brain – Highlight HEALTH Discover the Science of Health Mon, 16 Oct 2017 05:31:50 +0000 en-US hourly 1 Long-term Depression Elevates Stroke Risk in Older Adults Thu, 25 Jun 2015 02:23:06 +0000 A Harvard University study has found that long-term depression in people over 50 could more than double their risk of having a stroke.]]>

A Harvard University study has found that long-term depression in people over 50 could more than double their risk of having a stroke. The risk remains significantly high even after the depression eases.

Long term depression in 50s increases risk of stroke

The study, published in the Journal of the American Heart Association, is the first to evaluate how changes in depressive symptoms predict changes in stroke risk [1].

The study reviewed health information from over 16,000 men and women ages 50 and older participating in the Health and Retirement Study between 1998 and 2010. Every two years participants were interviewed about a variety of health measures, including depressive symptoms, history of stroke, and risk factors for stroke. During the study period, 7% of participants had a stroke (1,192 occurences).

Researchers found that people with high depressive symptoms at two consecutive interviews had a 114% higher risk of suffering a first stroke, compared with people without depression at either interview. Those who had depressive symptoms at one interview but not at the next had a 66% higher risk.

The study’s lead author, Paola Gilsanz, from Harvard University’s TH Chan School of Public Health, said [2]:

Our findings suggest that depression may increase stroke risk over the long term. Looking at how changes in depressive symptoms over time may be associated with strokes allowed us to see if the risk of stroke increases after elevated depressive symptoms start or if risk goes away when depressive symptoms do. We were surprised that changes in depressive symptoms seem to take more than two years to protect against or elevate stroke risk.

The scientists did not evaluate whether depressive symptoms diminished due to treatment. However, their findings suggest that even if treatment is effective, there may still be long-term impact on stroke risk. The authors say that their work, together with previous research, points to a need for clinicians to treat depressive symptoms as early as possible.

Although the cause for increased risk of stroke wasn’t studied, one possible mechanism may be an increase in inflammation in the brain. A study published earlier this year found significant elevation of brain inflammation in study participants with depression [3]. Inflammation can lead to reduced health of blood vessels and increased plaque formation, which may increase the risk of stroke.

Depression is a serious mental health condition that requires understanding, treatment and a good recovery plan. Left untreated, depression can be devastating, both for the people who have it and for their families. Symptoms of depression include changes in sleep, changes in appetite, lack of concentration, physical aches and pains, loss of energy and lack of interest, as well as feelings of low self esteem and hopelessness. Depression is an extremely complex disease that can be caused by something as simple as a major life event (including positive events such as starting a new job, graduating or getting married). Genetics is thought to play a role. Additional factors such as conflict, medications, abuse, death or loss, or serious illness may increase the chance of depression. If you’re feeling depressed or concerned about your risk of stroke, you should speak to your doctor.


  1. Gilsanz el al. Changes in Depressive Symptoms and Incidence of First Stroke Among Middle?Aged and Older US Adults. J Am Heart Assoc. 2015 May 13;4(5). pii: e001923. doi: 10.1161/JAHA.115.001923.
    View abstract
  2. Long-term depression may double stroke risk for middle-aged adults. Press release, Harvard T.H. Chan School of Public Health. 2015 May 13.
  3. Setiawan et al. Role of Translocator Protein Density, a Marker of Neuroinflammation, in the Brain During Major Depressive Episodes. JAMA Psychiatry. 2015;72(3):268-275. doi:10.1001/jamapsychiatry.2014.2427.
    View abstract
Brain Imaging in Children with Neurological Disorders Links Language Delay to Chromosome Deletion Fri, 20 Feb 2015 05:44:30 +0000 Children born with DNA copy number deletions on chromosome 16 show measurable delays in processing sound and language.]]>

A study team of radiologists and psychologists has found that children born with DNA copy number deletions in a specific region on chromosome 16 previously linked to neurodevelopmental problems show measurable delays in processing sound and language [1].

Child in a MEG machine


The study, published in the journal Cerebral Cortex, used magnetoencephalography (MEG), which detects magnetic fields in the brain (similar to electroencephalography (EEG), which detects electrical fields), to measure an auditory processing delay called the M100 response latency [1]. As each child heard a series of tones, the MEG machine analyzed changing magnetic fields in the child’s brain and measured M100 response latency.

