Tarenflurbil, a gamma-secretase modulator, does not seem to work in Alzheimer’s disease

Long-awaited results of a Phase III trial of tarenflurbil (Flurizan) have failed to achieve statistical significance on either of its two primary endpoints (cognition and activities of daily living). The company developing the drug, Myriad Genetics, is abandoning development of the compound for Alzheimer's disease.

Tarenflurbil had been shown in nonclinical studies to modulate gamma-secretase activity. The drug was in trials in people with mild Alzheimer's to determine if its ability to lower the amount of toxic beta-amyloid would slow or stop the course of the disease.

This was the largest and longest placebo-controlled Alzheimer disease treatment trial ever completed. The results were reported today at the Alzheimer's Association International Conference on Alzheimer's Disease being held in Chicago. Read more about the results of the study here.

What is nNOS? And why is nNOS histochemistry useful in muscle biopsies?

I recently sent a specimen out for histochemistry to see if the muscle had diminished dystrophin and/or dystrophin-associated proteins. One of the histochemical stains in the panel was neuronal nitric oxide synthase (nNOS). I honestly didn’t know what the deal was with that particular protein, so I thought I’d share with you what I found out.

In normal muscle, histochemistry for nNOS shows uniform sarcolemmal labeling. Internal sarcoplasmal labeling can also be present. Blood vessel walls are also positive. In Duchenne or Becker muscular dystrophy, nNOS is absent or reduced in the sarcolemma. Immature fibers will also lack nNOS histochemical staining.

An article by Ehmsen et al in the Journal of Cell Science states the following: “The production of nitric oxide (NO) by nNOS is important for increasing local blood flow to match the increased metabolic load of contracting muscles, such as during exercise… [P]atients with DMD [Duchenne muscular dystrophy] show abnormal blood vessel constriction presumably due to lack of nNOS at the sarcolemma… However, abolishing nNOS expression alone in mice does not cause overt dystrophy.”

So if it doesn’t cause overt dystrophy, what’s the point of doing this particular histochemical stain?

Dr. Steve Moore (pictured), muscle pathology guru at the University of Iowa, emailed me the following response when I queried him on the subject: “[nNOS] is quite sensitive to dystrophin mutations, meaning that it is virtually always absent in DMD and reduced to absent in BMD. In milder cases of BMD, nNOS sometimes can be the "canary in the mine" for detecting a dystrophinopathy. In the setting of a possible dystrophin mutation carrier, it provides one more marker for the muscle cells expressing either normal or mutant dystrophin. Dystrophin-negative fibers are also nNOS negative. This contrasts with the dystrophin-negative fibers being utrophin positive (utrophin is frequently expressed at the sarcolemma when dystrophin is missing or abnormal). Bottom line - using nNOS increases my confidence in the interpretation of the other immunostains in selected cases.”

References:

Dubowitz V and Sewry CA. Muscle Biopsy: A Practical Approach, 3^rd edition (2007) p 261 and 279.

Ehmsen J et al., The dystrophin-associated protein complex. Journal of Cell Science 115 (14) p. 2801-3.

Moore, Steven A. Univ. of Iowa, email communication (July 28, 2008).

Robert Novak has brain tumor

Conservative political columnist Robert Novak has a brain tumor, although the lesion has yet to be biopsied for diagnosis. According to an article in the on-line New York Times, "Last week, while driving in Washington, Mr. Novak struck a pedestrian, who was not seriously hurt, and said later that he had not been aware he had hit anyone. It is not clear whether the brain tumor contributed to that accident." Thanks to the illustrious Dr. Ranleigh Fleshman for alerting me to this piece of news. I'll let you know what the diagnosis is once it is made public.

