Wednesday, September 29, 2004

Abstract of the Day: Memory Distortion

Schacter DL, Slotnick SD. The cognitive neuroscience of memory distortion. Neuron. 2004 Sep 30;44(1):149-60.

Department of Psychology, Harvard University, Cambridge, MA 02138 USA.

Memory distortion occurs in the laboratory and in everyday life. This article focuses on false recognition, a common type of memory distortion in which individuals incorrectly claim to have encountered a novel object or event. By considering evidence from neuropsychology, neuroimaging, and electrophysiology, we address three questions. (1) Are there patterns of neural activity that can distinguish between true and false recognition? (2) Which brain regions contribute to false recognition? (3) Which brain regions play a role in monitoring or reducing false recognition? Neuroimaging and electrophysiological studies suggest that sensory activity is greater for true recognition compared to false recognition. Neuropsychological and neuroimaging results indicate that the hippocampus and several cortical regions contribute to false recognition. Evidence from neuropsychology, neuroimaging, and electrophysiology implicates the prefrontal cortex in retrieval monitoring that can limit the rate of false recognition.

PMID: 15450167 [PubMed - in process]

Tuesday, September 28, 2004

MRI During Brain Surgery

A press release from the Radiological Society of North America. Here is the abstract of the specific study mentioned in the release: [abstract].

MR imaging during brain surgery improves tumor removal

OAK BROOK, Ill. - A specially adapted magnetic resonance imaging (MRI) scanner can help physicians remove brain tumors and all of the residual cancer during one surgical procedure, according to a study published in the October issue of the journal Radiology. Using intraoperative MR-guidance, surgical strategy was changed in one out of four cases.

"Imaging during surgery provides intraoperative quality control. It presents valuable information during the procedure that allows the surgeon an opportunity to adjust the strategy," said lead author Christopher Nimsky, M.D., an associate professor at the University Erlangen-Nürnberg in Germany.

Prior to intraoperative imaging, small parts of the tumor could be inadvertently missed. This tumor residue usually required repeated surgery, surveillance or further treatment.

The researchers reported their first clinical experience with intraoperative high-field MRI of 200 patients. They evaluated the extent of tumor removal depicted by intraoperative imaging and how surgical strategy was altered. The investigators found that imaging quality was indistinguishable between the pre- and intraoperative scans. In 27.5 percent of cases, intraoperative MRI impacted surgical strategy, often depicting additional tissue that needed to be removed.

MR is the imaging modality of choice for preoperative diagnosis of brain tumors and epilepsy. In the mid 1990s the advancement of open MR systems extended its practicality to the operating room. The researchers have now applied high-field scanning capabilities to intraoperative MR. High-field MR produces better image quality with reduced scan time. However, high-field MR is still an expensive imaging modality and will be for at least the next few years.

Dr. Nimsky envisions that in the future, flat MR scanners might be placed underneath operating tables to further optimize the intraoperative application of MR imaging technology. He said that the optimal solution is a nearly invisible imaging system that provides real-time feedback to the neurosurgeon without disturbing the surgical workflow.

###

Public release date: 28-Sep-2004
Contact: Maureen Morley | mmorley@rsna.org | 630-590-7762
Radiological Society of North America

Radiology is a monthly scientific journal devoted to clinical radiology and allied sciences. The journal is edited by Anthony V. Proto, M.D., School of Medicine, Virginia Commonwealth University, Richmond, Va. Radiology is owned and published by the Radiological Society of North America Inc. (rsna.org/radiologyjnl)

RSNA is an association of more than 35,000 radiologists, radiation oncologists and related scientists committed to promoting excellence in radiology through education and by fostering research, with the ultimate goal of improving patient care. The Society is based in Oak Brook, Ill. (rsna.org)

"Intraoperative High-Field-Strength MR Imaging: Implementation and Experience in 200 Patients." Collaborating with Dr. Nimsky on this paper were Oliver Ganslandt, M.D., Boris von Keller, M.D., Johann Romstöck, M.D., and Rudolf Fahlbusch, M.D.

Monday, September 27, 2004

Business World: CombinatoRx and Brain Tumors

A company press release concerning an agreement to develop additional research efforts in the search for pharmaceutical treatments for brain tumors:

CombinatoRx and ABC2 Initiate Brain Cancer Collaboration: Partnership Speeds Search for Brain Cancer Cure
Monday September 27, 8:33 am ET

BOSTON and BURLINGAME, Calif., Sept. 27 /PRNewswire/ -- CombinatoRx, Incorporated, a privately held pharmaceutical company, and Accelerate Brain Cancer Cure (ABC2), a non-profit foundation dedicated to accelerating therapies leading to a cure for brain cancer, today announced that they have initiated a research collaboration aimed at identifying novel multi-target drugs for the treatment of brain cancer.

The sponsored research will leverage the CombinatoRx proprietary combination high throughput screening (cHTS) platform in an effort to discover novel drug combinations that hit multiple targets relevant to glioblastoma multiforme (GBM), a deadly form of brain cancer. The cHTS platform allows CombinatoRx to uncover synergistic activities of drug combinations acting on a network of molecular pathways.

[ ... Read the full press release ... ]

Business World: Guilford Pharm's Gliadel

A company press release regarding a treatment for brain tumors:

Guilford Pharmaceuticals Announces Orphan Drug Designation for GLIADEL(R) Wafer; Market Exclusivity for GLIADEL(R) Extends Until 2010

BALTIMORE, Sept. 27 /PRNewswire-FirstCall/ -- Guilford Pharmaceuticals Inc. (Nasdaq: GLFD) today announced that it has received notice from the United States Food and Drug Administration (FDA) that GLIADEL(R) Wafer (polifeprosan 20 with carmustine implant), the Company's proprietary brain cancer treatment, is entitled to seven years of market exclusivity for the treatment of patients with malignant glioma undergoing primary surgical resection. The seven-year period of exclusivity under the Orphan Drug Act commenced on the date of approval in February 2003 and extends until February 2010.

The FDA's orphan drug program is intended to encourage research, development and approval of products for diseases that affect fewer than 200,000 patients in the United States per year and provide a significant therapeutic advantage over existing treatments.

"Today's news is the latest in a series of positive developments for GLIADEL(R) announced over the last several weeks," commented Craig R. Smith. M.D., President and Chief Executive Officer. "In August, we reported that GLIADEL(R) had been assigned to a new Diagnosis Related Group (DRG) by the Centers for Medicare and Medicaid Services. The new DRG, which will take effect on October 1, 2004, is expected to improve access to GLIADEL(R) by providing increased payment to hospitals that provide it to their Medicare patients. In addition, last week we reported that GLIADEL(R) had received marketing authorization in Europe."

"Our patent protection for GLIADEL(R) ends in August 2006. Orphan Drug Designation for GLIADEL(R) gives us an additional four years of market exclusivity in the United States for patients undergoing primary surgical resection," continued Dr. Smith. "While we believe our manufacturing process for GLIADEL(R) is sufficiently complex to deter others from making the product, this new period of exclusivity ensures they cannot market it for this indication."

[ ... Read the full press release ... ]

Friday, September 24, 2004

In The Weeklies

Here are some relevant highlights from this week’s major scientific and medical weeklies:


Journal of the American Medical Association
22/29 September 2004

There are several contributions this week examining dietary intake and physical exercise habits in aging populations and their relationship to cognitive functioning and dementia. The issue also contains an editorial about these contributions.


New England Journal of Medicine
23 September 2004

This issue includes a Clinical Practice case vignette about Bell’s Palsy by Gilden.


Lancet
25 September 2004

This week’s Lancet includes a comment entitled, Parkinson's disease and dementia with Lewy bodies: A difference in dose? and two research letters on the topic of Parkinson’s: alpha-synuclein locus duplication as a cause of familial Parkinson's disease by Chartier-Harlin and colleagues and Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease by Ibáñez and colleagues.


Science
24 September 2004

This week’s issue includes a perspective entitled A Fresh Look at BSE by Chesebro and two technical comments on the topic of: Comment on "Role of NMDA Receptor Subtypes in Governing the Direction of Hippocampal Synaptic Plasticity" by Rusakov and colleagues and Response to Comment on "Role of NMDA Receptor Subtypes in Governing the Direction of Hippocampal Synaptic Plasticity" by Wong and colleagues.


Nature
23 September 2004

This week’s issue includes the article Impaired PtdIns(4,5)P 2synthesis in nerve terminals produces defects in synaptic vesicle trafficking by Di Paolo and colleagues.

What Can Artists Who Experience Brain Disease Teach Us About the Brain and Behavior?

A small but fascinating area of study in neuropsychology is the examination of the abilities of artists who have sustained some form or another of brain disease. Painters, musicians, writers have all been studied, usually in detailed individual case studies. Changes as a result of progressive disorders (e.g., Alzheimer disease) or as a result of an acute event (e.g., stroke) have been examined, as well as the artistic productions of nonprofessionals (e.g., autistic children).

