Alzheimer's Disease: The Promise of Diabetes Drugs

Current pharmacologic interventions in Alzheimer's disease (AD) have limited effectiveness.

Most of the current AD drugs available promise to slow the rate of progression but fail to reverse or prevent the disease.

Novel strategies for AD drug treatment are desperately needed and one promising class of agents are the newer drugs for treatment of diabetes. 

How might a diabetes treatment drug potentially treat a brain disease like AD?

A recent review article in World Journal of Diabetes summarizes what is known about the neuroprotective effect of the anti-diabetic drug liraglutide (trade name Saxenda in the U.S.). This review article is extensive but I will try to summarize the key points.

1. Long-acting glucagon-like peptide-1 (GLP-1) is a naturally occuring peptide known to promote insulinotropic activity and glucose homeostasis
2. GLP-1 is primarily excreted in the gut but receptors for the compound are found throughout the body including the brain.
3. GLP-1 is a key component of the gut-brain axis and along with the vagal nerve helps regulate energy metabolism, insulin secretion, appetite and weight control.
4. Liraglutide is a recently approved GLP-1 receptor agonist with an effect similar to naturally occuring GLP-1.
5. Liraglutide along with regulating glucose in type 2 diabetes has brain anti-inflammatory, anti-oxidant, microglia inhibition and neuroprotective actions.
6. Higher doses of liraglutide promote weight loss and the drug has recently been approved for weight loss in the U.S.
7. Preclinical trials suggest liraglutide may improve cognitive function in AD and may have beneficial effects on AD biomarkers such as beta amyloid brain levels.
8. Future research combining liraglutide with dipeptidyl peptidase-4 (DPP-4) inhibitors may lead to a "therapeutic dream team" combination for both diabetes and neurodegenerative diseases including AD
9. Basic research suggests brain insulin resistance is a key mechanism in AD and other central neurodegenerative disorders. Brain insulin resistance may be reduced or eliminated by the use of centrally acting anti-diabetic drugs like liraglutide.
10. Preclinical studies also find evidence that liraglutide "modulates synaptic plasticity by enhancing long-term potentiation" and improves learning an memory in rat models of AD.

This review makes some quite remarkable predictions about the potential for GLP-1 drugs in brain disorders including AD. Whether these predictions will be true is yet to be seen.

Certainly we can expect to see more research using anti-diabetic drugs in AD and other brain diseases.

Readers with more interest in this topic can access the free full-text manuscript by clicking on the PMID link below.

Photo of great egret is from the author's files.

Follow the author on Twitter @WRY999

Candeias EM, Sebastião IC, Cardoso SM, Correia SC, Carvalho CI, Plácido AI, Santos MS, Oliveira CR, Moreira PI, & Duarte AI (2015). Gut-brain connection: The neuroprotective effects of the anti-diabetic drug liraglutide. World journal of diabetes, 6 (6), 807-27 PMID: 26131323

Ticked About Lyme Disease?

Awareness and Prevention are Key.

The weather is warmer, the days are longer and all you and your family want to do is spend time outside. It really doesn’t matter if it’s hiking, camping, or playing sports -- as long as you are outdoors-- you are happy. It is important to remember that higher temperatures and the more time you spend outside increases the risks of being bitten by a tick and contracting Lyme disease.

Lyme disease is caused by the bacterium Borrelia burgdorferi, which is transmitted to humans from the bite of the deer tick. Most Lyme disease in the northeastern United States occurs during summer or fall, when the small nymphal ticks are most prevalent.

The early stage of Lyme disease is usually marked by one or more of these signs and symptoms:

• Tiredness
• Chills and fever
• Headache
• Muscle and/or joint pain
• Swollen lymph glands
• A characteristic skin rash (erythema migrans)

When caught early, Lyme disease is highly treatable and curable with a single course of oral antibiotics. If the disease is left untreated, it can cause neurologic complications, including facial palsy, numbness, tingling and headaches, abnormal heart rhythm and large-joint arthritis.

