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Archive for the ‘MRI’ Category


Medical Applications of Nano Magnetite

Author: Danut Dragoi, PhD

Nano magnetite refers to small crystals of Fe3O4 in nano-metric range that preserves some specific magnetic properties of the magnetite bulk crystal such as the magnetism at saturation, Curie temperature, coercive magnetic force, hysteresis loop, etc. A discussion of medical applications of nano-magnetic particles is shown in here.

Opportunities for magnetite nanoparticles to be effectively incorporated into environmental contaminant removal and cell separation ([1] Honda et al., 1998;[2] Ebner et al.,1999; [3] Rikers et al., 1998; [4] Navratil, 2003), magnetically guided-drug delivery (Roger et al., 1999), magnetocytolysis ([5] Roger et al., 1999), sealing agents (liquid O-rings) ([6] Enzel et al., 1999), dampening and cooling mechanisms in loudspeakers ([6] Enzel et al., 1999), and contrasting agents for magnetic resonance imaging (MRI) ([7] Schütt, 2004). Advancement of synthesis and stabilization procedures towards production of uniformly sized, dispersed (potentially embedded) magnetite nanoparticles has clearly inspired creative imagination and application in various fields. The following subsections address two topics, magnetic guided drug delivery and magnetic resonance tomography which  helps us  better understanding the capabilities offered by magnetite nanoparticles.

Magnetically Guided Drug Delivery

Ferrofluids containing encapsulated (with biologically compatible surface chemistries) magnetite nanoparticles, as described above, can be employed for drug delivery to specific locations. Exploitation of superparamagnetic magnetization of magnetite nanoparticles allows for “magnetic dragging” of internal (present in bloodstream or elsewhere) magnetite nanoparticles carrying DNA, enzymes, drugs to target-areas. Similarly, biological effectors, which are proteins (containing DNA specific to target cells) incorporated into encapsulated nanoparticle surface functionality, allow for target cell specificity. Once biological effector carrying magnetic nanoparticles bind to target-cells, the applied magnetic field is fluctuated (approximately 1 MHz) causing magnetocytolysis, or cell destruction, which eliminates target-cells. Similarly, after being dragged to target areas, magnetocytolysis of encapsulated nanoparticles can release drugs. Research towards these ends is currently being heavily investigated as potential for novel drug/cancer treatment abounds. ([5] Roger et al., 1999). Picture below shows schematically drug-loaded magnetic nanoparticles targeting for tumor therapy in which the magnetic nanoparticles are noninvasively moved toward the target.

Drug loaded NanoParicles

Image SOURCE:https://books.google.com/books?hl=en&lr=&id=oX32CwAAQBAJ&oi=fnd&pg=PA425&ots=1EDRtu7mDx&sig=fYjckTZEyXCkOBb4sjRAuWSR_U4#v=onepage&q&f=false

Magnetic Resonance Tomography

Magnetic Resonance Tomography (MRT) permits noninvasive visualization of cross-sectional images of the human body, tissues, and organs ([7] Schütt, 2004). The MRT technique provides better tissue resolution than traditional radiation based technologies; with addition of contrasting agents, this resolution can be further enhanced ([8] Shao et al., 2005). Magnetite nanoparticles (in ferrofluid form) are powerful contrasting agents due to their paramagnetic magnetization. Ferrofluid physico-morphosis under magnetic field Blaney 65 Human bloodstreams readily reject the nanoparticle colloidal solution, which quickly passes into the liver ([8] Shao et al., 2005). Consequently, ferrofluids have thus far only been useful in distinguishing between healthy and malignant liver cells. This limitation can be overcome through functionalization of magnetite nanoparticles with various ligands that allows for organ-specific transport; therefore, MRT imaging of various bodily organs can be possible. Furthermore, polymeric (i.e., polyethylene oxide – PEO) coating of functionalized magnetite particles permits ferrofluids longer bloodstream retention. ([7] Schütt, 2004) PEO coatings are applied through magnetite interaction with copolymer PEO-polypeptide; polypeptides interact with the positively charged magnetite surface and provide nanoparticle masking to allow longer bloodstream residence. These coated magnetite nanoparticles could also be employed as extremely efficient capsules for drug delivery systems, which are discussed by ([7] Schütt, 2004).

References

[1] Honda H, Kawabe A, Shinkai M, and Kobayashi T (1998). Development of chitosan-conjugated magnetite for magnetic cell separation. Journal of Fermentation and Bioengineering 86, 191-196

[2] Ebner AD, Ritter JA, Ploehn HJ, Kochen RL, and Navratil JD (1999). New magnetic field-enhanced process for the treatment of aqueous wastes. Separation Science and Technology 34, 1277-1300

[3] Rikers RA, Voncken JHL, and Dalmijn WL (1998). Cr-polluted soil studied by high gradient magnetic separation and electron probe. Journal of Environmental Engineering 124, 1159-1164

[4] Navratil JD (2003). Adsorption and nanoscale magnetic separation of heavy metals from water. U.S. EPA workshop on managing arsenic risks to the environment: characterization of waste, chemistry, and treatment and disposal. Denver, CO

[5] Roger J, Pons JN, Massart R, Halbreich A, and Bacri JC (1999). Some biomedical applications of ferro fluids. Eur. Phys. J. AP 5, 321-325

[6] Enzel P, Adelman N, Beckman KJ, Campbell DJ, Ellis AB, Lisensky GC (1999). Preparation of an aqueous-based ferrofluid. J. Chem. Educ. 76, 943-948

[7] Schütt D (2004). Magnetite colloids for drug delivery and magnetic resonance imaging. Institute Angewandte Polymerforschung: thesis Selim MS, Cunningham LP, Srivastava R, Olson JM (1997). Preparation of nano-size magnetic gamma ferric oxide (γ-Fe2O3) and magnetite (Fe3O4) particles for toner and color imaging applications. Recent Progress in Toner Technologies, 108- 111

[8] Shao H, Lee H, Huang Y, Kwak BK, and Kim CO (2005). Synthesis of nano-size magnetite coated with chitosan for MRI contrast agent by sonochemistry. Magnetics Conference, 2005. INTERMAG Asia 2005. Digests of the IEEE International, 461-462

https://books.google.com/books?hl=en&lr=&id=oX32CwAAQBAJ&oi=fnd&pg=PA425&ots=1EDRtu7mDx&sig=fYjckTZEyXCkOBb4sjRAuWSR_U4#v=onepage&q&f=false

 

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Schizophrenia, broken-links

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Runs in the Family

 New findings about schizophrenia rekindle old questions about genes and identity.
BY Annals of Science MARCH 28, 2016 ISSUE      http://www.newyorker.com/magazine/2016/03/28/the-genetics-of-schizophrenia

http://www.newyorker.com/wp-content/uploads/2016/03/160328_r27877-690.jpg

The author and his father have seen several relatives succumb to mental illness.CREDIT PHOTOGRAPH BY DAYANITA SINGH FOR THE NEW YORKER

In the winter of 2012, I travelled from New Delhi, where I grew up, to Calcutta to visit my cousin Moni. My father accompanied me as a guide and companion, but he was a sullen and brooding presence, lost in a private anguish. He is the youngest of five brothers, and Moni is his firstborn nephew—the eldest brother’s son. Since 2004, Moni, now fifty-two, has been confined to an institution for the mentally ill (a “lunatic home,” as my father calls it), with a diagnosis of schizophrenia. He is kept awash in antipsychotics and sedatives, and an attendant watches, bathes, and feeds him through the day.

My father has never accepted Moni’s diagnosis. Over the years, he has waged a lonely campaign against the psychiatrists charged with his nephew’s care, hoping to convince them that their diagnosis was a colossal error, or that Moni’s broken psyche would somehow mend itself. He has visited the institution in Calcutta twice—once without warning, hoping to see a transformed Moni, living a secretly normal life behind the barred gates. But there was more than just avuncular love at stake for him in these visits. Moni is not the only member of the family with mental illness. Two of my father’s four brothers suffered from various unravellings of the mind. Madness has been among the Mukherjees for generations, and at least part of my father’s reluctance to accept Moni’s diagnosis lies in a grim suspicion that something of the illness may be buried, like toxic waste, in himself.

Rajesh, my father’s third-born brother, had once been the most promising of the Mukherjee boys—the nimblest, the most charismatic, the most admired. But in the summer of 1946, at the age of twenty-two, he began to behave oddly, as if a wire had been tripped in his brain. The most obvious change in his personality was a volatility: good news triggered uncontained outbursts of joy; bad news plunged him into inconsolable desolation. By that winter, the sine curve of Rajesh’s psyche had tightened in its frequency and gained in its amplitude. My father recalls an altered brother: fearful at times, reckless at others, descending and ascending steep slopes of mood, irritable one morning and overjoyed the next. When Rajesh received news of a successful performance on his college exams, he vanished, elated, on a two-night excursion, supposedly “exercising” at a wrestling camp. He was feverish and hallucinating when he returned, and died of pneumonia soon afterward. Only years later, in medical school, did I realize that Rajesh was likely in the throes of an acute manic phase. His mental breakdown was the result of a near-textbook case of bipolar disorder.

Jagu, the fourth-born of my father’s siblings, came to live with us in Delhi in 1975, when I was five years old and he was forty-five. His mind, too, was failing. Tall and rail thin, with a slightly feral look in his eyes and a shock of matted, overgrown hair, he resembled a Bengali Jim Morrison. Unlike Rajesh, whose illness had surfaced in his twenties, Jagu had been troubled from his adolescence. Socially awkward, withdrawn from everyone except my grandmother, he was unable to hold a job or live by himself. By 1975, he had visions, phantasms, and voices in his head that told him what to do. He was still capable of extraordinary bursts of tenderness—when I accidentally smashed a beloved Venetian vase at home, he hid me in his bedclothes and informed my mother that he had “mounds of cash” stashed away, enough to buy “a thousand” replacement vases. But this episode was symptomatic: even his love for me extended the fabric of his psychosis and confabulation.

Unlike Rajesh, Jagu was formally diagnosed. In the late nineteen-seventies, a physician in Delhi examined him and determined that he had schizophrenia. But no medicines were prescribed. Instead, Jagu continued to live at home, half hidden away in my grandmother’s room. (As in many families in India, my grandmother lived with us.) For nearly a decade, she and my father maintained a fragile truce, with Jagu living under her care, eating meals in her room and wearing clothes that she stitched for him. At night, when Jagu was consumed by his fears and fantasies, she put him to bed like a child, with her hand on his forehead. She was his nurse, his housekeeper, his only friend, and, more important, his public defender. When my grandmother died, in 1985, Jagu joined a religious sect in Delhi and disappeared, until his death, a dozen years later.

……

at schizophrenia runs in families was evident even to the person who first defined the illness. In 1911, Eugen Bleuler, a Swiss-German psychiatrist, published a book describing a series of cases of men and women, typically in their teens and early twenties, whose thoughts had begun to tangle and degenerate. “In this malady, the associations lose their continuity,” Bleuler wrote. “The threads between thoughts are torn.” Psychotic visions and paranoid thoughts flashed out of nowhere. Some patients “feel themselves weak, their spirit escapes, they will never survive the day. There is a growth in their heads. Their bones have turned liquid; their hearts have turned into stone. . . . The patient’s wife must not use eggs in cooking, otherwise he will grow feathers.” His patients were often trapped between flickering emotional states, unable to choose between two radically opposed visions, Bleuler noted. “You devil, you angel, you devil, you angel,” one woman said to her lover.

Bleuler tried to find an explanation for the mysterious symptoms, but there was only one seemingly common element: schizophrenic patients tended to have first-degree relatives who were also schizophrenic. He had no tools to understand the mechanism behind the heredity. The word “gene” had been coined just two years before Bleuler published his book. The notion that a mental illness could be carried across generations by unitary, indivisible factors—corpuscles of information threading through families—would have struck most of Bleuler’s contemporaries as mad in its own right. Still, Bleuler was astonishingly prescient about the complex nature of inheritance. “If one is looking for ‘theheredity,’ one can nearly always find it,” he wrote. “We will not be able to do anything about it even later on, unless the single factor of heredity can be broken down into many hereditary factors along specific lines.”

In the nineteen-sixties, Bleuler’s hunch was confirmed by twin studies. Psychiatrists determined that if an identical twin was schizophrenic the other twin had a forty-to-fifty-per-cent chance of developing the disease—fiftyfold higher than the risk in the general population. By the early two-thousands, large population studies had revealed a strong genetic link between schizophrenia and bipolar disorder. Some of the families described in these studies had a crisscrossing history that was achingly similar to my own: one sibling affected with schizophrenia, another with bipolar disorder, and a nephew or niece also schizophrenic.

