Intranasal delivery of MSC-EVs shows promise for treating Alzheimer's disease

In the search for a cure for Alzheimer's disease, mesenchymal stem cells and their derived extracellular vesicles (MSC-EVs) offer much promise, thanks to their protective and anti-inflammatory properties. The results from a new study done on mice, released today in STEM CELLS Translational Medicine, strengthens this idea by showing for the first time that MSC-EVs delivered by way of the nasal passages reduce inflammation - believed to be a prime factor in Alzheimer's disease. They also trigger actions that guard the brain's neurons against further degenerative effects.
The study, led by Silvia Coco, Ph.D., at the University of Milano-Bicocca in Italy, lays the foundation for future studies that might point the way to a cure for this devastating disease.

Alzheimer's is an irreversible degeneration of the brain that causes disruptions in memory, cognition, personality and other functions that eventually lead to death. Worldwide, 50 million people are believed to be living with Alzheimer's or other dementias, according to a 2018 report by Alzheimer's Disease International, with the cost of care estimated at over US $1 trillion.

While abnormal protein buildups in the brain called amyloid plaques are thought to play a central role in Alzheimer's disease, mounting evidence suggests that inflammation is key to its development, too. This raises the need to target the brain's immune cells as a way to slow down the disease's progression.

MSC-EVs' beneficial effects in regulating inflammation seen in Alzheimer's have already been reported in some different studies on mice. This is due to the ability of MSCs to modulate the body's immune system, which in turn is believed to result from the release of EVs. These nanosized, membrane-bound vesicles transport cargo -- including DNA, RNA, and proteins -- between cells as a form of intercellular communication. They also are thought to rid the cell of damaging substances.
In the earlier studies, MSC-EVs were administered either intravenously or directly into the fluid within the chambers of the brain (cerebral ventricles) over an extended period of weeks or months. That is where this latest study differs. Administration of the MSC-EVs was done through the nasal passages, with dosing occurring over a much shorter period of time. "We believed that the possibility to administer MSC-EVs through a non-invasive route and the demonstration of their anti-inflammatory efficacy might accelerate the chance of exploiting MSC-EVs to treat Alzheimer's disease," Dr. Coco said.

The team conducted their study both in vitro (outside a living organism) and in vivo (within a living organism). They began by collecting MSCs from the bone marrow of healthy human donors and preconditioning them with proteins called cytokines, to increase the MSCs' anti-inflammatory abilities and boost their release of EVs. For the in vitro segment of their study, they added the resulting MSC-EVs to microglia - cells that mediate immune responses in the central nervous system and, as such, are targets in Alzheimer's - isolated from newborn C57BL/6 mice. (These mice are specially bred to be used in studying diseases including Alzheimer's.) The applications were done at intervals of two and 24 hours. The results were then analyzed 48 hours after the final application.
For the in vivo portion of the study, the research team administered two doses of MSC-EVs to a group of 7-month-old female mice with Alzheimer's. The applications were done through the nasal passages, with the second dose occurring just 18 hours after the first. When they assessed the results 21 days later, they found that, just as they had seen with the in vitro experiments, the MSC-EVs had dampened the activation of the microglia cells in the mice brains and increased the density of dendritic spines (structures in the brain that provide cognitive resilience).

We believe that the striking aspect of our study resides in the fact that the observed effects were achieved by only two intranasal injections of MSC-EVs delivered just hours apart. This might possibly have occurred because EVs delivered intranasally could reach higher levels than those delivered by other methods.

Our results strengthen the view that mechanisms of action other than removal of amyloid plaques from the brain should deserve a great attention when treating Alzheimer's," she added. "Undoubtedly, the possibility of obtaining greater effects by repeated intranasal injections has to be considered and will be a matter for future experiments."

Silvia Coco, Ph.D., University of Milano-Bicocca in Italy

"There are several important findings from this study. In the attempt to find a possible cure for Alzheimer's disease, mesenchymal stem cells and their derived extracellular vesicles are being investigated for therapeutic purposes thanks to their protective and anti-inflammatory properties," said Anthony Atala, MD, Editor-in-Chief of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. "The results from this study present an opportunity for potentially effective therapies to be tested by human pilot clinical trials. This work is worthy to progress forward."

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AI helps spot early signs of glaucoma progression to blindness

Using Artificial Intelligence (AI), researchers have developed a quick test to identify which people with glaucoma are at risk of rapid progression to blindness.