A new review article is available that discusses this work in detail. The article and its author are discussed in this press release from the University of Pennsylvania:

September 21, 2004

Artistic Expression Need Not End,
and Can Even Improve After Brain Damage

Penn Researcher Finds Neuropsychological Processes Offer Insights into Artistic Production

(Philadelphia, PA) – What happens to visual artists that experience brain damage? And what can it tell us about how humans represent the world? According to Anjan Chatterjee, MD, an Associate Professor in the Center for Cognitive Neuroscience at the University of Pennsylvania School of Medicine, brain damage does not necessarily end the ability to produce compelling works of art; additionally, artists with brain damage can provide useful information on the nature of artistic expression. In a review article published in Neuropsychologia (Volume 42, Issue 11), Chatterjee draws on nearly 50 research articles and books, and finds that, “Artists with neuropsychological deficits do not necessarily produce art of lesser quality. Rather, their art may change in content or in style, sometimes in surprising and aesthetically pleasing ways.” Not only does this collection illustrate various forms and changes in perception, but it also suggests that continuing research in the field could bring about new therapies that could help patients with brain damage.

In the article, Chatterjee surveys nearly a half-century of findings of medical researchers on neurological syndromes and brain disorders and their consequences for the production of art. The purpose of the survey is to bring these findings, which appear in disparate books and journal articles, together and finally synthesize them into a single site. Although the data are descriptive in nature, the reports are few, and artistic talents and styles can vary greatly, Chatterjee believes this field is a rich seam to mine. “This opens up the possibility of obtaining greater insights into how the brain produces rich, intricate cultural products that move, enlighten, and transform each of us,” explains Chatterjee.

[snip]

By bringing all of these scattered accounts into one body of literature, Chatterjee raises intriguing themes relevant to the nature of artistic expression and proposes that art is worth considering as a neuropsychological probe. Continuing research that focuses on these themes could bring exciting developments in various therapies for brain damage – including, of course, art therapy – and unlock perceptual mysteries of the mind. “Artists are especially adept at making their internal representations manifest,” explains Chatterjee. “Many more descriptions of the neuropsychology of artists could help determine and confirm the underlying principles of the consequences of brain damage on artistic expression.”
[ ... Read the full press release ... ]

Thursday, September 23, 2004

Business World: Ecopia's ECO-4601 and the Blood-Brain Barrier

This corporate press release on BusinessWire about a drug candidate for treatment of primary brain tumors:

Ecopia's Lead Cancer Compound Shown to Cross Blood-Brain Barrier
September 23, 2004 08:26 AM US Eastern Timezone

MONTREAL--(BUSINESS WIRE)--Sept. 23, 2004--Ecopia BioSciences Inc. (TSX:EIA) has obtained results demonstrating that its lead compound ECO-4601, a drug candidate to treat brain cancer, crosses the blood-brain barrier. This new data, coupled with previous efficacy data in glioma animal models as well as the compound's safety profile, reinforces the Company's strategy to pursue the development of ECO-4601 for treatment of primary brain cancer. This will allow Ecopia to rapidly access an underserved and growing market of patients with a very bleak prognosis.

Current treatment options for primary brain cancer are limited and often present challenges in delivering the drug to its target, which is protected by the blood-brain barrier. The barrier acts as a filter, allowing the passage of only certain compounds. Several treatments on the market and in development require invasive techniques, including surgery, to administer the compounds directly to the brain. Such invasive methods of administering chemotherapeutic agents can lead to complications including infections and swelling of the brain. The results obtained today with ECO-4601 demonstrate its potential for easy delivery by intravenous infusion, which is commonly used in chemotherapy to treat cancer.

"These results are very exciting because the ability of ECO-4601 to cross the blood-brain barrier gives our compound a major competitive advantage in serving the unmet needs of brain cancer patients," stated Dr. Pierre Falardeau, Ecopia's President and Chief Executive Officer. "We will continue to focus our efforts on developing this compound and begin to prepare a filing of an IND for the FDA, in order to start human trials as soon as possible."

Ecopia scientists will present this, and other, data during a poster session on October 1, 2004, at the 16th EORTC-NIC-AACR Symposium in Geneva. This symposium brings together three of the world's leading cancer organisations and oncologists.

ECO-4601 is a novel compound discovered using the Ecopia's unique DECIPHER(R) technology. The Company has already reported data demonstrating the compound's ability to significantly inhibit tumour growth in animal models for an aggressive form of primary brain cancer.

Current prognosis for patients diagnosed with primary brain cancer is poor, with a two-year survival rate of 35%, dropping as low as 8% for some more aggressive forms. Each year 8.2 out of every 100,000 individuals are diagnosed with primary brain cancer, representing an estimated 58,000 new cases per year in developed countries. Presently, the standard of care involves surgery to remove the tumour when accessible, radiation to shrink the tumour and chemotherapy to kill the cancer cells. The current chemotherapeutic standard of care for brain cancer costs an estimated US$25,000 per year, resulting in a potential market worth well over US$1 billion.

[ ... Read the full press release ... ]

Stroke and Acid-Sensing Ion Channels

A report at Science Daily concerning a new research study:

New Way To Protect Brain From Stroke Damage
Researchers have uncovered a new culprit behind the brain injury suffered by stroke victims. Their new study, published in the Sept. 17 issue of Cell, links brain cell damage to a rise in brain acidity following the oxygen depletion, or ischemia, characteristic of stroke. The results may lead to new therapies designed to avert the often debilitating effects of stroke, for which successful treatments are currently lacking, the researchers said.

A series of experiments in laboratory dishes and in animals implicates a recently described class of membrane ion channels, called acid-sensing ion channels (ASICs), to the influx of calcium in nerve cells starved of oxygen and subjected to acidic conditions. That calcium overload, long attributed to another group of cellular components, is essential for stroke injury as it sets off a cascade of events toxic to cells, said neurophysiologist and lead author of the study (Zhi-Gang Xiong of Robert S. Dow Neurobiology Laboratories in Portland, Oregon).

What's more, the team reports, rats injected with agents known to block ASICs--including the venom of a tarantula spider--exhibited a reduction in brain damage from ischemia. Mice lacking a functional copy of the ASIC gene were similarly resistant to stroke damage, they found.

"Our study offers multiple lines of evidence that reveal acid-sensing ion channels as major players in the damage suffered by stroke victims," Xiong said. "Furthermore, we found that existing pharmacologic agents that block those channels can dramatically reduce the amount of brain injury."

[snip]

The normal brain requires complete oxidation of glucose to fulfill its energy requirements, the researchers explained. During ischemia, oxygen depletion forces the brain to obtain energy through anaerobic glycolysis, a process which results in the accumulation of lactic acid. Earlier work indicated that such acidic conditions aggravate ischemic brain injury. However, the group added, the mechanisms had remained unclear.

The team's new work resolves that uncertainty. In laboratory dishes, acidic and ischemic conditions activate ASICs in mouse brain neurons, leading to an influx of calcium, they showed. Two agents known to block ASICs--the drug amiloride and the tarantula venom called PcTX--protected the nerve cells against acid-induced injury. Cells lacking ASIC1a, the calcium-permeable type of the acid-sensing channels, were resistant to acid injury.

To test that activation of ASIC1a is involved in ischemic brain injury in a live animal, the team tested the protective effect of ASIC blockers in an ischemic rat. Rats injected with PcTX, which is known to specifically block ASIC1a, showed a 60 percent reduction in the area of brain damage following ischemia compared to control animals. Mice lacking the ASIC1a gene also showed significantly less ischemic brain injury.

Scientists had long considered another class of cellular components, NMDA receptors, as the main target responsible for calcium overload in the ischemic brain, according to the researchers. "However, recent clinical efforts to prevent brain injury through the therapeutic use of NMDA receptor antagonists have been disappointing," they wrote.

The new study pinpoints a new target underlying toxic levels of calcium in the brain, disclosing a potential new therapeutic target for stroke, the researchers added. Blockers of ASIC1a, either alone or in concert with other neuroprotective methods, might therefore prove useful for stroke therapy, they said.

[ ... Read the full report ... ]

The full paper can be found at:

Zhi-Gang Xiong, Xiao-Man Zhu, Xiang-Ping Chu, Manabu Minami, Jessica Hey, Wen-Li Wei, John F. MacDonald, John A Wemmie, Margaret P Price, Michael J Welsh, and Roger P. Simon: Neuroprotection in Ischemia: Blocking Calcium-Permeable Acid-Sensing Ion Channels. Cell 2004; 118(6): 687–698.

Wednesday, September 22, 2004

Trained Olfactory Signalling in Rats

A curious report from New Scientist:

Rats' brain waves could find trapped people
19:00 22 September 04

Rats equipped with radios that transmit their brainwaves could soon be helping to locate earthquake survivors buried in the wreckage of collapsed buildings.

Rats have an exquisitely sensitive sense of smell and can crawl just about anywhere. This combination makes them ideal candidates for sniffing out buried survivors. For that, the animals need to be taught to home in on people, and they must also signal their position to rescuers on the surface.

In a project funded by DARPA, the Pentagon’s research arm, Linda and Ray Hermer-Vazquez of the University of Florida in Gainesville have worked out a way to achieve this.

Trained rats reach the places that sniffer dogs cannot

First the researchers identified the neural signals rats generate when they have found a scent that they are looking for. “When a dog is sniffing a bomb, he makes a unique movement that the handler recognises,” says John Chapin, a neuroscientist at the State University of New York in Brooklyn who is collaborating on the project. “Instead of the rat making a conditioned response, we pick up the response immediately from the brain.”

[ ... Read the full report ... ]

Abstract of the Day: Walking and Cognitive Function

This week's issue of JAMA is getting a good deal of media attention for several articles that assess dietary intake and exercise habits and their impact on cognitive functioning and dementia in older indviduals.

