Experimental AD drug that fights tau (not beta-amyloid)

There’s a lot of news coming out of Chicago during the big Alzheimer’s Disease conference there this week. The first part of this news article on an experimental drug fighting the protein tau is what caught my eye. Tau is the key protein involved in PSP and CBD. The article briefly mentions a second experimental tau-fighting drug that was used on those with mild cognitive impairment. The remainder of the article mentions Flurizan, where the development of this beta-amyloid-fighting drug has been halted, and the Elan/Wyeth experimental drug bapineuzumab. To my knowledge, beta-amyloid is NOT an issue in PSP or CBD. I read this article in the Miami Herald.

http://www.miamiherald.com/living/healt … 21968.html

Experimental Alzheimer’s drug shows early promise
Posted on Tue, Jul. 29, 2008
AP Medical Writer

CHICAGO — For the first time, an experimental drug shows promise for halting the progression of Alzheimer’s disease by taking a new approach: breaking up the protein tangles that clog victims’ brains.

The encouraging results from the drug called Rember, reported Tuesday at a medical conference in Chicago, electrified a field battered by recent setbacks. The drug was developed by Singapore-based TauRx Therapeutics.

Even if bigger, more rigorous studies show it works, Rember is still several years away from being available, and experts warned against overexuberance. But they were excited.

“These are the first very positive results I’ve seen” for stopping mental decline, said Marcelle Morrison-Bogorad, director of Alzheimer’s research at the National Institute on Aging. “It’s just fantastic.”

The federal agency funded early research into the tangles, which are made of a protein called tau and develop inside nerve cells.

For decades, scientists have focused on a different protein – beta-amyloid, which forms sticky clumps outside of the cells – but have yet to get a workable treatment.

The drug is in the second of three stages of development, and scientists are paying special attention to potential treatments because of the enormity of the illness, which afflicts more than 26 million people worldwide and is mushrooming as the population ages.

The four Alzheimer’s drugs currently available just ease symptoms of the mind-robbing disease.

TauRx’s chief is Claude Wischik, a biologist at the University of Aberdeen in Scotland who long has done key research on tau tangles and studies suggesting that Rember can dissolve them.

He is an “esteemed biologist,” and the research “comes with his credibility attached to it,” said Dr. Sam Gandy of Mount Sinai School of Medicine in New York. He heads the scientific advisory panel of the Alzheimer’s Association.

In the study, 321 patients were given one of three doses of Rember or dummy capsules three times a day. The capsules containing the highest dose had a flaw in formulation that kept them from working, and the lowest dose was too weak to keep the disease from worsening, Wischik said.

However, the middle dose helped, as measured by a widely used score of mental performance.

“The people on placebo lost an average of 7 percent of their brain function over six months whereas those on treatment didn’t decline at all,” he said.

After about a year, the placebo group had continued to decline but those on the mid-level dose of Rember had not. At 19 months, the treated group still had not declined as Alzheimer’s patients have been known to do.

Two types of brain scans were available on about a third of participants, and they show the drug was active in brain areas most affected by tau tangles, Wischik said.

“This is suggestive data,” not proof, Wischik warned. The company is raising money now for another test of the drug to start next year.

The main chemical in Rember is available now in a different formulation in a prescription drug sometimes used since the 1930s for chronic bladder infections – methylene blue. However, it predates the federal Food and Drug Administration and was never fully studied for safety and effectiveness, and not in the form used in the Alzheimer’s study, Wischik and other doctors cautioned.

On Monday at the International Conference on Alzheimer’s Disease, other researchers reported encouraging results from a test of a different experimental drug that also targets tau tangles. That drug, by British Columbia-based Allon Therapeutics Inc., was tested in people with an Alzheimer’s precursor, mild cognitive impairment.

The tau-drug results are in stark contrast to the flop of Flurizan, which was aimed at blocking enzymes that form the beta-amyloid clumps. Myriad Genetics announced in June that it would abandon development of Flurizan after the failure. Full results were presented at the conference Tuesday.

Also, fuller results were given from a closely watched test of bapineuzumab, an experimental drug that aims to enlist the immune system to clear out the sticky brain clumps.

Its developers – New Jersey-based Wyeth and the Irish company Elan Corp. PLC – previously announced that the 240-patient study missed its main goal of improving patients’ mental performance at 18 months.

But the company found a silver lining – the drug appeared to help the roughly 60 percent of people in the study who did not have a gene that scientists think makes Alzheimer’s disease more severe.

The results back up the company’s claims of potential effectiveness in some patients, but now there are concerns about possible side effects. Twelve cases of a type of brain swelling occurred in those on bapineuzumab and none in the placebo group. The swelling caused few if any symptoms, company scientists said, but outside experts said it may have contributed to other side effects.

