Alzheimer patients to get nerve growth factor directly injected into brain

The Alzheimer’s Disease Cooperative Study, a 19 year project funded by the NIA, has embarked on a clinical trial that delivers Nerve Growth Factor (NGF) directly into the brain as a possible treatment for Alzheimer’s.

 

A Phase II clinical study of Ceregene's CERE-110, a gene therapy product designed to deliver nerve growth factor (NGF) to the brain for the treatment of Alzheimer's disease (AD) is currently in progress.

This Phase II study is a randomized, double blind, placebo-controlled trial and employs gene therapy to deliver nerve growth factor (NGF) directly into the brain. The rationale behind this study is that NGF is known to promote survival of cholinergic neurons, that degenerate in AD, and therefore may provide sustained functioning of these neurons. Direct delivery of CERE-110 into the brain aims to selectively target the Nucleus Basalis of Meynert (NBM), where cholinergic neuronal degeneration occurs in AD.

A Phase I study at Rush University and the University of California San Diego indicated that a single administration of the therapy was generally safe and well tolerated. The Phase I participants underwent cognitive testing, measures of activities of daily living, MRI scans and PET (positron emission tomography) scans. Increases in brain metabolism were observed in several cortical regions of the brain at six months and 12 months in some of the subjects, as compared to other severity-matched individuals with AD, suggesting a potential reversal of patterns typically observed in AD.

This Phase II study will examine the safety and effectiveness of NGF on Alzheimer's disease in 50 patients at 11 research sites throughout the United States. All eligible participants will be randomized equally to one of two treatment groups: half of the subjects will initially receive placebo surgery, but no administration of gene therapy. In the other half, CERE-110 will be injected into the NBM of the brain. At the completion of the trial, subjects in the placebo arm will be given the opportunity to switch to the active treatment protocol if the efficacy and safety data are supportive.

For more information go to: http://www.adcs.org/Studies/NGF.aspx  or  http://www.alzheimers.org/clinicaltrials/fullrec.asp?PrimaryKey=308

Best Post of December '09: Doug Miller's Modern Surgical Neuropathology: "a rarity in medical publishing in the 21st century"

The next in our series of "Best Posts of the Month" is from December 17, 2009:

Modern Surgical Neuropathology by Dr. Doug Miller (pictured) was reviewed by Dr. Leroy Sharer in last month's Journal of Neuropathology and Experimental Neurology. (I published a post on this book in June of this year.) Dr. Sharer points out that Dr. Miller's book is extraordinary in that it is penned by a single author -- "a rarity in medical publishing in the 21st century", writes Sharer. Some may take issue with Dr. Miller's fiercely independent perspective on surgical neuropathology, but one must respect his courage to say what he thinks. He is not afraid to challenge mainstream concepts. For instance, in his review, Dr. Sharer notes that Dr. Miller "devised his own tumor grading and classification schema, which he relates to others in use, particularly the World Health Organization system from 2007". If more neuropathologists had the chutzpah to put their perspectives out in the public arena for debate, it would undoubtedly invigorate the field!

Free samples of IDH1, the next big thing in glioma IHC, is now available

Dianova, the German company that makes anti-human IDH1 antibody for use in immunohistochemical staining of gliomas versus gliosis, is providing free samples of its product. Just go to the site, click on "free sample", and make a request via email. This marker may well be a tremendous advancement in distinguishing reactive astrocytosis from diffuse astrocytoma, so I would encourage you to get your free sample! Thanks to Drs. Craig Horbinski and Ty Abel for assisting me in discovering this opportunity.

What's the diagnosis?

After examining this photomicrograph of a section taken from the hippocampus at autopsy, write your diagnosis in the comment section. I'll post the correct diagnosis on Monday (May 10). Good luck!

Another Neuropathologist Heads West

Dr. Alexander Judkins (pictured), currently a neuropathologist at the Children's Hospital of Philiadelphia, is moving to sunny California to become chair of  pathology at Children's Hospital of Los Angeles. Judkins joins another neuropathologist transplanting to the Golden State: Dr. Arie Perry leaves Washington University in St. Louis next month to take a job at UCSF.