Tips to avoid ticks

• Wear light-colored clothing. You’ll have a better chance of spotting a dark tick crawling around.
• Wear high socks, sneakers and long pants. Tuck your pant legs into your socks, your shirt into your pants and avoid wearing open-toed shoes to minimize areas where ticks can find its way to your skin.
• Use insect repellents. Apply repellent to any skin that is unprotected. You may need to apply every few hours. Make sure to avoid contact with your eyes!
• Shower or bathe within two hours. If possible, always wash off within a couple hours after being outdoors to wash away loose ticks. Do a daily tick check. Search all the places ticks love to hide: your hair, under your arms, between your legs, behind your knees and in your belly button.
• Don’t forget about the kids and pets. Be sure to check any children and pets before they enter the house. Ticks can easily drop off on carpets and furniture.
• Check all gear. Thoroughly examine all items you brought with you on your trek.
• Wash and dry your clothes. It is possible for ticks to survive the washing machine, even if hot water is used. Always dry your clothes in a dryer on high heat for an hour as well.
• Create a tick-free zone at home. Mow your lawn frequently, stack wood neatly and in a dry area and discourage animals by putting up fences. It is also good to keep playground equipment, decks, lawn chairs, etc. away from yard edges and trees.

“While Lyme disease can seem frightening, it is preventable! If you are vigilant about looking for ticks, and can pull the tick off the skin within 48 hours of the exposure, you can't get Lyme disease from that tick. If you're not sure how long the tick was on your body before you were able to remove it, contact your doctor to discuss a one-time dose of an antibiotic to help prevent the symptoms of Lyme disease from developing,” says Lori M. Noble, MD, a primary care physician at Spruce Internal Medicine.

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Brain Posts Hits 3 Million Pageviews

Dear Brain Posts Reader:

This week has been a fireworks experience for me as Brain Posts passed the 3 million pageview mark.

I started the blog in 2009 and have posted 676 posts over the last six years.

I started the blog primarily as a note-taking forum for my scientific reading. I select neuroscience research I feel is noteworthy and important from PubMed. Selecting a single study for more detailed notes has been a helpful focus and memory tool.

Over 400,000 Brain Posts pageviews have come via the research blogging aggregation website ResearchBlogging.org. They have a very helpful tool for adding citations to scientific blogs. I highly recommend adding their website to your RSS feed and following them on Twitter  @ResearchBlogs

I want say thanks to everyone who has been accessing Brain Posts. Readers from the U.S. are the top readers of the site. But I want to also thank readers from around the world including those from the United Kingdom, Canada, Australia, Germany and India who rank in the top 5 international Brain Posts pageviews. Thanks also to the growing number of readers from Russia and Ukraine in the last year

Brain Posts will remain a commercial free, non-profit site that does not accept sponsored or guest posts. 

I try to limit self promotion on Brain Posts, so you won't see another post like this until 4 million pageviews. Follow me on Twitter @WRY999 for real-time updates to the blog and other links I find informative. You can also subscribe to Brain Posts by using the subscribe by email button on the upper right.

Feel free to contact me directly with comments and recommendations at my email address WRY888 [at] gmail.com

Best wishes: Bill

Brain Imaging and Alzheimer's Disease Prediction

Enhanced early detection of risk for Alzheimer's dementia and other forms of dementia is key to prevention and early intervention.

Brain imaging holds promise as a pre-clinical disease risk assessment tool in Alzeimer's dementia.

Dementia risk has been linked to several brain imaging abnormalities found with magnetic resonance imaging. These abnormalities have included atrophy of the brain hippocampus, medial temporal lobe as well as white matter hyperintensities.

A recent study from France examined whether brain MRI findings can improve Alzheimer's and other dementia prediction over conventional known risk factors.

Here are the key elements of the design of this study:
Subjects: French citizens 65 years and old living at home participating in a longitudinal study of dementia with interviews two, four, six and ten years after baseline interview
Brain imaging: 1.5 Tesla MRI with estimation of white matter lesion volume, hippocampal volume (right and left summed) and total brain volume
Dementia diagnosis: all subjects screened at each interview, with targeted neuropsychological testing and neurologist consensus assessment
Standard dementia risk model variables: age, gender, education, smoking status, alcohol use, functional daily living skills, cognition screening tests, cardiovascular disease, diabetes status, systolic blood pressure and apolipoprotein epsilon 4 status.

The research team found a statistically significant smaller hippocampal and total brain volume at baseline in those later developing dementia. White matter lesion scores showed a trend (p.076) with later dementia.

However, adding the imaging data to the standard dementia risk model did not add statistically to the predictive power for all-cause dementia to the model.

The baseline imaging in this study took place around the year 1999 to 2000. Since then, more specific brain imaging tools targeted towards Alzheimer's have emerged including amyloid plaque markers. 

These enhanced imaging tools may have better power at adding power to our prediction models.

Readers with more interest in this research study can access the free full-text manuscript by clicking on the link in the citation below.