A new test can detect glaucoma progression 18 months earlier than the current gold standard method, said the study published in the journal Expert Review of Molecular Diagnostics.

Glaucoma, the leading global cause of irreversible blindness, affects over 60 million people, which is predicted to double by 2040 as the global population ages.

Loss of sight in glaucoma is caused by the death of cells in the retina, at the back of the eye.

“Being able to diagnose glaucoma at an earlier stage, and predict its course of progression, could help people to maintain their sight, as treatment is most successful if provided at an early stage of the disease,” said study first author Eduardo Normando from Imperial College London.

The test, called DARC (Detection of Apoptosing Retinal Cells), involves injecting into the bloodstream (via the arm) a fluorescent dye that attaches to retinal cells, and illuminates those that are in the process of apoptosis, a form of programmed cell death.

The damaged cells appear bright white when viewed in eye examinations — the more damaged cells detected, the higher the DARC count.

One challenge with evaluating eye diseases is that specialists often disagree when viewing the same scans, so the researchers have incorporated an AI algorithm into their method.

In the Phase II clinical trial of DARC, the AI was used to assess 60 of the study participants — 20 with glaucoma and 40 healthy control subjects.

The AI was initially trained by analysing the retinal scans (after injection of the dye) of the healthy control participants.

The AI was then tested on the glaucoma patients.

Those taking part in the AI study were followed up 18 months after the main trial period to see whether their eye health had deteriorated.

The researchers were able to accurately predict progressive glaucomatous damage 18 months before that seen with the current gold standard OCT retinal imaging technology, as every patient with a DARC count over a certain threshold was found to have progressive glaucoma at follow-up.

“These results are very promising as they show DARC could be used as a biomarker when combined with the AI-aided algorithm,” said lead researcher Francesca Cordeiro from University College London (UCL) Institute of Ophthalmology.

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A doctor is warning vegans not to believe internet rumors that vitamin B12 is unnecessary

• Vegan diets have been shown to protect against heart disease, lower cholesterol, and even clear up your skin
• But going vegan and cutting out animal products like milk and beef can also result in a vitamin B12 deficiency, which doctors say can spell disaster for a vegan's health. 
• A deficiency in vitamin B12 can cause fatigue, depression, and has even been linked to a higher chance of stroke. 
• However, there are alternatives to animal products that can help supplement your B12 intake, like over-the-counter B12 vitamins and foods like fortified cereals and nutritional yeast. 

In less than a decade, the number of people in the U.S. who identify as vegan jumped six-fold — from 1% in 2014 to 6% in 2017 according to a research.

And while the eating pattern has been linked to health benefits like lower cholesterol, clearer skin, and a lower risk of heart disease, a lack of animal products has also been connected to a number of vitamin deficiencies, in particularly, vitamin B12 deficiency.

And now, a doctor is speaking out about just how catastrophic the consequences of such a deficiency can be since a certain subject of vegans on the internet have reportedly floated the myth that additional B 12 is not necessary for vegans.

"There is a danger of young people going vegan, not having B12 and it could tip the balance to them getting a serious neuropathy," or nerve damage, Tom Sanders, professor emeritus of nutrition and dietetics at King's College London told.  "I'm concerned that many people think it is a myth."

In reality, vitamin B12 — commonly found in milk, beef, clams, tuna, and other animal products — is responsible for nervous system and blood cell health, meaning vitamin B12 is necessary for essential body functions like motor skills, bone health, mood control, and brain health. 

A deficiency in B12 can lead to fatigue, depression, and lower bone density.

These effects can be especially detrimental to children who are on a vegan diet, who in some cases develop peripheral neuropathy, or irreversible nerve damage that can cause weakness, numbness, and pain throughout the body, as well as other motor problems. 

Vitamin B12 deficiency has also been linked to a higher risk of stroke

A recent study found that the health benefits of going vegan may actually be linked to some of the more serious risks that come with a vitamin B12 deficiency. 

The researchers from Oxford University surveyed the eating habits and health of 48,188 adults in the UK over the course of 18 years. 

While the study authors supported earlier findings that a vegan diet is linked to lower cholesterol, the new findings also showed that because vegans' lack of animal products leads to lower levels of vitamin B12 and vitamin D, they also have a higher risk of hemorrhagic stroke. 

