Stanford Neuro @ SFN2011

What has the Stanford Neuroscience community been up to? Find out by visiting our presentations and posters at SFN2011! The Stanford Neuroscience affiliates presenting their research on Saturday, Nov 12 are:

Presentations

3:15-3:35 pm : John Huguenard (aka our valiant Program Director)

Title: Role for astrocytic GABA transporters in regulating synaptic activation of GABAB receptors in thalamus

Location: 202B

Posters

1:00-2:00 pm: Jaimie Adelson

Title: Lack of MHCI ligands or PirB receptor is neuroprotective following stroke.

Program#/Poster#: 62.01/FF7

Location: Hall A-C

Chronicles of a Graduate Student Let Loose in Europe (Part 2)

Georgia Panagiotakos is a senior graduate student in the labs of Drs. Ricardo Dolmestch and Theo Palmer, where she studies mechanisms by which mutations in the voltage gated calcium channel CaV1.2 influence neurogenesis in the developing brain and contribute to the pathophysiology of autism spectrum disorders. The spring/summer Georgia attended two scientific conferences in Europe, and graciously volunteered to write a two-part blog post chronicling her experiences.

Ironically, I intended this blog post to be short and sweet. Now I’m staring back at what has amounted to a novella. Let’s move on from Greece to Germany then. The cortical development meeting (ed. note: Cortical Development: Neural Stem Cells to Neural Circuits). proved to be a source of new friends, as well as the birth of a new collaboration that would benefit my work. I returned to Stanford excited to get back to my science. A mere three weeks later found me on yet another plane (and decidedly more nervous) headed for Washington, DC - the first stop on the way to Lindau, Germany, a picturesque, tiny (read: if you are walking in any direction for longer thanten minutes without seeing water, you have been walking in circles) island in Lake Constance that was the site of the 61st Lindau Meeting of Nobel Laureates. I must admit my ignorance in saying that I had no idea there was an island in Germany prior tothis meeting. I should also take a moment here to thank one of my advisors for nominating me for this meeting. It was such an exceptional opportunity that I didn’t quite appreciate until I was actually living it. The truth of the matter is that there is relatively little that I can say to accurately convey the extent to which I enjoyed this week in Germany (I never imagined that Broca’s area would actually fail me at some point). I met new colleagues from all over the world that I envision running into at other meetings several years from now. I had dinner and lunch, respectively, with the co-discovers of one of the most fundamental techniques in use in neuroscience today, the patch clamp. I struck up relationships with other young scientists that I can see myself collaborating with for many years to come. And all this came from an email I received from my advisor some time last year that said “Hey, I’m thinking of nominating you for this thing. Would you go?”

In lieu of describing the details of this meeting, much of which was focused on science as a career path and the responsibilities we have as scientists, I’ve decided to stop my chatter here and leave you with the series of memorable quotes that I promised at the beginning. I hope you’ll find them as enjoyable as I did. You’ll see that they run the gamut from hilarious to inspirational.

I’ll start with Oliver Smithies (arguably the most adorable scientist that ever lived, the darling of the Lindau meeting, and the winner of the Prize for his work in gene targeting and homologous recombination). He was by far one of the favorites of everyone in attendance, largely because he continues to do science to this day, at the age of 86, and has managed to retain a child-like enthusiasm for science that I can only wish to maintain through grad school, let alone an entire scientific career:

• “Because I still work at the bench, I am not the director of anything. I am still a child of science.. a grad student who never grew up.”- (this one I find especially meaningful in year four of graduate school)
• “My thesis was based on a complete myth! And my paper.. never quoted. And no one ever used my method. And I never did again either!”
• “What’s the point of it all? It doesn’t matter what you do for your PhD, as long as you are having fun. If you don’t enjoy it, ask your advisor to switch you to something else. If he won’t, switch advisors!”- (a personal favorite)
• “So.. out of laziness, I invented gel electrophoresis. You may notice there are no photographs.. You see, my lab had no camera!”- Smithies flashed up a photograph of his old-school PCR machine, literally pieced together from parts of other machines tagged by the maintenance people with “NBGBGFO: No bloody good, but good for Oliver”.
• “I’m still running gels.. and I’m still running them on Saturdays”.

