Tag Archives: vascular

Genetic Evidence Suggests Iron is Linked to Alzheimer’s Disease

According to a recent study, people with a rare variant in the HFE gene are three times less likely to develop dementia than the general population.

You’ve probably heard that consuming enough iron is important for overall health. However, too much iron can also be a bad thing. In particular, people with Alzheimer’s disease often have abnormally high levels of iron in their brains. (See The Role of Metals in Alzheimer’s Disease). The question of whether iron is a cause or consequence in Alzheimer’s still remains unanswered.

In a paper published this week in PLoS One, a group of Italian researchers investigated whether the genes that control levels of iron in the body could be related to the risk of dementia. They recruited 765 subjects who had Alzheimer’s disease, vascular dementia, or mild cognitive impairment, as well as 1,086 healthy controls of a similar age. Then they took DNA samples from the subjects and looked at four different genes that are involved in iron metabolism.

They found that one gene called High Ferrum (HFE), which is responsible for controlling absorption of iron from the blood, was protective against dementia. Specifically, subjects who had a particular variant of the HFE gene were one-third as likely to develop Alzheimer’s disease or vascular dementia compared to subjects who didn’t have the protective variant. The effect was even stronger for mild cognitive impairment, which the HFE variant reduced the risk to only one-fifth.

The researchers then looked at another gene called APOE, which has previously been shown to be involved in Alzheimer’s disease. People with the APOE4 variant of this gene were more than four times as likely to have Alzheimer’s. However, in subjects who also possessed the protective HFE variant, the impact of APOE4 was completely attenuated, and their risk of Alzheimer’s was normal.

How could the HFE gene protect people from dementia? One possibility, known as the metal hypothesis of Alzheimer’s disease, suggests that iron makes amyloid-beta plaques more toxic. Amyloid-beta, a protein that accumulates in Alzheimer’s patients’ brains, can interact with various metal ions to become extra toxic. Normally metals are blocked from entering the brain by the blood-brain barrier, but this barrier tends to become leaky in older people. Thus the hypothesis suggests that influx of iron and other metals into the brain may cause amyloid-beta to aggregate and become more toxic, thus contributing to the development of Alzheimer’s.

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The metal hypothesis suggests that the toxicity of beta-amyloid could be increased when it binds to metal ions. Image Source

However, the metal hypothesis can’t entirely explain these recent findings. For one thing, the variants in iron-controlling genes were also protective against vascular dementia, which does not involve amyloid-beta. In addition, the researchers did not observe any differences in blood iron levels based on these genetic variants, so it’s unclear exactly how these genes may be affecting iron metabolism. Future studies are needed to clarify if and how iron could be involved in Alzheimer’s and other types of dementia.

 

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Brain “Gatekeeper” Cells Could Cause Half of All Dementia Cases

Pericytes are a type of brain cell you’ve probably never heard of. But according to new research, these hard-working cells may be your brain’s most important defense against dementia.

Your brain, as you may know, is composed of grey matter and white matter. Grey matter mostly consists of the central regions, or “cell bodies”, of neurons, forming the outer layer of the brain. White matter is made of axons, which are long extensions that neurons use to send electrochemical signals to each other, kind of like telephone wires. Leaks or blockages of the brain’s arteries, known as cerebral small vessel disease (CSVD), can damage the surrounding white matter. Research has shown that CSVD contributes to 50% of all dementia cases, including Alzheimer’s disease.

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Neuronal cell bodies form the grey matter on the outside of the brain, while the inner white matter layers are made of long extensions called axons. Image Source

That brings us to the key player in this story: pericytes. These humble cells aren’t a part of our common vocabulary, but that doesn’t make them unimportant. Pericytes surround the blood vessels in your brain, maintaining the arterial wall and controlling the rate of blood flow. They also serve as “gatekeepers” by helping to regulate what can cross the blood-brain barrier. And now, thanks to research published this week in Nature Medicine, we now know of a new function for these little-known pericytes: protecting brain’s white matter from damage.

