Monthly Archives: May 2006

“Foiling Chemical Event May Combat Brain Breakdown”

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This post is about an interesting article on preventing misfolded protein accumulations (which occurs in AD, PD, and many related diseases), protecting an enzyme (called called protein disulphide isomerase), and stopping a chemical (nitric oxide) from wreaking havoc in the brain.

The Bloomberg News article talks about a study just published in the journal Nature. The aarticle notes:

“While previous studies showed that nitric oxide can be involved in the degeneration of brain cells through a variety of mechanisms, the new study shows a previously unrecognized relationship between the chemical and protein misfolding.”

Here’s a link to the article:

www.bloomberg.com/apps/news?pid=10000082&sid=avdCh4_MT55U

Foiling Chemical Event May Combat Brain Breakdown, Study Says
Bloomberg.com
May 24, 2006

Aricept and PSP (2001 study)

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A group member with progressive supranuclear palsy (PSP) asked me recently what I knew about two Alzheimer’s drugs — Aricept and Namenda — in treating PSP.

I’ve done a little bit of digging on the subject today and found a randomized, double-blind, placebo-controlled study funded by NIH done in 2001. The abstract follows.

Bottom line — these MDs do not recommend that those with PSP take Aricept (donepezil) because although the “Double Memory Test” scores will improve, status of activities of daily living (ADL) and mobility scores will worsen significantly.

I will search a bit on Namenda over the next few days. Since Namenda is NOT an acetylcholinesterase inhibit (Aricept is), this study will not apply.

Robin

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www.neurology.org/cgi/content/abstract/57/3/467
Randomized placebo-controlled trial of donepezil in patients with progressive supranuclear palsy

I. Litvan, MD; M. Phipps, BA;, V. L. Pharr, MA; M. Hallett, MD; J. Grafman, PhD; and A. Salazar, MD

From the Cognitive Neuropharmacology Unit (Dr. Litvan, M. Phipps, and V.L. Pharr) and the Defense and Veteran Head Injury Program (Dr. Salazar), Henry M. Jackson Foundation; and the Medical Neurology Branch (Dr. Hallett) and the Cognitive Neuroscience Section (Dr. Grafman), National Institute of Neurological Disorders and Stroke, National Institutes of Health. (Robin’s note: Dr. I. Litvan is now at the University of Louisville in KY.)

Objective:­ There is no effective treatment for progressive supranuclear palsy (PSP). Because results of immunochemical and pharmacologic studies suggest that the cholinergic system may play a role in the cognitive and motor features of PSP, the authors investigated the effects of donepezil (10 mg/day), an acetylcholinesterase inhibitor, in 21 patients with PSP (mean age ± SD; 65.7 ± 4.7 years) by a randomized, double-blind, placebo-controlled crossover trial.

Methods:­ Donepezil and placebo were administered for 6 weeks each with a 1-month washout period. Patients were evaluated before and at the end of each treatment phase. Outcome measures evaluated neuropsychiatric, global cognitive, frontal, memory, motor, and activities of daily living (ADL) status.

Results:­ Two patients withdrew during the washout phase because of unrelated medical problems. Donepezil-induced systemic side effects were transient and generally mild. Because of worsening of motor function, three patients received 5 mg/day of donepezil. All patients achieved blood and CSF therapeutic levels of donepezil. While the patients were taking donepezil, their Double Memory Test scores improved, whereas their ADL/mobility scores significantly worsened.

Conclusion:­ The findings suggest that acetylcholinesterase inhibitors such as donepezil have at best selective, modest effects on cognition in patients with PSP. In light of its deleterious effects on ADL/mobility, donepezil is not recommended for this patient population.

“A Surprising Clue to Parkinson’s” (MIT Technology Review)

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I saw an article in the May/June ’06 issue of Technology Review, an MIT publication, related to protein aggregations in those with PD and other diseases. What I found interesting was the fact that there is not scientific agreement over whether abnormal protein aggregations in the brain are a bad thing. The author says that the MIT biotechnology study demonstrates “that increased protein aggregation can improve the health of cells modeling neurodegenerative disease.”

That led to a related article published on the Technology Review’s website on 3/7/06. Excerpts from that March article:

“It’s easy to distinguish a healthy person from a person with advanced Parkinson’s: the Parkinson’s sufferer has large clumps of proteins in his or her brain cells. Scientists disagree, however, about the nature of these clumps. Some contend that they lead to the massive neuronal cell death and resulting movement disorders in Parkinson’s, others that the clumps are merely a byproduct of the disease — and some scientists contend that the clumps are actually protective, sequestering toxic proteins so they can’t hurt the cell. Mounting evidence points to the last possibility.”

“Existing research already suggests that the biggest clumps, known as inclusions, are helpful. Cells that form clumps of the mutant Huntington protein, for example, survive longer than clump-free cells. Now MIT scientists have discovered a compound that increases clumps in cell models of Huntington’s and Parkinson’s disease and makes the cells healthier. Scientists aren’t sure how the compound works, but they think it might be helping cells get rid of toxic forms of the proteins floating around in the cell by isolating them into clumps.”