Next up is Ada Yonath, winner of the Prize for her work on the structure of the ribosome. I attended her small discussion session and collected these pearls:

• “For the young women concerned about doing science and having a family... my granddaughter said this about me: ‘I know she is a busy scientist, but she always makes time for me’ to her kindergarten class... right before I lectured them on ribosomes at the age of five.’”
• “There are things in life much more difficult than science, put failures and successes into perspective.”
• (on trying to disconnect yourself from the burden of being promoted) “It needs to change. Free yourself and think about science. Good science cannot happen when worrying about papers.”

For the readers of this blog, no introduction is needed for Erwin Neher, co-recipient ofthe Nobel Prize (with Bert Sakmann) for “their discoveries concerning the function of single ion channels in cells”. I had the opportunity to have dinner with Neher and lunch with Sakmann, where I learned that Neher loved running around the lab with his soldering iron making constant improvements to the rig. It sounds like not much has changed in terms of how electrophysiology is done over the years. One quote from Neher’s talk that served to put time invested into a project into perspective:

• (on how long it took them to invent the patch clamp technique) “after a very tiny struggle.. just two to three years..”

Undeniably one of the most vocal personalities at this meeting, Sir Harold Kroto, winner of the Prize in chemistry for the discovery of C60, was not shy about expressing his opinions (as you’ll undoubtedly appreciate upon reading his quotes). An interesting fun fact, it turns out that Kroto acted in a play with Sir Ian McKellan in the fifth grade! That must have been some middle school. Below is a series of quotes from his plenary session and smaller discussion session:

• “If you make people think they are thinking, they’ll love you; but if you really make them think, they’ll hate you.”
• “Enjoy your beauty whilst you may, for it will not last.. This is what I used to look like [flashes a picture of himself when he was younger]. A lot of you are young and beautiful, but eventually you will all be old and decrepit like me.”
• “Find out the evidence for everything you accept.”
• “Beware of too focused research strategies.”
• Early in the day, at his plenary lecture, Kroto provided one of the most memorable moments of the meeting, unbuttoning his salmon colored shirt on stage and eliciting a collective gasp from the audience, until everyone saw a t-shirt he made underneath depicting Darwin’s phylogenetic tree of life (a wonderfully passive aggressive way of sticking it to everyone who continues to misunderstand evolution). “I got rid of all the bumper stickers on the way to Lindau,” he exclaimed.
• “It’s true, my finding was useless. They told me, the Nobel Committee, that I might have to give it back [the prize].. but I already spent all the money!”
• “Stupid educational systems think teachers can teach thirty students exactly the same way.. How many of you have brothers and sisters? Are you all the same? Of course not!”
• “If you want to know how to give a powerpoint.. I mean how I give a powerpoint.. which of course is the best way to do it..”
• (on what drives him to do good science) “You cannot do anything second rate!”
• (on what might provide the solution to antibiotic resistance) “somebody who is doing something totally different may come up with the real solution to this problem..”
• “Knowledge cannot guarantee good decisions - but common sense suggests that wisdom doesn’t come from ignorance.”
• (possibly my absolute favorite quote from the entire meeting) “Humans - evolution has created an animal for whom rational analysis is not essential for survival.” Let’s see if developmental neuroscience can explain that one :)

Moving on, we come to Roger Tsien, who received the Nobel Prize in Chemistry for “his discovery and the development of green fluorescent protein”. He has since pioneered the development of many of the calcium imaging dyes widely used today. His plenary session was both informative and entertaining, and I have collected some of those more memorable quotes and stories here:

• (on transitioning from GFP to dsRed) “I did it for the pretty videos - but GFP was never as pretty as a gorgeous red.”
• (on having ChR2 sitting in his freezer while his graduate student toiled with trying to use ChR1 to depolarize cells) “Just because you are a Nobel Prize winner doesn’t mean you don’t have some humiliating failures. I boggled with guy’s attempt to get famous! Just because I am here and supposedly eminent doesn’t mean I don’t make mistakes.”I should note here that Tsien was a really exceptional speaker and had a certain charm about him that I am not sure that I expected prior to hearing him speak.
• (advice to young scientists) “Get regular exercise to outlive your scientific competitors.”
• (more advice) “Look for a question that gives some internal sensual pleasure.. or at least puts your neuroses to constructive use.”