 

The researchers in this study first looked at postmortem brain tissues from 31 different people. They saw that the people with Alzheimer’s disease had 50% fewer pericyes than the healthy controls. As a result, the Alzheimer’s brains contained three times as much fibrinogen as the healthy brains. Fibrinogen is a protein found in the blood plasma, and its presence in the brain indicates the existence of capillary leaks. In other words, it seemed that the Alzheimer’s patients had leaky blood vessels in their brains, possibly as a result of having fewer pericytes. These leaks caused the Alzheimer’s brains to have substantially more white matter damage than the healthy brains.

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Pericytes, shown here in green, surround blood vessels in the brain and help to guard against damage. Image Source

To understand the mechanisms by which this might occur, the researchers then turned to experiments on laboratory animals. They utilized mice that had a mutation causing them to develop fewer pericytes than normal. Sure enough, these mice soon developed leaky capillaries, as evidenced by high levels of fibrinogen in their brains. The levels of fibrinogen progressively worsened with age. The mutant mice also had 30-40% fewer fibers within the white matter than non-mutant counterparts by the time they were 36-48 weeks old (which is middle-aged for a mouse). These results showed that the loss of pericytes was sufficient to cause leaks in the blood-brain barrier and white matter damage.

Next, the researchers analyzed whether this white matter damage had any functional effects on the mice’s behavior. They found that the mutant mice that were deficient for pericytes performed well at a young age, but began to show impairments on memory tests as they grew older. The older mice also had significant cell death in the hippocampus, the part of the brain responsible for long-term memory formation.

The final experiment was to determine whether treating the mice with capillary-strengthening drugs could reverse the defects caused by a lack of pericytes. Their drug of choice was ancrod, a substance derived from the venom of the Malayan pit viper. Ancrod by itself is not poisonous, and it has the interesting property of being able to prevent leaks in the brain’s capillaries. When the mutant mice were treated with ancrod, their blood-brain barriers were substantially less leaky and they also had less white matter damage.

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Ancrod, derived from the venom of the Malayan pit viper, could one day be used to fortify leaky brain capillaries and prevent the development of dementia. Image Source

The results of this study are exiting, because they suggest that dysfunctional pericytes could be one of the earliest factors leading to the development of Alzheimer’s disease. Furthermore, the white matter damage that contributes to 50% of all dementias could possibly be preventing by strengthening the integrity of our brain capillaries. In 2009, clinical trials using ancrod to repair brain capillary damage in ischemic stroke patients were terminated due to ineffectiveness of the drug. However, this study shows that it might be beneficial for dementia as well, and will need to be investigated in future trials.

 

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Vascular Damage May Affect Progression to Alzheimer’s Dementia

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Guest author: Rachana Tank has a master’s degree in Neuropsychology from Maastricht University in the Netherlands. Her goal is to pursue a PhD in psychology exploring cognitive ageing, where her research interests lie.

As we grow older, we tend to become a little forgetful which is thought to be a normal part of ageing, but when does forgetfulness turn into abnormal ageing? Sometimes even slight but noticeable changes in thinking skills can be symptoms of an underlying issue. Alzheimer’s dementia is a continuous process, a progression taking place over many years, during which individuals experience considerable deficits before reaching clinical dementia. Stages leading up to Alzheimer’s dementia are referred to as predementia stages and are considered to be on the spectrum of Alzheimer’s dementia. In such stages, cognitive deficits are typically experienced as deterioration of memory, attention, and language skills.

Predementia stages can include individuals who self-report a decline in cognitive abilities (subjective cognitive impairments), or experience cognitive impairments that can be diagnosed by standardised testing (mild cognitive impairments). Both of these can, but not always, indicate an initial phase of neurodegeneration that may suggest they are in an early stage of Alzheimer’s dementia.