Another interthalamic adhesion picture

This is a high-power picture of the interthalamic adhesion of an 81-year-old man with a clinical diagnosis of Dementia with Lewy Bodies. Again, see the collection of neuron cell bodies along with glial cells. I should remind you that not everyone has an interthalamic adhesion (about 20% are lacking this grey matter), and women are more likely to have this structure than do men. Nobody knows why this is, or what the function of the structure is. I supporse there are two possibilites, either it is of no practical importance, or there is an alternative way in which those lacking an interthalamic adhesion can process the information otherwise reserved for this structure.

Erratum regarding the interthalamic adhesion

I must revise a post from May 19, 2008 in which I quoted Dr. George R. Leichnetz, neuroanatomist at Virginia Commonwealth University and author of Digital Neuroanatomy: An Interactive CD Atlas with Text (Wiley-Liss, 2006). At that time, Dr. Leichnetz emailed me the following: “The 'interthalamic adhesion' or 'massa intermedia' is (as its name implies) an adherence of the ependymal lining of the midline third ventricle. Importantly, it is not a commissure, ie. there are no inter-thalamic fibers exchanged between the two thalami."

At that time, I said that I would confirm this view under the microscope by taking some sections of the interthalamic adhesion at autopsy. Well, it turns out that there are plenty of neuron cell bodies and nerve tracts within the massa intermedia. Above is pictured the massa intermedia from an 85-year-old lady with Alzheimer disease. Notice the bipolar neurons, particularly convincing is the neuron with the prominent nucleolus. Since this slide was stained with luxol fast blue, which stains myelin blue, you can see that there are indeed nerve tracts running through the massa intermedia. As I did further research on the internet, I found a consensus that the massa intermedia is indeed grey matter, and not simply an adherence of ependymal lining as was stated by Dr. Leichnetz. Sorry about any confusion I may have caused regarding this matter.

Estelle Getty suffered from Lewy Body Disease

Here's an article describing today's passing of Estelle Getty, 'The Golden Girls' actress.

There's money in blogging!

The esteemed Dr. Doug Shevlin fowarded me this New York Times article about another guy with an M.D. after his name who blogs. Dr. Arnold Kim, pictured above, writes MacRumors.com, which monitors new developments coming out of the notoriously secretive Apple. Dr. Kim recently quit his day job as a physician, which brought in a six-figure income, to blog full-time, saying "“on paper, it was an easy decision.” Sweet.

Best Post of March, 2008: A new disease which lawyers love

The next in my occasional "Best of the Month" series goes back to March '08 with this post:

Neuropathologists are always reviewing brain MRIs that use gadolinium contrast. I never thought much about the potential toxic effect of gadolinium. However, the illustrious Dr. Brajesh Argawal, resident in the Southern Illinois University School of Medicine neurology program, informed me yesterday of the risk of the use of gadolinium-based MRI contrast agents in patients with chronic renal failure. There is an emerging disorder, known as nephrogenic systemic fibrosis (NSF), that can arise in these patients. NSF involves the deposition of collagen in the skin and other organs in patients either on dialysis or with a glomerular filtration rate of less than 15 cc/min. According to an article on the topic by Philip Kuo et al. in the journal Radiology (2007;242:647-649), “NSF may develop rapidly and can sometimes result in patients becoming confined to a wheelchair within a few weeks… While NSF sometimes stabilizes, it rarely spontaneously remits.” Malpractice lawyers are, of course, all over NSF. For instance:
http://www.mri-contrast-lawsuit.com/

Radiologists now make it a practice to have patients sign a consent form which mentions the possibility of the development of NSF in those with renal insufficiency. Here’s a link to the FDA alert concerning gadolinium:
http://www.hpcbd.com/FDA%20Gadolinium%20Alert.pdf

Thanks for the information, Dr. Argawal!

'Moore as Lincoln' back in Profile

By popular demand, I have removed the respectable and professional picture on my profile and replaced it with me dressed as Abe Lincoln last February 12th.