Avram Hershko, who received the Nobel Prize for his work on the ubiquitin system, delivered an excellent overview of the ubiquitin pathway in health and disease. He closed his plenary talk with lessons learned throughout his career and advice for young scientists that included:

• find good mentors
• find an important subject that is not yet interesting to others (“because the big guys will get there before you”)
• some times great discoveries are made by accidental observation
• use whatever approach is necessary for your work
• never leave benchwork and your enthusiasm will stay high (he called it “a curiosity-driven adventure”)

There you have it. Overall, I have to say that what impressed me the most was how many of these laureates pursued questions simply because they were interesting to them and not because they would yield a “big result”. More impressive still is how many of them did not realize how seminal their work would turn out to be. I suppose this means that no matter how insignificant we think our science might be now (and I would argue it is easy to think this at various points throughout grad school), we might discover that other people will become interested later. So.. dream big I guess. How’s that for a positive note?

Chronicles of a Graduate Student Let Loose in Europe (Part 1)

Georgia Panagiotakos is a senior graduate student in the labs of Drs. Ricardo Dolmestch and Theo Palmer, where she studies mechanisms by which mutations in the voltage gated calcium channel CaV1.2 influence neurogenesis in the developing brain and contribute to the pathophysiology of autism spectrum disorders. The spring/summer Georgia attended two scientific conferences in Europe, and graciously volunteered to write a two-part blog post chronicling her experiences. This past month has marked the first time in my graduate career that I have had the opportunity to travel overseas for a scientific meeting and interact with giants in my field. In a stroke of remarkable luck, I was able to attend two different conferences, both of which took place in Europe. The first of these was small and specialized, an assortment of about two hundred scientists from around the world focused exclusively on understanding the mechanisms underlying brain development and the evolution of the human cortex (ed. note: the conference is question is entitled Cortical Development: Neural Stem Cells to Neural Circuits). The second meeting was quite broad, bringing together students and postdocs from over eighty countries to interact with twenty-six Nobel laureates in medicine and physiology (ed. note: this is the Lindau Nobel Laureate Meeting).

Admittedly, I approached this second meeting with some nerves (How difficult would it be to really have a stimulating scientific discussion with someone whose research interests are so distant from mine? Could I really convey the excitement I feel about what I do and the importance of neuroscience research to someone focused on understanding the structure of a protein or examining the life cycle of a virus?) - these fears proved to be moderately irrational and this experience was one that I will never forget. In telling some friends about these two wonderful experiences, I was prompted to transcribe some of what I heard into my first (and likely last) entry on the Stanford neuroblog. I needed a little pick-me-up today, so what follows is a pleasant distraction, a short description of each meeting, interspersed with a series of memorable quotes.

Surprisingly (read: not at all surprisingly), it appears that I am incapable of writing something “short”. I hope that this entry is sufficiently interesting to you to allow me some liberty with words.

During the third week of May, I flew to Greece (my homeland - conference for the win!) to attend a meeting on cortical development. I suppose I should preface everything I write here with the statement that I have been intrigued by cortical development, and how it is that specific cell types are generated and functionally connected in the developing brain, for about as long as I have been interested in neuroscience. This really reflects itself in the fact that a significant portion of my scientific career to date (young as it is) has centered around aspects of this very broad question. In light of this, the opportunity to attend this meeting was really a remarkable treat. An additional disclaimer: It didn’t hurt that the meeting was to take place on the island of Crete. And I cannot say that we didn’t take advantage of the beautiful weather and majestic Mediterranean sea - but the meeting itself proved to be on par with the exceptional location. Over the course of four days, we heard from the likes of Arnold Kriegstein, Pasko Rakic, Gord Fishell, Jeff Macklis, Arturo Alvarez-Buylla, Chris Walsh, and others, in sessions focused on stem cells, neurogenesis and neuronal differentiation, neuronal migration, circuit formation and neuronal circuits. I decided not to detail every talk here, in the interest of time (both mine and yours), and to focus instead on my impressions from the meeting now that I’ve had several weeks to ruminate.

Two over-arching themes that seem to be driving the field of cortical development really popped out for me at this meeting:

Neuronal subtype specification.