Carnivores, meanwhile, were found to have a higher risk of heart disease. 

There are ways for adults to get sufficient B12 without eating animal products 

Consulting your doctor about over-the-counter B12 supplements is an important first step when going vegan, according to dietitian.

If you want to get additional sources of B 12 aside from vitamins, foods like nutritional yeast, shitake mushrooms, and fortified cereals can all be good sources of supplemental B12. 

The dietitian recommends that vegans also get their levels of B12 checked regularly by a medical professional. 

For children, however, the  pediatrician recommends forgoing a vegan diet completely and feeding kids all five primary food groups, including dairy, meat, eggs, and fish. This is due to the risk of nutrient deprivation at key stages of development. 

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BP drug shows promise for treating Parkinson's

Felodipine, a prescribed drug to treat high blood pressure, has shown promise against Parkinson's, Huntington's and forms of dementia in studies carried out in mice and zebra-fish.

In a study, scientists have shown in mice that felodipine may be a candidate for re-purposing.

A common feature of neuro-degenerative diseases is the build-up of misfolded proteins.

These proteins, such as huntingtin in Huntington's disease and tau in some dementias, form "aggregates" that can cause irreversible damage to nerve cells in the brain.

A team led by a Prof. used mice that had been genetically modified to express mutations that cause Huntington's disease or a form of Parkinson's disease, and zebra-fish that model a form of dementia.

Felodipine was effective at reducing the build-up of "aggregates" in mice with the Huntington's and Parkinson's disease mutations and in the zebrafish dementia model.

The treated animals also showed fewer signs of diseases.

"This is the first time that we're aware of that a study has shown that an approved drug can slow the build-up of harmful proteins in the brains of mice using doses aiming to mimic the concentrations of the drug seen in humans," said the Prof.

The hypertension drug was able to slow down the progression of these potentially devastating conditions and "so we believe it should be trialed in patients," he added.

In healthy individuals, the body uses a mechanism to prevent the build-up of such toxic materials.
This mechanism is known as autophagy, or 'self-eating', and involves cells eating and breaking down the materials.

"This is only the first stage, though. The drug will need to be tested in patients to see if it has the same effects in humans as it does in mice. We need to be cautious, but I would like to say we can be cautiously optimistic," said the Prof. 

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Scientists revive brain funciton in dead pigs

Scientists have managed to restore cell function in the brains of pigs hours after they died, in a breakthrough that experts said threw into question the very notion of what makes animals of even humans--alive.

Authors said their research could one day be used to help treat victims of heart attacks and strokes and unravel the mysteries of brain trauma.

In human and large mammal brains, cells crucial for neural function begin to degrade as soon as blood supply is cut- a process long considered to be irreversible.

But the findings of the trial, show that the brains of pigs can have their blood flow and cell function restored even hours after death.

The team used the brains of 32 pigs that had been slaughtered for food and discarded, without blood or glucose flow for 4 hours each.

Then, using a tissue support system that pumps a liquid designed to mimic blood through organs, they rehydrated the brains for a further 6 hours.

Some brains received the patented life-support solution and others were given a control substance.
The results were astonishing: the brains that recived the artificial blood had basic cell function restored. Their blood vessel structure was revived, and the team even observed some localised processes- including in synapses and immune responses- flickering back to life.

Those that received the control solution turned within hours to what researchers described as something a bit like yoghurt.

I was tremendously surprised, a sresearcher and lead study author said.

We were surprised how well the structure was preserved. We found that cell death is reduced, which is very exciting and promising.

The main conceptual finding is this: cell death in the brain occurs across a longer time period than we previously thought , added the author.

The team stressed that they saw no higher level functional activity, such as electric signalling associated with consciousness in the revived brains.

That is a clinical sign that the brain is alive, and we never found it, he said. This is not a living brain, it is a cellularly active brain.

Had any such activity been detected, the team said they would have had to deliver anaesthetic to the brains to null any pain- despite then having been dead for hours.

If some activity shows up that indicated consciousness, we would have to stop the experiment, said a researcher.

This would be unique: inducing consciousness in an organ that's not connected to any living being.
The findings suggest that scientists may have under appreciated the brain's capacity for self-restoration after a patient is declared brain dead.

But for experts invited to comment on the study, it raised deeper philosophical and ethical questions.
Writing in a linked editorial, a Prof. of law and philosophy said that the study throws into question long-standing assumptions over what makes an animal or a human alive.