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The difference between normal brain ageing (purple line) and stages of cognitive decline experienced as part of abnormal brain ageing in dementia. Image source

Individuals with subjective or mild cognitive impairments tend to have a higher incidence of future cognitive decline than the general population and more often show Alzheimer related pathology. However, it is still difficult to predict which individuals in these stages will progress to Alzheimer’s dementia.

Differentiating between those who will progress and who will not is a difficult task. However, biomarkers can be utilised to indicate the presence of Alzheimer’s pathology to detect and diagnose predementia stages. Namely, amyloid protein plaques and neurofibrillary tau tangles are the hallmarks of Alzheimer’s disease, with amyloid pathology being the earliest identifiable change in the brain. Although amyloid and tau have both been fundamental to understanding and estimating the pathological cascade, there is a lot of emerging evidence to suggest that it is not just tau and amyloid in isolation that contribute to progression of Alzheimer’s pathology and subsequent cognitive symptoms.

As evidence indicates there is more to consider than amyloid and tau, recent research, including my master’s research, investigates mixed Alzheimer’s pathology in early stages. Mixed pathology refers to hallmark Alzheimer pathology, such as amyloid and tau, that coexist with additional abnormalities such as vascular disease. Vascular disease is of particular interest in predementia stages as it is the most common disease to coexist with typical Alzheimer pathology early in the disease process.

Vascular disease can be defined as any condition that affects the arteries, veins, and capillaries responsible for carrying blood to and from the heart. Vascular damage can compromise brain health by reducing blood flow to vital areas, leading to loss of neurons. Such damage to the brain affects how well certain areas function, sometimes leading to decreased cognitive abilities such as language difficulties, attention problems or memory issues. There is evidence that vascular disease shortens time to progression when coexisting with traditional Alzheimer pathology. However, the mechanisms by which they may interact is not known.

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Arterial plaques are one example of vascular disease. Image source

My research investigated mixed pathology in 269 memory clinic patients aged 39 or older with subjective or objective cognitive impairments. Levels of amyloid burden and vascular damage were recorded at baseline and at follow-up between 1 and 5 years later. Those who progressed to Alzheimer’s dementia were then compared to those who did not. Vascular damage was assessed using MRI scans, and level of amyloid pathology was determined via cerebrospinal fluid samples.

The results of my research found that Alzheimer’s disease patients with vascular damage had less amyloid in their brains than Alzheimer’s patients who did not have vascular damage. This suggests that vascular damage may worsen the effects of amyloid plaques on cognitive decline and Alzheimer’s. These findings are compatible with other studies that investigated vascular damage in relation to amyloid burden.

Different amounts of amyloid in patients did not show any direct relationship with vascular damage, suggesting that the presence or absence of vascular disease does not influence the presence of Abeta. However, both vascular damage and amyloid pathology increased the risk of progressing to Alzheimer’s dementia significantly, and 93% of individuals who progressed to Alzheimer’s dementia showed abnormal levels of both amyloid and vascular pathology, indicating that both contribute to the development of Alzheimer’s dementia. These research insights help us to better understand early stages and the influencing factors involved. This allows us to develop interventions, for example, promoting cardiovascular health in those at risk by encouraging memory clinic patients to participate in exercise programs.

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Homocysteine and Dementia: Impact of Nutrition on Neurodegeneration

This week’s article is a guest post by Dr. Nafisa Jadavji, a research associate and lecturer at Carleton University and the University of Ottawa. To submit your own guest post to AlzScience, please contact us.

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High levels of homocysteine have been implicated in neurodegenerative diseases, such as dementia, mild cognitive impairment, and Alzheimer’s disease. Homocysteine can be measured in blood easily, which has led to several studies in humans reporting that elevated levels of homocysteine lead to increased risk of developing neurodegenerative diseases or affect progression. Interestingly, homocysteine levels in our bodies increase as we age.