In particular, many of the talks centered around understanding the development, migration and maturation of cortical interneurons and exploring their role in sculpting cortical circuit function (a long standing interest of mine that I like to think of as a guilty pleasure of sorts). The conclusion of the series of talks surrounding this question requires me to, if I may, borrow a phrase that Jeff Macklis used during his excellent talk describing the acquisition of neocortical projection neuron identity - a “combinatorial multi-state logic” in the form of the activation or repression of specific transcription factors at different stages of development, responsiveness to guidance molecules, feedback mechanisms and neuronal activity (as beautifully depicted in a recent paper from the lab of Gord Fishell) is employed by the developing brain to generate remarkably diverse populations of interneurons that terminate in specific locations, exhibit different physiological properties and integrate into specific cortical circuits. Interesting to think about is how these strategies are integrated by individual cells as they mature and acquire their terminal fates.

Evolution of the human cortex.

The other point of emphasis at this meeting was the development of hypotheses regarding the evolution of the human cortex, in particular the expansion of the upper layers and the diversification of neuronal populations. A significant proportion of speakers, whether they were studying interactions of neural progenitor cells with the extracellular matrix, or basic mechanisms of cell division, or human-specific disease mutations, at the very least commented on how their finding might impact our understanding of human brain evolution. Arnold Kriegstein started the meeting off by presenting his beautiful work describing the behavior of outer radial glial cells, a new class of neural progenitor cell located in a separate anatomical zone in the developing monkey and human brain termed the outer subventricular zone (oSVZ). He showed us the elegant time-lapse images for which he is famous, depicting these cells translocating their somata (literally “jumping”) and subsequently dividing to give rise to daughter cells by undergoing characteristic modes of cell division. The massive expansion of the oSVZ during mid-gestation in humans prompted Kriegstein to argue the importance of these outer radial glial cells for the expansion of the human neocortex, through an increase in the number of neurons being generated. He further suggested that these different progenitor niches in the developing brain might allow for the emergence of heterogeneous cell types even at the same birthdate. That same afternoon, we heard Pasko Rakic (in a session chaired by Kriegstein himself) assert that the oSVZ is not the most important feature for the evolution of the cortex. Gauntlet thrown? We later heard from Chris Walsh, who described another approach at uncovering important players in human cortical development, the use of Next-Gen sequencing to identify disease mutations that cause cortical malformations. He went on to talk about a separate project in his lab that focused on the role secreted factors in the cerebrospinal fluid might play in instructing cell fate decisions and proliferation in the developing brain.

The meeting closed with what admittedly may have been one of my favorite talks, a beautiful story by Nenad Sestan describing the patterning of microcolumns in the developing human cortex and efforts towards completing a developing human brain transcriptome. I would be remiss if I didn’t also give a shout out to my friend and fellow Stanford neuroscience program graduate student, Alex Pollen, who (for once not talking about penile spines!) presented a wonderful poster describing his work aimed at identifying human-specific deletions of regulatory elements that may underly the evolution of human-specific brain features. Overall, I was left with the impression of a vibrant field in which a number of labs are using very different approaches to unravel the mechanisms underlying human-specific cortical expansion. It’s only fitting that I close this part with a quote from the man himself, Pasko Rakic: “It’s more complicated than I say, but they only gave me forty minutes.”

Editors Note: Blog Post Frequency

Eagle-eyed visitors to the Stanford Neuroblog may have noticed a decline in the volume of posts that are being published. Unfortunately, this reduced volume will likely continue into the summer months, as the editor is currently prepping for her qualifying examination. Following the completion of her quals (hopefully sometime in mid-July), the editor expects to resume full blogging duties. Until then, with many apologies, readers are warned that they should probably not expect too many updates.

The Rap Music that will teach you Evolutionary Biology

Via fellow Stanford-based blog Scope, news of a new website launched this week featuring the musical talents of evolutionary rapper Baba Brinkman. Last year, a post on this blog described Mr. Brinkman's evolutionary-themed music, which he was performing during a show entitled The Rap Guide to Evolution. The show is described on Mr. Brinkman's website as an exploration of "the history and current understanding of Darwin's theory, combining remixes of popular rap songs with storytelling rap/poems that cover Natural Selection, Artificial Selection, Sexual Selection, Group Selection, Unity of Common Descent, and Evolutionary Psychology." Notably, Mr. Brinkman's lyrics were throughly peer-reviewed by University of Birmingham's Dr. Mark Pallen, and are therefore highly scientifically and historically accurate.