Previous research has found that the genetic site p11.2 on chromosome 16 is associated with a subset of autism spectrum disorders, language impairments and developmental delays. In fact, patients with a deletion of the region have a disorder called 16p11.2 deletion syndrome. The region encompasses 29 genes, several of which are associated with autistic disorder (SEZ6L2, ALDOA, DOC2A, HIRIP3, MAZ, PPP4C, TAOK2, KCTD13), nerve degeneration (MAPK3) or developmental language impairment (SULT1A3 and SULT1A4) [2].


Lead by research leader Timothy P.L. Roberts, PhD, vice chair of Radiology Research at CHOP and a researcher at CHOP’s Center for Autism Research, scientists analyzed 115 children: 65 with copy number variants (43 with the 16p11.2 deletion and 23 with the 16p11.2 duplication) and 49 healthy controls. The children were from two centers, Children’s Hospital of Philadelphia (CHOP) and the University of California, San Francisco. Only 20% of the children had autism spectrum disorder diagnoses: 11 of the 43 with the deletion and 2 of the 23 with the duplication.

In children with the deletion, researchers found a significant delay of 23 milliseconds compared to the healthy children. In contrast, there was no observed delay in the children with the duplication, who tended to process sounds faster than the healthy controls.

According to Dr. Roberts:

This study shows an important connection between gene differences and differences in neurophysiology. It may also help to bridge a largely unexplored gap between genetics and behavior. We don’t yet know the significance of the 23-millisecond delay, but we have established its origin in genetics. It seems to be a proxy for something of biological significance.

The 23 millisecond delay was twice as high as an 11 millesecond delay observed in an earlier study of children with autism spectrum disorders [3]. In that study, Dr. Roberts remarked that although 11 milliseconds is a brief interval, it meant that a child hearing the word ‘elephant’ would still be processing the ‘el’ sound while other children moved on, with delays cascading as a conversation progressed.

Researchers are planning a very small pilot study of children with autism spectrum disorder who have the M100 response latency. Using a drug that acts on signals across nerve cells, they will analyze whether the drug reduces auditory delays.

Future studies will investigate other genes previously implicated in autism spectrum disorders and other psychiatric disorders to determine whether they also involve the M100 response delay. The ultimate goal is to unite diverse genes along a few common biological pathways, some of which researchers hope will be treatable with specific therapies.


  1. Jenkins et al. Auditory Evoked M100 Response Latency is Delayed in Children with 16p11.2 Deletion but not 16p11.2 Duplication. Cereb Cortex. 2015 Feb 11. pii: bhv008. [Epub ahead of print]
    View abstract
  2. Gene-disease association data were retrieved from the DisGeNET Database, GRIB/IMIM/UPF Integrative Biomedical Informatics Group, Barcelona. ( 2014 Feb 20.
  3. Roberts et al. MEG detection of delayed auditory evoked responses in autism spectrum disorders: towards an imaging biomarker for autism. Autism Res. 2010 Feb;3(1):8-18. doi: 10.1002/aur.111.
    View abstract
Cocoa Flavanols Improve Speed of Memory Tasks in Older Adults Thu, 30 Oct 2014 17:32:32 +0000 Dietary cocoa flavanolsA new study finds that naturally occurring bioactive molecules in cocoa can improve the speed of memory tasks in healthy older adults.]]> Dietary cocoa flavanols

A new study finds that dietary cocoa flavanols — naturally occurring bioactive molecules in cocoa — can improve the speed of a memory task in healthy older adults.

Dietary cocoa flavanols

The study, published in the advance online issue of Nature Neuroscience [1], provides the first direct evidence that one component of age-related memory decline is caused by changes in a specific region of the brain called the dentate gyrus and that age-related of memory decline can be modulated by dietary intervention.

Researchers at Columbia University Medical Center (CUMC) recruited 37 healthy volunteers 50 to 69 years of age to participate in the study. The volunteers were randomized to receive either a high- or a low-flavanol diet. Brain imaging to measure blood volume in the dentate gyrus and a memory test involving pattern recognition were done for each volunteer before and after the study. The scientists found enhanced function of the dentate gyrus, as measured by fMRI and by cognitive testing, in participants that consumed the high-cocoa-flavanol drink.