Following is the abstract one of the reports. This study is also important in neuropsychology as it is part of the Nurses' Health Study, which is a large scale study of aging that includes telephone-based cognitive assessments.

Jennifer Weuve, ScD; Jae Hee Kang, ScD; JoAnn E. Manson, MD; Monique M. B. Breteler, MD; James H. Ware, PhD; Francine Grodstein, ScD. Physical Activity, Including Walking, and Cognitive Function in Older Women. JAMA. 2004;292:1454-1461.

Context:  Physical activity may help maintain cognitive function in older adults.

Objective:  To examine the relation of long-term regular physical activity, including walking, to cognitive function.

Design:  Women reported participation in leisure-time physical activities on biennial mailed questionnaires beginning in 1986. We assessed long-term activity by averaging energy expenditures from questionnaires in 1986 through participants' baseline cognitive assessments (1995 to 2001). We used linear regression to estimate adjusted mean differences in baseline cognitive performance and cognitive decline over 2 years, across levels of physical activity and walking.

Setting and Participants:  Nurses' Health Study, including 18 766 US women aged 70 to 81 years.

Main Outcome Measure:  Validated telephone assessments of cognition administered twice approximately 2 years apart (1995 to 2001 and 1997 to 2003), including tests of general cognition, verbal memory, category fluency, and attention.

Results:  Higher levels of activity were associated with better cognitive performance. On a global score combining results of all 6 tests, women in the second through fifth quintiles of energy expenditure scored an average of 0.06, 0.06, 0.09, and 0.10 standard units higher than women in the lowest quintile (P for trend <.001). Compared with women in the lowest physical activity quintile, we found a 20% lower risk of cognitive impairment for women in the highest quintile of activity. Among women performing the equivalent of walking at an easy pace for at least 1.5 h/wk, mean global scores were 0.06 to 0.07 units higher compared with walking less than 40 min/wk (P.003). We also observed less cognitive decline among women who were more active, especially those in the 2 highest quintiles of energy expenditure. Women in the fourth and fifth quintiles had mean changes in global scores that were 0.04 (95% confidence interval, 0.02-0.10) and 0.06 (95% confidence interval, 0.02-0.11) standard units better than those in the lowest quintile.

Conclusion:  Long-term regular physical activity, including walking, is associated with significantly better cognitive function and less cognitive decline in older women.

Author Affiliations: Departments of Epidemiology (Drs Weuve, Manson, and Grodstein) and Biostatistics (Dr Ware), Harvard School of Public Health, and Channing Laboratory (Drs Kang, Manson, and Grodstein) and Division of Preventive Medicine (Dr Manson), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; and Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, the Netherlands (Dr Breteler). Dr Weuve is now with the Department of Environmental Health, Harvard School of Public Health, Boston, Mass.

Tuesday, September 21, 2004

Abstract of the Day: Neuropsychological Assessment

Garces-Redondo M, Santos S, Perez-Lazaro C, Pascual-Millan LF. The supermarket test: Preliminary normative data in our milieu (in Spanish). Rev Neurol. 2004 Sep 1-15; 39(5): 415-8.

Hospital Clinico Universitario Lozano Blesa, Zaragoza, Espana.

INTRODUCTION. Semantic verbal fluency (SVF) tests are often used in basic neuropsychological evaluation. They are not time consuming and are easy to apply, but the normative data have been validated mainly for the Anglo-Saxon population, which can lead us to make mistakes in classifying normality. AIMS. To evaluate the category 'things you can buy at a supermarket' as a task for exploring SVF applied to a Castilian-speaking population of Spaniards with the aim of conducting a pilot normative test in our milieu. SUBJECTS AND METHODS. The 'things you can buy at a supermarket' task was applied to a sample of 139 healthy subjects without cognitive impairment, whose mother tongue is Spanish. The subjects were subclassified according to their level of schooling in years, age groups and sex. RESULTS. Total mean production (1 minute) = 20.1 +/- 8. No differences were seen in the comparative analysis according to sexes. By age: < 50 years = 33 +/- 6; 50-59 = 24.6 +/- 6; 60-69 = 16.5 +/- 5; 70-79 = 15.5 +/- 6; > 79 years = 13.5 +/- 6. By years of schooling: < 10 years = 19 +/- 6; > 10 years = 29 +/- 5. CONCLUSIONS. Mean output of words is 20 in one minute, with a percentile distribution where the deficit criterion (p10) would be in an output below 10 words. Overall, greater output is observed in the first half minute. There are a number of socio-demographic factors, such as age and mean number of years of schooling, that have been proved statistically to exert an influence on semantic capacity in this test. No differences were observed according to sex. We present the mean results, as well as the overall percentile distribution and results according to age and schooling, because we think they can serve as preliminary normative data in our milieu.

PMID: 15378452 [PubMed - in process]

9.4 Tesla MRI Unveiled

From a University of Illinois at Chicago press release:

World’s Most Powerful MRI for Decoding the Human Brain

Newswise — The University of Illinois at Chicago unveiled today the world's most powerful magnetic resonance imaging machine for human studies, capable of imaging not just the anatomy but metabolism within the brain.

This advanced technology ushers in a new age of metabolic imaging that will help researchers understand the workings of the human brain, detect diseases before their clinical signs appear, develop targeted drug therapies for illnesses like stroke and provide a better understanding of learning disabilities.

Central to the technology is a 9.4-tesla magnet, larger than any other human-sized magnet, built by GE Healthcare, a unit of General Electric Company. A tesla is a large measuring unit of magnetic strength.

"This technological leap forward is as revolutionary to the medical community as the transition from radio to television was for society," said Dr. Keith Thulborn, director of the UIC Center for Magnetic Resonance Research, at the facility's grand opening today. "GE's magnet is introducing a whole new dimension to imaging by enabling researchers to better understand how the human brain thinks, learns, fights disease and responds to experimental therapies."

"UIC's new Center for Magnetic Resonance Research featuring GE's 9.4-tesla magnet will be a premier international center for human brain research," Thulborn said. "What we learn here in Chicago will be shared with researchers and physicians around the world."

[ ... Read the full article ... ]

Business World: Australia's CogState

An article from the Australian website, The Age:

CogState promotes brain tests to draw takeover offers
By Rebecca Urban
September 22, 2004

Frustrated by its diminishing value on the Australian sharemarket, diagnostic maker CogState is pitching itself to some of the world's leading pharmaceutical companies as a potential takeover target.

Just seven months after the company's public listing, chief executive Peter Bick told The Age that he had become impatient with the lack of trading in its shares and selling the business might be the only way to recoup lost value for shareholders.

Dr Bick would not confirm which companies he was talking to. But pharmaceutical giants Pfizer, Johnson & Johnson and Lundbeck are believed to be high on the hit-list given they are the only companies worldwide to have Alzheimer's disease drugs approved for the market.

CogState's computerised brain test helps diagnose Alzheimer's by alerting doctors to changes in a patient's cognitive function and can help verify whether a patient is responding to prescribed medication.

Dr Bick will travel to the US next week to meet several drug companies and plans to emphasise the value of the test as a marketing tool for their products.

[ ... Read the full article ... ] (free registration required)

Monday, September 20, 2004

Obit: Irving Diamond

James B. Duke professor emeritus dies at 81: Irving Diamond researched brain evolution, structure and function.
The Chronicle Online: The Independent Daily at Duke University
From Staff and Wire Reports
17 September 2004

Irving Diamond, a retired James B. Duke Professor of Psychology and a prominent researcher in human and animal sensory systems, died Tuesday at his Durham home. He was 81.

Diamond, born in Chicago Sept. 17, 1922, received his undergraduate and graduate degrees from the University of Chicago. After serving from 1943 to 1946 in the U.S. Army, Diamond joined the University of Chicago faculty and taught there for a decade before coming to Duke in 1958.

“He was an important figure in neuropsychology,” said George Washington Ivey Professor Emeritus of New Testament in the Divinity School Moody Smith, a friend and colleague to Diamond. “He loved intellectual controversy and was always open minded.”

The author or co-author of more than 100 scientific papers, including chapters in 11 books, Diamond focused his research on the evolution of the primate brain and the structure and function of the neocortex.

Diamond’s teaching methods included requiring students to analyze the original texts of great pioneers in the fields of evolution, genetics, embryology, neurophysiology and experimental psychology. “He was kind of a renaissance man—he was a very good teacher and his interests went beyond his discipline,” Smith said.

Diamond was named to the National Academy of Sciences in 1982 and he received the distinguished scientific contribution award from the American Psychological Association for having made a unique contribution, and one that has changed the direction of his field.

Medulloblastoma

Targeted therapy knocks out pediatric brain cancer in mice

Scientists have identified what may be the first nontoxic treatment for a subset of medulloblastoma, the most common type of malignant pediatric brain tumor. The finding is encouraging in that such precise, targeted therapies may someday replace traditional treatments that can have overwhelmingly negative side effects for pediatric cancer patients. The research is published in the September issue of Cancer Cell.

"Therapy for pediatric cancers of the central nervous system has not improved significantly in the last three decades," explains study author Dr. Tom Curran from St. Jude Children's Research Hospital in Memphis, Tennessee. "This is partly due to the absence of adequate model systems for testing novel therapies." Dr. Curran and colleagues used a mouse model of medulloblastoma that they had developed to examine whether selective inhibition of the Sonic Hedgehog (Shh) signaling pathway could interfere with the development and progression of the disease. Previous studies have implicated the Shh pathway in human medulloblastoma formation.

