Symptoms of clinical intolerance during an acute levodopa challenge in relation to MSA

In this interesting research out of Argentina, the authors conclude that “symptoms of clinical intolerance during an acute levodopa challenge do not appear to be useful in the diagnosis of” multiple system atrophy (MSA).  The idea was to give patients levodopa (one brand name is Sinemet) to learn if they could differentiate between those with MSA and those with Parkinson’s Disease.  “Clinical intolerance” means nausea, vomiting, hypotension, and profuse perspiration.

The abstract is copied below.

Robin

——————-

Int J Neurosci. 2009;119(12):2257-61.

Does clinical intolerance to a diagnostic acute levodopa challenge differentiate multiple system atrophy from pd?

Estévez S, Perez-Lloret S, Merello M.
Movement Disorders Section, Raúl Carrea Institute for Neurological Research (FLENI), Buenos Aires, Argentina.

BACKGROUND: The diagnosis of multiple system atrophy (MSA) remains challenging.

OBJECTIVE: To determine if the occurrence of symptoms of clinical intolerance such as nausea, vomiting, hypotension, and profuse perspiration during a standard acute levodopa challenge may be a useful marker of MSA.

METHODS: A total of 507 dopaminergic acute challenge tests performed for different purposes in the last 10 years in a movement disorders clinic were reviewed, identifying patients who manifested symptoms of clinical intolerance during test performance. Only those tests completed for diagnostic purposes were included and these were matched by the presence or absence of response to levodopa, sex, and age, with a group of patients undergoing acute challenge without any symptoms of clinical intolerance. Presumptive diagnosis for each patient was performed by means of accepted clinical criteria after a significant follow-up period. Only patients with a final diagnosis of Parkinson’s disease (PD) or MSA were analyzed.

RESULTS: Twenty-three out of the 507 patients (women: 50%) presented symptoms of clinical intolerance and received a final diagnosis of PD or MSA, and underwent further analysis. Four out the 23 patients with intolerance (17%) and one out the 16 patients from the control group (6%) were diagnosed as having MSA (Chi-square = 1.05, p = .3). Overall sensitivity and specificity of the presence of clinical intolerance to predict diagnosis of MSA were 80% (95%IC: 45%-100%) and 44% (95%CI: 27%-61%) respectively.

CONCLUSIONS: Symptoms of clinical intolerance during an acute levodopa challenge do not appear to be useful in the diagnosis of MSA.

PubMed ID #: 19916854  (see pubmed.gov for this abstract only)

PSP Research Update – Notes from Golbe Webinar (11/19/09)

I don’t know how many listened to tonight’s CurePSP webinar. Though it had been advertised as “PSP, CBD and MSA – Research for Dummies,” Dr. Golbe’s title slide made clear he was talking only about PSP. There was significant overlap with the last webinar (with Dr. Bordelon and Dr. Schellenberg) but I didn’t mind. I always like listening to Dr. Golbe because he is one of the top PSP experts in the world. Further, his explanations of complex topics are very clear.

I also appreciated the fact that all the CurePSP messages (from various staff members and Board members) were gone, and that the webinar was not pre-recorded. And I liked how the questions were handled this time around. (I do wish that we could improve the editing or even consider eliminating some of the duplicate questions that get asked at each webinar.)

I was rather busy typing notes and didn’t get a chance to ask any questions myself. And, when tonight’s moderator Kate was speaking, I couldn’t hear her so I missed a few of those questions.

Here are my notes from Dr. Golbe’s presentation, with a few comments of my own. (I’ve added headings.)

Robin

————

Topic – PSP Research for Dummies

Presenter – Lawrence Golbe, MD
Prof of Neurology, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ
Dir of Research and Clinical Affairs, CurePSP

The “for dummies” books are written for intelligent people. That’s how the talk is geared.

Most research in PSP is pretty molecular.

PSP SYMPTOMS

What does PSP stand for?
Progressive = tends to worsen with time
Supranuclear = not primarily in the “nuclei” (clusters of brain cells in the brain stem that control eye movement), but at higher (“supranuclear”) brain centers
Palsy = poor movement (in the case of the eyes)

Main features of PSP:
* balance: especially unheralded falls; 2/3 of people have this problem
* speech (“dysarthria”): these problems happen usually later in the disease; spastic speech; hypophonia can occur; ataxic speech – sounds like you are drunk
* swallowing: pneumonia is possible; the problem is with liquids (which is the hallmark of neurological disorders); gap in the seal between the throat and the windpipe
* slow movement (“bradykinesia”) and slow thought: parkinsonian symptom
* insufficient movement: person just sits there, without moving
* eye movement: sophisticated neurologist who knows how to look for this can detect this problem at even early stages; the issue is both up and down gaze, but especially down gaze
* “frontal” behavior: problems with prioritizing, abstraction, inhibiting behavior. With “frontal” behavior, people with PSP have serious complications given the balance problem and the swallowing problem. Those with PSP stuff their mouths. Those with PSP get up to

Balance:
* usually the first symptom
* irregular gait. Often a drunken gait.

Bradykinesia (slow, insufficient movement):
* resembles Parkinson’s disease
* some of it is actually “rigidity” or muscle stiffness (face, neck)
* makes it difficult to compensate for balance problem

Dysarthria:
* ataxic: irregular bursts of speech
* spastic: strained quality
* hypophonic: low volume
* PSP usually has at least two of these three speech problems
* can have constant “growling.” “Frontal” behavior symptom.

Dysphagia:
* first and worse with thin liquids
* aspiration common
* large piece of food in windpipe is not usually the problem

TAU

Tau protein acts as scaffolding:
* Tau microtubules stabilize the structure of brain cells (and the axon) and serve as “railroad tracks.”
* In PSP, tau protein isn’t working right. The cell breaks down, and stops working properly.*
* Neurofibrillary tangles (NFTs): hallmark of PSP in the brain
* What’s the chicken and what’s the egg? Do the tangled clumps of tau proteins serve a useful purpose? Probably just getting rid of the tangles won’t solve PSP.

CAUSES OF PSP – GENETICS

Is PSP inherited?
Very weakly hereditary: only about 1 in 100 patients has a relative with PSP

Intro to the H1 Haplotype:
H1 haplotype is the genetic marker for PSP. A haplotype is a string of genetic markers on a chromosome. In the case of PSP, this haplotype is on chromosome 17. This haplotype signals the presence of disease-causing mutation in or near that region.