Photo of meerkats from the Cincinnati Zoo are from the author's files.

Follow the author on Twitter @WRY999

Stephan BC, Tzourio C, Auriacombe S, Amieva H, Dufouil C, Alpérovitch A, & Kurth T (2015). Usefulness of data from magnetic resonance imaging to improve prediction of dementia: population based cohort study. BMJ (Clinical research ed.), 350 PMID: 26099688

7 Common Pains You Shouldn’t Ignore

Regardless of age, everyone experiences body aches at one time or another. These discomforts could be the direct result of a workout or sports injury, or from simply sleeping awkwardly one night.

Rahul Kapur, MD

Obviously, not all aches and pains require a visit to the doctor’s office. But, some do.

Rahul Kapur, MD, Penn Sports Medicine physician and lead medical physician for Penn Athletics, discusses certain pains that need your attention.

Wrist Pain

Oftentimes, minor wrist ailments occur from repetitive movement, such as writing or typing on a keyboard. Relieving this type of pain may be as simple as making a change to eliminate repetitive strain, performing stretches to relieve tension, or wearing a splint or brace to stabilize and put pressure on the joint.

More serious pains – for instance, discomfort on the thumb-side of your wrist – should be examined by a physician, as it could be a scaphoid fracture.

Groin Pain

Especially in athletes, this type of pain is typically caused by a muscle, tendon or ligament strain. It may occur immediately after an injury, or develop gradually over a period of weeks or months. In many cases, simply reducing the use of the injured area can help to alleviate the discomfort.

If you experience a sudden onset of sharp, intense pain in the groin, buttocks or thigh at the time of an injury, this could indicate a high-risk stress fracture of the femoral neck (a break in the neck of the femur or thigh bone). If this occurs, it is recommended you seek medical attention.

Shoulder Pain

Getting dressed or lifting an item over your head shouldn’t cause pain. The shoulder has a wide and versatile range of motion and when something is wrong, it can hinder your ability to move freely.

If you experience pain that radiates down your arm during one of those activities (or at all), this could indicate a disc issue in your neck - especially if you have numbness, tingling or weakness.

Heel Pain

Heel pain is most often caused by plantar fasciitis, which is inflammation of the band of tissue (the plantar fascia) that extends from the heel to the toes. This condition can be treated by performing stretching exercises, avoiding going barefoot and icing the heel several times a day.

If pain is present in the back of the heel or Achilles region and is accompanied by swelling or bruising, this could indicate a partial tear and should be examined by a physician.

Foot Pain

Don’t ignore or try to suffer through foot-related conditions simply because it’s “only your feet”. If you have trouble walking, you are more likely to stop being physically active, which can lead to further health issues down the road.

Nagging pain at the top of your foot, especially over the outside (pinky side), could be from a stress fracture. You may be told to keep pressure off the foot for a while or need a cast for a few weeks.

Shin Pain

If you train too hard over a short period of time, you may experience shin splints. They often plague runners who do not build their mileage gradually enough or who abruptly change their workout regimen. Treatment for shin splints can be as simple as decreasing, or completely stopping, your training until the pain subsides.

If there is pain in the lower leg, this could be the result of a stress fracture (an incomplete crack in the bone), which is much more serious. If it’s accompanied by numbness or tingling, you could have what is called exertional compartment syndrome (an exercise-induced muscle and nerve condition). It is important to see a physician so that they can perform the necessary tests to correctly diagnose the injury.

Big Toe Pain

Because we are constantly on our feet, there are many causes of toe pain. Cuts or scrapes and blisters can easily be treated at home. Your toe, though, supports the majority of your weight when you push off your foot and pain there could also be an indication of something more serious, such as gout or arthritis, or in some cases a tear or stress fracture.

While there are aches and pains that don’t warrant a visit to the doctor’s office, it is always better to err on the side of caution. If you have been experiencing pain for some time or are concerned about a recent development, it is best to get checked out by a physician.

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Brain Deficits in Visual Hallucinations

One the early things I was taught in my neuroscience training was that new-onset visual hallucinations need to be assessed for medical or "organic causes".

Auditory hallucinations were felt to be more characteristic of schizophrenia.

One medical disorder linked to visual hallucinations is dementia with Lewy bodies (DLB). 

DLB is second to Alzheimer's disease in producing neurodegenerative dementia. Visual hallucinations is a hallmark of DLB and is found in up to 70% of clinical samples with the disorder.

A recent study from France provides insight into the neuroanatomical correlates of visual hallucinations in DLB.