“The twin studies clarified two important features of schizophrenia and bipolar disorder,” Jeffrey Lieberman, a Columbia University psychiatrist who has studied schizophrenia for thirty years, told me. “First, it was clear that there wasn’t a single gene, but dozens of genes involved in causing schizophrenia—each perhaps exerting a small effect. And, second, even if you inherited the entire set of risk genes, as identical twins do, you still might not develop the disease. Obviously, there were other triggers or instigators involved in releasing the illness.” But while these studies established that schizophrenia had a genetic basis, they revealed nothing about the nature of the genes involved. “For doctors, patients, and families in the schizophrenia community, genetics became the ultimate mystery,” Lieberman said. “If we knew the identity of the genes, we would find the causes, and if we found the causes we could find medicines.”

In 2006, an international consortium of psychiatric geneticists launched a genomic survey of schizophrenia, hoping to advance the search for the implicated genes. With 3,322 patients and 3,587 controls, this was one of the largest and most rigorous such studies in the history of the disease. Researchers scanned through the nearly seven thousand genomes to find variations in gene segments that were correlated with schizophrenia. This strategy, termed an “association study,” does not pinpoint a gene, but it provides a general location where a disease-linked gene may be found, like a treasure map with a large “X” scratched in a corner of the genome.

The results, reported in 2009 (and updated in 2014) in the journal Nature, were a dispiriting validation of Bleuler’s hunch about multiple hereditary factors: more than a hundred independent segments of the genome were associated with schizophrenia. “There are lots of small, common genetic effects, scattered across the genome,” one researcher said. “There are many different biological processes involved.” Some of the putative culprits made biological sense—if dimly. There were genes linked to transmitters that relay messages between neurons, and genes for molecular channels that move electrical signals up and down nerve cells. But by far the most surprising association involved a gene segment on chromosome 6. This region of the genome—termed the MHC region—carries hundreds of genes typically associated with the immune system.

“The MHC-segment finding was so strange and striking that you had to sit up and take notice,” Lieberman told me. “Here was the most definitive evidence that something in the immune system might have something to do with schizophrenia. There had been hints about an immunological association before, but this was impossible to argue with. It raised an endlessly fascinating question: what was the link between immune-response genes and schizophrenia?”

The Rogue Immune Cells That Wreck the Brain

Beth Stevens thinks she has solved a mystery behind brain disorders such as Alzheimer’s and schizophrenia.

by Adam Piore   April 4, 2016            https://www.technologyreview.com/s/601137/the-rogue-immune-cells-that-wreck-the-brain/

In the first years of her career in brain research, Beth Stevens thought of microglia with annoyance if she thought of them at all. When she gazed into a microscope and saw these ubiquitous cells with their spidery tentacles, she did what most neuroscientists had been doing for generations: she looked right past them and focused on the rest of the brain tissue, just as you might look through specks of dirt on a windshield.

“What are they doing there?” she thought. “They’re in the way.’”

Stevens never would have guessed that just a few years later, she would be running a laboratory at Harvard and Boston’s Children’s Hospital devoted to the study of these obscure little clumps. Or that she would be arguing in the world’s top scientific journals that microglia might hold the key to understanding not just normal brain development but also what causes Alzheimer’s, Huntington’s, autism, schizophrenia, and other intractable brain disorders.

Microglia are part of a larger class of cells—known collectively as glia—that carry out an array of functions in the brain, guiding its development and serving as its immune system by gobbling up diseased or damaged cells and carting away debris. Along with her frequent collaborator and mentor, Stanford biologist Ben Barres, and a growing cadre of other scientists, Stevens, 45, is showing that these long-overlooked cells are more than mere support workers for the neurons they surround. Her work has raised a provocative suggestion: that brain disorders could somehow be triggered by our own bodily defenses gone bad.

A type of glial cell known as an oligodendrocyte

In one groundbreaking paper, in January, Stevens and researchers at the Broad Institute of MIT and Harvard showed that aberrant microglia might play a role in schizophrenia—causing or at least contributing to the massive cell loss that can leave people with devastating cognitive defects. Crucially, the researchers pointed to a chemical pathway that might be targeted to slow or stop the disease. Last week, Stevens and other researchers published a similar finding for Alzheimer’s.

This might be just the beginning. Stevens is also exploring the connection between these tiny structures and other neurological diseases—work that earned her a $625,000 MacArthur Foundation “genius” grant last September.

All of this raises intriguing questions. Is it possible that many common brain disorders, despite their wide-ranging symptoms, are caused or at least worsened by the same culprit, a component of the immune system? If so, could many of these disorders be treated in a similar way—by stopping these rogue cells?

Nature. 2016 Feb 11;530(7589):177-83. http://dx.doi.org:/10.1038/nature16549. Epub 2016 Jan 27.   Schizophrenia risk from complex variation of complement component 4.

Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia’s strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.

 

Science  31 Mar 2016;        http://dx.doi.org:/10.1126/science.aad8373      Complement and microglia mediate early synapse loss in Alzheimer mouse models.
Soyon Hong1Victoria F. Beja-Glasser1,*Bianca M. Nfonoyim1,*,…., Ben A. Barres6Cynthia A. Lemere,2Dennis J. Selkoe2,7Beth Stevens1,8,

 Synapse loss in Alzheimer’s disease (AD) correlates with cognitive decline. Involvement of microglia and complement in AD has been attributed to neuroinflammation, prominent late in disease. Here we show in mouse models that complement and microglia mediate synaptic loss early in AD. C1q, the initiating protein of the classical complement cascade, is increased and associated with synapses before overt plaque deposition. Inhibition of C1q, C3 or the microglial complement receptor CR3, reduces the number of phagocytic microglia as well as the extent of early synapse loss. C1q is necessary for the toxic effects of soluble β-amyloid (Aβ) oligomers on synapses and hippocampal long-term potentiation (LTP). Finally, microglia in adult brains engulf synaptic material in a CR3-dependent process when exposed to soluble Aβ oligomers. Together, these findings suggest that the complement-dependent pathway and microglia that prune excess synapses in development are inappropriately activated and mediate synapse loss in AD.
Genome-wide association studies (GWAS) implicate microglia and complement-related pathways in AD (1). Previous research has demonstrated both beneficial and detrimental roles of complement and microglia in plaque-related neuropathology (2, 3); however, their roles in synapse loss, a major pathological correlate of cognitive decline in AD (4), remain to be identified. Emerging research implicates microglia and immune-related mechanisms in brain wiring in the healthy brain (1). During development, C1q and C3 localize to synapses and mediate synapse elimination by phagocytic microglia (57). We hypothesized that this normal developmental synaptic pruning pathway is activated early in the AD brain and mediates synapse loss.

 

Complex machinery

It’s not surprising that scientists for years have ignored microglia and other glial cells in favor of neurons. Neurons that fire together allow us to think, breathe, and move. We see, hear, and feel using neurons, and we form memories and associations when the connections between different neurons strengthen at the junctions between them, known as synapses. Many neuroscientists argue that neurons create our very consciousness.

Glia, on the other hand, have always been considered less important and interesting. They have pedestrian duties such as supplying nutrients and oxygen to neurons, as well as mopping up stray chemicals and carting away the garbage.

Scientists have known about glia for some time. In the 1800s, the pathologist Rudolf Virchow noted the presence of small round cells packing the spaces between neurons and named them “nervenkitt” or “neuroglia,” which can be translated as nerve putty or glue. One variety of these cells, known as astrocytes, was defined in 1893. And then in the 1920s, the Spanish scientist Pio del Río Hortega developed novel ways of staining cells taken from the brain. This led him to identify and name two more types of glial cells, including microglia, which are far smaller than the others and are characterized by their spidery shape and multiple branches. It is only when the brain is damaged in adulthood, he suggested, that microglia spring to life—rushing to the injury, where it was thought they helped clean up the area by eating damaged and dead cells. Astrocytes often appeared on the scene as well; it was thought that they created scar tissue.

This emergency convergence of microglia and astrocytes was dubbed “gliosis,” and by the time Ben Barres entered medical school in the late 1970s, it was well established as a hallmark of neurodegenerative diseases, infection, and a wide array of other medical conditions. But no one seemed to understand why it occurred. That intrigued Barres, then a neurologist in training, who saw it every time he looked under a microscope at neural tissue in distress. “It was just really fascinating,” he says. “The great mystery was: what is the point of this gliosis? Is it good? Is it bad? Is it driving the disease process, or is it trying to repair the injured brain?”

 https://youtu.be/6DOYTpXkLOY

Barres began looking for the answer. He learned how to grow glial cells in a dish and apply a new recording technique to them. He could measure their electrical qualities, which determine the biochemical signaling that all brain cells use to communicate and coördinate activity.

“From the second I started recording the glial cells, I thought ‘Oh, my God!’” Barres recalls. The electrical activity was more dynamic and complex than anyone had thought. These strange electrical properties could be explained only if the glial cells were attuned to the conditions around them, and to the signals released from nearby neurons. Barres’s glial cells, in other words, had all the machinery necessary to engage in a complex dialogue with neurons, and presumably to respond to different kinds of conditions in the brain.

Why would they need this machinery, though, if they were simply involved in cleaning up dead cells? What could they possibly be doing? It turns out that in the absence of chemicals released by glia, the neurons committed the biochemical version of suicide. Barres also showed that the astrocytes appeared to play a crucial role in forming synapses, the microscopic connections between neurons that encode memory. In isolation, neurons were capable of forming the spiny appendages necessary to reach the synapses. But without astrocytes, they were incapable of connecting to one another.

Hardly anyone believed him. When he was a young faculty member at Stanford in the 1990s, one of his grant applications to the National Institutes of Health was rejected seven times. “Reviewers kept saying, ‘Nah, there’s no way glia could be doing this,’” Barres recalls. “And even after we published two papers in Science showing that [astrocytes] had profound, almost all-or-nothing effects in controlling synapses’ formation or synapse activity, I still couldn’t get funded! I think it’s still hard to get people to think about glia as doing anything active in the nervous system.”

Marked for elimination

Beth Stevens came to study glia by accident. After graduating from Northeastern University in 1993, she followed her future husband to Washington, D.C., where he had gotten work in the U.S. Senate. Stevens had been pre-med in college and hoped to work in a lab at the National Institutes of Health. But with no previous research experience, she was soundly rebuffed. So she took a job waiting tables at a Chili’s restaurant in nearby Rockville, Maryland, and showed up at NIH with her résumé every week.

After a few months, Stevens received a call from a researcher named Doug Fields, who needed help in his lab. Fields was studying the intricacies of the process in which neurons become insulated in a coating called myelin. That insulation is essential for the transmission of electrical impulses.

As Stevens spent the following years pursuing a PhD at the University of Maryland, she was intrigued by the role that glial cells played in insulating neurons. Along the way, she became familiar with other insights into glial cells that were beginning to emerge, especially from the lab of Ben Barres. Which is why, soon after completing her PhD in 2003, Stevens found herself a postdoc in Barres’s lab at Stanford, about to make a crucial discovery.

Barres’s group had begun to identify the specific compounds astrocytes secreted that seemed to cause neurons to grow synapses. And eventually, they noticed that these compounds also stimulated production of a protein called C1q.

Conventional wisdom held that C1q was activated only in sick cells—the protein marked them to be eaten up by immune cells—and only outside the brain. But Barres had found it in the brain. And it was in healthy neurons that were arguably at their most robust stage: in early development. What was the C1q protein doing there?

https://d267cvn3rvuq91.cloudfront.net/i/images/glia33.jpg?sw=590&cx=0&cy=0&cw=2106&ch=2106

A stained astrocyte.

The answer lies in the fact that marking cells for elimination is not something that happens only in diseased brains; it is also essential for development. As brains develop, their neurons form far more synaptic connections than they will eventually need. Only the ones that are used are allowed to remain. This pruning allows for the most efficient flow of neural transmissions in the brain, removing noise that might muddy the signal.

But it was unknown how exactly the process worked. Was it possible that C1q helped signal the brain to prune unused synapses? Stevens focused her postdoctoral research on finding out. “We could have been completely wrong,” she recalls. “But we went for it.”

It paid off. In a 2007 paper, Barres and Stevens showed that C1q indeed plays a role in eliminating unneeded neurons in the developing brain. And they found that the protein is virtually absent in healthy adult neurons.

Now the scientists faced a new puzzle. Does C1q show up in brain diseases because the same mechanism involved in pruning a developing brain later goes awry? Indeed, evidence was already growing that one of the earliest events in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s was significant loss of synapses.

When Stevens and Barres examined mice bred to develop glaucoma, a neurodegenerative disease that kills neurons in the optic system, they found that C1q appeared long before any other detectable sign that the disease was taking hold. It cropped up even before the cells started dying.