H1 Haplotype (% of chromosomes in those with PSP): (Houlden et al, 2001)
H1: 94% of (chromosomes in those with) PSP; 92% of CBD; 77% of control
H2: 6% PSP; 8% CBD; 23% control
So…PSP has an over-representation of the H1 haplotype.
Could it be that the H2 haplotype is protective?

H1/H1 Genotype (% of individuals): (Houlden et al, 2001)
H1/H1: 88% (of individuals with) PSP, 84% CBD, 60% control
H1/H2: 12% PSP, 16% CBD, 34% control
H2/H2: 0 PSP, 0 CBD, 7% control
H1/H1 = getting an H1 haplotype from each parent

Tau alternative splicing: (Hardy)
There are four exons that have the code for microtubule binding.
In normal brains: 1:1 ratio of 3 repeat tau protein isoforms and 4 repeat tau protein isoforms
In PSP: 4 repeat tau is abnormally abundant

Tau isoforms expressed in NFTs in various disorders:
Mostly 4 repeat tau disorders: PSP, CBD, FTD with exon 10 mutations, Guadeloupean parkinsonism, AGD
Mostly 3 repeat tau disorders: Pick’s disease, myotonic dystrophy
3 and 4 tau equally: AD, FTD without exon 10 mutations, Parkinson-dementia complex of Guam, Postencephalitic parkinsonism

Conclusions:
* the H1/H1 genotype is nearly necessary but far from sufficient for PSP to develop
* PSP has an excess of 4-repeat tau protein, but the significance of that remains unclear
* one chromosome 17 with the H2 haplotype reduces PSP risk
* both chromosome 17s with the H2 haplotype reduce PSP risk even more
* what “conditions” the genetic effect?

MITOCHONDRIA

Mitochondrial Genetics in PSP:
* mitochondrion = energy factories of cells
* make energy from oxygen and sugar
* have their own genes kept apart from the cell’s main set of genes
* mitochondrial genes do not work properly in PSP, PD, AD, etc.
* it’s very hard to study mitochondrial genes. Is the function genetic or toxic?

CAUSES OF PSP – ENVIRONMENT

Cause of PSP: Environment?
* Not well-studied at all
* Dr. Litvan is studying this now
* Those with PSP are less well-educated. May mean more industrial exposure or exposure to toxins? (Dr. Golbe published a study about 20 years ago. A French study just published last month found the same thing: less well-educated.)
* Not a consistent finding: more farming. May mean more exposure to pesticides, fresh fruits/vegetables.
* Environmental toxins can damage mitochondria.

[Robin’s note: You can find the abstract of the French study posted here — http://forum.psp.org/viewtopic.php?t=8205 — or look it up on pubmed.gov using PubMed ID#19864660.]

CAUSES OF PSP – DIET

Cause of PSP: Diet?
* The just-published French study didn’t find anything diet-related.
* Guadeloupe cluster of PSP-like illness. Those with PSP-like disease on Guadeoupe have consumed more sweetsop and soursop fruit. This fruit has been found to harbor toxins that act on the mitochondria. (Caparros-Lefebvre et al, Lancet 1999) Mouse experiments are currently underway. Maybe we have something in our diet with a similar toxin? (You might see this fruit in a Jamaican restaurant.)
* Guam cluster of PSP-like illness. Dietary theory now discounted. Genetic theory being re-examined. Mainly one ethnic group on Guam who get this disease. The disease is dying out.

EXCITING DEVELOPMENTS IN PSP GENETICS

New, exciting developments in genetics of PSP:
* hereditary FTD-17 as a human genetic “model” of PSP. Mouse, fruit fly, zebrafish genetic models. These animals are given FTD-17. Convenient to study drugs in such animals.
* whole genome analysis produced four new (previously unsuspected) genetic factors (plus the tau gene) implicated in PSP. We are awaiting confirmation. If confirmed, the research should be published in early 2010. This analysis will suggest new biochemical pathways and drug targets.

MEDICATIONS AND TREATMENT FOR PSP

Medications for PSP:
* levodopa/carbidopa: might help
* amantadine: might help, even if
* antidepressants: can help with depression and behavioral abnormalities
* sedatives: can help with behavioral abnormalities
* bladder medications: useful
* constipation medications: useful

Constipation can be a side effect of amantadine and antidepressants.

Treatment of Dysarthria and Dysphagia:
* swallowing evaluation (especially a modified barium swallow study – an xray movie of swallowing) is helpful. This evaluation may recommend: thicken thin liquids; avoid tough, dry food; etc.
* speech therapy rarely helpful but worth a try
* amplifying devices often useful
* hand signs
* if patient can direct gaze downward, these might be useful: pointing boards and electronic typing devices. Stroke and brain injury rehab centers have experience with these boards and devices.

TREATMENT TRIALS

Nypta (medication):
* GSK3 beta inhibitor (prevents phosphorylation of tau protein)
* trial being organized; it will start in March 2010 in the US
* Noscira is manufacturer
* may slow progression and help symptoms

[Robin’s note: As reported a couple of weeks ago by Dr. Bordelon, UCLA is one of the trial sites for the Nypta trial.]

Davunetide (medication):
* trial being planned
* Allon is manufacturer
* administered by nasal spray
* may slow progression and help symptoms

[Robin’s note: UCSF is the lead site for this trial, whenever it gets kicked off.]

DBS (deep brain stimulation) of the PPN (pedunculopontine nucleus) for PSP: (Stefani, et al, Brain 2007)
* electrodes (stiff wire) are passed into the PPN of the brain
* Univ of Toronto is experimenting with this
* preliminary results are favorable but we’ll just have to see
* he thinks this may be unwieldy but since it’s one of the few treatments available, people may give it a try
* this will mainly help the balance problem

[Robin’s note: You can find general info on this CurePSP-funded study here — http://forum.psp.org/viewtopic.php?t=7733]

—————–

QUESTIONS AND ANSWERS (all answers were given by Dr. Golbe)
[Robin’s note: I’ve edited the questions, grouped together similar items, and added headings]

TREATMENTS
Question: Are there any clinical trials going on?

Answer: Besides the trials just mentioned, there are others that have been going on for some time.

