin of Parkinson's patients.
They are contained in sebum - the oily secretion that coats everybody's skin, but which is often produced in greater quantity by people with Parkinson's, making them more likely to develop a skin complaint called seborrheic dermatitis.
Lead author Prof Perdita Barran, from the school of chemistry at the University of Manchester, told BBC Scotland: "What we found are some compounds that are more present in people who have got Parkinson's disease and the reason we've discovered them is because Joy Milne could smell a difference.
"She could smell people who've got Parkinson's disease.
"So we designed some experiments to mimic what Joy does, to use a mass spectrometer to do what Joy can do when she smells these things on people with Parkinson's."
One in 500 people in the UK has Parkinson's and that rises to about one in 100 among the over-60s.
Image captionJoy's noticed the musky smell on her husband Les before he was diagnosed
It can leave them struggling to walk, speak and sleep.
Currently there is no cure and no definitive test for the disease, with clinicians diagnosing patients by observing symptoms.
Prof Barran said she hoped the "volatile biomarkers" they identified could lead to a simple early detection test for the disease, such as wiping a person's neck with a swab and testing for the signature molecules.
She said: "What we might hope is if we can diagnose people earlier, before the motor symptoms come in, that there will be treatments that can prevent the disease spreading. So that's really the ultimate ambition."
Image captionLes died in 2015, 20 years after being diagnosed
Joy's husband Les, who died in 2015, was told he had Parkinson's at the age of 45 but Joy said she detected the unusual musky smell about a decade earlier.
The retired nurse only linked the odour to the disease after meeting people with the same distinctive smell at a Parkinson's UK support group.
She told BBC Scotland that not knowing Les had Parkinson's put her family in a "negative spiral".
"What if we did know?," she said
"It would have changed things dramatically.
"The fact that he became withdrawn, reserved, he had bouts of depression and mood swings, if I had understood what was happening it would have changed our total outlook on life."

Tuesday, March 26, 2019

Biomarkers of Alzheimer’s Disease

reposted from

Biomarkers of Alzheimer’s Disease

Alzheimer’s disease has very specific etiology that can typically only be confirmed postmortem. Are there ways to identify it in the dynamical features of brain activity?
Alzheimer’s disease (AD), a neurodegenerative disorder characterized by a decline in cognitive functioning, in particular memory loss, is the most common cause of dementia with an estimated 30 million people affected worldwide [1,2].  At a neurobiological level it is characterized by aggregations of beta-amyloid (Aβ) protein into plaques, the accumulation of tau protein neurofibrillary tangles and progressive neurodegeneration. One recent question of interest is how these structural changes translate into changes in brain activity. Can it be reliably measured in the EEG to provide biomarkers of disease onset and progression, allowing clinicians to make an early diagnosis and intervention?

Biomarkers for early intervention.

For most of its history, AD has been diagnosed solely through clinical observation and cognitive testing, with a confirmatory diagnosis only performed on postmortem examination. However, the neurobiological changes associated with AD, and a potential precursor, Mild Cognitive Impairment (MCI), often appear many years (or even decades) before any visible clinical signs in the patient.
The advent of neuroimaging and the development of new biomarkers offer clinicians the opportunity to do this [3,4]. However, the challenges of developing either structurally or functionally relevant AD biomarkers which provide accurate and reliable indicators of disease onset, progression and outcome, or which assist in drug development, are considerable.
Examples of currently accepted biomarkers involve measuring levels of brain chemicals related to amyloid or tau (e.g. in the cerebrospinal fluid, CSF), or through estimates of metabolic activity (e.g. with Positron Emission Tomography, PET). For example, CSF levels of amyloid-beta (Aβ42) and phosphorylated tau (p-Tau) are thought to reflect AD pathology. In addition, the formation of plaques and tangles disrupt the balance of excitatory and inhibitory activity in the brain, and also result in synaptic dysfunction, at least in mouse models [5], both of which affect brain dynamics.  This provides an opportunity for studying the progression of AD with techniques such as resting-state EEG.

LORETA and Alzheimer’s Disease.