Infamous Frontal Lobotomist was once President of the American Association of Neuropathologists

You may be surprised to learn that the infamous Walter J. Freeman,
MD (1895-1972), America's most prolific frontal lobotomist, was once president of the American Association of Neuropathologists. The AANP website lists Dr. Freeman (pictured) as having been president of the organization in 1946.

If you want to learn more about Dr. Freeman, get hold of a PBS documentary called The Lobotomist, which explores the background of the procedure popularization during the 1940’s through the ‘60’s. The neurologist Walter J. Freeman of Washington, DC was primarily responsible for the widespread performance of this surgery in the United States by developing the 10-minute, outpatient “ice pick lobotomy”. An ice pick-like instrument was inserted beneath the eyelid and over the eyeball of a patient who was rendered temporarily unconscious by electroshock. (The photo below from 1960 depicts the procedure performed on 12-year-old Howard Dully whose stepmother complained of the child's chronic misbehavior). When the instrument hit the thin orbital plate of the frontal bone, a few taps with a mallet would allow entrance into the intracranial cavity. The ice pick was then advanced upward, after which it was swept back and forth like a windshield wiper blade. The instrument was then extracted and the procedure was repeated on the opposite side. Approximately 30,000 of these procedures were performed before the medical establishment decided that it was ill-advised.

These procedures were designed to sever the connections of the brain with the prefrontal cortex. The goal was to leave patients with a degree of abulia, but with no focal deficits.

ATPase versus Immunohistochemistry for fiber typing in muscle biopsies: which is better?

When I receive a complex muscle biopsy case, I send my specimens to the excellent muscle specialists at the University of Iowa Department of Pathology. I recently got a consultation report back from Dr. Leslie Bruch (pictured) at that institution. In her report, she noted that immunoperoxidase staining for slow and fast myosin heavy chains were performed to assess fiber type distribution. For that purpose, I use ATPase at pH 9.4 and 4.6. I asked Dr. Bruch whether there were any advantages to the immunohistochemistry approach versus ATPase. Here's her response: "The reasons we changed to immunohistochemistry for fiber typing here was that it is more consistently reliable than our ATPase stains, as well as less expensive in terms of tech time and reagents, etc. One limitation is that you cannot subtype the type II fibers as you can with using ATPase at 3 different pHs. We have been happy with it since the change."

If anyone has any further thoughts on the relative advantages of the two methodologies, please comment.

Ellsworth C. "Buster" Alvord, Jr., MD (1923-2010)

Ellsworth C. “Buster” Alvord, Jr. died on January 19, 2010 at the age of 86. His career as a neuropathologist, scientist, and teacher spanned more than 6 decades.  He began his early research career investigating immune-mediated injury to the CNS and wrote seminal works on inflammatory models of demyelinating disease (experimental allergic encephalomyelitis, EAE).  Dr. Alvord was president of the American Association of Neuropathologists in 1965. 

Born in 1923, Alvord received an M.D. from Cornell University in 1946 and did postgraduate training in pathology and neuropathology. Buster moved to the University of Washington in Seattle in 1960, where he trained untold numbers of neurology, neurosurgery, and pathology residents. He also ran the diagnostic service and publishing 93 additional manuscripts that touched on virtually all facets of neurologic disease and neuropathology.  In Buster’s own words at his “retirement” party in 2002, “EAE was probably the high point” of a scientific career that included eight publications in Science and three in Nature.  In his later years, he focused on mathematical modeling of glioma growth.  At the time of his death, he had four manuscripts under preparation including one that described suffering a stroke from his own experience. 

Buster was an enthusiastic teacher with a keen wit and wry smile.  He was warm and encouraged critical thought, but did not ever allow his students to get away with sloppy thought or speech.  For decades, he would take residents and fellows on 6 AM road trips to Pacific Northwest hospitals to perform brain cuttings free of charge and to teach outlying pathologists the gospel of neuropathology.  He was so enthusiastic about teaching that he made arrangements for the donation of his own brain for teaching purposes with the instructions that it should be used for the benefit of all. 