One trial going on now of CoQ110 at Lahey Clinic in MA. There are other US sites where this trial is being conducted. Contact the CurePSP office to be referred to the Lahey Clinic researcher.

[Robin’s note: this is the first I heard that a CoQ10 trial is being conducted in other places in the US outside Lahey Clinic. I might’ve misunderstood this.]

The lithium trial is still going on but it has stopped recruiting. Most patients had severe side effects.

Dr. Litvan’s epidemiological study is ongoing. It’s not interventional.

Question: Does CoQ10 help any and what is it used for?

Answer: The German trial of CoQ10 (published in mid-2008) did show a benefit even though the treatment was only 6 weeks. The benefit seen was the amount of energy available in the brain was increased, as noted by a special scan. This needs to be confirmed.

[Robin’s note: You can find the abstract of the German study posted here — http://forum.psp.org/viewtopic.php?t=7334 — or look it up on pubmed.gov using PubMed ID#18464278.]

CoQ10 helps with overall brain energy and metabolism. It doesn’t really help symptoms.

Question: What evidence is there on the use of lithium to slow the progression of PSP and what are the associated risks? Does lithium work in the long term?

Answer: Unfortunately, lithium was not well-tolerated by the PSP population so we don’t know if it slows progression. There were many side effects: dizziness, nausea, etc. Lithium is not a realistic treatment for PSP.

Question: Has anyone looked at diet and micro-nutrients to reduce PSP symptoms? I am thinking of antioxidants.

Answer: Antioxidants have been tried in PSP without success.

Question: Are there any other possible treatments to slow the progression of PSP?

Answer: Nypta and Davunetide will be studied in 2010.

Question: Is there anyone who treats PSP with cord blood stem cells?

Answer: No.

We need to consider the goal of stem cell treatment. In PSP, many areas of the brain are affected (with many types of brain cells) so cell replacement therapy isn’t practical. Another issue is how can you get the replacement cells to form proper connections with other cells?

But maybe stem cells can be drug delivery vehicles: program a stem cell to make a drug. No one has gotten this far yet.

Question: Is there good news on the horizon?

Yes. In the past couple of years, there have been a lot of treatment trials in PSP, sponsored by drug companies and the NIH.

Question: What’s the difference between ubiquinone and ubiquinol?

Answer: I don’t know. Ubiquinone is CoQ10.

Question: [Robin’s note: Sorry but I didn’t hear the question. I think it was about the experimental drug Rember.]

Answer: Experts don’t think this works in Alzheimer’s Disease, and it hasn’t been tested for PSP.

[Robin’s note: If the question was about Rember, note that the manufacturer, TauRX in Singapore, has not been willing to supply this medication to be tested in PSP, despite the efforts of US-based researchers to initiate a trial.]

GENETICS STUDY AND SCREENING
Question: When will we see some concrete results from the PSP genetics study, and what kinds of follow-up studies are anticipated?

Answer: We’ll see the replication study results in December or January. Assuming the findings are confirmed, a paper will be published shortly thereafter.

There will be lots of follow-up studies: animal models utilizing the genes; how proteins are behaving and what they are interacting with; drug treatment screening. A “whole new world of research” will be opened up.

Question: What is it so important to confirm four new unsuspected genes?

Answer: This could help with new treatment.

Question: Are genetic screenings available to check for one’s chances of getting PSP?

Answer: No. Even checking for the presence of the H1 haplotype is not that useful.

STAGES AND SURVIVAL
Question: How long does it take for PSP to develop? How long prior to diagnosis has the disease been in place?

Answer: We don’t know for sure. The theory with most neurodegenerative diseases is that they’ve been going on for 5-10 years prior to symptoms appearing.

Question: Why is there such a difference in the survival times of PSP patients?

Answer: Actually, among PSP patients there is less variance in survival times than we see with PD. This may depend on one’s underlying health — how quickly you can fight off pneumonia and how quickly you can heal from injuries. May depend on how many genetic abnormalities you have.

Question: How long will I live after diagnosis?

Answer: No way to know for sure. Seems to be related to the skill and dedication of the caregiver.

Average survival after the first symptom appears is 7-8 years. Some people do better than this.

[Robin’s note: There’s no research evidence to support Dr. Golbe’s assertion that caregivers can influence survival time. It largely depends on what type of PSP you have, your gender, your age at onset, and the interval between disease onset and reaching the first clinical milestone. See, in particular, the “Clinical Outcomes” paper on this topic. At present, it is available for free here — http://brain.oxfordjournals.org/cgi/reprint/131/5/1362]

Question: How can I tell what stage I’m in?

Answer: See the PSP Rating Scale on psp.org. It is a prediction of future survival. There is a margin of error.

[Robin’s note: Dr. Golbe authored the rating scale several years ago. You can find it here — https://www.psp.org/materials/rating_scale.pdf

See this post about an article on interpreting the scale — http://forum.psp.org/viewtopic.php?t=2468]

SYMPTOMS
Question: Is the eye movement problem = downbeat nystagmus?

Answer: [Sorry, I didn’t hear the answer but I’m pretty sure he said “no.” I don’t think there is such a thing as “downbeat nystagmus.” There is downward gaze palsy in PSP and nystagmus.]

Question: Is the eye palsy always downwards?

Answer: No, it can start out upwards. Upward gaze palsy is common among the elderly.

Question: What physiologically causes the stiffness in the neck? Any treatment for this?

Answer: There is no research on this. There’s not even an informal recommendation on this.

Botox can be used for neck stiffness. Botox must be injected cautiously.

Question: Can hunching over occur in PSP?

Answer: Usually there is a very erect posture or a backwards posture. But the majority of PSP patients hunch forward and even sideways (“scoliosis”).

Question: Do you find that a low dose of Prozac can help the spastic speech and dysphagia in PSP?

Answer: I haven’t heard of this.

Question: We are using Seroquel for restlessness and Ambien for sleep. Should my loved one be sleeping/resting more? Are there better choices of drugs?

Answer: Sleep problems in PSP can worsen. Talk to your MD about medications.

PSP VS. CBD
Question: What’s the key difference between PSP and CBD?