The cocoa flavanol-containing test drink was prepared specifically for research purposes by the food company Mars, Incorporated, maker of M&M’s and Snickers bars, which has patented a way to extract flavanols from cocoa beans. However, don’t jump to the conclusion that all one needs to do is consume more chocolate. The cocoa flavanol drink is NOT the same as chocolate and will not produce the same effect. In fact, most methods of processing cocoa remove many of the flavanols found in the raw plant.

It’s important to note that the specially formulated cocoa-based drink high in flavanols made older people slightly faster, but not more accurate, in memory tests. Thus, the research is valuable from the perspective of gaining a better understanding of aging and brain function, but hasn’t been shown to be a treatment for cognitive decline. Moreover, the research was only done with 37 healthy people over a short period of time. Larger, longer studies that include patients with dementia need to be done before claims on reversing age-related and/or disease-related memory can be made.

Mars, Incorporated, is very focused on cocoa flavanols. In July, we wrote about a new study sponsored in part by Mars Inc. to see if pills containing the nutrients in dark chocolate (flavanols) can help prevent heart attacks and strokes. Mars is funding these studies to generate data to support flavanol’s use as a bioactive molecule.


  1. Brickman et a. Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults. Nat Neurosci. 2014 Oct 26. doi: 10.1038/nn.3850.
    View abstract
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The Brain’s GPS System and the Nobel Prize for Medicine Thu, 09 Oct 2014 02:40:00 +0000 On Monday, the 2014 Nobel Prize in Physiology or Medicine was awarded to three scientists for their discoveries of cells that constitute an “inner GPS” in the brain.]]>

nobel medal in medicine

On Monday, the 2014 Nobel Prize in Physiology or Medicine was announced [1]. The prize was awarded to a team of scientists for their discoveries of cells that constitute a positioning system — an “inner GPS” —in the brain that makes it possible to orient ourselves in space, demonstrating a cellular basis for higher cognitive function.

The prize of 8-million-Swedish-krona ($1.2-million USD) was divided, with one half to Dr. John O´Keefe, age 75, at at University College London and the other half jointly to a husband-and-wife team, Dr. May-Britt Moser, age 51, and Dr. Edvard I. Moser, age 52, at the Norwegian University of Science and Technology in Trondheim, for discovering how the brain creates a map of the space around us and how we can navigate our way through a complex environment.

The Brain’s Navigational Place and Grid Cell System

How do we know where we are? How can we find our way from one place to another? And how do we store this information such that we can find the way the next time we take the same path? Drs. John M. O’Keefe, May-Britt Moser and Edvard I. Moser discovered nerve cells in the brain that enable a sense of place and navigation, an “inner GPS” that shed new light onto how spatial memory might be created.

Schematic showing grid cells and place cells

In the 1970s, John O’Keefe discovered place cells in the hippocampus of rats that signal position and provide the brain with spatial memory capacity [2-4]. In the 2000s, May-Britt Moser and Edvard I. Moser discovered in the medial entorhinal cortex (a region of the brain next to hippocampus) a novel cell type called grid cells that shared characteristics with place cells and provide the brain with an internal coordinate system essential for navigation [5-6]. The combination of position and navigation functions are responsible for animals’ knowing where they are, where they’ve been, and where they’re going.

The Nobel Assembly at Karolinska Institutet in Sweden said in a statement [1]:

Recent investigations with brain imaging techniques, as well as studies of patients undergoing neurosurgery, have provided evidence that place and grid cells exist also in humans. In patients with Alzheimer’s disease, the hippocampus and entorhinal cortex are frequently affected at an early stage, and these individuals often lose their way and cannot recognize the environment. Knowledge about the brain’s positioning system may, therefore, help us understand the mechanism underpinning the devastating spatial memory loss that affects people with this disease.

The discovery of the brain’s positioning system by O’Keefe, Moser and Moser represents a paradigm shift in our understanding of how groups of specialized cells work together to execute higher cognitive functions and has implications for understanding other cognitive processes, such as memory, planning and thinking.