Multiple studies have attempted to examine changes in resting-state EEG dynamics, and to relate these to other markers of AD [6]. For example, in one recent small-scale study, resting-state EEG was used to explore whether there was a relationship between cortical hypometabolism – something commonly observed in AD – and cortical EEG rhythms [7]. To do this they measured cortical hypometabolism using fluorodeoxyglucose-PET and recorded resting EEG in 19 AD patients and compared this against 40 healthy controls and analyzed the results using LORETA. The EEG results showed higher levels of source localized delta band activity that correlated (r=0.579, p=0.009, N=19) with measures of cortical hypometabolism (other bands were not statistically different). This suggests that, in AD patients, delta activity at rest may be related to the PET biomarker of cortical hypometabolism. However, since the healthy patients did not agree to a PET scan, it limits the validity of this conclusion.  Also, such conclusion is confounded by similar results relating to a host of other mental health disorders and may simply be representative of a disorder in general, but not AD specifically.
Grand average across subjects of the normalized LORETA solutions. From [6]

CSF markers and Alzheimer’s disease

Another larger-scale study explored the relationship between EEG measures and CSF biomarkers [8]. In this study they compared patients with subjective cognitive decline (n=210) (i.e. they reported subjective complaints but had no significant cognitive deficit or clinical symptoms) against those with MCI (n=230) or AD (n=197). They analyzed resting-state EEG data using two different metrics – global field power (GFP) and global field synchronization (GFS). GFP is a reference-free method that reduces multichannel recordings to a single measure corresponding to the generalized EEG amplitude, resulting in a global measure of scalp potential field strength whilst GFS is a measure of global functional connectivity which resembles the global amount of instantaneous phase locked synchronization of oscillating neuronal networks across the scalp. Linear regression models showed that decreased levels of Aβ42 in the CSF significantly correlated with increased theta (β coefficient=0.514, p<0.001) and delta (β coefficient=0.304, p=0.001) GFP. In addition, decreased levels of Aβ42 in the CSF were significantly associated with decreased GFS alpha (β coefficient=0.024, p<0.001). and beta (β coefficient=0.013, p<0.001). These latter correlations were present in individuals with subjective cognitive decline, suggesting that GFS may be a potential pre-clinical marker of early AD.

Integrative Biomarkers

These two studies provide a snapshot into the direction of research and progress that is being made in the development of potential resting-state EEG biomarkers which track the progression of AD (other research focuses on task related ERP biomarkers which isn’t discussed here). However, it is unlikely that a single biomarker will be sufficient in adequately predicting the onset, progression and outcome of AD. One longitudinal study which has tried to address this monitored 86 patients initially diagnosed with MCI over a period of 2 years [9]. During this time 25 of the patients developed AD allowing them to search for a marker indicating the likelihood of a patient converting from MCI to AD. They measured multiple different biomarkers and found that several EEG biomarkers based around the alpha and beta range were associated with the conversion from MCI to AD. Rather than focusing on just one of these, they found that by integrating 6 of them together they were able to develop a diagnostic tool that predicted AD progression with a sensitivity of 88% and specificity of 82%. This was compared to a sensitivity of 64% and specificity of 62% when only a single biomarker was used.
The 6 Biomarkers of Interest. From [9]

The Verdict

EEG offers an opportunity to support the early identification of Alzheimer’s disease and so far there are promising directions. However as with many EEG biomarkers, this search is also hindered by inconsistencies in the methodological approach across studies [6].  More significantly, there is a substantial challenge of identifying markers that are specific to AD and not general to all cognitive and mental health function, one that may be  overcome by studying the EEG in multiple forms of Dementia together in combination with multiple other types of markers.

[1] McKhann, G., Knopman, D., Chertkow, H., Hyman, B., Jack, C., & Kawas, C. et al. (2011). The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia7(3), 263-269. doi: 10.1016/j.jalz.2011.03.005
[2] Holtzman, D., Morris, J., & Goate, A. (2011). Alzheimer’s Disease: The Challenge of the Second Century. Science Translational Medicine3(77), 77sr1-77sr1. doi: 10.1126/scitranslmed.3002369
[3] Maestú, F., Cuesta, P., Hasan, O., Fernandéz, A., Funke, M., & Schulz, P. (2019). The Importance of the Validation of M/EEG With Current Biomarkers in Alzheimer’s Disease. Frontiers In Human Neuroscience13. doi: 10.3389/fnhum.2019.00017
[4] Wurtman, R. (2015). Biomarkers in the diagnosis and management of Alzheimer’s disease. Metabolism64(3), S47-S50. doi: 10.1016/j.metabol.2014.10.034
[5] Selkoe, D. (2002). Alzheimer’s Disease Is a Synaptic Failure. Science298(5594), 789-791. doi: 10.1126/science.1074069
[6] Cassani, R., Estarellas, M., San-Martin, R., Fraga, F., & Falk, T. (2018). Systematic Review on Resting-State EEG for Alzheimer’s Disease Diagnosis and Progression Assessment. Disease Markers2018, 1-26. doi: 10.1155/2018/5174815
[7] Babiloni, C., Del Percio, C., Caroli, A., Salvatore, E., Nicolai, E., & Marzano, N. et al. (2016). Cortical sources of resting state EEG rhythms are related to brain hypometabolism in subjects with Alzheimer’s disease: an EEG-PET study. Neurobiology Of Aging48, 122-134. doi: 10.1016/j.neurobiolaging.2016.08.021
[8] Smailovic, U., Koenig, T., Kåreholt, I., Andersson, T., Kramberger, M., Winblad, B., & Jelic, V. (2018). Quantitative EEG power and synchronization correlate with Alzheimer’s disease CSF biomarkers. Neurobiology Of Aging63, 88-95. doi: 10.1016/j.neurobiolaging.2017.11.005
[9] Poil, S., de Haan, W., van der Flier, W., Mansvelder, H., Scheltens, P., & Linkenkaer-Hansen, K. (2013). Integrative EEG biomarkers predict progression to Alzheimer’s disease at the MCI stage. Frontiers In Aging Neuroscience5. doi: 10.3389/fnagi.2013.00058