She said researchers had inadvertently created an ethical grey area where the pigs used were not alive, but not completely dead.

A Prof. of medical ethics said that the study could have vital implications for future brain research.
This research reminds us that death is less an event, and more of a process that occurs over time, he said.

Cells within the human organism may be alive for some period of time after the person has died.

A researcher said the team planned to use their support system on dead brains for longer periods of time in order to see how the cells react.

We could potentially get some insight into how these brains could be saved, he said.

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Scientists have managed to restore cell function in the brai ..

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Everything You Ought To Know About Vitamin D

Everyone of us is aware that for normal functioning of our body, we all need various nutrients in proper proportions each day- they're carbohydrates, proteins, fat, minerals and vitamins. In case, there is deficiency of any of these nutrients, then it leads to diseases.One such vitamin is Vitamin B complex of which, there is a crucial vitamin known as Vitamin B12 or scientifically called as Cobalamin.

Vitamin B12 plays a major role by controlling several factors of the human body. These are necessary for the body to run well and stay healthy. Vitamin B12 is a powerhouse. It helps make DNA, nerve and blood cells, and is crucial for a healthy brain and immune system. Your metabolism wouldn't run smoothly without it. But B12 isn't like other vitamins. It's only found in animal products like eggs, meat, shellfish, and dairy. Up to 15% of people don't get enough B12, and they're more likely to be vegetarians, have celiac disease or other digestion problems, or be an adult over 50. The signs of vitamin B12 deficiency include exhaustion, rapid heartbeat, brain fog, and other symptoms, says a nutritionist.

Vitamin B12 occurs naturally in animal products. So if your diet largely consists of plant-based foods such as fruits, veggies, beans, and soy, you're at risk for deficiency. "Vegetarians who consume eggs and dairy should aim to include at least one source a day from both of these food groups," says a nutritionist. Vegans—who by definition consume no animal products—need to take a supplement or consume vitamin B12–fortified foods, such as breakfast cereal and grains. Other foods fortified with B12 include nondairy milks and meat substitutes, but not all are, so check the label first to make sure.

 9 health benefits of vitamin B12, all based on science.

1. Helps With Red Blood Cell Formation and Anemia Prevention

 Vitamin B12 plays a vital role in helping your body produce red blood cells.
Low vitamin B12 levels cause a reduction in red blood cell formation and prevent them from developing properly .
Healthy red blood cells are small and round, whereas they become larger and typically oval in cases of vitamin B12 deficiency.
Due to this larger and irregular shape, the red blood cells are unable to move from the bone marrow into the bloodstream at an appropriate rate, causing megaloblastic anemia .
When you’re anemic, your body doesn’t have enough red blood cells to transport oxygen to your vital organs. This can cause symptoms like fatigue and weakness.

2. May Prevent Major Birth Defects 

Adequate vitamin B12 levels are crucial to a healthy pregnancy.

Studies show that a fetus’s brain and nervous system require sufficient B12 levels from the mother to develop properly.
Vitamin B12 deficiency in the beginning stages of pregnancy may increase the risk of birth defects, such as neural tube defects. Furthermore, maternal vitamin B12 deficiency may contribute to premature birth or miscarriage.
One study found that women with vitamin B12 levels lower than 250 mg/dL were three times more likely to give birth to a child with birth defects, compared to those with adequate levels .
For women with a vitamin B12 deficiency and levels below 150 mg/dL the risk was five times higher, compared to women with levels above 400 mg/dL .

 3. May Support Bone Health and Prevent Osteoporosis
Maintaining adequate vitamin B12 levels may support your bone health.
One study in more than 2,500 adults showed that people with a vitamin B12 deficiency also had lower than normal bone mineral density.
Bones with decreased mineral density can become delicate and fragile over time, leading to an increased risk of osteoporosis.
Other studies have also shown a link between low vitamin B12 levels and poor bone health and osteoporosis, especially in women .