A New Prion Disease

The esteemed Dr. Doug Shevlin (pictured on left) sent me this article on a newly described prion disease known as protease-sensitive prionopathy (PSPr), a disease with a similar clinical presentation as sporadic Creutzfeldt-Jakob disease (sCJD), but with a stronger hereditary connection. The prions associated with sCJD are protease resistant, but (as the name indicates) this new prion disease is caused by proteins that are protease sensitive. The authors, Pierluigi Gambetti and colleagues at the National Prion Surveillance Center in Cleveland, conclude that PSPr "is not rare among prion diseases, and it may be even more prevalent than our data indicate because protease- sensitive prionopathy cases are likely also to be classified within the group of non-Alzheimer's dementias."

Best Post of February, 2008: The mechanism of post-traumatic cerebral fat emboli not well understood

The next in my occasional “Best Post Of The Month” series is for February, 2008:

I was giving a lecture on the pathology of cerebrovascular disease today, and showed a picture from Robbins of a brain with a shower of fat emboli after fracture of long bones. A student asked what the mechanism would be, pointing out that it would be difficult for marrow fat to get from the venous system of the leg into the arterial circulation of the brain without going through the filter of the pulmonary capillary bed.

The etiology of fat emboli after trauma is not clear. According to an article by Butteriss et al. in the American Journal of Neuroradiology, microemboli may pass into the systemic circulation either via cardiac or intrapulmonary right-left shunts or directly through the pulmonary capillary bed. Apparently a study of orthopedic surgery in dogs has shown that fat globules of <5 µm can traverse the pulmonary micovasculature. One could imagine these globules coalescing in the brain and causing significant infarcts, I suppose.

Whatever the mechanism, I imagine air emboli introduced when inserting or pulling out a central line might form in a similar manner.

(Source: D.J.A. Butteriss et al., Reversible Cytotoxic Cerebral Edema in Cerebral Fat Embolism . American Journal of Neuroradiology 27:620-623, March 2006.)

Curcumin, the yellow pigment in curry spice, may protect against Alzheimer's disease

The illustrious Dr. Amita Singh (Southern Illinois University Department of Neurology) alerted me to this article suggesting that a staple of the Indian diet may be the reason why Indians aged 70 to 79 are 4.4 times less likely to get Alzheimer's disease than are their American counterparts:

What is the second most common cause of dementia?

In a lecture delivered at the 2008 American Academy of Neurology meeting, Dr. Helena C. Chui, chair of neurology at UCLA, posed the following question: What is the second most common cause of dementia after Alzheimer disease? Her answer was that if you are talking about a primary neurodegenerative disease, it’s Dementia with Lewy Bodies. If, however, you are talking about any kind of dementia, vascular dementia takes the number two spot. The problem from the neuropathologist’s point of view is that it is difficult to arrive at criteria for the diagnosis of vascular dementia. Do four infarcts give you vascular dementia? Seven? It depends, of course, upon where those infarcts are located. Theoretically, a single infarct in the thalamus can result in dementia. All the neuropathologist can really do is list the locations and sizes of the infarcts identified at autopsy and let the neurologist make the call as to whether or not the patient’s dementia is due to a vascular cause.

Neuropathology quiz question

(Answer appears as a comment to this post.)

What rare disease is classically characterized by isolated demyelination, or sometimes cystic cavitation, of the corpus callosum?

a. Machado-Joseph disease

b. Marchiafava-Bignami disease

c. Pelezius-Merzbacher disease

d. McCune-Albright syndrome

e. The Miller-Donahue variant of Stoopa disease

Big Alzheimer Conference this month in Chicago

The Alzheimer’s Association International Conference on Alzheimer's Disease 2008 is coming up in Chicago on July 26-31. Among the more eagerly anticipated reports that will come out of the meeting will be preliminary results of the so-called GEM Study, which is looking at the putative protective effects that gingko biloba has against dementia. Also on the docket are preliminary results of a Phase III trial of gamma-secretase modulators (such as tarenflurbil) in the treatment of Alzheimer’s disease. I’ll let you know about any interesting developments coming out of this meeting.