  1. The 2014 Nobel Prize in Physiology or Medicine – Press Release. 6 Oct 2014.
  2. O’Keefe and Dostrovsky. The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. Brain Res. 1971 Nov;34(1):171-5.
    View abstract
  3. O’Keefe, J. Place units in the hippocampus of the freely moving rat. Exp Neurol. 1976 Apr;51(1):78-109.
    View abstract
  4. O’Keefe and Nadel. The Hippocampus as a Cognitive Map (Oxford Univeristy Press) 1978.
  5. Hafting et al. Microstructure of a spatial map in the entorhinal cortex. Nature. 2005 Aug 11;436(7052):801-6. Epub 2005 Jun 19.
    View abstract
  6. Solstad et al. Representation of geometric borders in the entorhinal cortex. Science. 2008 Dec 19;322(5909):1865-8.
    View abstract
Protein Overload May Kill Brain Cells as Parkinson’s Progresses Wed, 16 Apr 2014 03:41:16 +0000 Scientists may have discovered how the most common genetic cause of Parkinson’s disease destroys brain cells.]]>

Scientists may have discovered how the most common genetic cause of Parkinson’s disease destroys brain cells and devastates many patients worldwide.

Nerve cells, ribosomal protein

The study was published in the journal Cell and partially funded by the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (NINDS); the results may help scientists develop new therapies [1].

Changes in the way cells make proteins might be a common cause of Parkinson’s disease and possibly other neurodegenerative disorders.

Ted Dawson, M.D., Ph.D., director of the Johns Hopkins University (JHU) Morris K. Udall Center of Excellence for Parkinson’s Disease, Baltimore, MD, said:

This may be a major discovery for Parkinson’s disease patients.

Dr. Dawson and his wife Valina Dawson, Ph.D., director of the JHU Stem Cell and Neurodegeneration Programs at the Institute for Cell Engineering, led the study published in Cell.

The investigators found that mutations in a gene called leucine-rich repeat kinase 2 (LRRK2; pronounced “lark two” or “lurk two”) may increase the rate at which LRRK2 tags ribosomal proteins, which are key components of protein-making machinery inside cells. This could cause the machinery to manufacture too many proteins, leading to cell death.

Margaret Sutherland, Ph.D., a program director at NINDS, said:

For nearly a decade, scientists have been trying to figure out how mutations in LRRK2 cause Parkinson’s disease. This study represents a clear link between LRRK2 and a pathogenic mechanism linked to Parkinson’s disease.

Affecting more than half a million people in the United States, Parkinson’s disease is a degenerative disorder that attacks nerve cells in many parts of the nervous system, most notably in a brain region called the substantia nigra, which releases dopamine, a chemical messenger important for movement. Initially, Parkinson’s disease causes uncontrolled movements; including trembling of the hands, arms, or legs. As the disease gradually worsens, patients lose ability to walk, talk or complete simple tasks.

For the majority of cases of Parkinson’s disease, a cause remains unknown. Mutations in the LRRK2 gene are a leading genetic cause. They have been implicated in as many as 10 percent of inherited forms of the disease and in about 4 percent of patients who have no family history. One study showed that the most common LRRK2 mutation, called G2019S, may be the cause of 30-40 percent of all Parkinson’s cases in people of North African Arabic descent.

LRRK2 is a kinase enzyme, a type of protein found in cells that tags molecules with chemicals called phosphate groups. The process of phosphorylation helps regulate basic nerve cell function and health. Previous studies suggest that disease-causing mutations, like the G2019S mutation, increase the rate at which LRRK2 tags molecules. Identifying the molecules that LRRK2 tags provides clues as to how nerve cells may die during Parkinson’s disease.

In this study, the researchers used LRRK2 as bait to fish out the proteins that it normally tags. Multiple experiments performed on human kidney cells suggested that LRRK2 tags ribosomal proteins. These proteins combine with other molecules, called ribonucleic acids, to form ribosomes, which are the cell’s protein-making factories.

Further experiments suggested that disease-causing mutations in LRRK2 increase the rate at which it tags two ribosomal proteins, called s11 and s15. Moreover, brain tissue samples from patients with LRRK2 mutations had greater levels of phosphorylated s15 than seen in controls.

Next, the researchers investigated whether phosphorylation could be linked to cell death, by studying nerve cells derived from rats or from human embryonic stem cells. Genetically engineering the cells to have a LRRK2 mutant gene increased the amount of cell death and phosphorylated s15. In contrast, the researchers prevented cell death when they engineered the cells to also make a mutant s15 protein that could not be tagged by LRRK2.