Answer: PSP – mostly a disorder of balance (worst problem); symmetric

CBD – balance is not that big of a problem; mostly a problem of the use of limbs; very asymmetric (one side affected much worse than the other side; eventually both sides are affected); apraxia (limb loses the ability to perform a task that has been practiced in the past, such as saluting); issue with perceiving spatial concepts (eg, tracing a number on the palm)

PROTEINS
Question: What is the relationship between alpha-synuclein and tau, and the effect on them by hsp70?

Answer: Alpha-synuclein is associated with Parkinson’s Disease. AS is to PD as tau is to PSP. Complicated: it was recently discovered that in PD there can be a problem with tau. And the H1 haplotype is more common in PD than in normal controls.

hsp70 (heat shock protein 70) is a chaperone protein. They regulate the activity of other proteins. hsp70 help blobs of protein from forming. He can’t speak to the relevance of hsp70 as a treatment in PSP.

[Robin’s note: You can read about the University of South Florida study in mice here — http://forum.psp.org/viewtopic.php?t=8178]

RESEARCH
Question: My husband has been diagnosed with MSA. But PSP now sounds like a possibility. Should we spend more money/effort to study neurodegenerative disorders in general or does specificity help?

Answer: Lots of research is applicable to all neurodegenerative diseases.

OTHER
Question: Is there a connection between PSP and MS (multiple sclerosis)?

Answer: No. MS is an immune disorder. This doesn’t happen in PSP. MS is a disease of the cells that insulate the axons. MS isn’t primarily a disease of brain cell breakdown.

Question: I had a DNA test done and was diagnosed with SCA3. Is it possible that I could also have other forms of a movement disorder? Should I get tested for all disorders?

Answer: SCA3 is a completely different disease.

Question: Is cerebellar ataxia a type of PSP? Is PSP a type of Parkinson’s? Is SCA a type of PSP?

Answer: No (to all three questions).

Cerebellar ataxia is a collection of symptoms related to the cerebellum.

Planning for the End of Life: The Role of Hospice in PD Care

This new two-page Parkinson’s Disease Foundation publication was mentioned today during the “Care for the Caregiver” webinar. Though the title refers to PD and PDF is the publisher, I don’t think there’s anything here that is PD-specific. I especially liked the section on “How Should Hospice be Discussed with a Loved One?” though I thought it was too brief. I also liked the list of “Questions to Ask When Considering Hospice” but felt that some suggestions should’ve been provided for each question.

One note: it’s mentioned below that private health insurance may provide hospice benefits. Many insurance companies limit hospice benefits to a lifetime maximum of 6 months. One CBD family I know of in Arizona exhausted that benefit. Fortunately a non-profit hospice agency is providing free hospice care to this family.

http://www.pdf.org/pdf/fs_parkinson_rol … ice_09.pdf

Planning for the End of Life: The Role of Hospice in Parkinson’s Disease Care
Parkinson’s Disease Foundation
Fact Sheet, 2009

As Parkinson’s disease (PD) progresses into the advanced stages, its symptoms can often become increasingly difficult to manage. The daily care needs for a person with PD may overwhelm the family caregiver’s physical, mental and emotional capabilities and require more help than the caregiver alone can provide.

In such situations, hospice can be an option. Although hospice is often associated with a terminal disease such as cancer, it is an option for individuals with chronic diseases, such as PD. Hospice can provide services and support with the goal of providing a quality, peaceful death while allowing the person with PD to stay in a familiar environment.

What is Hospice?
Hospice is a program of care designed to improve quality of life through pain relief and symptom management for individuals who are
facing the end of life. It can also provide valuable caregiver and family support with bereavement services for up to 11 months after the death of a loved one.

What Benefits Will Hospice Provide for a Person and Family Living with Parkinson’s Disease?

Hospice care is provided through home care agencies or in a facility (nursing home or hospice facility). Home hospice services are the most common type of hospice service used by a person with Parkinson’s and offer the opportunity for the individual to remain at home during his or her last days and months of life surrounded by friends and family.

Hospice care provides a person with PD, his or her caregiver and family with health care providers who have expertise in the complex dying process. The core home hospice staff is comprised of a physician, nurse, social worker and home health aides. Other personnel may include physical, occupational and speech therapists, and pastoral services.

Hospice may also provide durable medical equipment, medical supplies,medications and counseling. Other services may be provided depending on the needs of the person with PD and the structure of the home hospice agency.

When is the Right Time for Hospice?
Determining when the time is right to consider hospice services can be a difficult decision for the person with Parkinson’s, their family and health care providers. Parkinson’s, while a chronic and progressive disease, has a course that can be uncertain with no clear indication of the end of life. Yet, those with PD often have additional significant medical problems — such as advanced dementia,
recurrent pneumonia, weight loss, urinary incontinence, infections and pain — that could be better managed through hospice.

Current Medicare benefit guidelines ask health care providers to project that an individual has six months or less to live to enroll in
Medicare reimbursed hospice programs. However, many individuals live beyond six months while enrolled in hospice. At the end of the initial six-month period, the hospice agency will reevaluate the care plan and needs of the person with Parkinson’s and either reenroll the individual for an additional three months or discharge the individual from hospice. Patients are discharged from hospice if the individual improves and doesn’t meet the criteria any longer.

How Should Hospice be Discussed with a Loved One?
There are four parties involved in enrolling a person in hospice and managing end-of-life care: the family/caregivers, the person with Parkinson’s, the hospice agency and the health care provider.

Hospice often has negative associations for individuals and is thought to be a sign of “giving up” or accepting “no hope.” Overcoming these negative associations is an important first step in having the conversation about the benefits of end-of-life care in hospice. Discussing end-of-life issues is difficult and often avoided. As part of the care team, individuals with PD, caregivers, and health care providers can participate equally in ongoing discussions about planning for end-of-life care.

How Does One Pay For Hospice?
Private health insurance may provide hospice benefits. Medicare does provide hospice coverage. More information on Medicare hospice benefits can be found at http://www.medicare.gov/publications/Pubs/pdf/02154.pdf.

What is the Application Process for Home Hospice Services?
Physicians initiate the enrollment process for a person with PD by making a referral to a hospice agency. Families can have input in the selection of the hospice agency by getting recommendations from outside resources (i.e., support groups) or by researching local hospices. The National Association of Home Care and Hospice provides information on how to locate hospice services at www.nahc.org/home.html.