This suggested the immune cells might in fact cause the disease, or at the very least accelerate it. And that offered an intriguing possibility: that something could be made to halt the process. Barres founded a company, Annexon Biosciences, to develop drugs that could block C1q. Last week’s paper published by Barres, Stevens, and other researchers shows that a compound being tested by Annexon appears to be able to prevent the onset of Alzheimer’s in mice bred to develop the disease. Now the company hopes to test it in humans in the next two years.

Paths to treatments

To better understand the process that C1q helps trigger, Stevens and Barres wanted to figure out what actually plays the role of Pac-Man, eating up the synapses marked for death. It was well known that white blood cells known as macrophages gobbled up diseased cells and foreign invaders in the rest of the body. But macrophages are not usually present in the brain. For their theory to work, there had to be some other mechanism. And further research has shown that the cells doing the eating even in healthy brains are those mysterious clusters of material that Beth Stevens, for years, had been gazing right past in the microscope—the microglia that Río Hortega identified almost 100 years ago.

Now Stevens’s lab at Harvard, which she opened in 2008, devotes half its efforts to figuring out what microglia are doing and what causes them to do it. These cells, it turns out, appear in the mouse embryo at day eight, before any other brain cell, which suggests they might help guide the rest of brain development—and could contribute to any number of neurodevelopmental diseases when they go wrong.

Meanwhile, she is also expanding her study of the way different substances determine what happens in the brain. C1q is actually just the first in a series of proteins that accumulate on synapses marked for elimination. Stevens has begun to uncover evidence that there is a wide array of protective “don’t eat me” molecules too. It’s the balance between all these cues that regulates whether microglia are summoned to destroy synapses. Problems in any one could, conceivably, mess up the system.

Evidence is now growing that microglia are involved in several neurodevelopmental and psychiatric problems. The potential link to schizophrenia that was revealed in January emerged after researchers at the Broad Institute, led by Steven McCarroll and a graduate student named Aswin Sekar, followed a trail of genetic clues that led them directly to Stevens’s work. In 2009, three consortia from around the globe had published papers comparing DNA in people with and without schizophrenia. It was Sekar who identified a possible pattern: the more a specific type of protein was present in synapses, the higher the risk of developing the disease. The protein, C4, was closely related to C1q, the one first identified in the brain by Stevens and Barres.

McCarroll knew that schizophrenia strikes in late adolescence and early adulthood, a time when brain circuits in the prefrontal cortex undergo extensive pruning. Others had found that areas of the prefrontal cortex are among those most ravaged by the disease, which leads to massive synapse loss. Could it be that over-pruning by rogue microglia is part of what causes schizophrenia?

To find out, Sekar and McCarroll got in touch with Stevens, and the two labs began to hold joint weekly meetings. They soon demonstrated that C4 also had a role in pruning synapses in the brains of young mice, suggesting that excessive levels of the protein could indeed lead to over-pruning—and to the thinning out of brain tissue that appears to occur as symptoms such as psychotic episodes grow worse.

If the brain damage seen in Parkinson’s and Alzheimer’s stems from over-pruning that might begin early in life, why don’t symptoms of those diseases show up until later? Barres thinks he knows. He notes that the brain can normally compensate for injury by rewiring itself and generating new synapses. It also contains a lot of redundancy. That would explain why patients with Parkinson’s disease don’t show discernible symptoms until they have lost 90 percent of the neurons that produce dopamine.

It also might mean that subtle symptoms could in fact be detected much earlier. Barres points to a study of nuns published in 2000. When researchers analyzed essays the nuns had written upon entering their convents decades before, they found that women who went on to develop Alzheimer’s had shown less “idea density” even in their 20s. “I think the implication of that is they could be lifelong diseases,” Barres says. “The disease process could be going on for decades and the brain is just compensating, rewiring, making new synapses.” At some point, the microglia are triggered to remove too many cells, Barres argues, and the symptoms of the disease begin to manifest fully.

Turning this insight into a treatment is far from straightforward, because much remains unclear. Perhaps an overly aggressive response from microglia is determined by some combination of genetic variants not shared by everyone. Stevens also notes that diseases like schizophrenia are not caused by one mutation; rather, a wide array of mutations with small effects cause problems when they act in concert. The genes that control the production of C4 and other immune-system proteins may be only part of the story. That may explain why not everyone who has a C4 mutation will go on to develop schizophrenia.

Nonetheless, if Barres and Stevens are right that the immune system is a common mechanism behind devastating brain disorders, that in itself is a fundamental breakthrough. Because we have not known the mechanisms that trigger such diseases, medical researchers have been able only to alleviate the symptoms rather than attack the causes. There are no drugs available to halt or even slow neurodegeneration in diseases like Alzheimer’s. Some drugs elevate neurotransmitters in ways that briefly make it easier for individuals with dementia to form new synaptic connections, but they don’t reduce the rate at which existing synapses are destroyed. Similarly, there are no treatments that tackle the causes of autism or schizophrenia. Even slowing the progress of these disorders would be a major advance. We might finally go after diseases that have run unchecked for generations.

“We’re a ways away from a cure,” Stevens says. “But we definitely have a path forward.”

Adam Piore is a freelance writer who wrote “A Shocking Way to Fix the Brain”  in November/December 2015.

 

Int Immunopharmacol. 2001 Mar;1(3):365-92.

Genetic, structural and functional diversities of human complement components C4A and C4B and their mouse homologues, Slp and C4.

Blanchong CA1Chung EKRupert KLYang YYang ZZhou BMoulds JMYu CY.

Author information

Abstract

The complement protein C4 is a non-enzymatic component of the C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. The covalent binding of C4 to immunoglobulins and immune complexes (IC) also enhances the solubilization of immune aggregates, and the clearance of IC through complement receptor one (CR1) on erythrocytes. Human C4 is the most polymorphic protein of the complement system. In this review, we summarize the current concepts on the 1-2-3 loci model of C4A and C4B genes in the population, factors affecting the expression levels of C4 transcripts and proteins, and the structural, functional and serological diversities of the C4A and C4B proteins. The diversities and polymorphisms of the mouse homologues Slp and C4 proteins are described and contrasted with their human homologues. The human C4 genes are located in the MHC class III region on chromosome 6. Each human C4 gene consists of 41 exons coding for a 5.4-kb transcript. The long gene is 20.6 kb and the short gene is 14.2 kb. In the Caucasian population 55% of the MHC haplotypes have the 2-locus, C4A-C4B configurations and 45% have an unequal number of C4A and C4B genes. Moreover, three-quarters of C4 genes harbor the 6.4 kb endogenous retrovirus HERV-K(C4) in the intron 9 of the long genes. Duplication of a C4 gene always concurs with its adjacent genes RP, CYP21 and TNX, which together form a genetic unit termed an RCCX module. Monomodular, bimodular and trimodular RCCX structures with 1, 2 and 3 complement C4 genes have frequencies of 17%, 69% and 14%, respectively. Partial deficiencies of C4A and C4B, primarily due to the presence of monomodular haplotypes and homo-expression of C4A proteins from bimodular structures, have a combined frequency of 31.6%. Multiple structural isoforms of each C4A and C4B allotype exist in the circulation because of the imperfect and incomplete proteolytic processing of the precursor protein to form the beta-alpha-gamma structures. Immunofixation experiments of C4A and C4B demonstrate > 41 allotypes in the two classes of proteins. A compilation of polymorphic sites from limited C4 sequences revealed the presence of 24 polymophic residues, mostly clustered C-terminal to the thioester bond within the C4d region of the alpha-chain. The covalent binding affinities of the thioester carbonyl group of C4A and C4B appear to be modulated by four isotypic residues at positions 1101, 1102, 1105 and 1106. Site directed mutagenesis experiments revealed that D1106 is responsible for the effective binding of C4A to form amide bonds with immune aggregates or protein antigens, and H1106 of C4B catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens. The expression of C4 is inducible or enhanced by gamma-interferon. The liver is the main organ that synthesizes and secretes C4A and C4B to the circulation but there are many extra-hepatic sites producing moderate quantities of C4 for local defense. The plasma protein levels of C4A and C4B are mainly determined by the corresponding gene dosage. However, C4B proteins encoded by monomodular short genes may have relatively higher concentrations than those from long C4A genes. The 5′ regulatory sequence of a C4 gene contains a Spl site, three E-boxes but no TATA box. The sequences beyond–1524 nt may be completely different as the C4 genes at RCCX module I have RPI-specific sequences, while those at Modules II, III and IV have TNXA-specific sequences. The remarkable genetic diversity of human C4A and C4B probably promotes the exchange of genetic information to create and maintain the quantitative and qualitative variations of C4A and C4B proteins in the population, as driven by the selection pressure against a great variety of microbes. An undesirable accompanying byproduct of this phenomenon is the inherent deleterious recombinations among the RCCX constituents leading to autoimmune and genetic disorders.

 

C4A isotype is responsible for effective binding to form amide bonds with immune aggregates or protein antigens, while C4B isotype catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens.

Derived from proteolytic degradation of complement C4, C4a anaphylatoxin is a mediator of local inflammatory process.

 

Schizophrenia and the Synapse

Genetic evidence suggests that overactive synaptic pruning drives development of schizophrenia.

By Ruth Williams | January 27, 2016

http://www.the-scientist.com/?articles.view/articleNo/45189/title/Schizophrenia-and-the-Synapse/

Compared to the brains of healthy individuals, those of people with schizophrenia have higher expression of a gene called C4, according to a paper published inNature today (January 27). The gene encodes an immune protein that moonlights in the brain as an eradicator of unwanted neural connections (synapses). The findings, which suggest increased synaptic pruning is a feature of the disease, are a direct extension of genome-wide association studies (GWASs) that pointed to the major histocompatibility (MHC) locus as a key region associated with schizophrenia risk.

“The MHC [locus] is the first and the strongest genetic association for schizophrenia, but many people have said this finding is not useful,” said psychiatric geneticist Patrick Sullivan of the University of North Carolina School of Medicine who was not involved in the study. “The value of [the present study is] to show that not only is it useful, but it opens up new and extremely interesting ideas about the biology and therapeutics of schizophrenia.”

Schizophrenia has a strong genetic component—it runs in families—yet, because of the complex nature of the condition, no specific genes or mutations have been identified. The pathological processes driving the disease remain a mystery.

Researchers have turned to GWASs in the hope of finding specific genetic variations associated with schizophrenia, but even these have not provided clear candidates.

“There are some instances where genome-wide association will literally hit one base [in the DNA],” explained Sullivan. While a 2014 schizophrenia GWAS highlighted the MHC locus on chromosome 6 as a strong risk area, the association spanned hundreds of possible genes and did not reveal specific nucleotide changes. In short, any hope of pinpointing the MHC association was going to be “really challenging,” said geneticist Steve McCarroll of Harvard who led the new study.

Nevertheless, McCarroll and colleagues zeroed in on the particular region of the MHC with the highest GWAS score—the C4 gene—and set about examining how the area’s structural architecture varied in patients and healthy people.

The C4 gene can exist in multiple copies (from one to four) on each copy of chromosome 6, and has four different forms: C4A-short, C4B-short, C4A-long, and C4B-long. The researchers first examined the “structural alleles” of the C4 locus—that is, the combinations and copy numbers of the different C4 forms—in healthy individuals. They then examined how these structural alleles related to expression of both C4Aand C4B messenger RNAs (mRNAs) in postmortem brain tissues.

…………..

Schizophrenia risk from complex variation of complement component 4

Aswin Sekar, Allison R. Bialas, Heather de Rivera, …, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Mark J. Daly, Michael C. Carroll, Beth Stevens & Steven A. McCarroll

Nature (11 Feb 2016); 530: 177–183 http://dx.doi.org:/10.1038/nature16549

Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia’s strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.

  1. Cannon, T. D. et al. Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia. Proc. Natl Acad. Sci. USA 99, 3228–3233 (2002)
  1. Cannon, T. D. et al. Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biol. Psychiatry 77,147–157 (2015)
  1. Garey, L. J. et al. Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J. Neurol. Neurosurg. Psychiatry 65, 446–453 (1998)
  1. Glantz, L. A. & Lewis, D. A. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch. Gen. Psychiatry 57, 65–73 (2000)
  1. Glausier, J. R. & Lewis, D. A. Dendritic spine pathology in schizophrenia. Neuroscience 251,90–107 (2013)
  1. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014)
  1. Shi, J. et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460, 753–757 (2009)
  1. Stefansson, H. et al. Common variants conferring risk of schizophrenia. Nature 460,744–747 (2009)
  1. International Schizophrenia Consortium et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009)
  1. Schizophrenia Psychiatric Genome-Wide Association Study Consortium. Genome-wide association study identifies five new schizophrenia loci. Nature Genet . 43, 969–976 (2011)

 

The strongest genetic association found in schizophrenia is its association to genetic markers across the major histocompatibility complex (MHC) locus, first described in three Nature papers in 2009. …

 

Schizophrenia: From genetics to physiology at last

Ryan S. DhindsaDavid B. Goldstein
Nature  (11 Feb 2016); 530:162–163   http://dx.doi.org:/10.1038/nature16874

  1. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Nature511,421–427 (2014).
  2. Stevens, B. et alCell131, 1164–1178 (2007).
  3. Cannon, T. D. et al Psychiatry77, 147–157 (2015).
  4. Glausier, J. R. & Lewis, D. A. Neuroscience251, 90–107 (2013).
  5. Glantz, L. A. & Lewis, D. A.  Gen. Psychiatry57, 65–73 (2000).