Friday, March 22, 2019

Smelling Parkinson's

reposted from

Friday, 22 March 2019

Smelling Parkinson's

In the news this week you might have seen a perplexing story about a lady who can smell Parkinson's! Her husband was diagnosed with Parkinson's and she noticed a strange smell. She only connected the dots when she attended a Parkinson's UK support group and was suddenly surrounded by the smell.

This is not the first report of people being able to smell diseases. Patients with Type 1 diabetes whose sugars have gone very high and blood acidic start to smell like pear drops. There are many reports of nurses who can smell specific types of bacteria.

This phenomena is not limited to humans either! One of my colleagues at medical school presented on the fascinating topic of animals that can smell diseases which included rats which can smell tuberculosis and dogs which can smell cancer. (Also a non-smell related one but equally interesting is that pidgeons can be trained to identify breast cancer on mammograms and pathology slides)

Joy Milne was given 12 t shirts to smell, 6 had been worn by Parkinson's patients and 6 were from people without Parkinson's. She correctly identified the 6 people with Parkinson's and also thought that one of the healthy controls had the smell as well, this person was subsequently diagnosed with Parkinson's so she had 100% accuracy at smelling Parkinson's.

From a scientific point of view, there must be a particular chemical that she is smelling and she has been working with a team in Manchester to try to identify the chemical that she is smelling. Fortunately they have found two chemicals that could be the source of this smell. This is a really important finding because it can lead to a potential quick test to diagnose Parkinson's. This test could even be used to diagnose Parkinson's earlier.

Discovery of volatile biomarkers of Parkinson’s disease from sebum
Drupad K Trivedi, Eleanor Sinclair, Yun Xu, Depanjan Sarkar, Camilla Liscio, Phine Banks, Joy Milne, Monty Silverdale, Tilo Kunath, Royston Goodacre, Perdita Barran
Parkinson’s disease (PD) is a progressive, neurodegenerative disease that presents with significant motor symptoms, for which there is no diagnostic test. We have serendipitously identified a hyperosmic individual, a ‘Super Smeller’ that can detect PD by odor alone, and our early pilot studies have indicated that the odor was present in the sebum from the skin of PD subjects. Here, we have employed an unbiased approach to investigate the volatile metabolites of sebum samples obtained noninvasively from the upper back of 64 participants in total (21 controls and 43 PD subjects). Our results, validated by an independent cohort, identified a distinct volatiles-associated signature of PD, including altered levels of perillic aldehyde and eicosane, the smell of which was then described as being highly similar to the scent of PD by our ‘Super Smeller’

Thursday, March 7, 2019

Germs in Your Gut Are Talking to Your Brain. Scientists Want to Know What They’re Saying

reposted from


Germs in Your Gut Are Talking to Your Brain. Scientists Want to Know What They’re Saying.