4. May Reduce Your Risk of Macular Degeneration

Macular degeneration is an eye disease that mainly affects your central vision.
Maintaining adequate levels of vitamin B12 may help prevent the risk of age-related macular degeneration.
Researchers believe that supplementing with vitamin B12 may lower homocysteine, a type of amino acid that is found in your bloodstream.
Elevated homocysteine levels have been associated with an increased risk of age-related macular degeneration .
A study involving 5,000 women aged 40 or older concluded that supplementing with vitamin B12, along with folic acid and vitamin B6, may reduce this risk .
The group receiving these supplements for seven years had fewer cases of macular degeneration, compared to the placebo group. The risk of developing any form of the condition was 34% lower, while it was 41% lower for more severe types .
Ultimately, further studies are needed to fully understand vitamin B12’s role in promoting vision health and preventing macular degeneration.

5. May Improve Mood and Symptoms of Depression

Vitamin B12 may improve your mood.
The effect of vitamin B12 on mood is not yet fully understood. However, this vitamin plays a vital role in synthesizing and metabolizing serotonin, a chemical responsible for regulating mood.
Therefore, vitamin B12 deficiency may lead to decreased serotonin production, which may cause a depressed mood.
Studies support the use of vitamin B12 supplements for improving symptoms of depression in people deficient in this vitamin.
One study in people with depression and low vitamin B12 levels found that those who received both antidepressants and vitamin B12 were more likely to show improved depressive symptoms, compared to those treated with antidepressants alone .
Another study discovered that vitamin B12 deficiency was associated with twice the risk of severe depression .
Additionally, high vitamin B12 levels have been linked to better treatment outcomes and an increased probability of recovery from major depressive disorder (MDD) .
Though vitamin B12 supplements may help improve mood and depression in people with a deficiency, research does not currently suggest that they have the same effect in those with normal B12 levels.

6. May Benefit Your Brain by Preventing the Loss of Neurons

Vitamin B12 deficiency has been associated with memory loss, especially in older adults.
The vitamin may play a role in preventing brain atrophy, which is the loss of neurons in the brain and often associated with memory loss or dementia.
One study in people with early-stage dementia showed that a combination of vitamin B12 and omega 3 fatty acid supplements slowed mental decline .
Another study found that even vitamin B12 levels on the low side of normal can contribute to poor memory performance. As a result, supplementing with this vitamin may improve memory, even in the absence of a clinically diagnosed deficiency .
More research is needed to make sound conclusions on the effect of vitamin B12 supplements on memory and cognitive function.

7. May Give You an Energy Boost

Vitamin B12 supplements have long been touted as the go-to product for a surge of energy.
All B vitamins play an important role in your body’s energy production, though they don’t necessarily provide energy themselves .
Currently, there is no scientific evidence to suggest that vitamin B12 supplements can boost energy in those with sufficient levels of this vitamin .
Since vitamin B12 is water-soluble, your body cannot store extra amounts. Any excess passes through your body and is eliminated when you urinate .
On the other hand, if you’re significantly deficient in vitamin B12, taking a supplement or increasing your intake will likely improve your energy level .
In fact, one of the most common early signs of vitamin B12 deficiency is fatigue or lack of energy.

8. May Improve Heart Health by Decreasing Homocysteine

High blood levels of the common amino acid homocysteine have been linked to an increased risk of heart disease.
If you’re significantly deficient in vitamin B12, your homocysteine levels become elevated.
Studies have shown that vitamin B12 helps decrease homocysteine levels, which may reduce your risk of heart disease .
However, there is currently no scientific evidence to confirm that vitamin B12 supplements are effective in this regard .
Therefore, further research is needed to understand the relationship between vitamin B12 and heart health.

9. Supports Healthy Hair, Skin and Nails

Given vitamin B12’s role in cell production, adequate levels of this vitamin are needed to promote healthy hair, skin and nails.
In fact, low vitamin B12 levels can cause various dermatologic symptoms, including hyperpigmentation, nail discoloration, hair changes, vitiligo (the loss of skin color in patches) and angular stomatitis (inflamed and cracked mouth corners) .
Supplementing with vitamin B12 has been shown to improve dermatologic symptoms in people with B12 deficiency .
However, if you’re well-nourished and not deficient in this vitamin, taking a supplement is unlikely to improve your skin, nail strength or hair health .

 SIGNS AND CAUSES OF DEFICIENCY
1.Early symptoms include weakness and fatigue
B12 isn't nicknamed the energy vitamin for nothing. Inadequate B12 intake makes a dent in red blood cell production, and some of the earliest signs of a deficiency include feeling dragged, confused, and weak. Problem is, says a nutritionist, these clues are so vague, and not everyone experiences them the same way. And since they can be attributed to so many other possible triggers, most people don't think to be tested. If these symptoms hit and stick around for weeks, it's best to consult your doctor and rule out other causes, she says. Similar tip-offs include dizziness, impaired thinking, and confusion.