Once the doctor has sent a referral to the hospice agency, a hospice nurse will come to the home for an initial assessment to determine if the person with PD is eligible for hospice. If the individual qualifies, he or she will be evaluated for their specific needs,
types of services, frequency of care and equipment.

Is Hospice the Only Option?
Not all people with Parkinson’s will decide to enroll in a hospice program for end-of-life care. There are alternatives to hospice. Persons with PD and caregivers who are not ready for hospice services but who need assistance with care might consider respite services, nursing home placement or home health aides to assist with care.

Respite care is a temporary care service that provides patients with care based on his or her needs and allows a break for the caregiver. Nursing homes or assisted living facilities may offer respite services. Often a caregiver uses this time for his or her own health care or to visit family members or friends that live at a distance. Nursing home placement is an option for persons who need full-time care that the caregiver or family is not able to provide in the home.

Questions to Ask When Considering Hospice:
1. Does the person with PD understand his or her prognosis and health care needs?
2. Does the person with PD want to remain at home until the end of life?
3. Has the family, caregiver and person with PD discussed long-term care options?
4. Has the person’s health care provider been consulted in planning for end­of-life care?
5. Is there a living will and/or power of attorney in place for the person with PD?
6. If the person with PD is unable to communicate their wishes for end-of-life care, can someone represent their wishes for end-of-life care?
7. How much does the person with PD know about hospice and how does he or she feel about it?
8. Does the person with PD have insurance or is he or she Medicare-eligible for hospice care?
9. What other resources can be used to ease caregiver burden?

Eileen Hummel, R.N., B.S.N., and HeidiWatson, R.N., B.S.N., are Clinical Nurse Coordinators at the Philadelphia VA PADRECC (Parkinson’s Disease Research, Education and Clinical Center). This fact sheet has been reviewed by Lisette Bunting-Perry, M.Sc.N., R.N., Assistant Clinical Director, PADRECC and Barbara Habermann, Ph.D., R.N.,Associate Professor, Indiana University.

To find additional resources for managing advanced Parkinson’s disease, visit www.pdf.org/en/resourcelink or order a copy of PDF’s Parkinson’s Disease Resource List at (800) 457-6676 or www.pdf.org/en/brochures.

If you have or believe you have Parkinson’s disease, then promptly consult a physician and follow your physician’s advice.
This publication is not a substitute for a physician’s diagnosis of Parkinson’s disease or for a physician’s prescription of drugs, treatment or operations for Parkinson’s disease.

Advance Directives – Link to Neurology Now Article and Robin’s Resources

The latest issue of Neurology Now magazine has a good article on advance directives.  If you are reading this email, you should have advance directives for yourself and any adult you may be caring for!

We are lucky in California that our state accepts the POLST form. This is the form that anyone with a neurodegenerative disorder should have filled out.  You can find info on the POLST form here:

POLST:
polst.org

POLST form for CA:
[Editor’s note:  the CA POLST form can be found at capolst.org]

If you live in California and don’t have a neurodegenerative disorder, you should consider completing this form:

Info on the California Medical Association (CMA) Advance Health Care Directive Kit:
www.cmanet.org/publicdoc.cfm?docid=7&parentid=4

Another resource I like a lot, which is not mentioned in this article below, is:

Five Wishes from Aging with Dignity:  (cost is $5)
www.fivewishes.org/

Many people (including myself) have completed the “Five Wishes” document, have added it to our living will, and have given it to our healthcare power of attorneys.

Here’s a link to the “Neurology Now” (neurologynow.com) article on advance directives:

neurologynow.com/pt/re/neuronow/fulltext.01222928-200905050-00026.htm

Get It in Writing!
Advance directives give you control over your health care.
by Lisa Phillips
Neurology Now, Volume 5(5), September/October 2009, p 35-36

Dealing with anosognosia (unawareness of decline)

AlzOnline.net is a caregiver support forum for Alzheimer’s caregivers. They have an interesting article on their website about anosognosia, which is a lack of self-awareness about one’s decline or condition. The best part of the article are “examples of how to approach, interact and speak to someone who has anosognia.”

Here’s the summary from the article: “The person who has anosognosia is unaware of deficits or the progressive decline in abilities to manage tasks and self-care. The person with anosognosia is not in denial; they have limited awareness or are unaware of the decline. When people with anosognosia confabulate, they believe what they are saying; they are not lying. Their remarks should be treated with respect, followed by a smooth transition to whatever tasks or activities need to occur next. Regular help for the home and family, planning ahead and working with a positive, partnership approach will help with the long-term, daily care management.”

Here’s a link to the full article and some additional excerpts.

http://alzonline.phhp.ufl.edu/en/readin … gnosia.pdf

“A lack of awareness of impairment, not knowing that a deficit or illness exists, in memory or other function is called anosognosia. The term anosognosia refers to brain cell changes that lead to a lack of self-awareness. … The impairment may be in memory, other thinking skills, emotion, or movement.”

“Anosognosia differs from denial. Denial is a strategy used to reject something that a person wants to ignore, partially avoid, or reject outright because it is too difficult or causes too much stress. The person may minimize a problem or accept part of the truth, for example, the person may accept the fact of being chronically ill but want to avoid dealing with it by not taking medicine. Sometimes a person is in denial in order to avoid taking any responsibility for an issue or situation. Anosognosia is not denial.”

“Anosognosia may occur in different progressive memory disorders. Often the progressive dementia (sometimes referred to as a progressive memory disorder) is of the Alzheimer’s disease type, sometimes it fits into the category of Lewy body disease or a frontal-temporal lobar degeneration.”

“Interaction Tips
Providing regular assistance with daily chores, transportation, and personal care and restricting unsafe activities are important. For example, someone may need to make sure that meals are readily available, that spoiled food is discarded, and that alcoholic beverages are not accessible. The controls for operating the stove and water heater should be inaccessible. Someone should be responsible for setting the home thermostat at an appropriate temperature and then locking the thermostat so that the person who is not accurately interpreting body temperature cannot reset the room temperature at too high or too low. Soiled clothing should be laundered immediately or kept unavailable (out of sight ­ out of mind) until the clothing is clean.”

“The Checklist for Family Matters, located at www.AlzOnline.net is a useful tool to help families with planning for long-term care management. Regular respite for the family caregiver(s) is essential!”

