Dementia Patients’ Awareness of their Own Illness May Predict Cognitive Decline

According to new research, anosognosia (“lack of self awareness”) may be used to predict whether patients with mild cognitive impairment will progress to Alzheimer’s disease.

Anosognosia describes the inability to recognize that one is experiencing a mental illness. It is most well-known in schizophrenia, where patients frequently cannot acknowledge that their delusions are the result of a mental condition and not based in reality. However, anosognosia can also occur with dementias, such as Alzheimer’s disease. In later stages of the disease, people with Alzheimer’s may lose their ability to recognize their own cognitive deficits.

In a paper published this week in Neurology, researchers from McGill University wanted to assess whether anosognosia could be used to predict whether patients with mild cognitive impairment would later progress to Alzheimer’s disease. Mild cognitive impairment (MCI) is a condition that affects nearly 20% of adults over 65. It is characterized by memory problems that are noticeable but not severe enough to interfere with daily life. Some people with MCI later progress to Alzheimer’s disease, while others do not, and we currently do not have a reliable method to predict whether a person with MCI will develop Alzheimer’s.

Mild cognitive impairment sometimes progresses to Alzheimer’s disease or other types of dementia. Image Source

The study included a total of 468 MCI patients recruited through the Alzheimer’s Disease Neuroimaging Initiative, a large consortium of researchers searching for reliable ways to predict and diagnose Alzheimer’s. The researchers looked at the subjects’ cognitive self-assessment and compared it to their spouse or caregiver’s assessment of the patient’s cognition. Individuals who rated their own cognition substantially higher than what their caregiver rated them were categorized as anosognosic.

The researchers then administered spinal taps on each subject. They found that the anosognosic patients had higher levels of the toxic tau protein in their cerebrospinal fluid. These patients also had higher levels of amyloid-beta in their brains. Additionally, PET scans revealed that the patients lacking self-awareness had reduced levels of activity in a part of their brains called the default mode network. The default mode network is a group of brain structures that become less active when you’re focusing on a particular task, and more active when you’re daydreaming. Studies have found that the default mode network is among the first parts of the brain to degenerate in Alzheimer’s disease, but its specific role in the disease still remains unclear.

This fMRI image shows the brain structures that make up the default mode network. Image Source

The final phase of the study involved a follow-up examination two years after the initial assessment. The researchers found that 28% the subjects with anosognosia progressed to Alzheimer’s disease, compared to only 12% of those with intact self-awareness. This shows that assessing MCI patients’ awareness to their own cognition could be a useful tool for predicting whether they will later develop Alzheimer’s disease. The study also suggests that the default mode network might be important for our ability to recognize our own mental status.

 

Enjoy this post? Help it to grow by sharing on social media!
Want more? Follow AlzScience via email, Facebook, or Twitter!

Amyloid-Beta: Villain or Hero in Alzheimer’s Disease? (Podcast)

Last week I was interviewed on Straight from a Scientist, a podcast series where scientists talk about their research for a general audience. In Part 1, which you can listen to here, we had an informal conversation about my research and background. You can now listen to Part 2, a roundtable segment where the host, Connor Wander, and I discuss current topics in Alzheimer’s disease research, including a new look at the physiological roles of amyloid-beta. Enjoy!

 

Enjoy this post? Help it to grow by sharing on social media!
Want more? Follow AlzScience via email, Facebook, or Twitter!

 

AlzScience Interview on Straight from a Scientist Podcast

Straight from a Scientist is a podcast series where scientists talk about their research for a general audience. I recently had the amazing opportunity to be interviewed on the show, and I’ve pasted the link below where you can listen to it. It was a great discussion about Alzheimer’s disease, axon guidance, and life as an undergraduate researcher. Be sure to stay tuned for the show’s Alzheimer’s Disease Roundtable episode, which should be coming out within the next week.

 

Banner image credit

Enjoy this post? Help it to grow by sharing on social media!
Want more? Follow AlzScience via email, Facebook, or Twitter!

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.

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.

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.

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.

 

Enjoy this post? Help it to grow by sharing on social media!
Want more? Follow AlzScience via email, Facebook, or Twitter!

Vascular Damage May Affect Progression to Alzheimer’s Dementia

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.

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.

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.

Enjoy this post? Help it to grow by sharing on social media!
Want more? Follow AlzScience via email, Facebook, or Twitter!