Vascular cognitive impairment (VCI) is the second leading cause of dementia after Alzheimer’s disease.  VCI is the result of reduced blood flow to the brain, however, the pathology is not well understood. Reduced blood flow ben be a result of age and health (e.g. high cholesterol). The clinical presentation of VCI varies, most the patients have some degree of cognitive decline. There are currently no treatments for VCI since the actual pathology remains unknown.

Nutrition is a risk factor for VCI, specifically high levels of homocysteine. High levels of homocysteine can be reduced by B-vitamins, like folates or folic acid. Folates are the natural occurring form of the vitamin, these are often found in food such as green leafy vegetables or liver. Whereas folic acid is the chemically synthesized form that is often taken in supplemental form.

My research program focuses on how nutrition affects the brain, specifically how folates affect neurodegeneration.

Using a mouse model of VCI we have reported that deficiencies in folates, either dietary or genetic, affect the onset and progression of VCI. Using the Morris water maze task, we report that mice with VCI and folate deficiency performed significantly worse compared to controls. We assessed changes in the brain using MRI and interestingly found that folate deficiency changed the vasculature in the brain of mice with VCI. Because of either a genetic or dietary folate deficiency, all the mice had increased levels of homocysteine. However, we did not observe any significant association between elevated levels of homocysteine and behavioral impairment or changes in the brain tissue of VCI affected mice.

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In the Morris water maze, a mouse is placed in a pool and must swim to find a hidden platform. The mouse’s memory is measured based on how long it takes to find the platform after it’s placed in the pool a second time. Image source

Our results suggest that it is not elevated levels of homocysteine making the brain more vulnerable to damage, but the deficiency in folates, either dietary or genetic that changes the brain. In the cell, folates are involved in DNA synthesis and repair as well as methylation. These are vital functions for normal cell function. Therefore, reduced levels of folate may be changing the cells in the brain and making them more vulnerable to any types of damage. I would like to suggest that high levels of homocysteine may just be out put measurement of some sort of deficiency (e.g. reduced dietary intake of folates). Several studies using brain cells that are grown in petri dishes have reported that extremely high levels of homocysteine need to be added to cells to cause damage. These levels are usually not observed in humans.

In terms of future directions, more research is required to understand how deficiencies in folates, homocysteine and other nutrients that reduce levels of homocysteine like choline change cells in the brain throughout life and how these changes are related to neurodegeneration.

For more information about my research please visit my personal website.

 

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Autoimmune Diseases May Be Linked to Dementia

Our immune system is pretty great. It helps us recover from injury and fight off deadly pathogens. However, sometimes the immune system does its job a little too well. In certain autoimmune diseases, immune cells can mistakenly recognize a part of our own body as a foreign invader and start attacking it. Depending on what type of tissue is being targeted, autoimmunity can lead to a variety of conditions including rheumatoid arthritis, celiac disease, and multiple sclerosis. Approximately 50 million Americans (20% of the population) have an autoimmune disease.

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Some of the most common autoimmune diseases. Image Source

A study published this week in the Journal of Epidemiology and and Community Health looked at the relationship between autoimmune diseases and dementia. The researchers used health records of more than 1.8 million people in England who were hospitalized for an autoimmune condition between 1998 and 2012. They found that these patients were 20% more likely to be later hospitalized for dementia compared to controls. They identified 18 autoimmune diseases that were significantly associated with dementia. When they examined the type of dementia, the autoimmune patients were at the greatest risk for vascular dementia, with a 28% higher risk than normal. The increased risk for Alzheimer’s disease was relatively small at 6%.

This study is in line with several previous papers that hinted at a possible link between autoimmunity and dementia. It’s been shown that people with two common autoimmune diseases, type 1 diabetes and thyroid autoimmune disease, are at an increased risk of dementia. The mechanism for this connection remains unknown, but it raises the interesting question of whether dementia may be related to the immune system.

Additionally, the study supports the possible use of NSAIDs as a way to reduce the risk of dementia. NSAIDs (which include aspirin, ibuprofen, and naproxen) are some of the most commonly-used painkillers and can also be used to combat inflammation in autoimmune conditions. People who take NSAIDs tend to have a reduced risk of Alzheimer’s disease, suggesting that using these drugs to treat an overactive immune system could have cognitive benefits as well.