“Examples of how to approach, interact and speak to someone who has anosognosia:

1. Down-size and decrease unnecessary chores and responsibilities.

Use a positive approach, such as, “It is time to plan ahead about moving to a retirement community where there are kind people and some of your friends so you have more time to do what you like, such as read and go for a walk every morning.”

Don’t use a negative approach, such as, “This house and yard are too much work for all of us. It is hard for you to take care of the house, the yard, and yourself. You need to move to a place where people are always around to help you.”

2. Partner with the person.

Use a positive approach, such as, “Let’s work together on the front porch, then go out for a nice dinner.”

Don’t use a negative approach, such as, “You really need to clean up that mess of old magazines, newspapers and piles of trash on the front porch.”

3. Focus on the person’s concern and subtly include your concern.

Use a positive approach, such as, “When you take this multi-vitamin, how about taking these “brain-vitamins” that the doctor prescribed to keep your memory strong?”

Don’t use a negative approach, such as, “The doctor prescribed these pills and you have to take them every morning.”

4. A gentle, positive voice should be part of a positive empathic approach.

Use a positive approach, such as, “To keep up with these bills, we should work as a team. I will come over on Saturday mornings with your favorite breakfast and we will write out the checks together. After you sign the checks, we will put them in their envelopes and take them to the mailbox.”

Don’t use a negative approach, such as, “You have to pay these bills on time. The utility companies have sent notices threatening to shut off the gas and electricity. I’ll handle the bills from now on.”

5. Provide available assistance and a structured schedule of tasks including personal care, activities including chores and leisure
activities, and “down-time” including a favorite activity or no activity.

Use a positive approach, such as, “After we walk the dog, we will finish the laundry and then sit down for some of that applesauce I cooked this morning.”

Don’t use a negative approach, such as, “There is so much to do? What do you want to do this morning? We have to walk the dog, finish the laundry, and clean the kitchen. The work really piles up fast around here.”

Checklist on Family Matters

This helpful “Checklist on Family Matters” allows families to review:

  • legal matters, such as durable power of attorney
  • family business, such as regular business, emergency plans, bank accounts, etc.
  • insurance
  • supervision of patient, including identity bracelet, safety locks on doors, etc.
  • items in the event of death, such as cemetery lot deed, funeral arrangements, etc.

Find it online here:

alzonline.phhp.ufl.edu/en/reading/CHECKLIST.pdf

Checklist on Family Matters
by L. Doty, University of Florida Memory Disorders Clinic
AlzOnline.net
2006?

This seems like an easy-to-use tool for a family discussion.

Robin

 

Dealing with anosognosia (unawareness of decline or difficulties)

AlzOnline.net is a caregiver support forum for Alzheimer’s caregivers.  They have an interesting article on their website about anosognosia, which is a lack of self-awareness about one’s decline or condition.  The best part of the article are “examples of how to approach, interact and speak to someone who has anosognia.”

Here’s the summary from the article:

“The person who has anosognosia is unaware of deficits or the progressive decline in abilities to manage tasks and self-care. The person with anosognosia is not in denial; they have limited awareness or are unaware of the decline. When people with anosognosia confabulate, they believe what they are saying; they are not lying. Their remarks should be treated with respect, followed by a smooth transition to whatever tasks or activities need to occur next. Regular help for the home and family, planning ahead and working with a positive, partnership approach will help with the long-term, daily care management.”

Here’s a link to the full article:

alzonline.phhp.ufl.edu/en/reading/Anosognosia.pdf

Anosognosia (Unawareness of Decline or Difficulties)
By Leilani Doty, PhD, Director, University of Florida Cognitive & Memory Disorder Clinics (MDC), McKnight Brain Institute
AlzOnline.net
2007

Below, I’ve provided a few more excerpts.  This article is definitely worth checking out!

Robin


Excerpts from
Anosognosia (Unawareness of Decline or Difficulties)
By Leilani Doty, PhD, Director, University of Florida Cognitive & Memory Disorder Clinics (MDC), McKnight Brain Institute
AlzOnline.net
2007

“A lack of awareness of impairment, not knowing that a deficit or illness exists, in memory or other function is called anosognosia. The term anosognosia refers to brain cell changes that lead to a lack of self-awareness. … The impairment may be in memory, other thinking skills, emotion, or movement.”

“Anosognosia differs from denial. Denial is a strategy used to reject something that a person wants to ignore, partially avoid, or reject outright because it is too difficult or causes too much stress. The person may minimize a problem or accept part of the truth, for example, the person may accept the fact of being chronically ill but want to avoid dealing with it by not taking medicine. Sometimes a person is in denial in order to avoid taking any responsibility for an issue or situation. Anosognosia is not denial.”

“Anosognosia may occur in different progressive memory disorders. Often the progressive dementia (sometimes referred to as a progressive memory disorder) is of the Alzheimer’s disease type, sometimes it fits into the category of Lewy body disease or a frontal-temporal lobar degeneration.”

“Interaction Tips
Providing regular assistance with daily chores, transportation, and personal care and restricting unsafe activities are important. For example, someone may need to make sure that meals are readily available, that spoiled food is discarded, and that alcoholic beverages are not accessible. The controls for operating the stove and water heater should be inaccessible. Someone should be responsible for setting the home thermostat at an appropriate temperature and then locking the thermostat so that the person who is not accurately interpreting body temperature cannot reset the room temperature at too high or too low. Soiled clothing should be laundered immediately or kept unavailable (out of sight – out of mind) until the clothing is clean.”

“Examples of how to approach, interact and speak to someone who has anosognosia:

1. Down-size and decrease unnecessary chores and responsibilities.

Use a positive approach, such as, “It is time to plan ahead about moving to a retirement community where there are kind people and some of your friends so you have more time to do what you like, such as read and go for a walk every morning.”

Don’t use a negative approach, such as, “This house and yard are too much work for all of us. It is hard for you to take care of the house, the yard, and yourself. You need to move to a place where people are always around to help you.”

2. Partner with the person.

Use a positive approach, such as, “Let’s work together on the front porch, then go out for a nice dinner.”

Don’t use a negative approach, such as, “You really need to clean up that mess of old magazines, newspapers and piles of trash on the front porch.”

3. Focus on the person’s concern and subtly include your concern.

Use a positive approach, such as, “When you take this multi-vitamin, how about taking these “brain-vitamins” that the doctor prescribed to keep your memory strong?”