Those were two or more times more common in patients on bapineuzumab than people given the dummy drug. For example, cases of anxiety occurred in 11 percent versus 4 percent on placebo; paranoia, 7 versus 1 percent. Other complaints were vomiting, high blood pressure, weight loss, and back pain.

Three deaths occurred among the 124 patients given bapineuzumab, but they were not related to the drug, said Dr. Sid Gilman of the University of Michigan, who headed the study’s data safety monitoring board. One death was due to pneumonia and two others to worsening Alzheimer’s disease.

Investors reacted to the news by driving down Wyeth’s shares $5.01, or 11.1 percent, in after-hours trading.

Wyeth and Elan have already said they will move on to late-stage testing of bapineuzumab in more than 4,000 patients.

“A Short Stay in Switzerland” movie about death with dignity (and PSP) – coming soon

This is an excerpt from an article in a London newspaper about a BBC movie that begins filming soon.  It is called “A Short Stay in Switzerland.”  The movie is about Dr. Anne Turner who went to Switzerland to die with dignity.  Dr. Turner had progressive supranuclear palsy.  Her husband died with multiple system atrophy.  Actress Julie Walters plays Dr. Turner.




Julie honours a woman who died with dignity
Daily Mail (London), July 19, 2008

Julie Walters, in the groove with hit film musical Mamma Mia!, is taking on a real-life role that will be the subject of passionate debate.

Walters will portray Dr Anne Turner, the former medical practitioner from Bath who hit the headlines in early 2006 when she gave notice of her intention to end her life by means of an assisted suicide.

Rehearsals begin next month in London on the BBC1 TV film called A Short Stay In Switzerland, a factually-inspired drama written by playwright Frank McGuinness.

Simon Curtis, the director, said McGuinness’s screenplay sensitively explores the final 18 months of Dr Turner’s life until she and her three children travel to a clinic in Zurich where arrangements had been made for her to die with dignity, which she argued ‘should be everybody’s right’.

It’s a highly emotive topic but, Curtis noted, the combination of McGuinness’s script and Julie Walters’s acting should be able to make it palatable for TV audiences.

Dr Turner died on January 26, 2006, a day before her 67th birthday.  She had been diagnosed with Progressive Supranuclear Palsy (PSP), a neurological degenerative disease.

Her husband had died in 2002 of Multiple System Atrophy (MSA). Sufferers lose their sense of balance and are unable to talk, swallow or blink.

Curtis, who directed the acclaimed Cranford serial with Judi Dench and Eileen Atkins, will meet Dr Turner’s family next week.

Her son and daughters have already collaborated with McGuinness and producers Liz Trubridge and Ruth Caleb on the screenplay.

‘The family has been very supportive, which is important in a drama of this nature,’ Curtis observed.

‘They’re a loving family and in difficult times you find glimpses of warmth, happiness, love and humour.’

He added that Walters has what he called ‘that extra ingredient the public responds to; Dame Judi has that, too.

‘The audience love to go on the journey she takes them on’.

A Short Stay In Switzerland will shoot in London for four weeks, with a brief location in Zurich.


“Alzheimer’s vaccine stopped plaque, not dementia”

Interesting news today out of London about an AD vaccine that removed beta-amyloid protein in the brain of 7 patients but did nothing for their dementia.

http://www.salon.com/wires/ap/scitech/2 … index.html

Alzheimer’s vaccine stopped plaque, not dementia
Associated Press Writer

Jul 17th, 2008 | LONDON — Some doctors have long suspected that if the plaque that builds up in the brains of patients with Alzheimer’s disease could be removed, they could be saved. But a new vaccine that did just that suggests the theory is wrong.

British researchers gave 64 patients with moderate Alzheimer’s disease an experimental vaccine designed to eliminate plaque from their brains. Some patients were followed for up to six years.

Autopsies on seven patients who died of Alzheimer’s during the study showed that nearly all of the sticky beta-amyloid protein thought to be dangerous had been removed. But all patients still had severe dementia.

“It may be that these toxic plaques trigger the neurodegeneration, but don’t have an ongoing role,” said Clive Holmes of the University of Southampton, lead author, in a press statement. The study was published Friday in the medical journal, The Lancet.

The study was paid for by the Alzheimer’s Research Trust, a British charity.

Alzheimer’s disease is the most common cause of dementia and affects about 25 million people worldwide.

Other experts said that the study’s findings pointed to a major gap in our understanding of the disease. Doctors have never been sure whether the brain plaques are the cause of Alzheimer’s disease or just a side effect.

“We still don’t have enough understanding of what we should target,” said Dr. Bengt Winblad, director of the Alzheimer’s Centre at Sweden’s Karolinska Institute. Winblad was not connected to the study.