Treatment of the mice with a small molecule inhibitor of Shh, HhAntag, resulted in elimination of medulloblastoma. HhAntag administration was associated with the suppression of multiple genes expressed in medulloblastoma as well as reduced cell proliferation and an increase in tumor cell death. Importantly, high doses of HhAntag completely eradicated the tumors, and long-term treatment prolonged medulloblastoma-free survival. No toxic side effects of HhAntag treatment were observed in the mice.

The researchers conclude that the development of compounds that selectively block Shh may be an appropriate direction for designing effective, nontoxic treatments for medulloblastoma. "Ultimately, it is likely that success in treating cancer will require the use of several compounds in concert that target distinct pathways important for tumor cell growth. Our mouse studies with HhAntag offer the hope that such precise, targeted molecular interventions could spare children from the devastating effects of surgery, toxic chemotherapy, and exposure to high doses of radiation," offers Dr. Curran.

###
Press Release
Contact: Heidi Hardman
hhardman@cell.com
617-397-2879
Cell Press

Justyna T. Romer, Hiromichi Kimura, Susan Magdaleno, Ken Sasai, Christine Fuller, Helen Baines, Michele Connelly, Clinton F. Stewart, Stephen Gould, Lee L. Rubin, and Tom Curran: "Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1++/-p53+/- mice" Publishing in Cancer Cell, Volume 6, Number 3, September 2004, page 229-240.

New Neuroscience Director at MIT

MIT to name new director of McGovern brain center
The Boston Globe
By Marcella Bombardieri, Globe Staff  |  September 20, 2004

The McGovern Institute for Brain Research at the Massachusetts Institute of Technology will announce today that Robert Desimone, scientific director of the National Institute of Mental Health, has been chosen as its new director, according to MIT officials.

Desimone will replace Phillip A. Sharp, the Nobel laureate biologist who has led the McGovern Institute since it was created four years ago with a $350 million gift from International Data Group founder Patrick J. McGovern and his wife, Lore Harp McGovern. It was the largest gift ever pledged to a university at the time, and the McGovern Institute is a key part of MIT's efforts to develop the best neuroscience program in the world.

[ ... Read the full article ...]

Sunday, September 19, 2004

Abstract of the Day: Deficit Awareness in Traumatic Brain Injury

Hart T, Sherer M, Whyte J, Polansky M, Novack TA. Awareness of behavioral, cognitive, and physical deficits in acute traumatic brain injury. Arch Phys Med Rehabil 2004; 85:1450-6.

OBJECTIVE: To compare awareness of deficit in 3 domains of function (physical, cognitive, behavioral/emotional) in acute traumatic brain injury (TBI), controlling for severity of impairment in the different domains. DESIGN: Inception cohort. SETTING: Three inpatient rehabilitation programs. PARTICIPANTS: People with acute TBI (N=161), tested as soon as feasible after posttraumatic amnesia. INTERVENTIONS: Not applicable. Main outcome measures Awareness Questionnaire (AQ) completed by the person with TBI and the treating neuropsychologist; and self- and clinician-rating scores calculated in the 3 domains. RESULTS: For participants who were rated by clinicians as more impaired in at least 1 domain (ie, scored lower on the AQ), self-ratings differed significantly from one another in all 3 domains, with behavioral self-ratings highest, physical self-ratings lowest, and cognitive self-ratings intermediate. In subgroups of participants rated at the same level by clinicians in all 3 domains, physical self-ratings were also lowest, that is, more consonant with clinician ratings. Participants tended to rate themselves as relatively unchanged in cognitive and behavioral domains regardless of the level of clinician ratings on these factors. CONCLUSIONS: Patterns of discrepant awareness of deficit in different functional areas seen in postacute TBI also appear to be present acutely and are not entirely related to differential severity of deficit. We discuss several possible reasons for discrepant awareness of deficit, including differences in internal and external feedback, cultural and psychologic factors, and different levels of ambiguity inherent in causal explanations for different types of problems.

PMID: 15375815 [PubMed - as supplied by publisher]

Friday, September 17, 2004

Dementia Voting Project

As a follow-up to this week's news about dementia and the voter, I note that the senior author of the JAMA article has a funded project to examine this issue, called the Dementia Voting Project [project website].

According to the site's homepage:

"Welcome to the Dementia Voting Project. The goal of this project is to identify and address the ethical, legal, political, medical and practical issues regarding the rights and abilities of individuals with dementia and other causes of cognitive impairment to vote."

According to the site, some of the questions they are examining include:

How should we understand the construct of "the capacity to vote"?
How can a person assess another person's "capacity to vote?"
What kind of assistance in voting is appropriate to provide to a person with cognitive impairment who retains sufficient residual capacity to cast a meaningful vote?
What role should long-term care staff have in providing voting assistance to residents?
What are the political consequences of voting by persons who lack the capacity to vote?

Abstract of the Day: Neuropsychological Assessment

Au R, Seshadri S, Wolf P, Elias M, Elias P, Sullivan L, Beiser A, D'Agostino R. New norms for a new generation: Cognitive performance in the Framingham Offspring Cohort. Exp Aging Res. 2004 Oct-Dec; 30(4): 333-58.

Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.

A previous publication presented normative data on neuropsychological tests stratified by age, gender, and education based on the Original Cohort of the Framingham Heart Study. Many contemporary investigations include subject samples with higher levels of education, a factor known to affect cognitive performance. Secular change in education prompted the reexamination of norms in the children of the Original Cohort. The study population consisted of 853 men and 988 women from the Offspring Study, free of clinical neurological disease, who underwent a neuropsychological examination, which included tests given to their parents in 1974 to 1976 as well as additional newer tests to provide a more comprehensive battery. The Offspring population overall was more evenly distributed by gender and better educated. Their performance on cognitive tests was superior to that of the Original Cohort. Multivariable analyses revealed that more years of education explained only a part of the cohort differences. These findings suggest that continued surveillance of each generation is necessary to document the impact that unique social and economic variables have on cognitive function. Here, the authors provide updated normative data.

PMID: 15371099 [PubMed - in process]

In The Weeklies

Here are some relevant highlights from the new issues of the major medical and scientific weeklies:

Journal of the American Medical Association
15 September 2004

JAMA’s contents this week include the report about dementia and the voter by Karlawish and colleagues, which has been quite newsworthy (see earlier posts).

This issue also includes an editorial concerning pharmaceutical clinical-trials registration: Clinical Trial Registration: A Statement From the International Committee of Medical Journal Editors.

British Medical Journal
18 September 2004

This week’s BMJ also publishes the editorial concerning clinical-trials registration.

New England Journal of Medicine
16 September 2004

This week’s issue contains a review article about Turner’s Syndrome by Sybert and McCauley. The clinical-trials editorial also appears.

Nature
16 September 2004

Includes the letter, Early brain growth in Homo erectus and implications for cognitive ability by Coqueugniot and colleagues, which begins, “Humans differ from other primates in their significantly lengthened growth period. The persistence of a fetal pattern of brain growth after birth is another important feature of human development. Here we present the results of an analysis of the 1.8-million-year-old Mojokerto child (Perning 1, Java), the only well preserved skull of a Homo erectus infant, by computed tomography.”

Medicare to Cover PET in Diagnosis of Some Suspected Dementias

Medicare has announced that it will begin authorizing coverage for obtaining PET scans to aid in diagnosis for patients with atypical symptoms of Alzheimer's disease or those suspected of rarer dementing diseases, such as the "fronto-temporal" dementias.

Reuters quotes Mark McClellan, administrator of the agency that oversees Medicare, saying, "We ought to approve coverage for patients who've been worked up but whose diagnosis is uncertain."

From the Washington Post:

Medicare Will Pay for Alzheimer's Scan
Doubts About Technology Lead Agency to Cover Only Some Patients

By Rick Weiss and David Brown
The Washington Post
Friday, September 17, 2004; Page A02

Medicare will start paying for specialized brain scans in some patients to help determine if they have Alzheimer's disease, the federal agency that runs the reimbursement program announced yesterday.

The decision caps a four-year struggle by makers of the technology -- known as positron emission tomography, or PET -- to gain approval from the Centers for Medicare and Medicaid Services for PET's use in patients suspected of having Alzheimer's disease.

But in the absence of convincing evidence that PET scans can, by themselves, tell whether a person has Alzheimer's, the agency settled on a much narrower application.

[ ... Read the full article ...] (free registration required)

Thursday, September 16, 2004

Business World: Neuromodulation

This Canadian National Post report, among many yesterday and today, outlines ANS [company website] and Cyberonics [company website] issues:

Advanced Neuromodulation Systems bids US$22 a share for Cyberonics
Canadian Press (copyright)
Thursday, September 16, 2004

DALLAS (AP) - Advanced Neuromodulation Systems Inc. said Wednesday that it offered to buy fellow medical-device maker Cyberonics Inc. for $22 US a share, putting a price on the business combination it proposed last month.

The combination of the only two publicly held companies solely devoted to neuromodulation would make them both more competitive and lead to more innovation in the field, said Chris Chavez, president and chief executive of ANS, in a statement.

Neuromodulation uses implanted devices to stimulate and manipulate nervous system response. ANS makes radio-wave devices that disrupt pain signals sent by the nervous system. Cyberonics makes a device for epileptics that is implanted under the collarbone and helps control seizures by stimulating the vagus nerve.