Now, Mr. Brinkman, with support from the Wellcome Trust, has launched The Rap Guide to Evolution website, featuring videos of his songs (1 video is currently posted, with 11 more on their way), for the purpose of providing an educational tool to enhance the teaching of basic evolutionary concepts. A DVD compilation is in the works (which will include a handbook of lesson plans) with a scheduled release date for the September 2011 semester.

In total, the website will feature 12 videos. As of the publishing of this post, video for one song, Performance, Feedback Revision, has been uploaded. As I wrote last year, this song is one of my favorites, beginning with a lyrical account of how Mr. Brinkman creates his songs, and expanding into a description of the concept of descent-with-modification.

And sometimes people ask me: How does your show get written. Like this: Performance. Feedback. Revision … And how do human’s beings ever learn to do anything Like this: Performance. Feedback. Revision And evolution is really just kind of an algorithm that goes Like this: Performance. Feedback. Revision So the genetic code of every living thing was written Like this: Performance. Feedback. Revision So the genes are like a text with a thousand pages And revisions occur in the random changes that come from mutations. And when they see the light, well that’s the performance, that’s the phenotype.

Professional scientists, teachers, and members of the general public will all find Baba Brinkman's musical stylings highly enjoyable and remarkably educational. Personally, I am looking forward to the upcoming videos, and plan to use The Rap Guide to Evolution the next time I have to explain evolutionary biology to my parents.

Deisseroth Lab leaving Stanford for Detriot

Breaking news, Dr. Karl Deisseroth, professor, practicing physician and pioneer of the field of optogenetics has left Stanford University. Backyard Brains, based in Detroit, MI, has announced the hiring of Karl as their first salaried employee. The announcement, posted this morning on the Backyard Brains website, called the hiring a "neurotechnology coup". An "official statement" from the company reads, “Please join us as Detroit and Backyard Brains welcomes Karl to his new home in the state of Michigan. We are looking forward to Karl building on his 13-year experience at Stanford by bringing Neuroscience to the people. We are cautiously optimistic to see what Karl has in store in the years to come.”

Members of Karl's laboratory were surprised by this news, of which they were informed this morning via the email below.

just noticed this come online-- did not want you to find out this way. http://backyardbrains.com/news/index.php/tag/karl/ everyone think about this and decide on the lab move, take into account your family, project, and other considerations. Please let me know if you want to come along. I need to have a list of the people moving with me by next Thursday.

thanks K

Members of the lab are quoted as responding:

..."It's a tough decision, but really--a basement is a basement, right?" "The tipping point for me was when Karl was able to recruit Shatz Lab member Jaimie Adelson to the autonomous cockroach project." "FML" "Look, windows!"

Good luck to the Deisseroth lab basement dwellers as they mull over this big decision.

(quotations kindly provided by the Deisseroth lab)

Happy Valentines Day, from PNAS

[Blog post conceived and written by Kelly Zalocusky, Deisseroth lab] Since the writings of Charles Darwin, female sexual selection has been used to explain flashy-but-costly male traits, from the colorful dances of birds-of-paradise, to the boisterous song of tungara frogs, to the violent posturing of elephant seals. Today in PNAS, researchers from the State University of New York reveal that, at least when it comes to fruit fly pheromones, the effects of this sexual selection are bound by the limits of natural selection. After 7 generations, the prevalence of the gene for high levels of sexy pheromones increased in their mating population from 12% to 35% before hitting a bound and increasing no further. It seems there is a hard limit on the proportion of "sexy" males that can be sustained within a given population.

Sorry ladies.

Happy Valentines Day.