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Advil, Aleve, and Motrin are some of the most common NSAIDs available over-the-counter. Image Source

Many doctors have begun prescribing baby aspirins to their patients in the hopes of decreasing their risk of dementia as well as cardiovascular disease. However, caution is necessary when considering an NSAID regimen. It’s possible that for some people, NSAIDs could be doing more harm than good, as one study suggested that these drugs may reduce the risk of Alzheimer’s but increase the risk of vascular dementia. More research is needed before we can say conclusively whether NSAIDs may be beneficial for cognitive health.

 

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Is It Really Alzheimer’s? 10 common misdiagnoses you should know about

Doctors misdiagnose a patient with Alzheimer’s disease at alarmingly high rates, when the true cause may be a different (and often treatable) disease. In 2011, researchers conducted autopsies on the brains of 211 men who had been diagnosed with Alzheimer’s while they were alive. They found that nearly half of the brains did not possess the necessary pathology to meet an Alzheimer’s diagnosis [1]. A 2012 study reported similar misdiagnosis rates by physicians at the National Institute on Aging’s Alzheimer’s Disease Centers [2].

An incorrect Alzheimer’s diagnosis can cause a person to pay $9,500 to $14,000 annually in unnecessary medical procedures and medications [3]. Even worse, it may result in the true cause of the dementia symptoms going untreated, hastening the rate of cognitive decline. To give you the tools to reduce the risk of a misdiagnosis, I’ve compiled this list of ten common conditions that can mimic the symptoms of Alzheimer’s disease. If you or a loved one has been diagnosed with Alzheimer’s disease, be sure that you request tests to rule out these other possibilities.

1. Medication side effects

More than 100 medications can have side effects resembling symptoms of Alzheimer’s. These include a wide variety of common meds including Benadryl, Ambien, Valium, Xanax, and Lipitor [4]. It is particularly important to inform your doctor if you are on anticholinergic drugs, which include many antihistamines, antipsychotics, antidepressants, and muscle relaxants, among others [5]. These drugs block the function of a neurotransmitter called acetylcholine, which can lead to cognitive impairment [6].

2. Normal pressure hydrocephalus

The central nervous system is surrounded by cerebrospinal fluid, which cushions the brain and regulates cerebral blood flow. For unknown reasons, cerebrospinal fluid can sometimes build up in the brain cavities (ventricles) and cause them to swell, resulting in a condition called normal pressure hydrocephalus (NPH). The symptoms of NPH include progressive dementia, difficulty walking, and urinary incontinence [7]. According to the Hydrocephalus Association, NPH affects an estimated 700,000 Americans, though only 1 in 5 of these people receive the correct diagnosis [8]. As many as 10% of patients diagnosed with Alzheimer’s or other forms of dementia may actually have NPH [9]. This condition is easily detected using brain scans and can often be treated by surgically draining the excess fluid from the ventricles. Additional reading on NPH: [10], [11], [12]

3. Vascular dementia

Vascular dementia is the second most common form of dementia after Alzheimer’s. It is caused by a stroke, multiple “mini strokes,” or other cardiovascular disturbances, and can cause similar symptoms to Alzheimer’s [13]. A 2013 study found that 17% of vascular dementia patients were previously given an incorrect diagnosis for Alzheimer’s disease, which led to significantly increased medical costs [14]. Vascular dementia is very difficult to distinguish from Alzheimer’s, and the possibility of misdiagnosis should be considered if the patient has risk factors such as high blood pressure, diabetes, or smoking. There is currently no cure for vascular dementia, but steps may be taken to improve cardiovascular health and reduce the risk of further cognitive decline [15].