ANS said its cash-and-stock offer represents a premium of 47 per cent over Cyberonics' closing price of $14.95 US on Aug. 19 and a premium of 29 per cent over the closing price of $17.05 on Sept. 13.

ANS reported on Aug. 20 that it had acquired 14.9 per cent of Cyberonics' outstanding common stock and said then that it hoped to combine the two companies. Cyberonics said at that time that it had no interest in any business combination or merger.

[ ... Read the full report ...]

Meningitis and Prevnar

CDC Lifts Limits on Meningitis Vaccine
By THE ASSOCIATED PRESS (copyright)
16 September 2004
Filed at 1:20 p.m. ET

ATLANTA (AP) -- Replenished supplies of a childhood meningitis vaccine has prompted health officials Thursday to lift a previous recommendation that doctors postpone some of the shots.

All four shots of the vaccine Prevnar may now be given to children between 2 months and 15 months. Because of shortages earlier this year, the Centers for Disease Control and Prevention recommended in March that doctors give just two doses.

The CDC's Advisory Committee on Immunization Practices, the American Academy of Family Physicians and the American Academy of Pediatrics lifted the limits placed on the vaccine because manufacturer Wyeth Pharmaceuticals now is able to make more of the vaccine.

The prior shortages were attributed to production problems.

Prevnar is used to protect children against invasive pneumococcal disease, which can lead to meningitis or bloodstream infections.

Families of Alzheimer Patients

Newspapers such as the New York Times, Washington Post, and Philadelphia Inquirer have done an admirable job over the past several years in occasionally detailing the daily life of caregivers and family members of people who have developed Alzheimer disease. Today's New York Times again provides a profile, this time of the Dillon family:

The Long Goodbye:
Alzheimer's in the Living Room: How One Family Rallies to Cope

By JANE GROSS
Published: September 16, 2004

After his retirement as a New York City carpenter four years ago, and before he faded into the incoherent fog of Alzheimer's disease, Christopher Dillon and his two grown sons renovated a bathroom in the basement of the family's Queens home.

It would be the last multigeneration home-improvement project for the Dillons. But the tiny room with its stall shower would soon become center stage in a family's determined effort to care for a failing loved one at home.

Giving Mr. Dillon, 66, a shower is unbearable for his wife, Kitty, 63, despite her long experience working in a nursing home. She has only to lay out towels, washcloth and soap and Mr. Dillon becomes agitated, sometimes shoving her or pulling her hair, she said.

So the task falls to her strapping boys, Chris, 36, a sanitation worker, and David, 34, a police officer. The National Guard, Mrs. Dillon calls them, riding to her rescue each evening with stores of patience and good cheer that she, as the primary caregiver, feels seeping away.

"It's overwhelming, worse every day," Mrs. Dillon said recently, wincing from stomach pain and steadily losing weight. "I don't have any life. Whatever happened to the golden years? Both of us have been robbed of everything we worked for."

[ ... Read the full article ... ] (free registration required)

Wednesday, September 15, 2004

Dementia and The Voter - Part 2

Snips from an article in The Philadelphia Inquirer concerning the JAMA article:

Dementia poses challenge when it's time to vote
The Philadelphia Inquirer
By Stacey Burling
INQUIRER STAFF WRITER
Posted on Tue, Sep. 14, 2004

Snip:

"It's clear the states have paid woefully inadequate attention to this issue," said Paul S. Appelbaum, chair of psychiatry at the University of Massachusetts Medical School and one of the authors.

"Everybody with dementia at some point will cross the line from being able to do lots of tasks, including voting, to not being able to do that," he added. "There is a need to define the line."

Snip:

They say people with dementia should be encouraged - and helped - to vote as long as they understand the process. That includes thinking about how people with dementia or other mental problems react to something as confusing as Florida's notorious butterfly ballot. Simpler ballots with larger type and possibly even pictures might make them better voters.

"We need to think about cognitive accessibility, not just physical accessibility," said Jason Karlawish, an assistant professor of medicine at the University of Pennsylvania who is one of the research group's leaders.

Snip:

Karlawish became interested in the issue after the 2000 election, when he read an Internet discussion by Alzheimer's caregivers. One wrote: "Since we have been married, he has always voted a straight Democratic ticket, so I did the same for him. . . . I do not feel guilty."

Voting rights cannot be transferred from one person to another, Karlawish said, but many caregivers don't know that.

He has also come across a handful of examples of questionable voting from nursing homes. Leonard Kiczek, a lawyer in Bayonne, N.J., discovered one of them during the Democratic primary in June. A bloc of absentee votes from a single nursing home swung a local election to candidates promoted by a rival Democratic faction. One of the candidates worked for the nursing home. Kiczek filed suit after he learned that party loyalists had been involved in helping people with dementia fill out their ballots.

Kiczek, a former Bayonne mayor who later dropped the suit, said the incident convinced him that lawmakers needed to pay attention to this issue. "People took advantage of these residents," he said.

A conversation with two sisters illustrates the other end of the spectrum, Karlawish said. He asked them if their father, who has Alzheimer's disease, wants to vote. "I don't think my dad is capable of doing that," one said. The other said: "Well, maybe he is. How would you know?" Karlawish talked to the man and thinks he could vote.

Snip:

Lillian Carter, 86, of South Philadelphia, said voting was important to her husband, Leroy, who continued to vote after being diagnosed in his last couple of years of life with Alzheimer's. He went to the polls right up to his death at age 92.

"He always wanted to vote. I can't remember him ever missing a year," said Carter, who was attending a Bible study class today at the Philadelphia Senior Center on South Broad Street. Their son would drive them to the polling place, and her husband would go into the voting booth alone.

"We didn't force him to go," she said. "He understood. . . . He never got completely out of it like some people."

[ ... Read the full article ... ] (free registration required)

Tuesday, September 14, 2004

Dementia and the Voter

A fascinating piece in the Washington Post, as well as in the New York Times and in this week's issue of the Journal of the American Medical Association:

Dementia and the Voter:
Research Raises Ethical, Constitutional Questions

By Shankar Vedantam
Washington Post Staff Writer
Tuesday, September 14, 2004; Page A01

Florida neurologist Marc Swerdloff was taken aback when one of his patients with advanced dementia voted in the 2000 presidential election. The man thought it was 1942 and Franklin D. Roosevelt was president. The patient's wife revealed that she had escorted her husband into the booth.

"I said 'Did he pick?' and she said 'No, I picked for him,' " Swerdloff said. "I felt bad. She essentially voted twice" in the Florida election, which gave George W. Bush a 537-vote victory and the White House.

As swing states with large elderly populations such as Florida gear up for another presidential election, a sleeper issue has been gaining attention on medical, legal and political radar screens: Many people with advanced dementia appear to be voting in elections -- including through absentee ballot. Although there are no national statistics, two studies in Pennsylvania and Rhode Island found that patients at dementia clinics turned out in higher numbers than the general population.

[ ... Read the full article ...] (free registration required)

Here is the abstract of the JAMA article:

Jason H. Karlawish, MD; Richard J. Bonnie, JD; Paul S. Appelbaum, MD; Constantine Lyketsos, MD; Bryan James, MBioethics; David Knopman, MD; Christopher Patusky, JD; Rosalie A. Kane, PhD; Pamela S. Karlan, JD. Addressing the Ethical, Legal, and Social Issues Raised by Voting by Persons With Dementia. Journal of the American Medical Association. 2004; 292:1345-1350.

This article addresses an emerging policy problem in the United States participation in the electoral process by citizens with dementia. At present, health care professionals, family caregivers, and long-term care staff lack adequate guidance to decide whether individuals with dementia should be precluded from or assisted in casting a ballot. Voting by persons with dementia raises a series of important questions about the autonomy of individuals with dementia, the integrity of the electoral process, and the prevention of fraud. Three subsidiary issues warrant special attention: development of a method to assess capacity to vote; identification of appropriate kinds of assistance to enable persons with cognitive impairment to vote; and formulation of uniform and workable policies for voting in long-term care settings. In some instances, extrapolation from existing policies and research permits reasonable recommendations to guide policy and practice. However, in other instances, additional research is necessary.

The New York Times article (Change Urged for Nursing-Home Voters by Denise Grady) talks about the recommendations offered in the JAMA paper:

The recommendations have two purposes, the authors say. The first is to prevent fraud by political groups that would take advantage of patients with dementia by completing their absentee ballots, telling them what to fill in or accompanying them into the voting booth and casting votes for them.

Workers for a party or a candidate who show up at a nursing home to "assist" with voting can accomplish "wholesale fraud," essentially stealing a bloc of votes, said Pamela S. Karlan, a law professor at Stanford University and an author of the journal article. That kind of fraud can have a big impact on small local elections where voter turnout is low, Ms. Karlan said.

"We want to make sure there aren't a pool of people whose names can be used," she said. "It's a sort of identity theft."

The second purpose of the recommendations is to protect the right to vote for people who are in the early stages of dementia but are still competent. If they can answer a few simple questions, no one can bar them from voting just because they have an Alzheimer's diagnosis, and it would then be considered reasonable to give them whatever help they needed to cast their votes.

Testers would ask how people elect a governor or president (by voting) and what determines who wins an election (whoever gets the most votes), the article states. Then the tester would describe two candidates and ask the voter to pick one. It would not matter which one the voter picked; the point is to find out whether the person can make a choice.

Most people with mild dementia could easily pass that test, said Dr. Jason H. Karlawish, the first author of the article and a geriatrician at the University of Pennsylvania's Institute on Aging. Those with severe dementia could not.