Here’s a link to the older article:

www.technologyreview.com/read_article.aspx?id=16517&ch=biotech

A Surprising Clue to Parkinson’s
Drugs that boost the protein clumping that occurs during neurodegenerative disease could provide a new route to treatment.
Technology Review (MIT)
By Emily Singer
March 7, 2006

And a link to the newer article:

www.technologyreview.com/read_article.aspx?ch=biotech&sc=&id=16825&pg=2

A Curious Clue to Parkinson’s
Drugs that boost protein aggregation could provide a new route to treatment
Technology Review (MIT)
May/June 2006

PSP Research Study- NIH-Funded and Parkinson’s Institute is a Site

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I just received this email from the Society for PSP (in Maryland) about an important NIH grant given to Dr. Irene Litvan, one of the top researchers in the US on progressive supranuclear palsy. One of the eight sites is The Parkinson’s Institute (thepi.org) in Sunnyvale. The site coordinator there is our friend Dr. James Tetrud, a neurologist with wide knowledge of PSP. (He spoke at the Society’s recent PSP Family Conference. He mentioned the arctic ground squirrel. Most of you received an email from me about that.)

If you are interested in participating in this PSP research study, please contact Whitney Rogers, the Clinical Coordinator for the main study and for the University of Louisville site in particular. Her contact info is: 502-852-4612 or [email protected].

I have just spoken with Whitney to get some general info; she is very nice. She explained that every person with PSP who wants to be involved in the study needs to bring with them two controls. The controls should: not have PSP, not be a blood relative, and be similar in age to the person with PSP (plus or minus 5 years). One control must be the same gender as the person with PSP; this is usually an in-law. The other control can be a different gender as the person with PSP; this is usually the spouse.

Please let me know if you do contact Whitney and run into some issues that the rest of the group should know about. Also, I’d appreciate knowing who eventually signs up to participate in this study!

Thanks,
Robin

PS. The “Mayo Clinic” mentioned below is the one in Jacksonville, FL.

Subject: NIH Grant to Irene Litvan
Date: Mon, 22 May 2006 13:10:25 -0400
From: CurePSP
To: Support Group Leaders

Movement Disorder Program Awarded Novel NIH Clinical Research Grant to Study Rare Neurodegenerative Disease

Dr. Irene Litvan, Raymond Lee Lebby Professor of Neurology and Director of the Movement Disorder Program has been awarded a $3.4 million NIH grant to study the genetic and environmental risk factors for progressive supranuclear palsy. Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian movement disorder. Dr. Litvan will lead a team of movement disorder specialists from 8 sites across the country (Baylor, Case Western, Emory, Mayo Clinic, Parkinson Institute, Massachusetts General Hospital, University of Maryland) and basic science researchers (Duke, Johns Hopkins, Mayo Clinic, Washington University, University of Louisville), in determining the role of genetic, occupational and environmental components in the development of PSP. Specifically, this large case/control study that will involve 500 PSP patients and 1000 controls will seek to determine if there is an association between PSP and specific H1 tau genotypes, alpha-synuclein polymorphisms, parkin gene deficits or other gene-gene interactions. The study will also explore whether there is an association between PSP and occupational and or environmental chemical exposures functionally or structurally similar to known parkinsonian toxicants. This is the first major research award to focus on PSP.

The Movement Disorder Program has begun recruiting patients with PSP for inclusion in the study. Interested parties should contact the Movement Disorder Program at 502-852-4612. It is hoped that this major effort will in turn help find ways to prevent or treat this devastating disease.

Journal article on MRIs to distinguish PSP, MSA, and PD

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This article in the Movement Disorder Society magazine (of the UK) is on using MRIs to distinguish between Progressive supranuclear palsy (PSP), Multiple system atrophy (MSA), and Parkinson’s disease (PD). Apparently the technique is most (only?) effective in later stages. This was published online on 4/6/06. The abstract is below.

Robin

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Regional brain volumes distinguish PSP, MSA-P, and PD: MRI-based clinico-radiological correlations
Dominic C. Paviour, MRCP, Shona L. Price, BSc, Marjan Jahanshahi, PhD , Andrew J. Lees, MD, FRCP , Nick C. Fox, MD, FRCP

Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are neurodegenerative disorders, each with a prevalence of around 5 per 100,000. Regional brain atrophy patterns differ in the two disorders, however, and magnetic resonance imaging is sometimes helpful in distinguishing them in the later stages. We measured whole brain and regional volumes, including cerebellum, pons, midbrain, superior cerebellar peduncle (SCP), and ventricular volumes as well as frontal and posterior-inferior cerebral regions in 18 subjects with PSP, 9 with MSA-P (parkinsonian phenotype), 9 with Parkinson’s disease (PD), and 18 healthy controls. Associations between these volumes, cognitive profiles, and clinical measures of disease severity and motor disability were assessed. Mean midbrain volume was 30% smaller in PSP than in PD or controls (P < 0.001) and 15% smaller than in MSA-P (P = 0.009). The mean SCP volume in PSP was 30% smaller than in MSA-P, PD, or controls (P < 0.001). Mean cerebellar volumes in MSA-P were 20% smaller than in controls and PD and 18% smaller than in PSP (P = 0.01). Mean pontine volume in MSA-P was 30% smaller than in PD or controls (P < 0.001) and 25% smaller than in PSP (P = 0.01). Motor disability was most strongly associated with midbrain volume, and more severe executive dysfunction was associated with reduced frontal volume. These distinct patterns of cortical and subcortical atrophy, when considered together rather than independently, better differentiate PSP and MSA-P from each other and also from healthy controls. © 2006 Movement Disorder Society