The body’s microbial community may influence the brain and behavior, perhaps even playing a role in dementia, autism and other disorders.
CreditSean McSorley
CreditSean McSorley
In 2014 John Cryan, a professor at University College Cork in Ireland, attended a meeting in California about Alzheimer’s disease. He wasn’t an expert on dementia. Instead, he studied the microbiome, the trillions of microbes inside the healthy human body.
Dr. Cryan and other scientists were beginning to find hints that these microbes could influence the brain and behavior. Perhaps, he told the scientific gathering, the microbiome has a role in the development of Alzheimer’s disease.
The idea was not well received. “I’ve never given a talk to so many people who didn’t believe what I was saying,” Dr. Cryan recalled.
A lot has changed since then: Research continues to turn up remarkable links between the microbiome and the brain. Scientists are finding evidence that microbiome may play a role not just in Alzheimer’s disease, but Parkinson’s disease, depression, schizophrenia, autism and other conditions.
For some neuroscientists, new studies have changed the way they think about the brain.
One of the skeptics at that Alzheimer’s meeting was Sangram Sisodia, a neurobiologist at the University of Chicago. He wasn’t swayed by Dr. Cryan’s talk, but later he decided to put the idea to a simple test.
“It was just on a lark,” said Dr. Sisodia. “We had no idea how it would turn out.”
He and his colleagues gave antibiotics to mice prone to develop a version of Alzheimer’s disease, in order to kill off much of the gut bacteria in the mice. Later, when the scientists inspected the animals’ brains, they found far fewer of the protein clumps linked to dementia.
Just a little disruption of the microbiome was enough to produce this effect. Young mice given antibiotics for a week had fewer clumps in their brains when they grew old, too.
“I never imagined it would be such a striking result,” Dr. Sisodia said. “For someone with a background in molecular biology and neuroscience, this is like going into outer space.”
Following a string of similar experiments, he now suspects that just a few species in the gut — perhaps even one — influence the course of Alzheimer’s disease, perhaps by releasing chemical that alters how immune cells work in the brain.
He hasn’t found those microbes, let alone that chemical. But “there’s something’s in there,” he said. “And we have to figure out what it is.”
Scientists have long known that microbes live inside us. In 1683, the Dutch scientist Antonie van Leeuwenhoek put plaque from his teeth under a microscope and discovered tiny creatures swimming about.
But the microbiome has stubbornly resisted scientific discovery. For generations, microbiologists only studied the species that they could grow in the lab. Most of our interior occupants can’t survive in petri dishes.
In the early 2000s, however, the science of the microbiome took a sudden leap forward when researchers figured out how to sequence DNA from these microbes. Researchers initially used this new technology to examine how the microbiome influences parts of our bodies rife with bacteria, such as the gut and the skin.
Few of them gave much thought to the brain — there didn’t seem to be much point. The brain is shielded from microbial invasion by the so-called blood-brain barrier. Normally, only small molecules pass through.
“As recently as 2011, it was considered crazy to look for associations between the microbiome and behavior,” said Rob Knight, a microbiologist at the University of California, San Diego.
He and his colleagues discovered some of the earliest hints of these links. Investigators took stool from mice with a genetic mutation that caused them to eat a lot and put on weight. They transferred the stool to mice that had been raised germ-free — that is, entirely without gut microbiomes — since birth.
After receiving this so-called fecal transplant, the germ-free mice got hungry, too, and put on weight.
Altering appetite isn’t the only thing that the microbiome can do to the brain, it turns out. Dr. Cryan and his colleagues, for example, have found that mice without microbiomes become loners, preferring to stay away from fellow rodents.
The scientists eventually discovered changes in the brains of these antisocial mice. One region, called the amygdala, is important for processing social emotions. In germ-free mice, the neurons in the amygdala make unusual sets of proteins, changing the connections they make with other cells.
Studies of humans revealed some surprising patterns, too. Children with autism have unusual patterns of microbial species in their stool. Differences in the gut bacteria of people with a host of other brain-based conditions also have been reported.
But none of these associations proves cause and effect. Finding an unusual microbiome in people with Alzheimer’s doesn’t mean that the bacteria drive the disease. It could be the reverse: People with Alzheimer’s disease often change their eating habits, for example, and that switch might favor different species of gut microbes.
Fecal transplants can help pin down these links. In his research on Alzheimer’s, Dr. Sisodia and his colleagues transferred stool from ordinary mice into the mice they had treated with antibiotics. Once their microbiomes were restored, the antibiotic-treated mice started developing protein clumps again.
“We’re extremely confident that it’s the bacteria that’s driving this,” he said. Other researchers have taken these experiments a step further by using human fecal transplants.
If you hold a mouse by its tail, it normally wriggles in an effort to escape. If you give it a fecal transplant from humans with major depression, you get a completely different result: The mice give up sooner, simply hanging motionless.