Hine, McGuigan and Blows. Natural selection stops the evolution of male attractiveness. PNAS (2011). DOI: 10.1073/pnas.1011876108

Arsenic Based Life: the story continues

An update to the debate regarding the possibility of bacteria that can incorporate arsenic into DNA and other biomolecules (as described in the recent Science paper by Felicia Wolfe-Simon et al): the first published rebuttal has appeared in the chemical literature (n.b. many thanks to @BoraZ and @bmossop on Twitter for the alert). The rebuttal by Fekry, Tipton and Gates was published in ACS Chemical Biology on January 18th, and examines the potential consequences for DNA's chemical kinetics of a switch from arsenic to phosphate within the backbone structure.  This argument should sound familiar to those who have been following the online debate regarding the Wolfe-Simon's paper, and the article details the problems the GFAJ-1 would need to overcome if it replaced incredibly stable phosphate bonds with inherently unstable arsenate bonds. As quantified by the authors, the half-life of hydrolytic cleavage of the normal phosphate DNA backbone has been estimated as approximately 30 million years. This is in stark comparison with the estimated half-life for hydrolytic cleavage of the proposed arsenate-containing DNA backbone, 0.06 seconds. Such a difference would present a rather extreme challenge for GFAJ-1. As the article notes:

The estimates presented in preceding paragraphs suggest that, if exposed to bulk water, half of the arsenodiester linkages in the genome of Halomonadacea GFAJ-1 would be hydrolytically cleaved in less than 0.1 s. While some bacteria have evolved mechanisms for protecting their DNA under conditions of stress,(36, 37) overcoming such dramatic kinetic instability in its genetic material would be a significant feat for Halomonadacea GFAJ-1. Finally, we note that the use of arsenate esters in cell signaling, enzyme regulation, and cellular respiration would present a similar set of difficulties to the microbe.

This article moves the debate regarding the interpretations of the Wolfe-Simon's paper into arena of the official publication record. It is to be hoped that the original authors will now respond (as they promised to do), thus allowing a somewhat one-sided barrage of criticisms to evolve into a productive scientific discussion.

To celebrate this anticipated shift (and to remind readers of the reported results/interpretations plus major criticisms of the Wolfe-Simon's paper), a video presentation of the article from a recent session of the Stanford Neurosciences Ph.D Program Journal Club.

Unfortunately, the video did not preserve the projected slides as well as expected, so underneath the video readers will find the slides posted (fullscreen view is suggested - an option that can accessed by selecting the Menu button).

Neurosciences Journal Club Presentation Pt 1

Neuroscience Journal Club Presentation Pt 2

Presentation Slides

[slideshare id=6715316&doc=winter2011jc-110126233904-phpapp01]

Predicting Alzheimer's Disease

Welcome to the first Stanford Neuroblog live blogging event of 2011, covering a panel discusion entitled:

Predicting Alzheimer’s Disease: Intersection of Science, Medicine, and Society

From the official description:

We may soon be able, with good accuracy, to tell a healthy 60 year old whether or not he or she will have Alzheimer’s Disease - and, perhaps, how soon the symptoms will appear.  Join our panel of clinicians, lawyers, and health care workers in a discussion about the sciences that may allow us to predict the onset of alzheimer’s disease, and its implications for the health care system, patients, families, and society.

Tonight’s panelists are:

• Hank Greely, J.D. Deane F. and Kate Edelman Johnson Professor of Law; Professor, by courtesy, of Genetics; Director, Center for Law and the Biosciences; Stanford University
• Michael D. Greicius, M.D., M.P.H., Assistant Professor, Department of Neurology and Neurological Diseases, Stanford Medical School; Medical Director, Stanford Memory Clinic
• Michael Gilfix, J.D., expert in Elder Law, Gilfix & La Poll, Palo Alto
• Frank M. Longo, M.D., Ph.D., George E. and Lucy Becker Professor in Medicine; Chair, Department of Neurology and Neurological Diseases; Stanford University

The talk is sponsored by the Stanford Interdisciplinary Group in Neuroscience and Society, the same group that put on the previously blogged panel on Neuroscience in the Courtroom.

The talk begins with Hank Greely opening with a soliloqy regarding the prediction of disease. He notes that disease prediction is nothing new for the human race, and that Alzheimer's Disease (AD) holds a certain resonance, attacking our minds (a scary prospect for most people) as well as being remarkably common. He previews tonights discussion by stating that our ability to predict AD is increasing due to scientific advances. Tonights panel will cover those advances, as well as the effect on patients of this new ability, and both the legal and social implications of an ability to predict AD.