Dr. Dawson said:

These results suggest that s15 ribosome protein may play a critical role in the development of Parkinson’s disease.

How might phosphorylation of s15 kill nerve cells? To investigate this, Dr. Dawson and his colleagues performed experiments on fruit flies.

Previous studies on flies showed that genetically engineering dopamine-releasing nerve cells to overproduce the LRRK2 mutant protein induced nerve cell damage and movement disorders. Dr. Dawson’s team found that the brains of these flies had increased levels of phosphorylated s15 and that engineering the flies so that s15 could not be tagged by LRRK2 prevented cell damage and restored normal movement.

Interestingly, the brains of the LRRK2 mutant flies also had abnormally high levels of all proteins, suggesting that increased s15 tagging caused ribosomes to make too much protein. Treating the flies with low doses of anisomycin, a drug that blocks protein production, prevented nerve cell damage and restored the flies’ movement even though levels of s15 phosphorylation remained high.

Dr. Dawson said:

Our results support the idea that changes in the way cells make proteins might be a common cause of Parkinson’s disease and possibly other neurodegenerative disorders.

Dr. Dawson and his colleagues think that blocking the phosphorylation of s15 ribosomal proteins could lead to future therapies as might other strategies which decrease bulk protein synthesis or increase the cells’ ability to cope with increased protein metabolism. They also think that a means to measure s15 phosphorylation could also act as a biomarker of LRRK2 activity in treatment trials of LRRK2 inhibitors.

Source: NIH News


  1. Martin et al. Ribosomal Protein s15 Phosphorylation Mediates LRRK2 Neurodegeneration in Parkinson’s Disease. Cell. 2014 Apr 10;157(2):472-85. doi: 10.1016/j.cell.2014.01.064.
    View abstract
Disorganized Patches in the Brain Suggest Prenatal Origin of Autism Thu, 27 Mar 2014 14:49:22 +0000 A new study suggests that brain irregularities in children with autism can be traced back to prenatal development.]]>

The architecture of the autistic brain is speckled with patches of abnormal neurons, according to research partially funded by the National Institute of Mental Health (NIMH), part of the National Institutes of Health. Recently published in the New England Journal of Medicine, the study suggests that brain irregularities in children with autism can be traced back to prenatal development [1].

Patch-like areas of disrupted neurons

Thomas R. Insel, M.D., director of NIMH, said:

While autism is generally considered a developmental brain disorder, research has not identified a consistent or causative lesion. If this new report of disorganized architecture in the brains of some children with autism is replicated, we can presume this reflects a process occurring long before birth. This reinforces the importance of early identification and intervention.

Eric Courchesne, Ph.D. and Rich Stoner, Ph.D., of the Autism Center of Excellence at the University of California, San Diego joined colleagues from the Allen Institute for Brain Science to investigate the cellular architecture of the brain’s outermost structure, the cortex, in children with autism. Courchesne recently reported an overabundance of neurons in the prefrontal cortex of children with autism.

For the current study, the researchers analyzed gene expression in postmortem brain tissue from children with and without autism, all between 2 and 15 years of age.

As the prenatal brain develops, neurons in the cortex differentiate into six layers. Each is composed of particular types of brain cells with specific patterns of connections. The research team focused on genes that serve as cellular markers for each of the cortical layers as well as genes that are associated with autism.

The study found that the markers for several layers of the cortex were absent in 91 percent of the autistic case samples, as compared to 9 percent of control samples. Further, these signs of disorganization were not found all over the brain’s surface, but instead were localized in focal patches that were 5-7 millimeters (0.20-0.28 inches) in length and encompassed multiple cortical layers.

These patches were found in the frontal and temporal lobes of the cortex — regions that mediate social, emotional, communication, and language functions. Considering that disturbances in these types of behaviors are hallmarks of autism, the researchers conclude that the specific locations of the patches may underlie the expression and severity of various symptoms in a child with the disorder.

The patchy nature of the defects may explain why early treatments can help young infants and toddlers with autism improve. According to the researchers, since the faulty cell layering does not occur over the entire cortex, the developing brain may have a chance to rewire its connections by sidestepping the pathological patches and recruiting cells from neighboring brain regions to assume critical roles in social and communication functions.