"The extremes are easy," Dr. Karlawish said, adding that the test may be most useful for people in the middle, whose mental ability might not be clear to family members or others taking care of them.

The experts said the questions were based on a 2001 decision by a federal district court in Maine in the case of Doe v. Rowe. The court ruled that people have the "capacity to vote" if they understand the nature and effect of voting and can choose among candidates and questions.

[ ... Read the full article ...] (free registration required)

Abstract of the Day: Choroid Plexus Cell Neuroprotection

Borlongan CV, Skinner SJ, Geaney M, Vasconcellos AV, Elliott RB, Emerich DF. Intracerebral transplantation of porcine choroid plexus provides structural and functional neuroprotection in a rodent model of stroke. Stroke, 2004 Sep; 35(9): 2206-10.

Department of Neurology, School of Medicine, and the Institute of Molecular Medicine and Genetics, School of Graduate Studies, Medical College of Georgia, Augusta, Ga 30912-3200, USA. cborlongan@mail.mcg.edu

BACKGROUND AND PURPOSE: Choroid plexus (CP) secretes a cocktail of neurotrophic factors. In the present study, CP from neonatal pigs was encapsulated within alginate microcapsules for in vitro and in vivo neuroprotective studies.
METHODS: In vitro studies involved serum deprivation of rat embryonic cortical neurons and treatment with a range of concentrations of conditioned media from CP. For in vivo studies, rats received a 1-hour middle cerebral artery occlusion
followed by intracranial transplantation of encapsulated or unencapsulated CP, empty capsules, or no transplant. Behavioral testing was conducted on days 1 to 3 after transplantation. Cerebral infarction was analyzed using 2,3,5-triphenyl-tetrazolium chloride staining at 3 days after transplantation.
RESULTS: Conditioned media from CP produced a significant dose-dependent protection of serum-deprived cortical neurons. Enzyme-linked immunosorbent assay confirmed secretion of GDNF, BDNF, and NGF from CP. Parallel in vivo studies showed that CP transplants improved behavioral performance and decreased the volume of infarction. Both encapsulated and unencapsulated CP transplants were effective; however, more robust benefits accompanied encapsulated transplants.
CONCLUSIONS: These data are the first to demonstrate the neuroprotective potential of transplanted CP and raise the intriguing possibility of using these cells as part of the treatment regimen for stroke and other neurological disorders.

PMID: 15284450 [PubMed - in process]

Déjà Vu, All Over Again

Today's Science Times in the New York Times has a piece about the phenomenon of déjà vu:

Déjà Vu: If It All Seems Familiar, There May Be a Reason
By BENEDICT CAREY

Excerpt:

...But the point, psychologists who study memory say, is that people take in a rich banquet of information without noticing it, or noticing and simply forgetting where it came from. It is entirely possible to read an Anne Rice novel and years later, after having forgotten the book, find that a first visit to New Orleans seems like a glimpse into a former life. Or to see one of the bar scenes from the movie "L.A. Confidential" and later walk into the Formosa Cafe for the first time and catch your breath.

The familiarity can come from a variety of sources, some real and some not, said Dr. Kathleen McDermott, a colleague of Dr. Jacoby's at Washington University who studies memory.

"It's well known that even if you imagine something now that may not have happened in the past, it can create a feeling of familiarity if it does happen later on," she said, adding, "You don't need objective outside information to create these situations; you can do so internally, on your own." ...

[ ... Read the full article ...] (free registration required)

Monday, September 13, 2004

Abstract of the Day: Stroke and Cognition

VK Srikanth et al. Progressive dementia after first-ever stroke: A community-based follow-up study. Neurology 2004; 63:785-792.

Address correspondence and reprint requests to Prof. Geoffrey A. Donnan, Director, National Stroke Research Institute, Neurosciences Building, Repatriation Hospital, Austin Health, 300 Waterdale Rd., Heidelberg Heights, Victoria 3081, Australia.

Objectives: To examine the risk and determinants of a progressive dementia syndrome and cognitive impairment not dementia (CIND) in community-based nonaphasic first-ever stroke cases 1 year after stroke, relative to a matched community-based stroke-free group.

Methods: Matched cohort design, with cognitive tests given on two occasions 9 months apart to 99 mild-to-moderate first-ever stroke patients and 99 age- and sex-matched people without stroke. At follow-up, progressive dementia or CIND were diagnosed, with judges blinded to stroke/nonstroke status.

Results: Progressive dementia was diagnosed in 12.5% of stroke patients and 15.4% of those without strokes (RR 1.1, 95% CI 0.5 to 2.2, p = 0.85). CIND was diagnosed in 37.5% of stroke patients and 17.6% of participants without strokes (RR 2.1, 95% CI 1.2 to 3.4, p = 0.003). In multivariable regression, age (p = 0.04) and baseline cognition (p < 0.001) were independently associated with dementia whereas stroke (p = 0.002), age (p = 0.05), baseline cognition (p = 0.001), and baseline mood (p = 0.03) were independently associated with CIND at follow-up.

Conclusions: In this community-based nonaphasic sample, mild-to moderate first-ever stroke was not associated with the presence of progressive dementia 1 year later, but was clearly associated with a greater risk of cognitive impairment not dementia (CIND). Baseline mood impairment remained independently associated with CIND at 1 year after taking into account stroke, age, and baseline cognitive ability.

Creutzfeldt-Jakob Disease

News being reported from several news agencies in Australia about concern over risk of disease transmission via contaminated surgical instruments. Here is a report by The Australian:

Killer brain disease hangs over patients
Gosia Kaszubska
September 14, 2004

MORE than 1000 people have been warned they may been exposed to a rare and fatal brain disease through contaminated surgical instruments used at the Royal Melbourne Hospital since March last year.

The 1056 former patients face years of waiting to discover if they will develop Creutzfeldt-Jakob disease, an incurable illness that can lay dormant for decades.

Concerns arose when it was confirmed a man who underwent brain surgery at the hospital twice last year had died of CJD.

The hospital yesterday sent letters warning all patients who had undergone brain or spinal surgery in the past 18 months that there was an "extremely remote chance" the disease may have been transmitted through instruments used in their operations.

The hospital is destroying all 15,000 neurosurgical instruments and has begun sterilising its entire stock of 300,000 surgical instruments to a higher standard that usual, on the advice of the National CJD Incidents Committee.

Neurology director Stephen Davis said the hospital was taking an "extra conservative" approach by sterilising all instruments, even though they had not been used in operations on the CJD-affected patient.

It is believed to be the first time an Australian hospital has been forced to contact patients after confirming a case of CJD in a former patient.

[ ... read the full report ... ]

Sunday, September 12, 2004

Auditory Asymmetries in the Newborn

A press release from UCLA highlights the work of some of their researchers, which is published in the 10 September 2004 issue of Science:

Left and Right Ears Not Created Equal as Newborns Process Sound, UCLA/University of Arizona Scientists Discover
Date: September 9, 2004
Contact: Elaine Schmidt ( elaines@support.ucla.edu )
Phone: 310-794-2272

Challenging decades of scientific belief that the decoding of sound originates from a preferred side of the brain, UCLA and University of Arizona scientists have demonstrated that right-left differences for the auditory processing of sound start at the ear.

Reported in the Sept. 10 edition of Science, the new research could hold profound implications for rehabilitation of persons with hearing loss in one or both ears, and help doctors enhance speech and language development in hearing-impaired newborns.

"From birth, the ear is structured to distinguish between various types of sounds and to send them to the optimal side in the brain for processing," said Yvonne Sininger, visiting professor of head and neck surgery at the David Geffen School of Medicine at UCLA. "Yet no one has looked closely at the role played by the ear in processing auditory signals."

Scientists have long understood that the auditory regions of the two halves of the brain sort out sound differently. The left side dominates in deciphering speech and other rapidly changing signals, while the right side leads in processing tones and music. Because of how the brain's neural network is organized, the left half of the brain controls the right side of the body, and the left ear is more directly connected to the right side of the brain.

Prior research had assumed that a mechanism arising from cellular properties unique to each brain hemisphere explained why the two sides of the brain process sound differently. But Sininger's findings suggest that the difference is inherent in the ear itself.

"We always assumed that our left and right ears worked exactly the same way," she said.  "As a result, we tended to think it didn't matter which ear was impaired in a person. Now we see that it may have profound implications for the individual's speech and language development."

Working with co-author Barbara Cone-Wesson, associate professor of speech and hearing sciences at the University of Arizona, Sininger studied tiny amplifiers in the outer hair cells of the inner ear.

"When we hear a sound, tiny cells in our ear expand and contract to amplify the vibrations," Sininger said. "The inner hair cells convert the vibrations to neural cells and send them to the brain, which decodes the input."

"These amplified vibrations also leak back out to the ear in a phenomena call otoacoustic emission (OAE)," Sininger said. "We measured the OAE by inserting a microphone in the ear canal."

In a six-year study, the UCLA/University of Arizona team evaluated more than 3,000 newborns for hearing ability before they left the hospital. Sininger and Cone-Wesson placed a tiny probe device in the baby's ear to test its hearing. The probe emitted a sound and measured the ear's OAE.

The researchers measured the babies' OAE with two types of sound. First, they used rapid clicks and then sustained tones. They were surprised to find that the left ear provides extra amplification for tones like music, while the right ear provides extra amplification for rapid sounds timed like speech.