2.Heartburn drugs can cause it

Some prescription heartburn drugs suppress the production of, which is needed to absorb vitamin B12. A 2013 study from the backs this up. Researchers found that taking meds called proton pump inhibitors (like Prilosec and Nexium) for more than two years was linked to a 65% higher risk of vitamin B12 deficiency. And two years or more using H2 receptor blocker drugs (such as Pepcid and Zantac) is associated with a 25% boost in deficiency odds. If you take these regularly, talk to your doctor about steps you can take to protect yourself.

3.It can be mistaken for dementia
"Symptoms of a deficiency often mimic those of dementia, such as memory loss, disorientation, and difficulty thinking and reasoning," says the nutritionist. It can be hard distinguishing deficiency from dementia, especially since older folks are at risk for both. And the two conditions often overlap; 75% to 90% of B12 deficient people also have neurological complications such as dementia, says Moon. But even when a B12 shortage strikes younger people, it still typically resembles dementia. Experts aren't exactly sure of the relationship between the two, but patients with unexplained cognitive decline should be tested for B12 deficiency, suggests a Dr..

4. Taking birth control pills sets you up for it
"Women who have been on oral contraceptives for extended periods of time tend to have issues absorbing vitamin B12," says the nutritionist. "Studies show that pills that are higher in estrogen are more strongly associated with B12 and folate (folic acid, or vitamin B6) deficiencies, leading to the assumption that the estrogen in the pill is the reason for this impaired absorption." If you're on the pill, talk to your doctor about the risks, and if you should take B12 supplements as a backup.


5.The best sources are meat and fish
Beef liver and clams are top in B 12, according to the experts. If you're not a fan of either, plenty of good options abound. Beef, turkey, oysters, chicken, trout, and salmon are B12 superstars; a serving of each delivers close to or more than 100% of your RDA (2.4 mcg for men and women over 14, going up to 2.6 and 2.8 for pregnant and breastfeeding women respectively, says Moon). Eggs (0.6 mcg per egg, 10% of daily value) and milk (1.2 mcg per cup of low-fat, 18% of daily value) are also solid sources.

6.Fortified foods and supplements can help

Both can help vegans, vegetarians, and older adults and others who are unable to absorb naturally occurring B12, says the Dr. When absorption is an issue, "simply loading up on foods naturally high in B12 may not solve the problem," she says. "The synthetic form of B12 is more readily absorbed." Best places to find it in food: fortified cereals, many of which have 100% of your RDA.

7.Heavy drinking increases your odds
More than a few drinks on average each day can cause gastritis, or irritation of the stomach lining, and this can lead to low stomach acid and reduced B12 absorption, says a nutritionist. Alcohol plays a role in deficiency in another way too. B12 is stored in the liver, and  can impair liver function and deplete B12 stores or make it harder for the liver to use it

8.It can trigger a false positive on a Pap test

Vitamin B12 deficiency even affects the Pap test you get at your regular gyne checkup to screen for cervical cancer. Low B12 levels can change the way some cervical cells look, potentially triggering a false positive, according to the experts. Yet another reason to shore up your intake of the nutrient.

9. It's linked to pernicious anemia

There's a specific type of anemia that's triggered by a B12 deficiency. Called pernicious (which means "dangerous," because it was potentially life-threatening in the past) anemia, it is a red blood cell deficiency that happens when the stomach doesn't make enough of a protein called intrinsic factor, which helps the intestine absorb B12, says a Dr . Pernicious anemia can be the result of an autoimmune issue, a problem with the stomach lining, or even a congenital condition passed down through families. Treatment usually involves B12 shots, possibly combined with supplements.

10. It can be hard to recognize a deficiency
"Because the body can store B12 for three to five years, early symptoms of a deficiency usually appear gradually, so you're unlikely to notice them," says the nutritionist. After initial clues like fatigue, weakness, and brain fog set in, says the nutritionist, more advanced tip-offs show up, such as numbness and tingling of the limbs, depression, and paranoia, even hallucinations. The signs are so varied and they don't strike everyone, so it's tough to diagnose even at a later stage. "Which symptoms hit when depends also on what caused the deficiency—mal-absorption, which could mean they are absorbing some B12 and the deficiency is occurring more slowly, or total lack of animal products, which would likely cause the deficiency to develop more quickly," says the nutritionist.