 

 Jianxin Shi1, et al.   Common variants on chromosome 6p22.1 are associated with schizophrenia.  Nature 460, 753-757 (6 August 2009) | doi:10.1038/nature08192; Received 29 May 2009; Accepted 10 June 2009; Published online 1 July 2009; Corrected 6 August 2009

Schizophrenia, a devastating psychiatric disorder, has a prevalence of 0.5–1%, with high heritability (80–85%) and complex transmission1. Recent studies implicate rare, large, high-penetrance copy number variants in some cases2, but the genes or biological mechanisms that underlie susceptibility are not known. Here we show that schizophrenia is significantly associated with single nucleotide polymorphisms (SNPs) in the extended major histocompatibility complex region on chromosome 6. We carried out a genome-wide association study of common SNPs in the Molecular Genetics of Schizophrenia (MGS) case-control sample, and then a meta-analysis of data from the MGS, International Schizophrenia Consortium and SGENE data sets. No MGS finding achieved genome-wide statistical significance. In the meta-analysis of European-ancestry subjects (8,008 cases, 19,077 controls), significant association with schizophrenia was observed in a region of linkage disequilibrium on chromosome 6p22.1 (P = 9.54 × 10-9). This region includes a histone gene cluster and several immunity-related genes—possibly implicating aetiological mechanisms involving chromatin modification, transcriptional regulation, autoimmunity and/or infection. These results demonstrate that common schizophrenia susceptibility alleles can be detected. The characterization of these signals will suggest important directions for research on susceptibility mechanisms.

Editor’s Summary   6 August 2009
Schizophrenia risk: link to chromosome 6p22.1

A genome-wide association study using the Molecular Genetics of Schizophrenia case-control data set, followed by a meta-analysis that included over 8,000 cases and 19,000 controls, revealed that while common genetic variation that underlies risk to schizophrenia can be identified, there probably are few or no single common loci with large effects. The common variants identified here lie on chromosome 6p22.1 in a region that includes a histone gene cluster and several genes implicated in immunity.

Letter

Hreinn Stefansson1,48, et al. Common variants conferring risk of schizophrenia.
Nature 460, 744-747 (6 August 2009) | doi:10.1038/nature08186; Received 16 March 2009; Accepted 5 June 2009; Published online 1 July 2009

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders1, 2, 3. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the ‘genomic disorders’, have not yet been characterized4. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

 

Letter

The International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.  Nature 460, 748-752 (6 August 2009) | doi:10.1038/nature08185; Received 11 February 2009; Accepted 8 June 2009; Published online 1 July 2009; Corrected 6 August 2009

Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%1, 2. We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.

 

The Psychiatric GWAS Consortium Steering Committee. A framework for interpreting genome-wide association studies of psychiatric disorders.  Molecular Psychiatry (2009) 14, 10–17; doi:10.1038/mp.2008.126; published online 11 November 2008

Genome-wide association studies (GWAS) have yielded a plethora of new findings in the past 3 years. By early 2009, GWAS on 47 samples of subjects with attention-deficit hyperactivity disorder, autism, bipolar disorder, major depressive disorder and schizophrenia will be completed. Taken together, these GWAS constitute the largest biological experiment ever conducted in psychiatry (59 000 independent cases and controls, 7700 family trios and >40 billion genotypes). We know that GWAS can work, and the question now is whether it will work for psychiatric disorders. In this review, we describe these studies, the Psychiatric GWAS Consortium for meta-analyses of these data, and provide a logical framework for interpretation of some of the conceivable outcomes.

Keywords: genome-wide association, attention-deficit hyperactivity disorder, autism, bipolar disorder, major depressive disorder, schizophrenia

The purpose of this article is to consider the ‘big picture’ and to provide a logical framework for the possible outcomes of these studies. This is not a review of GWAS per se as many excellent reviews of this technically and statistically intricate methodological approach are available.789101112 This is also not a review of the advantages and disadvantages of different study designs and sampling strategies for the dissection of complex psychiatric traits. We would like to consider how the dozens of GWAS papers that will soon be in the literature can be synthesized: what can integrated mega-analyses (meta-analysis is based on summary data (for example, odds ratios) from all available studies whereas ‘mega-analysis’ uses individual-level genotype and phenotype data) of all available GWAS data tell us about the etiology of these psychiatric disorders? This is an exceptional opportunity as positive or negative results will enable us to learn hard facts about these critically important psychiatric disorders. We suggest that it is not a matter of ‘success versus failure’ or ‘optimism versus pessimism’ but rather an opportunity for systematic and logical approaches to empirical data whereby both positive and appropriately qualified negative findings are informative.

The studies that comprise the Psychiatric GWAS Consortium (PGC; http://pgc.unc.edu) are shown in Table 1. GWAS data for ADHD, autism, bipolar disorder, major depressive disorder and schizophrenia from 42 samples of European subjects should be available for mega-analyses by early 2009 (>59 000 independent cases and controls and >7700 family trios). To our knowledge, the PGC will have access to the largest set of GWAS data available.

A major change in human genetics in the past 5 years has been in the growth of controlled-access data repositories, and individual phenotype and genotype data are now available for many of the studies in Table 1. When the PGC mega-analyses are completed, most data will be available to researchers via the NIMH Human Genetics Initiative (http://nimhgenetics.org). Although the ready availability of GWAS data is a benefit to the field by allowing rapid application of a wide range of analytic strategies to GWAS data, there are potential disadvantages. GWAS mega-analysis is complex and requires considerable care and expertise to be done validly. For psychiatric phenotypes, there is the additional challenge of working with disease entities based largely on clinical description, with unknown biological validity and having both substantial clinical variation within diagnostic categories as well as overlaps across categories.13 Given the urgent need to know if there are replicable genotype–phenotype associations, a new type of collaboration was required.

The purpose of the PGC is to conduct rigorous and comprehensive within- and cross-disorder GWAS mega-analyses. The PGC began in early 2007 with the principal investigators of the four GAIN GWAS,14 and within six months had grown to 110 participating scientists from 54 institutions in 11 countries. The PGC has a coordinating committee, five disease-working groups, a cross-disorder group, a statistical analysis and computational group, and a cluster computer for statistical analysis. It is remarkable that almost all investigators approached agreed to participate and that no one has left the PGC. Most effort is donated but we have obtained funding from the NIMH, the Netherlands Scientific Organization, Hersenstichting Nederland and NARSAD.

The PGC has two major specific aims. (1) Within-disorder mega-analyses: conduct separate mega-analyses of all available GWAS data for ADHD, autism, bipolar disorder, major depressive disorder, and schizophrenia to attempt to identify genetic variation convincingly associated with any one of these five disorders. (2) Cross-disorder mega-analyses: the clinically-derived DSM-IV and ICD-10 definitions may not directly reflect the fundamental genetic architecture.15 There are two subaims. (2a) Conduct mega-analysis to identify genetic variation convincingly associated with conventional definitions of two or more disorders. This nosological aim could assist in delineating the boundaries of this set of disorders. (2b) An expert working group will convert epidemiological and genetic epidemiological evidence into explicit hypotheses about overlap among these disorders, and then conduct mega-analyses based on these definitions (for example, to examine the lifetime presence of idiopathic psychotic features without regard to diagnostic context).

The goal of the PGC is to identify convincing genetic variation-disease associations. A convincing association would be extremely unlikely to result from chance, show consistent effect sizes across all or almost all samples and be impervious to vigorous attempts to disprove the finding (for example, by investigating sources of bias, confirmatory genotyping, and so on). Careful attention will be paid to the impact of potential sources of heterogeneity17 with the goal of assessing its impact without minimizing its presence.

Biological plausibility is not an initial requirement for a convincing statistical association, as there are many examples in human genetics of previously unsuspected candidate genes nonetheless showing highly compelling associations. For example, multiple SNPs in intron 1 of the FTO gene were associated with body mass index in 13 cohorts with 38 759 participants18 and yet ‘FTO’ does not appear in an exhaustive 116 page compilation of genetic studies of obesity.19 Some strong associations are in gene deserts: multiple studies have found convincing association between prostate cancer and a region on 8q24 that is ~250 kb from the nearest annotated gene.20 Both of these examples are being intensively investigated and we suspect that a compelling mechanistic ‘story’ will emerge in the near future. The presence of a compelling association without an obvious biological mechanism establishes a priority research area for molecular biology and neuroscience of a psychiatric disorder.

The PGC will use mega-analysis as the main analytic tool as individual-level data will be available from almost all samples. To wield this tool appropriately, a number of preconditions must be met. First, genotype data from different GWAS platforms must be made comparable as the direct overlap between platforms is often modest. This requires meticulous quality control for the inclusion of both SNPs and subjects and attention to the factors that can cause bias (for example, population stratification, cryptic relatedness or genotyping batch effects). Genotype harmonization can be accomplished using imputation (2122, for example) so that the same set of ~2 million2324 directly or imputed SNP genotypes are available for all subjects. Second, phenotypes need to be harmonized across studies. This is one of the most crucial components of the PGC and we are fortunate to have world experts directing the work. Third, the mega-analyses will assess potential heterogeneity of associations across samples.

A decision-tree schematic of the potential outcomes of the PGC mega-analyses is shown in Figure 1. Note that many of the possibilities in Figure 1 are not mutually exclusive and different disorders may take different paths through this framework. It is possible that there eventually will be dozens or hundreds of sequence variants strictly associated with these disorders with frequencies ranging from very rare to common.

………

 

GWAS has the potential to yield considerable insights but it is no panacea and may well perform differently for psychiatric disorders. Even if these psychiatric GWAS efforts are successful, the outcomes will be complex. GWAS may help us learn that clinical syndromes are actually many different things—for example, proportions of individuals with schizophrenia might evidence associations with rare CNVs of major effect,56 with more common genetic variation in dozens (perhaps hundreds) of genomic regions, between genetic variation strongly modified by environmental risk factors, and some proportion may be genetically indistinguishable from the general population. Moreover, as fuel to long-standing ‘lumper versus splitter’ debates in psychiatric nosology, empirical data might show that some clinical disorders or identifiable subsets of subjects might overlap considerably.

The critical advantage of GWAS is the search of a ‘closed’ hypothesis space. If the large amount of GWAS data being generated are analyzed within a strict and coherent framework, it should be possible to establish hard facts about the fundamental genetic architecture of a set of important psychiatric disorders—which might include positive evidence of what these disorders are or exclusionary evidence of what they are not. Whatever the results, these historically large efforts should yield hard facts about ADHD, autism, bipolar disorder, major depressive disorder and schizophrenia that may help guide the next era of psychiatric research.

  1. Pe’er I, Yelensky R, Altshuler D, Daly MJ. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet Epidemiol 2008; 32: 381–385. | Article | PubMed |
  2. Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 2008; 358: 667–675. | Article | PubMed | ChemPort |

 

Letter

Hreinn Stefansson1,36, et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232-236 (11 September 2008) | doi:10.1038/nature07229; Received 17 April 2008; Accepted 8 July 2008; Corrected 11 September 2008

Reduced fecundity, associated with severe mental disorders1, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism2, schizophrenia3 and mental retardation4. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation4, 5 and autism2. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novoCNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.

 

The C4 gene can exist in multiple copies (from one to four) on each copy of chromosome 6, and has four different forms: C4A-short, C4B-short, C4A-long, and C4B-long. The researchers first examined the “structural alleles” of the C4 locus—that is, the combinations and copy numbers of the different C4 forms—in healthy individuals. They then examined how these structural alleles related to expression of both C4Aand C4B messenger RNAs (mRNAs) in postmortem brain tissues.