Source: NIH News


  1. Stoner et al. Patches of disorganization in the neocortex of children with autism. New England Journal of Medicine. 2014 Mar 27.
Brain-mapping Projects to Collaborate, Share Data Thu, 20 Mar 2014 14:00:26 +0000 Two ambitious and controversial government-backed initiatives that aim to decode the brain are poised to join forces.]]>

Two ambitious and controversial government-backed initiatives that aim to decode the brain are poised to join forces.

Brain mapping projects to collaborate

Officials from the United States’ $1-billion BRAIN Initiative (Brain Research through Advancing Innovative Neurotechnologies, also referred to as the Brain Activity Map Project) and the European Union’s $1.3-billion Human Brain Project (HBP) have announced they will launch a collaboration later this year.

Although the details have yet to be worked out, according to Kathy Hudson, the National Institutes of Health deputy director for science, outreach and policy, the ultimate goal is to ensure that the two research programs do as much as they can without duplicating efforts.

The collaboration will help both programs: the BRAIN Initiative is creating tools for imaging and controlling brain activity, and needs a system to integrate all the data collected, while the HBP is creating a system — a computational model of the brain — and needs brain data to design its model.

The coordination between the two brain initiatives will begin with a workshop later this year where they will discuss the extent to which they want to work together. Issues such as the ethics of brain mapping and policies for data sharing are also likely to surface.

Source: Nature News

Minding Your Memory: Brain Awareness Week 2014 Wed, 12 Mar 2014 15:40:01 +0000 This year for Brain Awareness Week, we're highlighting some practical tips for minding your memory.]]>

Every year in March, Brain Awareness Week (BAW) unites the efforts of partner organizations worldwide in a celebration of the brain for people of all ages. We’ve been celebrating it since 2011 and this year, wanted to highlight some practical tips for minding your memory.

Brain Awareness Week 2014

BAW was founded and is coordinated by the Dana Alliance for Brain Initiatives and European Dana Alliance for the Brain. Based on what brain science tells us about memory, there are a number of simple strategies that everyone can use to improve the ability to learn and remember new things.

Everything begins as sensory input from our environment. We have a mechanism to filter out and discard irrelevant or background data, such as the feel of the carpet as we walk or the sound of the air conditioner. To establish a more durable memory, we need to prevent incoming information from being discarded. The use of strategies plays a critical role in structuring input to help it move into long-term memory in a meaningful and memorable format.

10 tips to mind your memory

  1. Pay attention: engage your brain and live in the moment. Actively attend to what you’re trying to learn. This can be hard, so don’t give up! Overriding the distraction reflex takes intentionality and practice.
  2. Stay focused: concentrate on what you’re doing. Reduce distractions and interruptions to help stay centered. If you’re working on your computer, close your email and/or social media clients. Turn off the radio or TV.
  3. Repeat it: as children, we learn by repetition. This also works as an adult. Repetition increases the strength of relevant connections in your brain and enhances a process called consolidation, whereby memories are moved from temporary storage in the hippocampus to more permanent storage in the cortex.
  4. Write it down: writing down important things is useful for two reasons: (1) it is another way to repeat the information, and (2) it provides a visual reminder.
  5. Make associations: relate new information to things you already know. This uses existing synaptic connections in the brain to learn something new.
  6. Stay organized: keep things you regularly use in the same place. The hard part — especially when we’re busy — is always returning items to their place.
  7. Plan and prioritize: the human brain isn’t meant to multitask. Planning our time and prioritizing activities is critical. No one can “do it all” — let yourself off the hook, reduce stress and regain control over your time and your life.

For more information, see Brain Awareness Week: Staying Sharp.

To see additional stories and materials from past BAW events, see Brain Awareness Week 2013, Brain Awareness Week 2012, and Brain Awareness Week 2011.

Genetic Risk Factor for Alzheimer’s Disease Impacts the Blood Brain Barrier Wed, 26 Feb 2014 22:15:05 +0000 According to a recent study, the most common genetic risk factor for Alzheimer's disease disrupts the blood brain barrier.]]>

The most common genetic risk factor for Alzheimer’s disease (AD) disrupts the blood brain barrier, impeding oxygen and nutrient flow to the brain and exposing the brain to systemic toxins, according to a recent investigation led by scientists from the University of Rochester Center for Neurodegenerative and Vascular Brain Disorders [1].