Aside from the plaque build-up, scientists also think that tangles of another brain protein called tau play a major role in Alzheimer’s. Because those tangles form later than the plaque, some experts think they should be the focus instead.

“It may be harder to get a response from targeting plaque because that forms years before people actually have Alzheimer’s,” said Dr. Simon Lovestone, professor of Old Age Psychiatry at King’s College in London. “By the time you do something, it may be too late.”

Winblad said there was a better connection between brain tangles and Alzheimer’s symptoms, but that no studies so far had looked at whether removing tangles might improve or even reverse Alzheimer’s disease in patients.

Still, experts say that attacking toxic plaque in the brain shouldn’t be abandoned just yet, since the formation of such plaques might be what sparks Alzheimer’s disease in the first place.

“Removal of the initial motor for the disease might slow progression,” wrote Peter H. St. George-Hyslop and John C. Morris of the University of Cambridge and the University of Toronto in an accompanying commentary in the Lancet.

Salon provides breaking news articles from the Associated Press as a service to its readers, but does not edit the AP articles it publishes.

Copyright 2008 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.

CJD-like Dementia in US Called “PSPr”

Thought you might want to know that a US scientist has identified a new dementia in the US, and given it a name that includes “PSP.” The new dementia is a prion disorder, is similar to CJD, Creutzfeldt-Jakob disease — a “fast advancing dementia but with additional loss of movement and speech.” Confusingly, the name given to the disorder is “PSPr” for protease-sensitive prionopathy I read about this on a PSP-related Yahoo!Group tonight. What follows is a MedicalNews Today article as well as the abstract from the scientific journal about this new dementia.


New Fatal CJD-Like Dementia Discovered In America
MedicalNews Today
10 Jul 2008

A new dementia that is distinct from but resembles known forms of CJD, Creutzfeldt-Jakob disease, has been discovered in America, affecting 16 people, 10 of whom have died after gradually losing their mental and motor functions and being unable to think, speak or move.

Yesterday’s issue of New Scientist reported that Pierluigi Gambetti, the director of the US National Prion Disease Pathology Surveillance Center based at Case Western Reserve University in Cleveland, Ohio, said nobody knows how the disease starts or spreads, or how many people may have it.

Gambetti and colleagues wrote a paper on the discovery of the disease, called PSPr (for protease-sensitive prionopathy), in a paper that was published online in the Annals of Neurology on 20th June 2008.

Gambetti said he believed the disease had been around for some time and may have been mistaken for other forms of dementia. The 16 cases include the 11 he described in the paper and another 5 that have since been diagnosed. Ten of the 16 patients have died of the disease. Their brains had the trademark damage that is normally associated with CJD (note this is not variant or vCJD that is linked to mad cow disease or BSE), except that in the case of PSPr, Gambetti and colleagues suggest the cause is genetic.

According to BBC news, experts in the UK are now checking records to see how many cases there may be in the UK, where there are between 50 and 100 cases of so-called sporadic CJD every year.

A representative of the UK’s National CJD Surveillance Unit, in Edinburgh, Dr Mark Head, said they were reviewing cases of sporadic CJD for clues that there might be some that are really PSPr. He also said it may mean there are other prion disease genes waiting to be discovered.

Sporadic CJD has no known cause, unlike the BSE-linked vCJD that is contracted from eating infected cows’ brains or spinal cord tissue.

In the US, PSPr came to light when cases were referred to CJD surveillance centers because the symptoms appeared to be CJD-like (fast advancing dementia but with additional loss of movement and speech). But tests for CJD proved negative.

Yet post mortems on the patients who died showed the familiar sponginess in the brain tissue that results when misshapen brain proteins or “prions” accumulate in the brain.

Gambetti suggested there might be a genetic link because the patients all had a family history of dementia but did not carry they CJD gene.

In the paper published earlier this year, Gambetti and colleagues reported their investigation of 11 cases at the National Prion Disease Pathology Surveillance Center for clinical, histopathological, immunohistochemical, genotypical, and prion protein (PrP) characteristics.

They wanted to report on what they believed to be a new form of prion disease where like the more common prion diseases there was a misshapen prion protein, but there was a difference in that the protein was sensitive to protease digestion.

In their conclusion they wrote that their histological, immunochemical, physicochemical and genetic investigation indicated that:

“This is a previously unidentified type of disease involving the PrP [prion protein], which we designated protease-sensitive prionopathy (or PSPr). Protease-sensitive prionopathy 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.”