From this the researchers had a clear picture of how the architecture of the C4 locus affected expression ofC4A and C4B. Next, they compared DNA from roughly 30,000 schizophrenia patients with that from 35,000 healthy controls, and a correlation emerged: the alleles most strongly associated with schizophrenia were also those that were associated with the highest C4A expression. Measuring C4A mRNA levels in the brains of 35 schizophrenia patients and 70 controls then revealed that, on average, C4A levels in the patients’ brains were 1.4-fold higher.

C4 is an immune system “complement” factor—a small secreted protein that assists immune cells in the targeting and removal of pathogens. The discovery of C4’s association to schizophrenia, said McCarroll, “would have seemed random and puzzling if it wasn’t for work . . . showing that other complement components regulate brain wiring.” Indeed, complement protein C3 locates at synapses that are going to be eliminated in the brain, explained McCarroll, “and C4 was known to interact with C3 . . . so we thought well, actually, this might make sense.”

McCarroll’s team went on to perform studies in mice that revealed C4 is necessary for C3 to be deposited at synapses. They also showed that the more copies of the C4 gene present in a mouse, the more the animal’s neurons were pruned.

Synaptic pruning is a normal part of development and is thought to reflect the process of learning, where the brain strengthens some connections and eradicates others. Interestingly, the brains of deceased schizophrenia patients exhibit reduced neuron density. The new results, therefore, “make a lot of sense,” said Cardiff University’s Andrew Pocklington who did not participate in the work. They also make sense “in terms of the time period when synaptic pruning is occurring, which sort of overlaps with the period of onset for schizophrenia: around adolescence and early adulthood,” he added.

“[C4] has not been on anybody’s radar for having anything to do with schizophrenia, and now it is and there’s a whole bunch of really neat stuff that could happen,” said Sullivan. For one, he suggested, “this molecule could be something that is amenable to therapeutics.”

 

 

UniProtKB

Derived from proteolytic degradation of complement C4, C4a anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes.

Non-enzymatic component of C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. Covalently binds to immunoglobulins and immune complexes and enhances the solubilization of immune aggregates and the clearance of IC through CR1 on erythrocytes. C4A isotype is responsible for effective binding to form amide bonds with immune aggregates or protein antigens, while C4B isotype catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens.

 

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Dense Breast Mammogram

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

The Problem With Mammograms

http://forward.com/culture/324003/the-problem-with-mammograms/#ixzz3queBnx00

 

Hallie Leighton had dense breasts — a fact she discovered only in her late 30s, via a mammogram. She grew up in an Ashkenazi family in New York, pursued a career in writing and worked with organizations promoting peace between Israelis and Arabs. By 2013 she was making a documentary on her father Jan Leighton, an actor who set the record as an actor for appearing in the most roles (2,407 according to the 1985 Guinness Book of World Records). She was never able to complete it. She died that year, at the age of 42.

Every woman in Leighton’s family had breast cancer, so she began getting annual mammograms at 35 — five years earlier than the recommended age. In 2009 the results of Leighton’s mammogram came in as “negative” or “normal”; by 2013 she was bedridden, undergoing her final days of chemotherapy.

When Leighton was first diagnosed in 2010, her doctor told her, “You have breast cancer, and it was there in 2009.” The tumor in Leighton’s breast went undiscovered until it was palpable — and at that point, the cancer was already in stage 4.

Happygram,” a documentary which exposes some of the shortcomings in mammography, chronicles Leighton’s struggle with cancer and the implications of having dense breasts.

“Most women simply aren’t informed that they have dense breast tissue,” said Leighton’s best friend Julie Marron. She wrote and directed the documentary, which is currently screening at film festivals around the country.

Breast density is defined by the relative amount of fat in relation to the amount of connective and epithelial tissue (tissue that lines blood vessels and cavities). When more than 50% of breast tissue is connective and epithelial tissue, instead of fatty tissue, the breasts are considered dense. Mammography is the only way to determine breast density.

“If you have dense breasts, what looks dense on a mammogram looks the same as a cancer would look. It tends to confuse or confound the physician, and reduces the sensitivity of the mammogram,” said Gerald Kolb, founder and president of The Breast Group, which counsels clients on different technologies in breast care. “Hallie Leighton’s breasts looked like snowballs; there was no chance they were going to find anything with the mammogram.”

Forty percent of women who are screened for breast cancer have dense breast tissue. These women also account for more than 70% of all invasive cancers. “Mammograms are not very effective screening tools for these women, as they miss between 50% and 75% of all invasive cancers in dense breast tissue,” Marron said. “This is obviously a very critical issue when you are dealing with a population that is more likely to develop cancer.”

Ashkenazi women are even more at risk. They are 1.6 times more likely than the general population to have dense breast tissue, according to Kolb. Moreover, one in 40 Ashkenazi women will test positive for one or both of BRCA gene mutations responsible for breast cancer. For the general population, that number is between one in 350 and one in 800.The BRCA 1 or 2 genes don’t cause cancer, they fight cancer, Kolb says. But if the gene is mutated, the body is not as well equipped to fight the cancer.

“A woman with a BRCA mutation has a lifetime risk of around 33% to 87%, depending on the gene and mutation,” Marron said. “Compare this to a lifetime risk of 12% for developing breast cancer for the overall population.” BRCA gene mutations can be inherited from either or both parents, and therefore they can be present in men as well as in women.

Breast density and BRCA gene mutations are not directly related, but both independently present an increased susceptibility to breast cancer.

“The biggest risk is that a doctor is not going to find the cancer when it’s really small,” Kolb said. When a tumor is detected at a centimeter or smaller, there’s a 95% cure rate. But if the cancer is the size of a golf ball by the time it’s detected, Kolb says, the woman has a 60% chance of living for five years, and then her mortality increases dramatically.

The good news is that mammography isn’t the only method of detecting breast cancer; the bad news is that very few people know this. “What we’re trying to do in the density movement is give women enough information so they can ask appropriate questions of a doctor,” Kolb said.

Kolb advises high-risk women to get a genetic risk analysis, which can be performed by a genetic counselor or a radiologist. He advises getting the risk analysis as early as age 25, but doing so is a personal decision. Not every woman is emotionally prepared to know the results.

“Mammography is a starting point,” said Dr. Dennis McDonald, a California-based women’s imager. Additionally, doctors recommend that women with dense breasts get an MRI, which McDonald says is reserved for high-risk women. It’s an expensive, invasive and time-consuming procedure that requires the injection of fluid in order to read the MRI. As of yet, doctors do not know the side effects of getting an annual MRI.

“A doctor should have started [Leighton] on an MRI right away. She was high risk and they chose to just monitor with a mammogram,” Kolb said. “That’s insufficient.”

Breast ultrasound is another alternative for women with dense breast tissue. “Most of the time, breast density doesn’t present a problem [with ultrasounds],” McDonald said. Though the ultrasound is effective in detecting cancer, he says the downside is that radiologists are often not that comfortable with the technology, simply because they have little experience with it. There are also a lot of false positives, he adds, which result in unnecessary exams or biopsies.

As “Happygram” documents, informing women of their breast density and of alternatives to mammography is a highly charged political issue.

“The whole breast cancer industry has grown up around mammograms,” Marron said. “Physicians weren’t educated on [breast density], deliberately so to a certain extent, and refused to inform patients on this issue, which is really outrageous if you think about it.” Marron says that doctors are required by law and ethical guidelines to inform patients of “material” medical information. “There is no legitimate reason that women have not been informed of this information,” she noted.

After Leighton’s diagnosis, she wanted to ensure that other women didn’t suffer the same misfortune of all-too-late tumor discovery on account of dense breast tissue. She gave media interviews, lobbied in Albany and starred in “Happygram,” all the while undergoing chemotherapy. She died four months after the Breast Density Information Bill passed in New York.

The law requires that every mammography report given to a patient with dense breasts inform the patient in plain language that she has dense breast tissue and that she should talk to her physician about the possible benefits of additional screenings. In New York, the first state in the nation to pass this kind of law, at least 2,500 women with dense breasts and invasive breast cancer received “normal” or “negative” results on their mammograms.

Similar legislation has been passed in more than 20 states throughout the country, but not without objection. Many well-intentioned radiologists, poorly informed about alternative screening options, feared that telling women the limitations of mammography would cause them to lose faith in it altogether and not get tested. Others argued that the information would make women anxious, and that it wouldn’t be fair for those who couldn’t afford additional testing. And still further arguments against informing women were possibly impacted by financial considerations, Marron added.

“Women aren’t getting the benefit of full notification across the board yet,” Marron said. “I think that has to change through education. That’s the primary reason we made this movie. There’s been so much resistance within the medical community to telling women. Change isn’t going to come from the medical community, it has to come from the patients.”

Ashkenazi women shouldn’t panic, Kolb says, but they need to carefully examine their breast density and alternative screening options: “Anytime you have a preventative tragedy like that, you have to do everything in your power to stop it from happening.”

Madison Margolin is a freelance writer based in New York. She writes frequently for the Village Voice.

Read more: http://forward.com/culture/324003/the-problem-with-mammograms/#ixzz3qufQOSmn

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Twitter Offers Valuable Insights Into The Experience Of MRI Patients, Charles Sturt University Study

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Twitter offers valuable insights into the experience of MRI patients

Tweets can give medical professionals a window into the minds of patients, according to a new study published in the Journal of Medical Imaging and Radiation Sciences

Philadelphia, PA, October 28, 2015 – Magnetic Resonance Imaging (MRI) can be a stressful experience for many people, but clinicians have few ways to track the thoughts and feelings of their patients regarding this procedure. While the social networking site Twitter is known for breaking news and celebrity tweets, it may also prove to be a valuable feedback tool for medical professionals looking to improve the patient experience, according to a new study published in the December issue of the Journal of Medical Imaging and Radiation Sciences.

Johnathan Hewis, MSc, PgCert (LTHE), PgCert (BE), BSc Hon, an investigator from Charles Sturt University in Australia, analyzed 464 tweets related to MRI over the course of one month and found that patients, their friends, and family members were sharing their thoughts and feelings about all aspects of the procedure through the microblogging site. Tweets were categorized into three themes: MRI appointment, scan experience, and diagnosis.

Twitter is a giant in the social media space. In 2014, 19% of the entire adult population of the U.S. used Twitter, with almost 90% of those individuals accessing the service from their mobile phones. Because it is so ubiquitous, Twitter can provide crucial new insights to which practitioners would otherwise not be privy. In the study, patients expressed anxiety about many aspects of the process, including a lot of stress over the possibility of bad news. “The findings of this study indicate that anticipatory anxiety can manifest over an extended time period and that the focus can shift and change along the MRI journey,” explained Hewis. “An appreciation of anxiety related to results is an important clinical consideration for MRI facilities and referrers.”

The study found that tweets encapsulated patient thoughts about many other parts of the procedure including the cost, the feelings of claustrophobia, having to keep still during the scan, and the sound the MRI machine makes. One particularly memorable tweet about the sound read, “Ugh, having an MRI is like being inside a pissed off fax machine!”

Not all the tweets were centered around stress. Many friends and family members expressed sentiments of support including prayers and offering messages of strength. Some patients used Twitter to praise their healthcare team or give thanks for good results. Others spoke about the fact they liked having an MRI because it gave them some time to themselves or offered them a chance to nap.

Twitter isn’t just words, it’s also a way to share pictures. “An unexpected discovery of the examination preparation process was the ‘MRI gown selfie,'” revealed Hewis. “Fifteen patients tweeted a self-portrait photograph taken inside the changing cubicle while posing in their MRI gown/scrubs. Anecdotally, the ‘MRI gown selfie’ seemed to transcend age.”

During the course of his analysis, Hewis discovered that many patients took issue with the fact that they were not allowed to select the music they listened to during the MRI. “Music choice,” said Hewis, “is a simple intervention that can provide familiarity within a ‘terrifying’ environment.’ The findings of this study reinforce the ‘good practice’ of enabling patients’ choice of music, which may alleviate procedural anxiety.”

With such a broad reach, social networks like Twitter offer medical practitioners the opportunity to access previously unavailable information from their patients, which can help them continuously improve the MRI experience. “MRI patients do tweet about their experiences and these correlate with published findings employing more traditional participant recruitment methods,” concluded Hewis. “This study demonstrates the potential use of Twitter as a viable platform to conduct research into the patient experience within the medical radiation sciences.”

Media Contact

Chris Baumle
hmsmedia@elsevier.com
215-239-3731

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Schizophrenia Brain

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

http://health-innovations.org/2015/10/27/neuroimaging-matches-specific-schizophrenia-behaviour-to-the-brains-anatomy/

Neuroimaging studies using fMRI and PET to examine functional differences in brain activity in patients with schizophrenia have shown that differences seem to most commonly occur in the frontal lobes, hippocampus, and temporal lobes. These differences are heavily linked to the neurocognitive deficits which often occur with schizophrenia, particularly in areas of memory, attention, problem solving, executive function and social cognition.