First to speak is:

Dr. Michael Greicius;  Novel Diagnostic and Predictive Tests for Alzheimer's Disease.

Currently, the clinical criteria for probable AD includes: dementia (change in cognition), deficits in two or more cognitive area (visual spatial, memory, etc), progressive decline in memory and other realms (such as executive function), no disturbance of consciousness, onset age 40-90 (mostly 65 and up), and no other explanation. Using these clinical criteria, sensitivity is fairly good , however specificity is rather poor - the distinction being that there are many false positives, but few false negatives. In speciality clinics, diagnosis is accurate 85-90% of the time, which leaves plenty of room for uncertainty. Indeed, the differential diagnosis is rather broad, including mild cognitive impairment, dementia with Lewy bodies, mass lesion, frontotemporal dementia, vascular dementia, depression, and others. Teasing these different possibilites apart can be tricky. For example, take mild cognitive impairment, which can be thought of as a middle ground between normal aging and AD. So a patient with MCI would have memory troubles, but would be able to overcome them. Conversion from MCI to AD is thought to be approximately 12%, and it would be beneficial to have the capability to predict which patients would convert.

Revising AD criteria is ongoing, mostly involving adding biological markers. These markers are preferably diagnostic, predictive, dynamic (tracking the course of the disease, useful as a measure of treatment efficacy), and a gold standard, that it could act as a surrogate for the condition (aka becomes something to treat itself).

Some examples of biological markers:

• Apolipoprotein E (ApoE): polymorphisms, some of which confer risk for AD. It is a susceptibility gene, and is therefore not useful as a general screening tool. However, it may be predictive for how patients will respond to treatment.
• Plaques and Tangles: Beta-Amyloid and Tau. These two proteins are positive markers of AD, that are used in post-mordem confirmation of an AD diagnosis. A group from Pittsburg, Klunk et al, developed a radioactive tracer that can be used to selectively image amyloid plaques in patients. Some limitations are that healthy controls can be positive for the tracer (as high as 51% positivity in health older controls). In addition, amyloid imaging is not dynamic, with signal peaking early in the condition, and not necessarily getting worse during disease progression. In terms of prediction, amyloid imaging is strongly predictive of which MCI patients will convert to AD.
• Spinal fluid markers: Tau is increased and Beta-amyloid is decreased within the spinal fluid of patients - this pattern is predictive in MCI to AD conversion, as well as being sensitive and specific for AD. In addition, a recent study (Fagan et al, Arch Neurol 2007) showed that spinal levels of tau/beta-amyloid can predict the conversion from healthy aging to mild dementia.

Predictive use of biological markers: amyloid imaging is used in selecting people for clinical trials, will soon be used in clinical settings. More ethically dubious is the use of predictive screens for healthy control (this will be covered later in the discussion). Greicius concludes by stating that all the clinical advances are paving the way toward development and early initiation of a definitive AD treatment.

Next to speak is:

Frank Longo, who is discussing the impact of predictive ability on patients.

Longo comments that the ability to predict onset of neurodegenerative diseases is currently available, in the case of Huntington's disease (HD). In the case of HD, genetic testing can confirm with 100% accuracy whether a patient will develop HD during the course of their lifetime. So HD can serve as a model for the ability to apply AD prediction within a clinical setting. Longo describes the protocol for HD genetic testing, saying that it includes genetic counseling, speaking with a trained neurologist, and finally DNA testing, with predetermined follow-up testing. Given a definite protocol, Longo describes his experience with patients, and with the process of giving news. He describes that process that people given a positive prediction for a neurodegenerative disease go through several stages, including resignation, relief because they at least know what the future is bringing, but also highly individualized stress. He describes some of the effects on family and significant others, who are also affected by a positive predictive diagnosis. Longo describes studies on stress in patients given good and bad news regarding their Huntington's diagnosis, saying that generally, data show a general reduction in stress. Longo says that this reduction in stress holds true for positive diagnoses of abnormal BRCA1/2 genes. Longo concludes by stating that the ability to predict AD must be considered in the context of the effect it will have on patients, and patient-family dynamics.

And next is Michael Gilfix.