Researchers in this study used single-photon emission computed tomography (SPECT) in a group of 36 subjects with DLB who reported visual hallucinations.

This group of cases was compared to 30 subjects with DLD who did not report visual hallucinations.

Specific differences in blood flow were noted with visual hallucinations. Visual hallucinations subjects had diminished cerebral perfusion in the following regions.

• Left anterior cingulate cortex
• Left orbitofrontal cortex
• Left cuneus

Deficits in regional cerebral perfusion in several areas correlated with the severity of visual hallucinations:

• Bilateral anterior cingulate cortex
• Left orbitofrontal cortex
• Right parahippocampal gyrus
• Right inferior temporal cortex
• Left cuneus

The authors note the cuneus (also known as Brodmann's area 18). This region is known as a secondary visual integration area. Reduced blood flow to this region may contribute to visual processing errors and the subjective sensation of visual hallucinations. Perfusion deficits in more anterior regions may contribute to inability to recognize the visual hallucinations as abnormal.

This study is one of many emerging showing specific clinical features of neuropsychiatric disorders may relate to specific neuroanatomical deficits and impairment.

Readers with more interest in this topic can access the free full-text manuscript by clicking on the citation below.

Image of left cingulate cortex is an iPad screen shot from the app 3D Brain from the author's files.

Follow the author on Twitter @WRY999

Heitz C, Noblet V, Cretin B, Philippi N, Kremer L, Stackfleth M, Hubele F, Armspach JP, Namer I, & Blanc F (2015). Neural correlates of visual hallucinations in dementia with Lewy bodies. Alzheimer's research & therapy, 7 (1) PMID: 25717349

How to Beat the Summer Heat

Lori M. Noble, MD, a primary care physician at Spruce Internal Medicine, located at the new Penn Medicine Washington Square offers tips on how to stay safe in the summer heat.

Lori M. Noble, MD

Summer is a time for family fun in the sun, lazy days by the pool or ocean and countless outdoor activities.

As the summer heat beats down, though, it can sometimes seem like it’s impossible to stay cool. Not only can it be uncomfortable, but in some cases, it can actually be serious or even life-threatening. It is important to be able to recognize the signs of both heat exhaustion and heat stroke, and to know how to treat and prevent them.

Heat exhaustion is due to either not having enough water or salt in the body, both of which come from a combination of excess sweating and lack of hydration. Common symptoms that you should be on the lookout for include:

• Pale skin or cool, moist skin with goose bumps when in the heat
• Fatigue
• Confusion
• Dizziness
• Fainting
• Headache
• Muscle cramps
• Nausea
• Heavy sweating
• Dark-colored urine, (a sign of dehydration)
• Rapid heartbeat

If you or someone you know is experiencing these symptoms, the most important step is to get out of the heat as quickly as possible. Preferably, get to an air-conditioned space or at least out of the sun. Then, drink water, remove tight clothing and take a cool bath or shower. If the symptoms continue for more than 30 minutes despite these treatments, call your doctor. If untreated, heat exhaustion can progress to a more dangerous heat-related illness, called heat stroke.

The common symptoms of heat stroke are:

• Body temperature over 105° F
• Throbbing headache
• Dizziness and light-headedness
• Lack of sweating despite the heat
• Red, hot and dry skin
• Muscle weakness or cramps
• Nausea and vomiting
• Rapid heartbeat (which may be either strong or weak)
• Rapid, shallow breathing
• Behavioral changes (such as confusion, disorientation or staggering)
• Seizures
• Unconsciousness

If you see someone demonstrating these symptoms, immediately call 911. While waiting for the paramedics to arrive, some simple first aid should be administered, which can be life-saving: fan air over the patient while wetting his or her skin with water from a sponge or hose, apply ice packs to the patient's armpits, groin, neck and back to help reduce body temperature, and if the patient is conscious, help them get into to a shower or tub of cool water, or an ice bath.

Preventing heat-related illness is just as important as being able to recognize and treat the common symptoms. Children under age four and adults over 65 or with chronic medical illnesses (like heart disease, lung disease, kidney disease, and diabetes) are at increased risk for both heat exhaustion and heat stroke, so be sure to check in on your loved ones during these hot summer months.

When the temperatures soar above 90 degrees, encourage people without air conditioning to go to a public place that does have air conditioning, like a shopping mall or senior center.

Finally, keep plenty of water on hand and always wear loose, breathable clothing.

Taking these simple steps can help insure that you and your loved ones have a healthy, happy summer.

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