Earlier studies from the researchers reported evidence suggesting that schizophrenia is not a single disease but a group of eight genetically distinct disorders, each with its own set of symptoms. Results found that distinct sets of genes were strongly associated with particular clinical symptoms.

The current study investigates the brain’s anatomy and shows that there are distinct subgroups of patients with a schizophrenia diagnosis that correlates with symptoms.  This also explains the difficulty in past studies to identify a single set of biomarkers for a single type of schizophrenia.

The current study evaluated scans taken with magnetic resonance imaging (MRI) and a technique called diffusion tensor imaging in 36 healthy volunteers and 47 people with schizophrenia. Results show that the scans of patients with schizophrenia had various abnormalities in portions of the corpus callosum, a bundle of fibers that connects the left and right hemispheres of the brain and is considered critical to neural communication. Characteristics across the corpus callosum revealed in the brain scans matched specific symptoms of schizophrenia. Patients with specific features in one part of the corpus callosum typically displayed bizarre and disorganized behaviour. In other patients, irregularities in a different part of that structure were associated with disorganized thinking and speech and symptoms such as a lack of emotion; other brain abnormalities in the corpus callosum were associated with delusions or hallucinations.  The lab conclude that their findings provide further evidence that schizophrenia is a heterogeneous group of disorders rather than a single disorder.

The team surmise that they didn’t start with people who had certain symptoms and then look to see whether they had corresponding abnormalities in the brain. They note that they just looked at the data, and the patterns began to emerge. They go ony to add that this kind of granular information, combined with data about the genetics of schizophrenia, one day will help physicians treat the disorder in a more precise way.

Many genes responsible for the creation of synaptic proteins have previously shown to be strongly linked to schizophrenia and other brain disorders, however, until now the reasons have not been understood.  Now, researchers from Cardiff University have identified a critical function of what they believe to be schizophrenia’s ‘Rosetta Stone’ gene that could hold the key to decoding the function of all genes involved in the disease.  The team state that the breakthrough has revealed a vulnerable period in the early stages of the brain’s development that they hope can be targeted for future efforts in reversing schizophrenia.  The study is published in the journal Science.

The gene identified in the current study is known as ‘disrupted in schizophrenia-1’ (DISC-1). Earlier studies have shown that when mutated, the gene is a high risk factor for mental illness including schizophrenia, major clinical depression and bipolar disorder.  The aim of the current study was to determine whether DISC-1’s interactions with other proteins early on in the brain’s development had a bearing on the brain’s ability to adapt its structure and function, also known as ‘plasticity’, later on in adulthood.

In order for healthy development of the brain’s synapses to take place, the DISC-1 gene first needs to bind with two other molecules known as ‘Lis’ and ‘Nudel’.  The experiments in mice revealed that by preventing DISC-1 from binding with these molecules prevents cortical neurons in the brain’s largest region from being able to form synapses.  The ability to form coherent thoughts and to properly perceive the world is damaged as a consequence of this.

Preventing DISC-1 from binding with ‘Lis’ and ‘Nudel’ molecules when the brain was fully formed had no effect on its plasticity. However, the researchers were able to pinpoint a seven-day window early on in the brain’s development, one week after birth, where failure to bind had an irreversible effect on the brain’s plasticity later on in life.

The researchers hypothesize that DISC-1 is schizophrenia’s Rosetta Stone gene and could hold the master key to help unlock the understanding of the role played by all risk genes involved in the disease.  They go on to add that they have identified a critical period during brain development that will assist in testing whether other schizophrenia risk genes affecting different regions of the brain create their malfunction during their own critical period.

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Imaging Technology in Cancer Surgery

Author and curator: Dror Nir, PhD

The advent of medical-imaging technologies such as image-fusion, functional-imaging and noninvasive tissue characterisation is playing an imperative role in answering this demand thus transforming the concept of personalized medicine in cancer into practice. The leading modality in that respect is medical imaging. To date, the main imaging systems that can provide reasonable level of cancer detection and localization are: CT, mammography, Multi-Sequence MRI, PET/CT and ultrasound. All of these require skilled operators and experienced imaging interpreters in order to deliver what is required at a reasonable level. It is generally agreed by radiologists and oncologists that in order to provide a comprehensive work-flow that complies with the principles of personalized medicine, future cancer patients’ management will heavily rely on computerized image interpretation applications that will extract from images in a standardized manner measurable imaging biomarkers leading to better clinical assessment of cancer patients.

As consequence of the human genome project and technological advances in gene-sequencing, the understanding of cancer advanced considerably. This led to increase in the offering of treatment options. Yet, surgical resection is still the leading form of therapy offered to patients with organ confined tumors. Obtaining “cancer free” surgical margins is crucial to the surgery outcome in terms of overall survival and patients’ quality of life/morbidity. Currently, a significant portion of surgeries ends up with positive surgical margins leading to poor clinical outcome and increase of costs. To improve on this, large variety of intraoperative imaging-devices aimed at resection-guidance have been introduced and adapted in the last decade and it is expected that this trend will continue.

The Status of Contemporary Image-Guided Modalities in Oncologic Surgery is a review paper presenting a variety of cancer imaging techniques that have been adapted or developed for intra-operative surgical guidance. It also covers novel, cancer-specific contrast agents that are in early stage development and demonstrate significant promise to improve real-time detection of sub-clinical cancer in operative setting.

Another good (free access) review paper is: uPAR-targeted multimodal tracer for pre- and intraoperative imaging in cancer surgery

Abstract

Pre- and intraoperative diagnostic techniques facilitating tumor staging are of paramount importance in colorectal cancer surgery. The urokinase receptor (uPAR) plays an important role in the development of cancer, tumor invasion, angiogenesis, and metastasis and over-expression is found in the majority of carcinomas. This study aims to develop the first clinically relevant anti-uPAR antibody-based imaging agent that combines nuclear (111In) and real-time near-infrared (NIR) fluorescent imaging (ZW800-1). Conjugation and binding capacities were investigated and validated in vitro using spectrophotometry and cell-based assays. In vivo, three human colorectal xenograft models were used including an orthotopic peritoneal carcinomatosis model to image small tumors. Nuclear and NIR fluorescent signals showed clear tumor delineation between 24h and 72h post-injection, with highest tumor-to-background ratios of 5.0 ± 1.3 at 72h using fluorescence and 4.2 ± 0.1 at 24h with radioactivity. 1-2 mm sized tumors could be clearly recognized by their fluorescent rim. This study showed the feasibility of an uPAR-recognizing multimodal agent to visualize tumors during image-guided resections using NIR fluorescence, whereas its nuclear component assisted in the pre-operative non-invasive recognition of tumors using SPECT imaging. This strategy can assist in surgical planning and subsequent precision surgery to reduce the number of incomplete resections.

INTRODUCTION
Diagnosis, staging, and surgical planning of colorectal cancer patients increasingly rely on imaging techniques that provide information about tumor biology and anatomical structures [1-3]. Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) are preoperative nuclear imaging modalities used to provide insights into tumor location, tumor biology, and the surrounding micro-environment [4]. Both techniques depend on the recognition of tumor cells using radioactive ligands. Various monoclonal antibodies, initially developed as therapeutic agents (e.g. cetuximab, bevacizumab, labetuzumab), are labeled with radioactive tracers and evaluated for pre-operative imaging purposes [5-9]. Despite these techniques, during surgery the surgeons still rely mostly on their eyes and hands to distinguish healthy from malignant tissues, resulting in incomplete resections or unnecessary tissue removal in up to 27% of rectal cancer patients [10, 11]. Incomplete resections (R1) are shown to be a strong predictor of development of distant metastasis, local recurrence, and decreased survival of colorectal cancer patients [11, 12]. Fluorescence-guided surgery (FGS) is an intraoperative imaging technique already introduced and validated in the clinic for sentinel lymph node (SLN) mapping and biliary imaging [13]. Tumor-specific FGS can be regarded as an extension of SPECT/PET, using fluorophores instead of radioactive labels conjugated to tumor-specific ligands, but with higher spatial resolution than SPECT/PET imaging and real-time anatomical feedback [14]. A powerful synergy can be achieved when nuclear and fluorescent imaging modalities are combined, extending the nuclear diagnostic images with real-time intraoperative imaging. This combination can lead to improved diagnosis and management by integrating pre-intra and postoperative imaging. Nuclear imaging enables pre-operative evaluation of tumor spread while during surgery deeper lying spots can be localized using the gamma probe counter. The (NIR) fluorescent signal aids the surgeon in providing real-time anatomical feedback to accurately recognize and resect malignant tissues. Postoperative, malignant cells can be recognized using NIR fluorescent microscopy. Clinically, the advantages of multimodal agents in image-guided surgery have been shown in patients with melanoma and prostate cancer, but those studies used a-specific agents, following the natural lymph drainage pattern of colloidal tracers after peritumoral injection [15, 16]. The urokinase-type plasminogen activator receptor (uPAR) is implicated in many aspects of tumor growth and (micro) metastasis [17, 18]. The levels of uPAR are undetectable in normal tissues except for occasional macrophages and granulocytes in the uterus, thymus, kidneys and spleen [19]. Enhanced tumor levels of uPAR and its circulating form (suPAR) are independent prognostic markers for overall survival in colorectal cancer patients [20, 21]. The relatively selective and high overexpression of uPAR in a wide range of human cancers including colorectal, breast, and pancreas nominate uPAR as a widely applicable and potent molecular target [17,22]. The current study aims to develop a clinically relevant uPAR-specific multimodal agent that can be used to visualize tumors pre- and intraoperatively after a single injection. We combined the 111Indium isotope with NIR fluorophore ZW800-1 using a hybrid linker to an uPAR specific monoclonal antibody (ATN-658) and evaluated its performance using a pre-clinical SPECT system (U-SPECT-II) and a clinically-applied NIR fluorescence camera system (FLARE™).

Fig1 Fig2 Fig3

Robotic surgery is a growing trend as a form of surgery, specifically in urology. The following review paper propose a good discussion on the added value of imaging in urologic robotic surgery:

The current and future use of imaging in urological robotic surgery: a survey of the European Association of Robotic Urological Surgeons

 Abstract

Background

With the development of novel augmented reality operating platforms the way surgeons utilize imaging as a real-time adjunct to surgical technique is changing.

Methods

A questionnaire was distributed via the European Robotic Urological Society mailing list. The questionnaire had three themes: surgeon demographics, current use of imaging and potential uses of an augmented reality operating environment in robotic urological surgery.

Results

117 of the 239 respondents (48.9%) were independently practicing robotic surgeons. 74% of surgeons reported having imaging available in theater for prostatectomy 97% for robotic partial nephrectomy and 95% cystectomy. 87% felt there was a role for augmented reality as a navigation tool in robotic surgery.

Conclusions

This survey has revealed the contemporary robotic surgeon to be comfortable in the use of imaging for intraoperative planning it also suggests that there is a desire for augmented reality platforms within the urological community. Copyright © 2014 John Wiley & Sons, Ltd.

 Introduction

Since Röntgen first utilized X-rays to image the carpal bones of the human hand in 1895, medical imaging has evolved and is now able to provide a detailed representation of a patient’s intracorporeal anatomy, with recent advances now allowing for 3-dimensional (3D) reconstructions. The visualization of anatomy in 3D has been shown to improve the ability to localize structures when compared with 2D with no change in the amount of cognitive loading [1]. This has allowed imaging to move from a largely diagnostic tool to one that can be used for both diagnosis and operative planning.

One potential interface to display 3D images, to maximize its potential as a tool for surgical guidance, is to overlay them onto the endoscopic operative scene (augmented reality). This addresses, in part, a criticism often leveled at robotic surgery, the loss of haptic feedback. Augmented reality has the potential to mitigate this sensory loss by enhancing the surgeons visual cues with information regarding subsurface anatomical relationships [2].

Augmented reality surgery is in its infancy for intra-abdominal procedures due in large part to the difficulties of applying static preoperative imaging to a constantly deforming intraoperative scene [3]. There are case reports and ex vivo studies in the literature examining the technology in minimal access prostatectomy [3-6] and partial nephrectomy [7-10], but there remains a lack of evidence determining whether surgeons feel there is a role for the technology and if so for what procedures they feel it would be efficacious.

This questionnaire-based study was designed to assess first, the pre- and intra-operative imaging modalities utilized by robotic urologists; second, the current use of imaging intraoperatively for surgical planning; and finally whether there is a desire for augmented reality among the robotic urological community.