He will speak as a practicing attorney, who will discuss his experience working with patients and planning of their legal affairs. He notes that the first reaction many patients have is planning for long term medical costs. Proactivity is important, as is applying for government benefits. There appears to be many legal ways to protect personal assets, as well as protocols for transferring legal responsibilities. Gilfix counsels the importance of taking proactive steps while they are still proactive - the sooner a legal plan is in place the better, appears to be his message. He concludes that the advent of predictive testing would allow much more sophisticated planning.

And lastly, Hank Greely takes the podium.

He will discuss the wider societal implications of AD. He starts by noting the differences between HD and AD, primarily the rates of incidence (very low in HD and common in AD) and the distinction between having a risk and knowing for sure (AD or HD, respectively). Now he speaks regarding the topic of regulation of predictive testing. Who will administer the test, who will decide whether any particular test works, who will regulate how the healthcare system will use this predictive information. As he has commented in other discussions, discrimination against those with positive predictive tests will assuredly be an issue. For example, spinal fluid tests are not protected against discriminate as predictive genetic tests are. And even so, employment discrimination against those with positive genetic tests is illegal, which does not mean that it will not happen (see racial and gender discrimination). Furthermore, genetic tests cannot be discriminated against in the realm of health insurance, but not long-term care insurance. In terms of predictive tests that denote "high risk", there are no specific protections against discrimination. He concludes that our society is really unready to handle the consequences of predictive tests for a variety of neurodegenerative conditions.

Question and Answer Session:

Question one, directed to Greicius, regards the cost of the biomarkers for AD, and why he did not recommend more cost-effective tests (such as hippocampal volume)?

Greicius respondes that many of the more cost-effective tests are, in his opinion (and in the opinion of the American Academy of Neurologists), not as accurate as the more expensive diagnostic tests mentioned during his presentation, and cannot be used as a predictive assay for AD.

Question two, mentions the use of calcium channel blockers in an AD mouse model, and asks whether any members of the panel can discuss the study.

Longo responds, saying the calcium channel blockers is just one of many, many drugs that have been shown to be effective in mouse models of AD. Should we use these medications (which are often used in humans to treat other conditions) on the basis of mouse models alone? He notes that no medications identified in mouse models have been shown to be ineffectual in humans, in addition carrying significant side effects.

Question three, what is the youngest age at which tangles/plaques have been identified?

Answer: Perhaps late 40s, early 50s. Patients with Down's Syndrome will have AD by the time they are in their 30's, and will therefore have tangles/plaques at that age. A neuropathologist in the audience points out that although neuropathology is considered the gold standard, there is still a good deal of variation between people in terms of the amount of pathological markers and cognitive deficits. This is probably due to individual differences in susceptibility to the cellular dysfunction and its translation into cognitive phenotype.

Question four: The audience member is concerned about the possibility that not having the test will end up being frowned upon. He asks whether people have thought about mandating privacy regarding results? Greely notes that in terms of genetic testing, employers/insurance companies are not allowed to take into account genetic testing no matter what their status is - and that something similar would probably be required in terms of predictive tests. However he notes that in terms of AD, employers might not care so much, given that people will probably develop AD long after they are no longer working at the company in question.

Question five: How much do these test help us improve accuracy over the current clinical diagnostic tools?

Answer: It ups your likelihood for a correct diagnosis in atypical presentations.

The questions continue as more a discussion, with speakers going too quickly for this typist to capture in any detail. Therefore, I'm ending my coverage, encouraging readers to discuss the panel discussion in the comments.

[Mice] Singing in the Lab

Happy New Year everyone! To celebrate the start of 2011, here is a story from the end of last year: "singing" mice.

These mice, generated by a team of Japanese scientists, vocalize in a manner startlingly similar to that of songbirds. These mice are the product of the University of Osaka's Evolved Mouse Project, which screens mice prone to mis-copying DNA for the presence of random mutations. So far, there are no details as to what exact mutation resulted in these mice exhibiting the song-like vocalizations.

For video of the mice, see this Youtube video.

Interestingly, it appears that non-mutant mice do vocalize extensively, just at ultrasonic frequencies (see this video detailing the research of Dr. Christine Portfors). Could the mutation in the Osaka mice be affecting the frequency of mouse vocalizations, reducing them to levels discernible by human ears? Any commentators out there with greater familiarity in songbird and mouse vocalizations, please sing out in the comments.