"We were intrigued to discover that the clicks triggered more amplification in the baby's right ear, while the tones induced more amplification in the baby's left ear," Sininger said. "This parallels how the brain processes speech and music, except the sides are reversed due to the brain's cross connections."

"Our findings demonstrate that auditory processing starts in the ear before it is ever seen in the brain," Cone-Wesson said. "Even at birth, the ear is structured to distinguish between different types of sound and to send it to the right place in the brain."

[ ... Read the full report ...]

Friday, September 10, 2004

Outcome of FDA Meeting About Exanta

The Associated Press reported this evening about today's FDA meeting (see yesterday's post: Forthcoming Meeting...):

FDA Panel Urges More Studies of Stroke Med
By THE ASSOCIATED PRESS (copyright)
Filed at 8:51 p.m. ET

WILMINGTON, Del. (AP) -- A U.S. advisory panel on Friday recommended against approving AstraZeneca's new stroke prevention medication, Exanta, citing concerns about the drug's effect on the liver.

An advisory panel of physicians, meeting in Bethesda, Md., advised the Food and Drug Administration that more long-term studies are needed to assess the drug's safety, The (Wilmington) News Journal reported.

The FDA usually follows the recommendations of its advisory panels. The agency is expected to announce a decision on Exanta next month.

At the hearing, AstraZeneca made its case for Exanta's approval to the panel. Hamish Cameron, a company vice president, told the panel that Exanta represents a "real advance'' in the prevention of strokes.

But Ruyi He, an FDA official, told the panel that clinical testing of Exanta raised concerns that the drug could cause severe liver damage. He also raised concerns that patients taking Exanta may have a higher risk of heart attack.

AstraZeneca executives have portrayed Exanta as an alternative to the widely prescribed drug warfarin. Both drugs are supposed to reduce the risk of stroke by preventing blood clots.

AstraZeneca closed down 66 cents, to $43.73, on the New York Stock Exchange. The panel's recommendations were announced after the close of trading.

Dreaming

Several news organizations are publishing reports about a forthcoming paper in the Annals of Neurology concerning a case study about the loss of dreaming as a consequence of a stroke.

One of the authors of the report, Dr. Claudio L. Bassetti, is quoted in these published reports as stating, "How dreams are generated, and what purpose they might serve, are completely open questions at this point. These results describe for the first time in detail the extent of lesion necessary to produce loss of dreaming in the absence of other neurological deficits. As such, they offer a target for further study of the localization of dreaming."

Here is the abstract from Annals of Neurology:

M. Bischof & C.L. Bassetti. Total dream loss: A distinct neuropsychological dysfunction after bilateral PCA stroke.

Correspondence to Claudio L. Bassetti, Neurologische Poliklinik, Universitatsspital, Frauenklinikstrasse 26, CH-8091 Zurich, Switzerland

The term Charcot-Wilbrand syndrome (CWS) denotes dream loss following focal brain damage. We report the first case of CWS, in whom neuropsychological functions, extension of the underlying lesion, and sleep architecture changes were assessed. A 73-year-old woman reported a total dream loss after acute, bilateral occipital artery infarction (including the right inferior lingual gyrus), which lasted for over 3 months. In the absence of sleep-wake complaints and (other) neuropsychological deficits, polysomnography demonstrated an essentially normal sleep architecture with preservation of REM sleep. Dreaming was denied also after repeated awakenings from REM sleep. This observation suggests that CWS (1) can represent a distinct and isolated neuropsychological manifestation of deep occipital lobe damage, and (2) may occur in the absence of detectable REM sleep abnormalities.

(DOI) 10.1002/ana.20246

Thursday, September 09, 2004

In The Weeklies

For those new to this area, there are a number of major medical and scientific journals that publish on a weekly basis. These journals include: Journal of the American Medical Association, British Medical Journal, New England Journal of Medicine, Lancet, Science, and Nature.

Here are some relevant highlights for the week:

British Medical Journal
11 September 2004

Parkinson’s disease figures prominently in this week’s BMJ, from the cover featuring Muhammad Ali to an editorial, a “patient’s journey” article, and a research paper by Ives and colleagues - Monoamine oxidase type B inhibitors in early Parkinson's disease: Meta-analysis of 17 randomised trials involving 3525 patients. The abstract for the Ives et al. paper concludes, “MAOBIs reduce disability, the need for levodopa, and the incidence of motor fluctuations, without substantial side effects or increased mortality. However, because few trials have compared MAOBIs with other antiparkinsonian drugs, uncertainty remains about the relative benefits and risks of MAOBIs. Further large, long term comparative trials that include patient rated quality of life measures are needed.”

New England Journal of Medicine
09 September 2004

One of the NEJM’s Images in Clinical Medicine deals with Marchiafava–Bignami Disease.

Nature
09 September 2004

Several scientific articles and letters are of note:

Neurobiology: Feeding the brain by C. Peppiatt & D. Attwell. In computationally active areas of the brain, the blood flow is increased to provide more energy to nerve cells. New data fuel the controversy over how this energy supply is regulated.

Recollection-like memory retrieval in rats is dependent on the hippocampus by N.J. Fortin and colleagues.

Restricted growth of Schwann cells lacking Cajal bands slows conduction in myelinated nerves by F.A. Court and colleagues.

Forthcoming Meeting: Exanta and Stroke Prevention

Reuters reports that the FDA will be holding a meeting tomorrow to discuss Exanta and its use as an anti-stroke medication. Here is the text of the FDA announcement about this meeting: FDA Announcement and the text of the FDA Briefing Note: FDA Briefing Note. Here is the report as published on the New York Times website (free registration required):

FDA Queries AstraZeneca Drug's Efficacy
By REUTERS (copyright). Filed at 8:54 a.m. ET

LONDON (Reuters) - Officials at the U.S. Food and Drug Administration have questioned both the efficacy and safety of AstraZeneca Plc's new anti-stroke pill Exanta, according to documents posted on the agency's Web site on Thursday.

Shares in the Anglo-Swedish drug maker fell 4.2 percent to 25.08 pounds as the news shook widespread confidence among investors that the potential blockbuster would be recommended for approval.

A briefing note, posted on the FDA Web site one day ahead of an committee meeting on the drug, said the company may have been "too liberal'' in the way it assessed the effectiveness of Exanta against warfarin, the standard treatment.

One industry analyst said the efficacy of the product had been taken as a given and that the questions about its effectiveness against warfarin amounted to a setback for approval hopes.

FDA officials also questioned the drug's possible toxic effects on the liver and said the company's risk plan for the product did not address some possible concerns.

The FDA was expected to focus on safety, since Exanta has been associated with raised liver enzymes in some patients, although AstraZeneca argues the benefits outweigh the risks.

Exanta is the first new anticoagulant pill since the introduction of warfarin, a notoriously difficult drug to use, 60 years ago.

Along with Crestor, the cholesterol-lowering drug launched last year, Exanta is a pivotal product for AstraZeneca, which needs to make up for declining sales of its aging ulcer pill Losec/Prilosec, now facing generic competition.

The consensus peak annual sales forecast for Exanta is $3.7 billion, according to pharmaceutical consultancy Evaluate.

Exanta is already on sale in Europe as a treatment to prevent blood clotting after orthopedic surgery. But the big commercial opportunity -- estimated by analysts to account for over 80 percent of sales -- lies in preventing stroke in patients with atrial fibrillation, or an irregular heartbeat.

The FDA's Cardiovascular and Renal Drugs Advisory Committee will consider both uses of the drug at the Sept. 10 meeting.

Wednesday, September 08, 2004

Abstract of the Day: Aphasia

Saygin AP, Wilson SM, Dronkers NF, Bates E. Action comprehension in aphasia: Linguistic and non-linguistic deficits and their lesion correlates. Neuropsychologia. 2004; 42(13): 1788-804.

Department of Cognitive Science, University of California, San Diego, 9500 Gilman Drive 0515, La Jolla, CA 92093-0515, USA.

We tested aphasic patients' comprehension of actions to examine processing deficits in the linguistic and non-linguistic domains and their lesion correlates. Twenty-nine left-hemisphere injured patients and 18 age-matched control subjects matched pictured actions (with the objects missing) or their linguistic equivalents (printed sentences with the object missing) to one of two visually-presented pictures of objects. Aphasic patients performed poorly not only in the linguistic domain but also in the non-linguistic domain. A subset of the patients, largely consisting of severe and non-fluent aphasics, showed a
greater deficit in the linguistic domain compared with the non-linguistic domain and across the patient group, deficits in the linguistic and non-linguistic domains were not tightly correlated. Poor performance in pantomime interpretation was associated with lesions in the inferior frontal, premotor and motor cortex, a portion of somatosensory cortex, and the caudate, while poor reading comprehension of actions was associated with lesions around the anterior superior temporal lobe, the anterior insula and the anterior portion of the inferior parietal lobe. Lesion size did not correlate with deficits. The lesion results for pantomime interpretation deficits demonstrate that lesions in the frontal component of the human analog of the "mirror neuron system" are associated with deficits in non-linguistic action understanding. For reading comprehension deficits, the lesion correlates are brain areas known to be involved in linguistic tasks including sentence processing and speech articulation; the parietal lesion site may also correspond to a subpart of the human mirror neuron system. These results indicate that brain areas important for the production of language and action are also recruited in their comprehension. Similar findings have been reported in electrophysiological and neuroimaging studies. Our findings now also lend neuropsychological support to an embodied view of brain organization for action processing.