Blood brain barrier

Apolipoprotein E (ApoE), a lipid binding protein that plays a central role in cholesterol metabolism, occurs in three different forms or alleles, E2, E3, and E4. The E4 allele is associated with significantly increased risk of late onset AD, and is found among 40% of all AD subjects. Inheritance of two E4 alleles carries with it a 90% risk of AD. In contrast, the E3 allele has no influence on risk of developing AD, while the rare E2 allele confers a limited protection against this disease [2].

In the current study, published in the journal Nature, scientists used mice transgenic for the three different ApoE alleles to demonstrate that the E4 allele activates a pro-inflammatory pathway leading to the activation of enzymes that destroy the molecular scaffold that supports the blood brain barrier (BBB), leading to vascular defects [1].

In this study, different mouse strains were established with targeted replacement of the endogenous mouse ApoE gene with each of the three human ApoE alleles. Expression of the E4 allele, but not the E2 or E3 allele resulted in breakdown of the BBB as shown by the movement of labeled high molecular weight proteins from the blood stream into the brain. In E4 expressing animals, levels of the pro-inflammatory signal molecule cyclophilin A (CypA) were found to be elevated in cerebral blood vessels. CypA is known to work via nuclear factor kappa-B (NF-kappa-B)to stimulate matrix metalloproteinases which dissolve the matrix proteins that would normally hold cells in close apposition to form a barrier to molecules exiting the blood stream. Scientists reported evidence for the activation of this pathway, and demonstrated that knockout of the CypA gene, or inhibition of CypA with drugs prevented the breakdown of the BBB in the presence of the E4 allele.

The BBB is the physical, chemical and immunological separation of the central nervous system from the circulating blood, and this barrier is essential for the normal function of the brain. Breakdown of the barrier may elicit auto-immune diseases such as multiple sclerosis, and may leave the brain susceptible to a host of circulating proteins which may be toxic to nerve cells. The blood brain barrier (BBB) not only prevents influx of toxins into the brain, it is responsible for the clearance of toxins from the brain such as the neurotoxic peptide that is believed to play a central role in pathogenesis in AD, the Alzheimer’s A-beta peptide. The BBB is increasingly being viewed as a therapeutic target for drugs which might increase the transport of such toxins [3].

Although the link between ApoE and AD has been long established, the molecular basis for the link remains uncertain. Because of its role in lipid metabolism, ApoE has been viewed as the nexus between cardiovascular risk factors and AD. Carriers of the E2 allele are at increased risk of type III hyperlipoproteinemia — a genetic disorder characterized by accumulation of remnant lipoproteins in the plasma and development of premature atherosclerosis — while carriers of the E4 allele have increased plasma cholesterol levels and face an elevated risk for coronary heart disease. Also, ApoE is a transporter of A-beta, and is reported to play a role in the proteolysis and clearance of A-beta, with the E4 allele being the least active in these functions [4]. However, the E4 allele of ApoE promotes aggregation of A-beta peptide into amyloid, forming some of the characteristic pathological lesions of the disease, including senile plaques and vascular amyloid angiopathy. The E4 allele is also associated with increased risk for developing other neurodegenerative diseases such as Parkinson’s disease, and with poorer prognosis for traumatic brain injury patients. This study suggests that pharmacological targeting of the CypA pathway may be beneficial for these diseases.


  1. Bell et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012 May 16;485(7399):512-6. doi: 10.1038/nature11087.
    View abstract
  2. Corder et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993 Aug 13;261(5123):921-3.
    View abstract
  3. Bell and Zlokovic. Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease. Acta Neuropathol. 2009 Jul;118(1):103-13. doi: 10.1007/s00401-009-0522-3. Epub 2009 Mar 25.
    View abstract
  4. Jiang et al. ApoE promotes the proteolytic degradation of Abeta. Neuron. 2008 Jun 12;58(5):681-93. doi: 10.1016/j.neuron.2008.04.010.
    View abstract
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Pain and the Prognosis for Dementia Wed, 19 Feb 2014 16:00:04 +0000 Pain may provide one of the strongest predictors yet identified for Alzheimer's disease.]]>

While researchers are busy developing sophisticated laboratory tests to predict who will eventually succumb to Alzheimer’s disease, a seemingly mundane observation may provide one of the strongest predictors yet identified: pain.