Don’t use a negative approach, such as, “The doctor prescribed these pills and you have to take them every morning.”

4. A gentle, positive voice should be part of a positive empathic approach.

Use a positive approach, such as, “To keep up with these bills, we should work as a team. I will come over on Saturday mornings with your favorite breakfast and we will write out the checks together. After you sign the checks, we will put them in their envelopes and take them to the mailbox.”

Don’t use a negative approach, such as, “You have to pay these bills on time. The utility companies have sent notices threatening to shut off the gas and electricity. I’ll handle the bills from now on.”

5. Provide available assistance and a structured schedule of tasks including personal care, activities including chores and leisure
activities, and “down-time” including a favorite activity or no activity.

Use a positive approach, such as, “After we walk the dog, we will finish the laundry and then sit down for some of that applesauce I cooked this morning.”

Don’t use a negative approach, such as, “There is so much to do? What do you want to do this morning? We have to walk the dog, finish the laundry, and clean the kitchen. The work really piles up fast around here.”

 

Anticipatory Caregiver Grief- Nov 09

I attended a local Parkinson’s Disease caregivers support group meeting a few months ago. The group leader handed out this Dear Abby column on anticipatory caregiver grief (dated 9/24/09).
Robin

http://www.uexpress.com/dearabby/?uc_full_date=20090924

CAREGIVER’S GRIEF BEGAN LONG BEFORE HER HUSBAND’S DEATH

DEAR ABBY: I am responding to “Alone But Happy in Canada” (July 12), who feels guilty because she feels relieved following the death of her husband from a long, difficult illness.

Everyone grieves differently, but I don’t think grieving a loved one’s loss BEFORE his or her death is uncommon. I’ve known several people who watched loved ones wither away into helpless, needy and miserable individuals. I can’t think of one who didn’t feel the same as “Alone But Happy.”

I have begun referring to it as “grieve-as-you-go guilt.” A person grieves through the decline and eventual demise of a beloved mate, and when she fails to feel sadness, she substitutes guilt where she believes her grief should be. But actually she has been grieving all along, and needs to acknowledge that fact. Only then will she be able to enjoy not only her clean house, but her clear conscience as well. — AZY IN WASHINGTON

DEAR AZY: You have keen insight. Other readers wrote wanting to offer reassurance to “Alone But Happy.” Read on:

DEAR ABBY: Your answer to “Alone” was appreciated by all caregivers, I’m sure. Nobody knows, unless they have walked that particular path, how difficult and lonely it is to watch a spouse disappear over a long time, losing the history you share together, making hard decisions alone, and rebuilding an identity not tied to the past. Every morning brings a new bout of grief from the moment of wakening — every day another day you don’t want to face.

Keeping healthy and planning ahead for yourself, not as a caregiver but as a participant in the “real world,” is the only way to maintain sanity sometimes. Though I love my husband dearly, I look forward to having a life again that is not centered on his disease. No one should be made to feel guilty for restarting life when he or she has given so much. — DAY AT A TIME

DEAR ABBY: I also lost my husband of 35 years just a month ago. He endured several years of health problems and as his caregiver, I, too, felt a great sense of relief with his passing. I do not, however, feel guilty about it.

I realize that I have been grieving for several years already, as I knew this time would be coming. In many ways it is as if I am in the final stage of the process even though my husband’s death has only just occurred.

Our son put it best when he said at my husband’s bedside, “I lost my dad several years ago, but my father died tonight.” He, too, understands that his grief began a long time ago. — MOVING FORWARD

DEAR ABBY: Having to put another person’s needs and wants before one’s own can be very stressful. Not everyone is able to do that and stay pleasant and patient at all times. Fortunately, I found a local caregivers’ support group. Our weekly meetings help us see that we are not alone in experiencing the trials and tribulations of family caregiving.

For those who are laboring to do their best for their sick or disabled loved ones, let me suggest they find a Senior Information and Assistance office in their area. Another resource is the National Family Caregivers Association (www.thefamilycaregiver.org; phone (800) 896-3650). These may be helpful in allowing caregivers mental and physical relief by connecting them with hourly in-home care services.

It is important that people experiencing this kind of stress get respite time to themselves, away from their care recipient, in order to be able to keep on helping them. — ONE OF THE MANY

Dear Abby is written by Abigail Van Buren, also known as Jeanne Phillips, and was founded by her mother, Pauline Phillips. Write Dear Abby at www.DearAbby.com or P.O. Box 69440, Los Angeles, CA 90069.

Dr. Bordelon’s webinar (11/5/09) – Notes

Last Thursday’s (11/5/09) CurePSP webinar with Dr. Yvette Bordelon was definitely a winner! Not only was the speaker excellent but the material covered has not been made available to laypeople by an expert in the field in this consolidated manner previously.

I had two issues with the content of Dr. Bordelon’s presentation: she seems relatively uninformed about the davunetide (NAP) study in PSP and CBD, and about the Azilect study in MSA-P.

I appreciate the fact that the CurePSP introductory information was completely different from the previous webinars. This certainly makes the repeat of the fundraising message in the middle of the webinar far more tolerable.

One item of improvement to the webinars overall remains on my wish list since the Hermanowicz webinar in early October: the questions given during the Q&A need to be consolidated and massaged. It is so frustrating to hear questions brought up along the lines of “what treatments are available now,” when the speaker just covered that very question. CurePSP needs a totally different approach to the Q&A section.

Also, while I thought the Schellenberg info on the genetics in PSP and CBD was great to hear, it really warranted it’s own (shorter) webinar and, of course, was not relevant to the MSA attendees. (I have posted my Schellenberg notes separately.)

What follows are my notes on Dr. Bordelon’s presentation and the Q&A session following. As this is being posted to PSP and CBD online groups, I’ve maintained the info on PSP and CBD, and shortened the info on MSA. I’ve added lots of my own notes, especially about the various trials underway and in the pipeline. I’ve added some headings, and re-organized the Q&A section.

Robin

Yvette Bordelon
Neurologist and Movement Disorder Specialist at UCLA
Her clinical research is focused on biomarkers.

Translational research: how does lab research (“bench research”) get translated into the clinical setting?