“A novel human disease with abnormal prion protein sensitive to protease.”
Pierluigi Gambetti, Zhiqian Dong, Jue Yuan, Xiangzhu Xiao, Mengjie Zheng, Amer Alshekhlee, Rudy Castellani, Mark Cohen, Marcelo A. Barria, D. Gonzalez-Romero, Ermias D. Belay, Lawrence B. Schonberger, Karen Marder, Carrie Harris, James R. Burke, Thomas Montine, Thomas Wisniewski, Dennis W. Dickson, Claudio Soto, Christine M. Hulette, James A. Mastrianni, Qingzhong Kong, Wen-Quan Zou.
Annals of Neurology, Volume 63 Issue 6, Pages 697 – 708.
Published Online: 20 Jun 2008.
DOI: 10.1002/ana.21420

Source: BBC, New Scientist, Annals of Neurology abstract.

Written by: Catharine Paddock, PhD
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

Here’s the abstract of the article in the Annals of Neurology:

A novel human disease with abnormal prion protein sensitive to protease

Pierluigi Gambetti, MD 1 *, Zhiqian Dong, PhD 1, Jue Yuan, BA 1, Xiangzhu Xiao, PhD 1, Mengjie Zheng, PhD 1, Amer Alshekhlee, MD 1, Rudy Castellani, MD 2, Mark Cohen, MD 1, Marcelo A. Barria, PhD 3, D. Gonzalez-Romero, PhD 3, Ermias D. Belay, MD 4, Lawrence B. Schonberger, MD, MPH 4, Karen Marder, MD 5, Carrie Harris, BA 1, James R. Burke, MD, PhD 6, Thomas Montine, MD 7, Thomas Wisniewski, MD 8, Dennis W. Dickson, MD 9, Claudio Soto, PhD 3, Christine M. Hulette, MD 10, James A. Mastrianni, MD, PhD 11, Qingzhong Kong, PhD 1, Wen-Quan Zou, MD, PhD 1 *

1Institute of Pathology, Case Western Reserve University, Cleveland, OH
2Department of Pathology, University of Maryland, Baltimore, MD
3Department of Neurology, Neuroscience and Cell Biology, George and Cynthia Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX
4Centers for Disease Control and Prevention, Atlanta, GA
5Department of Neurology, Columbia University, New York, NY
6Department of Medicine, Division of Neurology, Duke University, Durham, NC
7Harborview Medical Center, University of Washington, Seattle, WA
8Department of Neurology, New York University, New York, NY
9Department of Neuropathology, Mayo Clinic College of Medicine, Jacksonville, FL
10Department of Pathology, Duke University, Durham, NC
11Department of Neurology, University of Chicago, Chicago, IL

email: Pierluigi Gambetti ([email protected]) Wen-Quan Zou ([email protected])

*Correspondence to Pierluigi Gambetti, Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106
*Correspondence to Wen-Quan Zou, Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106

Funded by:
NIH; Grant Number: AG14359, AG08702, NS049173
Centers for Disease Control and Prevention; Grant Number: CCU 515004
Britton Fund
CJD Foundation


To report a novel prion disease characterized by distinct histopathological and immunostaining features, and associated with an abnormal isoform of the prion protein (PrP) that, contrary to the common prion diseases, is predominantly sensitive to protease digestion.

Eleven subjects were investigated at the National Prion Disease Pathology Surveillance Center for clinical, histopathological, immunohistochemical, genotypical, and PrP characteristics.

Patients presented with behavioral and psychiatric manifestations on average at 62 years, whereas mean disease duration was 20 months. The type of spongiform degeneration, the PrP immunostaining pattern, and the presence of microplaques distinguished these cases from those with known prion diseases. Typical protease-resistant PrP was undetectable in the cerebral neocortex with standard diagnostic procedures. After enrichment, abnormal PrP was detected at concentrations 16 times lower than common prion diseases; it included nearly 4 times less protease-resistant PrP, which formed a distinct electrophoretic profile. The subjects examined comprised about 3% of sporadic cases evaluated by the National Prion Disease Pathology Surveillance Center. Although several subjects had family histories of dementia, no mutations were found in the PrP gene open reading frame.

The distinct histopathological, PrP immunohistochemical, and physicochemical features, together with the homogeneous genotype, indicate that this is a previously unidentified type of disease involving the PrP, which we designated protease-sensitive prionopathy (or PSPr). Protease-sensitive prionopathy 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. Ann Neurol 2008;63:697-708
Received: 5 November 2007; Revised: 1 April 2008; Accepted: 4 April 2008

The Sandwich Generation (story of one challenged family)

Tonight I watched two online videos of 18 months of life in the sandwich generation, where a couple is caring for the wife’s father (with dementia) and their two children. Both videos are worthwhile but if you only watched one I’d vote for the second video. 


First video: (about 11 minutes) 

Second video: (about 15 minutes) 

Short news story about this family: (New York Times 7/1/08)