PMID: 15351628 [PubMed - in process]

Disclosure of Clinical Trials: Ongoing Debate

Today's New York Times provides a report about the ongoing debate concerning clinical-trials findings and the ability to balance favorable against unfavorable findings in an environment where unfavorable findings do not easily come to the fore:

Expected Call for Advance Registration of Drug Tests

By BARRY MEIER

The debate over the disclosure of clinical drug trials could reach a turning point this week, with editors of influential medical journals expected to call for fundamental changes in the way such tests are reported.

The journal editors, gatekeepers for the medical profession, are expected to begin requiring that drug trials be registered at the outset as a prerequisite for the subsequent publication of their results. Requiring such registration as a condition for reaching the journals' vast audience of doctors would make it difficult for drug companies to hide the results of unflattering tests - as some have been accused of doing.

The journal editors declined yesterday to discuss the new policy before the announcement, but the group said several months ago that it was considering such a step.

Details of the policy by the group - which includes prestigious publications like The Journal of the American Medical Association, The New England Journal of Medicine, The Lancet and The Annals of Internal Medicine - are to be presented Thursday at a House Commerce subcommittee hearing on disclosure of data from pediatric trials of antidepressants.

Meanwhile, both House and Senate Democrats say they expect to introduce legislation as early as Thursday that would require drug trials involving human subjects to be registered in a public database before the tests were allowed to proceed.

Congressional Republicans, though, have not announced any plans for such legislation. And an official of the drug industry's trade group, which yesterday announced a voluntary plan to disclose trial results, said his organization thought that legislation was not necessary.

Some academic researchers have long argued that drug companies unduly influence medical practice by highlighting positive trial findings while not publishing negative ones. The subject gained public prominence earlier this year with the disclosure that unpublished test data from trials of some widely used antidepressants had indicated that some adolescents and children who took the drugs had a greater tendency toward suicidal thoughts than those given placebos.

"People have been concerned for quite some time that nondisclosure of unfavorable studies has skewed the scientific literature and possibly medical practice," said Dr. Ronald M. Davis, a trustee of the American Medical Association. "But recently, tangible evidence of that concern has arisen."

Makers of antidepressants have denied concealing any data. But in recent months, they and other drug producers have scrambled to address criticism about disclosure in the industry of trial results.

[ ... Read the full article ... ] (free registration required)

Tuesday, September 07, 2004

Cymbalta and Diabetic Peripheral Neuropathy

The Food and Drug Administration (FDA) today announced its approval of this medication as a treatment for a common neurological complication of diabetes. From the press release:

FDA Approves Drug for Neuropathic Pain Associated With Diabetes

Today the Food and Drug Administration (FDA) announced the approval of Cymbalta (duloxetine hydrochloride) capsules for the management of the pain associated with diabetic peripheral neuropathy. This is the first drug specifically approved for this indication. Cymbalta received a priority review.

"Diabetes affect millions of Americans," said Dr. Lester M. Crawford, Acting FDA Commissioner. "With this new treatment we will hopefully be able to help relieve the pain associated with this terrible disease."

Diabetic peripheral neuropathy is a problem associated with long standing diabetes or poor glucose control. Peripheral neuropathy is the most common complication of diabetes mellitus, affecting up to 62% of Americans with diabetes. Diabetic peripheral neuropathy can manifest in a variety of ways but is usually characterized by burning, tingling, and numbing sensations beginning in the feet, and later affecting the legs and/or hands.

The safety and effectiveness of Cymbalta were established in two randomized, controlled studies of approximately 1074 patients. Although the mechanism of action is unknown, patients treated with Cymbalta reported a greater decrease in pain compared to placebo. In these trials, 58 percent of patients treated with Cymbalta reported at least a 30 percent sustained reduction in pain. In comparison, 34 percent of patients treated with placebo reported this magnitude of sustained pain reduction.

The most commonly reported side effects were nausea, dry mouth, constipation, and diarrhea. In some cases, patients experienced dizziness and hot flashes.

Cymbalta is manufactured by Eli Lilly and Company in Indianapolis, Ind.

Today's Reading: Apoptosis

Topics of increasing contemporary neuroscientific study are programmed neuron death, the messaging signals for the phenomenon, and potential ways to alter those signals in disease conditions. This review, in the September 2004 issue of Nature Reviews: Neuroscience, provides a detailed look.

Benn SC & Woolf CJ. Adult neuron survival strategies — Slamming on the brakes. Nature Reviews Neuroscience. 2004; 5: 686-700.
 
Developing neurons are programmed to die by an apoptotic pathway unless they are rescued by extrinsic growth factors that generate an anti-apoptotic response. By contrast, adult neurons need to survive for the lifetime of the organism, and their premature death can cause irreversible functional deficits. The default apoptotic pathway is shut down when development is complete, and consequently growth factors are no longer required to prevent death. To protect against accidental apoptotic cell death, anti-apoptotic mechanisms are activated in mature neurons in response to stress. Loss or reduced activity of these intrinsic anti-apoptotic 'brakes' might contribute to or accelerate neurodegeneration, whereas their activation might rescue neurons from injury or genetic abnormalities.


As the online summary for this review states:

An anti-apoptotic brake is an intrinsic molecule that can inhibit the apoptotic pathway at one or more points to promote neuronal survival. A cohort of molecules with anti-apoptotic properties or the ability to promote cell survival pathways are induced following acute or chronic neuronal injury, including anti-apoptotic members of the BCL2 family, heat shock proteins, inhibitor of apoptosis proteins, uncoupling proteins and activated protein C.

Apoptotic brakes can be categorized on the basis of their primary site of anti-apoptotic action, as molecules that take effect upstream of mitochondria, at the mitochondrion to prevent the release of cytochrome c and other pro-apoptotic factors, or downstream of mitochondria on effector molecules such as the apoptosome and caspases.

Apoptosis can be suppressed upstream of mitochondria by two main strategies — decoy receptor or ligand proteins, and sequestration or inhibition of pro-apoptotic proteins. Apoptotic brakes that function at the level of the mitochondrion prevent mitochondrial membrane permeabilization and release of apoptotic factors into the cytosol. Downstream of the mitochondria, intrinsic brakes can suppress activation of the executioners of apoptosis, caspases 3, 7 and 9.

An important challenge will be to identify all the anti-apoptotic brakes that are expressed in neurons, along with their mechanisms of action and regulation, and to determine whether induction of specific combinations of anti-apoptotic molecules in selected neuronal populations is beneficial for the treatment of neurological and neurodegenerative diseases.

doi:10.1038/nrn1477

Monday, September 06, 2004

Neuroergonomics

From the September 2004 issue of The Monitor on Psychology comes this brief overview to a novel application of neuroscience:

The baggage screener's brain scan
The emerging field of neuroergonomics seeks to improve work safety and make everyday tasks, like driving, safer.

BY CHARLOTTE HUFF

Imagine if employers monitored the performance of air traffic controllers and baggage screeners not just for mistakes, but--through on-the-job brain monitoring--for insights into their brain functioning. The idea: Anticipate cognitive decline or fatigue in the workers to prevent safety problems.

A group of psychologists, neurologists and other medical professionals is pursuing such a vision of improved worker functioning in an increasingly high-tech world through a melding of neuroscience and ergonomics. Through research in the area, they hope to better understand and improve the brain's functioning at work.

The results could be far ranging, from altering training of assembly-line workers to reconfiguring automation in airplane cockpits so pilots aren't overwhelmed with tasks during high-stress situations. Closer to home, the developing field could help redesign tomorrow's cars to minimize sensory overload from navigation systems, media gadgets and other devices so the real work--driving--isn't jeopardized.

"Technology that is supposed to help us sometimes can have unintended consequences like increased mental demands," says Raja Parasuraman, PhD, a George Mason University psychology professor, who in 1998 proposed the creation of the neuroergonomics field.

In the past, ergonomics studies were confined to performance measures, such as error rates and reaction times. By taking advantage of brain imaging technology, pioneers in neuroergonomics hope to gain a broader window into mental workload, vigilance and other aspects of how the brain learns and processes information.

"Combining the neuroscience techniques allows us to expand our investigative powers," says Carryl Baldwin, PhD, an assistant professor of psychology at Old Dominion University, who is applying neuroergonomics techniques to better understand mental workload and driving.

[ ... Read the full article ... ]

Today's Reading: Structural MRI

The current issue of the journal, Journal of Neurology, Neurosurgery, and Psychiatry, contains an excellent review of the state of contemporary structural uses of MRI (magnetic resonance imaging). Here is the reference and abstract for this recommended review:

Symms M, Jager HR, Schmierer K, Yousry TA. A review of structural magnetic resonance neuroimaging. J Neurol Neurosurg Psychiatry. 2004 Sep;75(9):1235-44.

Department of Clinical and Experimental Epilepsy, Institute of Neurology, London, UK.

Magnetic resonance imaging (MRI) is often divided into structural MRI and functional MRI (fMRI). The former is a widely used imaging technique in research as well as in clinical practice. This review describes the more important developments in structural MRI in recent years, including high resolution imaging, T2 relaxation measurement, T2*-weighted imaging, T1 relaxation measurement, magnetisation transfer imaging, and diffusion imaging. The principles underlying these techniques, as well as their use in research and in clinical practice, will be discussed.

PMID: 15314108 [PubMed - in process]