11. A blood test is the only way to confirm it 
The CDC defines vitamin B12 deficiency as blood levels below 200 pg/mL (picograms/milliliter), says a Dr.. "Blood tests are generally accurate, but a false positive is possible related to certain cancers, oral contraceptives, folate (folic acid) deficiency, and pregnancy," she says. "False negatives are also possible, as sometimes seen in people with liver disease, poorly functioning kidneys, or certain blood cell disorders." Your GP or primary care physician can take care of testing you.       

12. It's linked to immune system issues
"B12 plays an important role in white blood cell production, and white blood cells are essential for proper immune system functioning," says a Dr. Not only can a lack of B12 lower your immunity, some immune system disorders can increase your likelihood of becoming deficient. Grave's disease, for example, an autoimmune condition of the thyroid causing hyperthyroidism, is a risk factor for developing pernicious anemia, which in turn leads to B12 deficiency.                   

13. Digestive problems can cause it

People who deal with GI issues are at a higher risk of a B12 shortage because digestive problems can make absorbing the nutrient more difficult, says the nutritionist. "Those with gut issues, such as colitis, Crohn's disease, inflammatory bowel disease, and leaky gut syndrome are at a higher risk," she says. Celiac disease sufferers can also have problems with absorption. If you have any of these, talk to your doctor about supplements or B12 shots, since all the B12-rich food in the world won't help your body shore up its reserves if it can't be absorbed by the GI tract.

14. It can happen after weight loss surgery
"Some surgeries that affect the GI tract, like gastric bypass surgery, make it hard to absorb B12," says the Dr. One reason has to do with the decrease in the body's ability to digest food; it's also caused by iffy levels of intrinsic factor, a protein that helps the body absorb B12. The absorption problem could be a permanent one, and people who undergo gastric bypass may need to take vitamin B12 supplements for the rest of their life or risk a shortage.

15. It can cause tingling, weakness, and balance issues

Depletion of your vitamin B12 stores leads to nerve damage. No wonder pins and needles in your hands and feet, shaky body movements, and trouble walking are all consequences of long-term B12 deficiency, says the nutritionist. Like so many other B12 deficiency signs, these can be attributed to other causes, including old age. The only way to know for sure is to see your doctor for a test.

16. Babies can get it too

In infants, vitamin B12 deficiency is serious—it can lead to symptoms such as anemia, problems with movement, difficulty reaching developmental milestones, and failure to thrive, which may be fatal. Low B12 levels are rare in infants but it can happen if a baby is fed a strict diet free of any animal products or if a breastfeeding mom is a vegan who doesn't take vitamin B12 supplements (and breast milk is the only source of nutrition.) B12 supplementation can reverse the course, one study shows, and taking prenatal vitamins fortified with B12 in pregnancy can help prevent it.

17. Visible signs include pale skin, a sore tongue, and mouth ulcers

Paleness; mouth sores; a red, swollen, beefy tongue—these are some of the visible signs of a B12 shortage. Caused by deficiency-related changes in blood flow, these signs can show up years after the depletion sets in, says the nutritionist. A rapid heartbeat or heart palpitations is another blood flow-related sign, and sometimes bruising easily is also a result of a longstanding deficiency. But these seemingly unrelated signs don't show in all B12 deficient people, or they come on so slowly, it's hard to notice them, she says .

18. It might cause permanent damage

Vitamin B12 deficiency that persists for years can cause severe, irreversible neurological damage—think memory loss, disorientation, and an inability to concentrate. Other permanent side effects include nerve damage, insomnia, erectile dysfunction, even difficulty with bowel and bladder control, says the Dr. The upside: "Many symptoms can be reversed if caught early and treated with B12," she adds.

19. It's hard to overdo vitamin B12

Unlike fat-soluble vitamins that accumulate in your body and can have side effects in excess, B12 is a water-soluble vitamin, meaning your body only absorbs a small amount and the rest is excreted through urine, says the nutritionist. Good news if you need to refill your stores of this nutrient, but worry about taking too much. But keep in mind that large amounts of B12 at one time may cause diarrhea and all-over itchiness, she adds. If your doctor recommends supplements, read the label and take only the amount recommended by your GP.

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