Methods

Recruitment

A web based survey instrument was designed and sent out, as part of a larger survey, to members of the EAU robotic urology section (ERUS). Only independently practicing robotic surgeons performing robot-assisted laparoscopic prostatectomy (RALP), robot-assisted partial nephrectomy (RAPN) and/or robotic cystectomy were included in the analysis, those surgeons exclusively performing other procedures were excluded. Respondents were offered no incentives to reply. All data collected was anonymous.

Survey design and administration

The questionnaire was created using the LimeSurvey platform (www.limesurvey.com) and hosted on their website. All responses (both complete and incomplete) were included in the analysis. The questionnaire was dynamic with the questions displayed tailored to the respondents’ previous answers.

When computing fractions or percentages the denominator was the number of respondents to answer the question, this number is variable due to the dynamic nature of the questionnaire.

Demographics

All respondents to the survey were asked in what country they practiced and what robotic urological procedures they performed. In addition to what procedures they performed surgeons were asked to specify the number of cases they had undertaken for each procedure.

 Current imaging practice

Procedure-specific questions in this group were displayed according to the operations the respondent performed. A summary of the questions can be seen in Appendix 1. Procedure-nonspecific questions were also asked. Participants were asked whether they routinely used the Tile Pro™ function of the da Vinci console (Intuitive Surgical, Sunnyvale, USA) and whether they routinely viewed imaging intra-operatively.

 Augmented reality

Before answering questions in this section, participants were invited to watch a video demonstrating an augmented reality platform during RAPN, performed by our group at Imperial College London. A still from this video can be seen in Figure 1. They were then asked whether they felt augmented reality would be of use as a navigation or training tool in robotic surgery.

f1

Figure 1. A still taken from a video of augmented reality robot assisted partial nephrectomy performed. Here the tumour has been painted into the operative view allowing the surgeon to appreciate the relationship of the tumour with the surface of the kidney

Once again, in this section, procedure-specific questions were displayed according to the operations the respondent performed. Only those respondents who felt augmented reality would be of use as a navigation tool were asked procedure-specific questions. Questions were asked to establish where in these procedures they felt an augmented reality environment would be of use.

Results

Demographics

Of the 239 respondents completing the survey 117 were independently practising robotic surgeons and were therefore eligible for analysis. The majority of the surgeons had both trained (210/239, 87.9%) and worked in Europe (215/239, 90%). The median number of cases undertaken by those surgeons reporting their case volume was: 120 (6–2000), 9 (1–120) and 30 (1–270), for RALP, robot assisted cystectomy and RAPN, respectively.

 

Contemporary use of imaging in robotic surgery

When enquiring about the use of imaging for surgical planning, the majority of surgeons (57%, 65/115) routinely viewed pre-operative imaging intra-operatively with only 9% (13/137) routinely capitalizing on the TilePro™ function in the console to display these images. When assessing the use of TilePro™ among surgeons who performed RAPN 13.8% (9/65) reported using the technology routinely.

When assessing the imaging modalities that are available to a surgeon in theater the majority of surgeons performing RALP (74%, 78/106)) reported using MRI with an additional 37% (39/106) reporting the use of CT for pre-operative staging and/or planning. For surgeons performing RAPN and robot-assisted cystectomy there was more of a consensus with 97% (68/70) and 95% (54/57) of surgeons, respectively, using CT for routine preoperative imaging (Table 1).

Table 1. Which preoperative imaging modalities do you use for diagnosis and surgical planning?

  CT MRI USS None Other
RALP (n = 106) 39.8% 73.5% 2% 15.1% 8.4%
(39) (78) (3) (16) (9)
RAPN (n = 70) 97.1% 42.9% 17.1% 0% 2.9%
(68) (30) (12) (0) (2)
Cystectomy (n = 57) 94.7% 26.3% 1.8% 1.8% 5.3%
(54) (15) (1) (1) (3)

Those surgeons performing RAPN were found to have the most diversity in the way they viewed pre-operative images in theater, routinely viewing images in sagittal, coronal and axial slices (Table 2). The majority of these surgeons also viewed the images as 3D reconstructions (54%, 38/70).

Table 2. How do you typically view preoperative imaging in the OR? 3D recons = three-dimensional reconstructions

  Axial slices (n) Coronal slices (n) Sagittal slices (n) 3D recons. (n) Do not view (n)  
RALP (n = 106) 49.1% 44.3% 31.1% 9.4% 31.1%
(52) (47) (33) (10) (33)
RAPN (n = 70) 68.6% 74.3% 60% (42) 54.3% 0%
(48) (52) (38) (0)
Cystectomy (n = 57) 70.2% 52.6% 50.9% 21.1% 8.8%
(40) (30) (29) (12) (5)

The majority of surgeons used ultrasound intra-operatively in RAPN (51%, 35/69) with a further 25% (17/69) reporting they would use it if they had access to a ‘drop-in’ ultrasound probe (Figure 2).

f2

Figure 2. Chart demonstrating responses to the question – Do you use intraoperative ultrasound for robotic partial nephrectomy?

Desire for augmented reality

Overall, 87% of respondents envisaged a role for augmented reality as a navigation tool in robotic surgery and 82% (88/107) felt that there was an additional role for the technology as a training tool.

The greatest desire for augmented reality was among those surgeons performing RAPN with 86% (54/63) feeling the technology would be of use. The largest group of surgeons felt it would be useful in identifying tumour location, with significant numbers also feeling it would be efficacious in tumor resection (Figure 3).

f3

Figure 3. Chart demonstrating responses to the question – In robotic partial nephrectomy which parts of the operation do you feel augmented reality image overlay would be of assistance?

When enquiring about the potential for augmented reality in RALP, 79% (20/96) of respondents felt it would be of use during the procedure, with the largest group feeling it would be helpful for nerve sparing 65% (62/96) (Figure 4). The picture in cystectomy was similar with 74% (37/50) of surgeons believing augmented reality would be of use, with both nerve sparing and apical dissection highlighted as specific examples (40%, 20/50) (Figure 5). The majority also felt that it would be useful for lymph node dissection in both RALP and robot assisted cystectomy (55% (52/95) and 64% (32/50), respectively).

f4

Figure 4. Chart demonstrating responses to the question – In robotic prostatectomy which parts of the operation do you feel augmented reality image overlay would be of assistance?

f5

Figure 5. Chart demonstrating responses to the question – In robotic cystectomy which parts of the operation do you feel augmented reality overlay technology would be of assistance?

Discussion

The results from this study suggest that the contemporary robotic surgeon views imaging as an important adjunct to operative practice. The way these images are being viewed is changing; although the majority of surgeons continue to view images as two-dimensional (2D) slices a significant minority have started to capitalize on 3D reconstructions to give them an improved appreciation of the patient’s anatomy.

This study has highlighted surgeons’ willingness to take the next step in the utilization of imaging in operative planning, augmented reality, with 87% feeling it has a role to play in robotic surgery. Although there appears to be a considerable desire for augmented reality, the technology itself is still in its infancy with the limited evidence demonstrating clinical application reporting only qualitative results [3, 7, 11, 12].

There are a number of significant issues that need to be overcome before augmented reality can be adopted in routine clinical practice. The first of these is registration (the process by which two images are positioned in the same coordinate system such that the locations of corresponding points align [13]). This process has been performed both manually and using automated algorithms with varying degrees of accuracy [2, 14]. The second issue pertains to the use of static pre-operative imaging in a dynamic operative environment; in order for the pre-operative imaging to be accurately registered it must be deformable. This problem remains as yet unresolved.

Live intra-operative imaging circumvents the problems of tissue deformation and in RAPN 51% of surgeons reported already using intra-operative ultrasound to aid in tumour resection. Cheung and colleagues [9] have published an ex vivo study highlighting the potential for intra-operative ultrasound in augmented reality partial nephrectomy. They report the overlaying of ultrasound onto the operative scene to improve the surgeon’s appreciation of the subsurface tumour anatomy, this improvement in anatomical appreciation resulted in improved resection quality over conventional ultrasound guided resection [9]. Building on this work the first in vivo use of overlaid ultrasound in RAPN has recently been reported [10]. Although good subjective feedback was received from the operating surgeon, the study was limited to a single case demonstrating feasibility and as such was not able to show an outcome benefit to the technology [10].

RAPN also appears to be the area in which augmented reality would be most readily adopted with 86% of surgeons claiming they see a use for the technology during the procedure. Within this operation there are two obvious steps to augmentation, anatomical identification (in particular vessel identification to facilitate both routine ‘full clamping’ and for the identification of secondary and tertiary vessels for ‘selective clamping’ [15]) and tumour resection. These two phases have different requirements from an augmented reality platform; the first phase of identification requires a gross overview of the anatomy without the need for high levels of registration accuracy. Tumor resection, however, necessitates almost sub-millimeter accuracy in registration and needs the system to account for the dynamic intra-operative environment. The step of anatomical identification is amenable to the use of non-deformable 3D reconstructions of pre-operative imaging while that of image-guided tumor resection is perhaps better suited to augmentation with live imaging such as ultrasound [2, 9, 16].

For RALP and robot-assisted cystectomy the steps in which surgeons felt augmented reality would be of assistance were those of neurovascular bundle preservation and apical dissection. The relative, perceived, efficacy of augmented reality in these steps correlate with previous examinations of augmented reality in RALP [17, 18]. Although surgeon preference for utilizing augmented reality while undertaking robotic prostatectomy has been demonstrated, Thompson et al. failed to demonstrate an improvement in oncological outcomes in those patients undergoing AR RALP [18].

Both nerve sparing and apical dissection require a high level of registration accuracy and a necessity for either live imaging or the deformation of pre-operative imaging to match the operative scene; achieving this level of registration accuracy is made more difficult by the mobilization of the prostate gland during the operation [17]. These problems are equally applicable to robot-assisted cystectomy. Although guidance systems have been proposed in the literature for RALP [3-5, 12, 17], none have achieved the level of accuracy required to provide assistance during nerve sparing. In addition, there are still imaging challenges that need to be overcome. Although multiparametric MRI has been shown to improve decision making in opting for a nerve sparing approach to RALP [19] the imaging is not yet able to reliably discern the exact location of the neurovascular bundle. This said, significant advances are being made with novel imaging modalities on the horizon that may allow for imaging of the neurovascular bundle in the near future [20].

 

Limitations

The number of operations included represents a significant limitation of the study, had different index procedures been chosen different results may have been seen. This being said the index procedures selected were chosen as they represent the vast majority of uro-oncological robotic surgical practice, largely mitigating for this shortfall.

Although the available ex vivo evidence suggests that introducing augmented reality operating environments into surgical practice would help to improve outcomes [9, 21] the in vivo experience to date is limited to small volume case series reporting feasibility [2, 3, 14]. To date no study has demonstrated an in vivo outcome advantage to augmented reality guidance. In addition to this limitation augmented reality has been demonstrated to increased rates of inattention blindness among surgeons suggesting there is a trade-off between increasing visual information and the surgeon’s ability to appreciate unexpected operative events [21].

 

Conclusions

This survey shows the contemporary robotic surgeon to be comfortable with the use of imaging to aid intra-operative planning; furthermore it highlights a significant interest among the urological community in augmented reality operating platforms.

Short- to medium-term development of augmented reality systems in robotic urology surgery would be best performed using RAPN as the index procedure. Not only was this the operation where surgeons saw the greatest potential benefits, but it may also be the operation where it is most easily achievable by capitalizing on the respective benefits of technologies the surgeons are already using; pre-operative CT for anatomical identification and intra-operative ultrasound for tumour resection.

 

Conflict of interest

None of the authors have any conflicts of interest to declare.

Appendix 1

Question Asked Question Type
Demographics
In which country do you usually practise? Single best answer
Which robotic procedures do you perform?* Single best answer
Current Imaging Practice
What preoperative imaging modalities do you use for the staging and surgical planning in renal cancer? Multiple choice
How do you typically view preoperative imaging in theatre for renal cancer surgery? Multiple choice
Do you use intraoperative ultrasound for partial nephrectomy? Yes or No
What preoperative imaging modalities do you use for the staging and surgical planning in prostate cancer? Multiple choice
How do you typically view preoperative imaging in theatre for prostate cancer? Multiple choice
Do you use intraoperative ultrasound for robotic partial nephrectomy? Yes or No
Which preoperative imaging modality do you use for staging and surgical planning in muscle invasive TCC? Multiple choice
How do you typically view preoperative imaging in theatre for muscle invasive TCC? Multiple choice
Do you routinely refer to preoperative imaging intraoperativley? Yes or No
Do you routinely use Tilepro intraoperativley? Yes or No
Augmented Reality
Do you feel there is a role for augmented reality as a navigation tool in robotic surgery? Yes or No
Do you feel there is a role for augmented reality as a training tool in robotic surgery? Yes or No
In robotic partial nephrectomy which parts of the operation do you feel augmented reality image overlay technology would be of assistance? Multiple choice
In robotic nephrectomy which parts of the operation do you feel augmented reality image overlay technology would be of assistance? Multiple choice
In robotic prostatectomy which parts of the operation do you feel augmented reality image overlay technology would be of assistance? Multiple choice
Would augmented reality guidance be of use in lymph node dissection in robotic prostatectomy? Yes or No
In robotic cystectomy which parts of the operation do you feel augmented reality image overlay technology would be of assistance? Multiple choice
Would augmented reality guidance be of use in lymph node dissection in robotic cystectomy? Yes or No
*The relevant procedure related questions were displayed based on the answer to this question

References

1. Foo J-L, Martinez-Escobar M, Juhnke B, et al.Evaluating mental workload of two-dimensional and three-dimensional visualization for anatomical structure localization. J Laparoendosc Adv Surg Tech A 2013; 23(1):65–70.