Buster had a love of fleece jackets, white socks, outlandish ties, and fresh oysters.  Outside of neuropathology, he and his family were generous patrons of the arts in Seattle.  He was a thoughtful scientist, keen researcher, outstanding diagnostic neuropathologist, generous benefactor and giving teacher.  We are all diminished by his passing, but were enriched by his life.

The above memorial was contributed by Drs. Joshua A. Sonnen and Thomas Montine, neuropathologists at the University of Washington in Seattle.

John J. Kepes, MD (1928-2010)

"His death epitomizes the dwindling generation of classic neuropathologists." That's what the Mayo Clinic's Bernd Scheithauer, MD  had to say in a recent obituary for John Janos Kepes in the journal Brain Pathology. Dr. Kepes was born on March 31, 1928. He was the son of a Budapest otorhinolaryngologist and a mother who died when young John was only four years old. Dr. Kepes grew up to attend medical school in Budapest. He later escaped from Hungary with his young family as Russian forces invaded the country. Dr. Kepes ultimately made his way to the United States, where he did a neuropathology fellowship at the Mayo Clinic. He then settled in Kansas City, Missouri, where he devoted the next 48 years of his life to the University of Kansas Pathology Department. Scheithauer writes: "Key career contributions had included a 1982 monograph entitled 'Meningiomas: Biology, Pathology and Differential Diagnosis,' his 1991 co-discovery with Dr. Lucien Rubinstein of 'Pleomorphic Xanthoastrocytoma,' as well as his detailed 1993 description of 'Tumefactive Demyelination.' "

I myself had the honor of looking at slides with Dr. Kepes once in 2005. I'll always remember his insightful observations on the cytology of a case of papillary ependymoma.

In an obituary in the Journal of Neuropathology and Experimental Neurology, Dr. Lucy Rorke-Adams remembers that, "John was the ultimate in erudition, and no diagnostic problem was too difficult for him to unravel." The JNEN article continues to quote Dr. Rorke-Adams: "Dr. Kepes grew up in Hungary, 'a land he loved but which rejected him and his family at a stage in their lives when they were ready to contribute gifts of healing to their countrymen. The Kepeses' desperate escape from horrors brought them to our country, where John ripened into one of the most learned and distinguished neuropathologists of our generation.' "

After the loss of his beloved wife, Magda, in 2006, Dr. Kepes moved to an assisted living residence in the Kansas City area. It was there, according to his obituary in the Kansas City Star, in the early hours of February 2, 2010, that Dr. Kepes passed away peacefully, with his daughter by his side.

The skull's shape takes its cues from the brain's topography

I recently received the brain specimen pictured above from an outside institution in a form I had never seen before: with the skull cap still attached! If you look closely, you can see how the subtle undulations of the skull's inner surface coincide with the gyral pattern of the brain's outer surface. As the skull ossifies during development, it seems to adjust to the pattern present on the brain surface. That patterning persists for the rest of one's life. Cool.

New Neuropathologist Job Opening at the University of Michigan

It has been said that Neuropathology Blog has the most complete neuropathology job listing on the web. That has a lot to do with the ever-helpful Sherry Miller, wife of University of Missouri neuropathologist Doug Miller. This morning, Sherry sent me this newly listed job opening:

ANN ARBOR, MICHIGAN (USA). The Department of Pathology at the University of Michigan Health System is seeking an academic neuropathologist with subspecialty expertise in interpretation of nerve and muscle biopsies. Interested candidates should submit curriculum vitae, and the names and addresses of five individuals who can provide letters of recommendation to:
 
Jeffrey L. Myers, M.D.
A. James French Professor and Director,
Division of Anatomic Pathology
1500 E. Medical Center Drive, 2G332 UH
Ann Arbor, MI 48109-5054

Telephone: (734) 936-1888
Email: myerjeff@umich.edu



Thanks, Sherry!