Pharmacology of aging why age matters

Molly Zimmerman from the Albert Einstein College of Medicine summarized research implicating pain as a risk factor for dementia and Alzheimer’s disease at a symposium last year at the New York Academy of Sciences entitled, The Pharmacology of Aging: Why Age Matters.

Discussing her work with the Einstein Aging Study in the Bronx, NY, she reported that pain is prevalent among the elderly, with nearly 50% reporting the experience of some level of pain on a daily basis. However, when pain becomes intense enough to prevent normal activities, a condition termed “pain interference,” the risks of developing new-onset dementia double. Furthermore, pain is associated with reduced hippocampal volume as measured by structural MRI and a reduction in the ratio of N-acetylaspartate to creatine (NAA/Cr) as measured by MRS, a marker of hippocampal integrity [1]. Reductions in both hippocampal volume and NAA/Cr ratio are associated with diminished cognitive function [2].

Pain is a complex and highly subjective experience, and it is unclear precisely how pain interferes with cognition. Previous studies suggest that pain modulates brain networks involved in attention [3], which are necessary for both cognition and pain perception. In another report, treatment of chronic pain was observed to improve cognition and reverse brain abnormalities, in this case the thinning of certain areas of the prefrontal cortex [4].

Dementia patients are typically under-treated for pain [5], and there was once debate regarding whether dementia patients experience pain in the same manner as non-demented subjects. For example, frontotemporal dementia patients are reported to have an elevated pain threshold and tolerance as measured by changes in fMRI [6], and there have been case reports of dementia patients who were seemingly oblivious to horrific lesions or injuries [7]. However, others report no reductions in fMRI measured activities of pain pathways in subjects with dementia [8].

Kunz et al. measured multiple readouts of pain including subjective assessment, facial response (using a facial action coding system, FACS), motor reflex (using the nociceptive flexion reflex), and autonomic measures (sympathetic skin response, heart rate) in response to noxious stimuli, and although subjects with dementia reported similar subjective pain ratings as those reported by control subjects, their facial responses were greater and the threshold for their motor reflex was decreased compared to control subjects (their autonomic response, in contrast, was reduced) [9]. Their results suggest that the experience of pain in the dementia patient may be more intense than is reported by the patient.


  1. Zimmerman et al. Hippocampal correlates of pain in healthy elderly adults: a pilot study. Neurology. 2009 Nov 10;73(19):1567-70. doi: 10.1212/WNL.0b013e3181c0d454.
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  2. Zimmerman et al. Hippocampal neurochemistry, neuromorphometry, and verbal memory in nondemented older adults. Neurology. 2008 Apr 29;70(18):1594-600. doi: 10.1212/ Epub 2008 Mar 26.
    View abstract
  3. Seminowicz and Davis. Pain enhances functional connectivity of a brain network evoked by performance of a cognitive task. J Neurophysiol. 2007 May;97(5):3651-9. Epub 2007 Feb 21.
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  4. Seminowicz et al. Effective treatment of chronic low back pain in humans reverses abnormal brain anatomy and function. J Neurosci. 2011 May 18;31(20):7540-50. doi: 10.1523/JNEUROSCI.5280-10.2011.
    View abstract
  5. Plooij et al. Pain medication and global cognitive functioning in dementia patients with painful conditions. Drugs Aging. 2012 May 1;29(5):377-84. doi: 10.2165/11630850-000000000-00000.
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  6. Carlino et al. Pain perception and tolerance in patients with frontotemporal dementia. Pain. 2010 Dec;151(3):783-9. doi: 10.1016/j.pain.2010.09.013. Epub 2010 Oct 8.
    View abstract
  7. Fisher-Morris and Gellatly. The experience and expression of pain in Alzheimer patients. Age Ageing. 1997 Nov;26(6):497-500.
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  8. Cole et al. Pain sensitivity and fMRI pain-related brain activity in Alzheimer’s disease. Brain. 2006 Nov;129(Pt 11):2957-65. Epub 2006 Sep 2.
    View abstract
  9. Kunz et al. Influence of dementia on multiple components of pain. Eur J Pain. 2009 Mar;13(3):317-25. doi: 10.1016/j.ejpain.2008.05.001. Epub 2008 Jun 17.
    View abstract