As intriguing as this sort of research can be, it has a major limitation. Because researchers are transferring hundreds of bacterial species at once, the experiments can’t reveal which in particular are responsible for changing the brain.
Now researchers are pinpointing individual strains that seem to have an effect.
To study autism, Dr. Mauro Costa-Mattioli and his colleagues at the Baylor College of Medicine in Houston investigated different kinds of mice, each of which display some symptoms of autism. A mutation in a gene called SHANK3 can cause mice to groom themselves repetitively and avoid contact with other mice, for example.
In another mouse strain, Dr. Costa-Mattioli found that feeding mothers a high-fat diet makes it more likely their pups will behave this way.
When the researchers investigated the microbiomes of these mice, they found the animals lacked a common species called Lactobacillus reuteri. When they added a strain of that bacteria to the diet, the animals became social again.
Dr. Costa-Mattioli found evidence that L. reuteri releases compounds that send a signal to nerve endings in the intestines. The vagus nerve sends these signals from the gut to the brain, where they alter production of a hormone called oxytocin that promotes social bonds.
Other microbial species also send signals along the vagus nerve, it turns out. Still others communicate with the brain via the bloodstream.
It’s likely that this influence begins before birth, as a pregnant mother’s microbiome releases molecules that make their way into the fetal brain.
Mothers seed their babies with microbes during childbirth and breast feeding. During the first few years of life, both the brain and the microbiome rapidly mature.
To understand the microbiome’s influence on the developing brain, Rebecca Knickmeyer, a neuroscientist at Michigan State University, is studying fMRI scans of infants.
In her first study, published in January, she focused on the amygdala, the emotion-processing region of the brain that Dr. Cryan and others have found to be altered in germ-free mice.
Dr. Knickmeyer and her colleagues measured the strength of the connections between the amygdala and other regions of the brain. Babies with a lower diversity of species in their guts have stronger connections, the researchers found.
Does that mean a low-diversity microbiome makes babies more fearful of others? It’s not possible to say yet — but Dr. Knickmeyer hopes to find out by running more studies on babies.
CreditSean McSorley
CreditSean McSorley
As researchers better understand how the microbiome influences the brain, they hope doctors will be able to use it to treat psychiatric and neurological conditions.
It’s possible they’ve been doing it for a long time — without knowing.
In the early 1900s, neurologists found that putting people with epilepsy on a diet low in carbohydrates and high in protein and fat sometimes reduced their seizures.
Epileptic mice experience the same protection from a so-called ketogenic diet. But no one could say why. Elaine Hsiao, a microbiologist at the University of California, Los Angeles, suspected that the microbiome was the reason.
To test the microbiome’s importance, Dr. Hsiao and her colleagues raised mice free of microbes. When they put the germ-free epileptic mice on a ketogenic diet, they found that the animals got no protection from seizures.
But if they gave the germ-free animals stool from mice on a ketogenic diet, seizures were reduced.
Dr. Hsiao found that two types of gut bacteria in particular thrive in mice on a ketogenic diet. They may provide their hosts with building blocks for neurotransmitters that put a brake on electrical activity in the brain.
It’s conceivable that people with epilepsy wouldn’t need to go on a ketogenic diet to get its benefits — one day, they may just take a pill containing the bacteria that do well on the diet.
Sarkis Mazmanian, a microbiologist at Caltech, and his colleagues have identified a single strain of bacteria that triggers symptoms of Parkinson’s disease in mice. He has started a company that is testing a compound that may block signals that the microbe sends to the vagus nerve.
Dr. Mazmanian and other researchers now must manage a tricky balancing act. On one hand, their experiments have proven remarkably encouraging; on the other, scientists don’t want to encourage the notion that microbiome-based cures for diseases like Parkinson’s are around the corner.
That’s not easy when people can buy probiotics without a prescription, and when some companies are willing to use preliminary research to peddle microbes to treat conditions like depression.
“The science can get mixed up with what the pseudoscientists are doing,” said Dr. Hsiao.
Dr. Costa-Mattioli hopes that L. reuteri some day will help some people with autism, but he warns parents against treating their children with store-bought probiotics. Some strains of L. reuteri alter the behavior of mice, he’s found, and others don’t.
Dr. Costa-Mattioli and his colleagues are still searching for the most effective strain and figuring out the right dose to try on people. “You want to go into a clinical trial with the best weapon, and I’m not sure we have it,” he said.
Katarzyna B. Hooks, a computational biologist at the University of Bordeaux in France, warned that studies like Dr. Costa-Mattioli’s are still unusual. Most of these findings come from research with fecal transplants or germ-free mice — experiments in which it’s especially hard to pinpoint the causes of changes in behavior.
“We have the edges of the puzzle, and we’re now trying to figure out what’s in the picture itself,” she said.
A version of this article appears in print on , on Page D1 of the New York edition with the headline: Beyond a Gut FeelingOrder Reprints | Today’s Paper | Subscribe