4. Vision or hearing loss

Cognitive evaluations such as the Mini-Mental State Examination (MMSE) may yield an incorrect diagnosis of Alzheimer’s disease if a patient is experiencing undiagnosed vision or hearing loss. Studies have shown that individuals with visual [16] or auditory [17] impairments score lower on the MMSE, despite being cognitively normal. Both of these conditions are common among the elerly population. Studies estimate that among individuals over the age of 70, 18% are visually impaired, 33% are hearing impaired, and 8% are both visually and hearing impaired [18]. Regular vision and hearing exams could not only prevent an incorrect diagnosis but also improve the overall quality of life for these patients [19], [20].

5. Depression

Depression can often mimic the early symptoms of Alzheimer’s disease. These include mood changes, withdrawal from daily activities, sleep disruptions, and difficulty concentrating [21]. Depression affects more than 1 in 20 elderly adults and the risk may be increased by the death of a spouse or chronic illness, as well as certain medical or psychological conditions [22]. The symptoms of depression can often be improved through a combination of medications and psychotherapy.

6. Thyroid problems

The thyroid gland produces hormones that regulate metabolism and other body functions. The American Thyroid Association reports that 12% of Americans will develop thyroid problems in their lifetime, and more than half of them are unaware of their condition. Both hypothyroidism and hyperthyroidism can have symptoms resembling Alzheimer’s, including forgetfulness, mood changes, and sleep disturbances. Thyroid problems are often treatable but can cause serious complications if left undiagnosed [23].

7. Vitamin B12 deficiency

Vitamin B12 plays multiple important roles in the nervous and circulatory systems. It is most commonly found in meat, fish, and dairy products. As many as 9% of Americans are deficient in this essential nutrient [24]. Risk factors include a vegetarian or vegan diet without B12 supplements, heavy alcohol consumption, and long-term use of acid-reflux medications. Vitamin B12 deficiency can lead to dementia and changes in mood or personality, which may be mistaken for Alzheimer’s [25]. Individuals with an Alzheimer’s diagnosis might consider requesting a blood test for B12 levels, or increasing their intake of B12 in the form of supplements, fortified cereals, and B12-rich foods to see if their cognitive symptoms improve.

8. Urinary tract infection

Urinary tract infections (UTI’s) are the most common bacterial infection in the United States. They primarily affect women; nearly half of all women will experience at least one UTI in their lifetime [26]. When diagnosed correctly, UTI’s are easily treated using antibiotics and rarely cause complications. However, the little-known neurological symptoms can result in a misdiagnosis as Alzheimer’s. An elderly person with a UTI is at an increased risk of experiencing delirium, which is characterized by sudden behavioral changes such as confusion, agitation, fatigue, or delusions. Be suspicious of Alzheimer’s-like symptoms if they are accompanied by symptoms of a UTI, which include frequent, painful urination and discolored or foul-smelling urine [27].

9. Sleep disorders

We all know the importance of getting 8 hours of sleep each night, but few of us are aware of just how much sleep depravation can affect our cognitive function. A 1999 study reported that 1 in 5 individuals over the age of 65 experience sleep disturbances, though only a minority seek treatment [28]. Sleep disorders such as sleep apnea, chronic insomnia, and restless leg syndrome can lead to fatigue, difficulty focusing, irritability, and memory loss [29]. These conditions can be easily detected by visiting a sleep clinic.

10. Gluten allergy

This might be the most surprising item on this list: a simple dietary change can completely reverse the symptoms of some people’s dementia. Celiac disease is an allergic reaction to gluten, a protein found in wheat, barley, and rye. Celiac was once believed to be rare, but is now classified as one of the most common autoimmune conditions. The University of Chicago’s Celiac Disease Center estimates that 1 in 133 people have celiac disease, of whom an astounding 97% remain undiagnosed [30]. Though people with celiac can live a healthy life on a gluten-free diet, undiagnosed celiac disease can have serious and even fatal consequences, including progressive dementia and other neurological conditions [31]. For individuals with celiac-induced dementia, switching to a gluten-free diet might completely reverse their symptoms [32].

 

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