2. Hughes-Hallett A, Mayer EK, Marcus HJ, et al.Augmented reality partial nephrectomy: examining the current status and future perspectives. Urology 2014; 83(2): 266–273.

3. Sridhar AN, Hughes-Hallett A, Mayer EK, et al.Image-guided robotic interventions for prostate cancer. Nat Rev Urol 2013; 10(8): 452–462.

4. Cohen D, Mayer E, Chen D, et al.Eddie’ Augmented reality image guidance in minimally invasive prostatectomy. Lect Notes Comput Sci 2010; 6367: 101–110.

5. Simpfendorfer T, Baumhauer M, Muller M, et al.Augmented reality visualization during laparoscopic radical prostatectomy. J Endourol 2011; 25(12): 1841–1845.

6. Teber D, Simpfendorfer T, Guven S, et al.In vitro evaluation of a soft-tissue navigation system for laparoscopic prostatectomy. J Endourol 2010; 24(9): 1487–1491.

7. Teber D, Guven S, Simpfendörfer T, et al.Augmented reality: a new tool to improve surgical accuracy during laparoscopic partial nephrectomy? Preliminary in vitro and in vivo Eur Urol 2009; 56(2): 332–338.

8. Pratt P, Mayer E, Vale J, et al.An effective visualisation and registration system for image-guided robotic partial nephrectomy. J Robot Surg 2012; 6(1): 23–31.

9. Cheung CL, Wedlake C, Moore J, et al.Fused video and ultrasound images for minimally invasive partial nephrectomy: a phantom study. Med Image Comput Comput Assist Interv 2010; 13(Pt 3): 408–415.

10. Hughes-Hallett A, Pratt P, Mayer E, et al.Intraoperative ultrasound overlay in robot-assisted partial nephrectomy: first clinical experience. Eur Urol 2014; 65(3): 671–672.

11. Nakamura K, Naya Y, Zenbutsu S, et al.Surgical navigation using three-dimensional computed tomography images fused intraoperatively with live video. J Endourol 2010; 24(4): 521–524.

12. Ukimura O, Gill IS. Imaging-assisted endoscopic surgery: Cleveland clinic experience. J Endourol2008; 22(4):803–809.

13. Altamar HO, Ong RE, Glisson CL, et al.Kidney deformation and intraprocedural registration: a study of elements of image-guided kidney surgery. J Endourol 2011; 25(3): 511–517.

14. Nicolau S, Soler L, Mutter D, Marescaux J. Augmented reality in laparoscopic surgical oncology. Surg Oncol2011; 20(3): 189–201.

15. Ukimura O, Nakamoto M, Gill IS. Three-dimensional reconstruction of renovascular-tumor anatomy to facilitate zero-ischemia partial nephrectomy. Eur Urol2012; 61(1): 211–217.

16. Pratt P, Hughes-Hallett A, Di Marco A, et al. Multimodal reconstruction for image-guided interventions. In:Yang GZ, Darzi A (eds) Proceedings of the Hamlyn symposium on medical robotics: London. 2013; 59–61.

17. Mayer EK, Cohen D, Chen D, et al.Augmented reality image guidance in minimally invasive prostatectomy. Eur Urol Supp 2011; 10(2): 300.

18. Thompson S, Penney G, Billia M, et al.Design and evaluation of an image-guidance system for robot-assisted radical prostatectomy. BJU Int 2013; 111(7): 1081–1090.

19. Panebianco V, Salciccia S, Cattarino S, et al.Use of multiparametric MR with neurovascular bundle evaluation to optimize the oncological and functional management of patients considered for nerve-sparing radical prostatectomy. J Sex Med 2012; 9(8): 2157–2166.

20. Rai S, Srivastava A, Sooriakumaran P, Tewari A. Advances in imaging the neurovascular bundle. Curr Opin Urol2012; 22(2): 88–96.

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Imaging-guided cancer treatment


Imaging-guided cancer treatment

Writer & reporter: Dror Nir, PhD

It is estimated that the medical imaging market will exceed $30 billion in 2014 (FierceMedicalImaging). To put this amount in perspective; the global pharmaceutical market size for the same year is expected to be ~$1 trillion (IMS) while the global health care spending as a percentage of Gross Domestic Product (GDP) will average 10.5% globally in 2014 (Deloitte); it will reach ~$3 trillion in the USA.

Recent technology-advances, mainly miniaturization and improvement in electronic-processing components is driving increased introduction of innovative medical-imaging devices into critical nodes of major-diseases’ management pathways. Consequently, in contrast to it’s very small contribution to global health costs, medical imaging bears outstanding potential to reduce the future growth in spending on major segments in this market mainly: Drugs development and regulation (e.g. companion diagnostics and imaging surrogate markers); Disease management (e.g. non-invasive diagnosis, guided treatment and non-invasive follow-ups); and Monitoring aging-population (e.g. Imaging-based domestic sensors).

In; The Role of Medical Imaging in Personalized Medicine I discussed in length the role medical imaging assumes in drugs development.  Integrating imaging into drug development processes, specifically at the early stages of drug discovery, as well as for monitoring drug delivery and the response of targeted processes to the therapy is a growing trend. A nice (and short) review highlighting the processes, opportunities, and challenges of medical imaging in new drug development is: Medical imaging in new drug clinical development.

The following is dedicated to the role of imaging in guiding treatment.

Precise treatment is a major pillar of modern medicine. An important aspect to enable accurate administration of treatment is complementing the accurate identification of the organ location that needs to be treated with a system and methods that ensure application of treatment only, or mainly to, that location. Imaging is off-course, a major component in such composite systems. Amongst the available solution, functional-imaging modalities are gaining traction. Specifically, molecular imaging (e.g. PET, MRS) allows the visual representation, characterization, and quantification of biological processes at the cellular and subcellular levels within intact living organisms. In oncology, it can be used to depict the abnormal molecules as well as the aberrant interactions of altered molecules on which cancers depend. Being able to detect such fundamental finger-prints of cancer is key to improved matching between drugs-based treatment and disease. Moreover, imaging-based quantified monitoring of changes in tumor metabolism and its microenvironment could provide real-time non-invasive tool to predict the evolution and progression of primary tumors, as well as the development of tumor metastases.

A recent review-paper: Image-guided interventional therapy for cancer with radiotherapeutic nanoparticles nicely illustrates the role of imaging in treatment guidance through a comprehensive discussion of; Image-guided radiotherapeutic using intravenous nanoparticles for the delivery of localized radiation to solid cancer tumors.

 Graphical abstract

 Abstract

One of the major limitations of current cancer therapy is the inability to deliver tumoricidal agents throughout the entire tumor mass using traditional intravenous administration. Nanoparticles carrying beta-emitting therapeutic radionuclides [DN: radioactive isotops that emits electrons as part of the decay process a list of β-emitting radionuclides used in radiotherapeutic nanoparticle preparation is given in table1 of this paper.) that are delivered using advanced image-guidance have significant potential to improve solid tumor therapy. The use of image-guidance in combination with nanoparticle carriers can improve the delivery of localized radiation to tumors. Nanoparticles labeled with certain beta-emitting radionuclides are intrinsically theranostic agents that can provide information regarding distribution and regional dosimetry within the tumor and the body. Image-guided thermal therapy results in increased uptake of intravenous nanoparticles within tumors, improving therapy. In addition, nanoparticles are ideal carriers for direct intratumoral infusion of beta-emitting radionuclides by convection enhanced delivery, permitting the delivery of localized therapeutic radiation without the requirement of the radionuclide exiting from the nanoparticle. With this approach, very high doses of radiation can be delivered to solid tumors while sparing normal organs. Recent technological developments in image-guidance, convection enhanced delivery and newly developed nanoparticles carrying beta-emitting radionuclides will be reviewed. Examples will be shown describing how this new approach has promise for the treatment of brain, head and neck, and other types of solid tumors.

The challenges this review discusses

  • intravenously administered drugs are inhibited in their intratumoral penetration by high interstitial pressures which prevent diffusion of drugs from the blood circulation into the tumor tissue [1–5].
  • relatively rapid clearance of intravenously administered drugs from the blood circulation by kidneys and liver.
  • drugs that do reach the solid tumor by diffusion are inhomogeneously distributed at the micro-scale – This cannot be overcome by simply administering larger systemic doses as toxicity to normal organs is generally the dose limiting factor.
  • even nanoparticulate drugs have poor penetration from the vascular compartment into the tumor and the nanoparticles that do penetrate are most often heterogeneously distributed

How imaging could mitigate the above mentioned challenges

  • The inclusion of an imaging probe during drug development can aid in determining the clearance kinetics and tissue distribution of the drug non-invasively. Such probe can also be used to determine the likelihood of the drug reaching the tumor and to what extent.

Note: Drugs that have increased accumulation within the targeted site are likely to be more effective as compared with others. In that respect, Nanoparticle-based drugs have an additional advantage over free drugs with their potential to be multifunctional carriers capable of carrying both therapeutic and diagnostic imaging probes (theranostic) in the same nanocarrier. These multifunctional nanoparticles can serve as theranostic agents and facilitate personalized treatment planning.

  • Imaging can also be used for localization of the tumor to improve the placement of a catheter or external device within tumors to cause cell death through thermal ablation or oxidative stress secondary to reactive oxygen species.

See the example of Vintfolide in The Role of Medical Imaging in Personalized Medicine

vinta

Note: Image guided thermal ablation methods include radiofrequency (RF) ablation, microwave ablation or high intensity focused ultrasound (HIFU). Photodynamic therapy methods using external light devices to activate photosensitizing agents can also be used to treat superficial tumors or deeper tumors when used with endoscopic catheters.

  • Quality control during and post treatment

For example: The use of high intensity focused ultrasound (HIFU) combined with nanoparticle therapeutics: HIFU is applied to improve drug delivery and to trigger drug release from nanoparticles. Gas-bubbles are playing the role of the drug’s nano-carrier. These are used both to increase the drug transport into the cell and as ultrasound-imaging contrast material. The ultrasound is also used for processes of drug-release and ablation.

 HIFU

Additional example; Multifunctional nanoparticles for tracking CED (convection enhanced delivery)  distribution within tumors: Nanoparticle that could serve as a carrier not only for the therapeutic radionuclides but simultaneously also for a therapeutic drug and 4 different types of imaging contrast agents including an MRI contrast agent, PET and SPECT nuclear diagnostic imaging agents and optical contrast agents as shown below. The ability to perform multiple types of imaging on the same nanoparticles will allow studies investigating the distribution and retention of nanoparticles initially in vivo using non-invasive imaging and later at the histological level using optical imaging.

 multi

Conclusions

Image-guided radiotherapeutic nanoparticles have significant potential for solid tumor cancer therapy. The current success of this therapy in animals is most likely due to the improved accumulation, retention and dispersion of nanoparticles within solid tumor following image-guided therapies as well as the micro-field of the β-particle which reduces the requirement of perfectly homogeneous tumor coverage. It is also possible that the intratumoral distribution of nanoparticles may benefit from their uptake by intratumoral macrophages although more research is required to determine the importance of this aspect of intratumoral radionuclide nanoparticle therapy. This new approach to cancer therapy is a fertile ground for many new technological developments as well as for new understandings in the basic biology of cancer therapy. The clinical success of this approach will depend on progress in many areas of interdisciplinary research including imaging technology, nanoparticle technology, computer and robot assisted image-guided application of therapies, radiation physics and oncology. Close collaboration of a wide variety of scientists and physicians including chemists, nanotechnologists, drug delivery experts, radiation physicists, robotics and software experts, toxicologists, surgeons, imaging physicians, and oncologists will best facilitate the implementation of this novel approach to the treatment of cancer in the clinical environment. Image-guided nanoparticle therapies including those with β-emission radionuclide nanoparticles have excellent promise to significantly impact clinical cancer therapy and advance the field of drug delivery.

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