Research pipeline:
In the lab: basic science; pre-clinical trials in animals
In the clinic: clinical trials
The outcome of all of this research are new treatments

CAUSES

Determine causes:
Who is affected
What is the pathology
When does it begin
Where is the pathology
Why does it occur and what are the consequences

Who and when:
PSP: 6 per 100K prevalence; average age of onset is mid-60s
CBD: 4-5 per 100K; average age of onset is mid-60s
MSA: 3-4 per 100K; average age of onset is early 50s
For comparison, PD: 500 per 100K; average age of onset late 50s

[Robin’s note: I could believe 1-2 per 100K for CBD, but not 4-5, especially when that’s higher than MSA. I think Dr. Golbe said CBD prevalence hadn’t been studied so I’m curious as to the source of Dr. Bordelon’s figures.]

These are disorders of abnormal protein accumulation in the brain. In all neurodegenerative disorders there is cell loss in the brain.

PATHOLOGY

What is the pathology:
PSP and CBD: tau protein
MSA: alpha-synuclein protein
Alzheimer’s Disease: tau protein and amyloid protein
Parkinson’s Disease: alpha-synuclein protein

Where: the location and type of protein that accumulates determines the disease. Parkinsonism symptoms are produced in the brain when there is protein accumulation in the brain stem and basal ganglia.

PSP: some places where tau accumulates are the brain stem, basal ganglia, the frontal lobe (cortex), and the cerebellum. (Frontal lobe pathology may lead to issues with multi-tasking, higher level cognitive functions, and apathy. Cerebellum pathology leads to issues with balance.)

CBD: some places where tau accumulates are the brain stem (a much smaller area compared to PSP), basal ganglia, and the cortex (a much larger area compared to PSP and a different area than PSP; the parietal area of the cortex is affected). The pathology in CBD is asymmetric – one side of the brain is more affected than the other side. This is why one side of the body usually has more symptoms initially than the other side. (The parietal area corresponds to how we figure out how to do things. This is why apraxia is a problem in CBD.)

MSA: some places where alpha-synuclein accumulates are the brain stem (a much larger area than PSP and different areas than PSP), basal ganglia, and the cerebellum (a much larger area compared to PSP). One area of the brain stem affected in MSA is called the pons. Ataxia or difficulty walking and balance problems are related to pathology in the pons and cerebellum. Other brain stem areas are responsible for blood pressure control and other symptoms we see with MSA.

RISK FACTORS

Why: identification of risk factors for these three disorders
Genes: we think that genes contribute to this
Environmental exposure or experience in general: play a large role
The overlap or interaction between genes and the environment is where the true risk factors lie.
There are other risk factors yet to be determined.

Consequences:
* sticky proteins: clumps; accumulation
* clearance problem: the cell can’t get rid of the sticky proteins
* further consequences: decreased energy stores (mitochondria are sick or diseased); inflammation (inflammatory cells invade the brain; these cells secrete cytokines or other proteins that may be toxic); cell death (neurons die)

Genetic causes of PSP and CBD:
* The only genetically confirmed finding from research: certain version of tau (the H1 haplotype) confer a greater risk in PSP and CBD. In those with PSP and CBD, the H1:H2 ratio is 3:1. In the general population, there is a 1:1 ratio.
* Direct inheritance of any atypical parkinsonian syndrome is extremely rare. But there have been isolated cases of families where tau, parkin, or LRRK2 genetic mutations in PSP are inherited. Examining these isolated cases helps us determine causes.

Ongoing genetics research:
* Genes that make someone susceptible (a) in combination with other genes, and (b) in certain situations (given environmental exposure)
* Example of PD: if someone has pesticide exposure and a gene that causes them to metabolize these toxins more slowly, their risk of developing PD is increased
* There are genome-wide screens going on for all these diseases

Clusters of diseases can guide our research into environmental risk factors. Two PSP clusters are:
* Atypical parkinsonism of Guadeloupe. Linked to the ingestion of pawpaw fruit and boldo tea, which contain a high level of toxins. Most of these patients with this exposure have the H1 haplotype. Double typical prevalence of PSP. This is an example of the interplay of genetics and the environment.
* Lytico-Bodig disease (aka, Parkinsonism-dementia complex of Guam). No definitive environmental exposure identified yet. Possible exposures are: guano from the fruit bat, cycad seeds (ingested by the bat), and aluminum

RISK FACTORS – CLINICAL TRIALS

Two clinical trials are underway to identify risk factors:

#1: PSP – “Genetic and Environmental Risk Factors,” organized by Dr. Irene Litvan. 12 sites in the US (including UCLA and the Univ of Washington in Seattle) and 1 site in Canada. (For a complete list of sites, see pspstudy.com.)

This study wants to enroll 500 PSP patients and 1000 controls. More participants are needed! If the study does not meet its recruitment goal, the data may not reach statistical significance. Further, the study may not be eligible for continued NIH funding if recruitment remains low.

Patient requirements: clinically diagnosed PSP; 40 years of age or older; able to participate in a 25-40 minute phone interview; can visit one of the screening sites; no other major neurological disorders. Note: patients are no longer required to bring two healthy controls into the study with them.

Study involves: neurologic exam, past history, blood draw for genetics research, consideration of brain donation.

Contact the study team directly: pspstudy.com, phone 866-PSP-0448

#2: PSP and MSA – “Neuroprotection and Natural History in Parkinson’s Plus Syndromes,” NNIPPS, Dr. Peter Leigh (UK). 44 sites in Europe (UK, Germany and France).

[Robin’s note: I first learned about NNIPPS in June, and may’ve posted about it at that time. This 3-year longitudinal natural history study is attempting to establish a database of early diagnostic criteria. I believe the study is limited to PSP and MSA; I don’t think CBD is included. The NNIPPS study group is the team that already investigated the use of riluzole in PSP and MSA.]

GENOME WIDE SCREENS

Genome wide screens:
* Search for genes in all patients with these disorders
* These screens are happening in the ongoing observational studies
* PSP and CBD: One specific genome-wide screen that is taking place is the Peebler PSP and CBD Genetics Program, headed by Dr. Jerry Schellenberg, involving researchers in the US, UK, and Germany.
* These screens will contribute to our understanding of the genetics and environmental factors with these disorders

PROTEIN ACCUMULATION

Tau protein accumulation in PSP and CBD:
Tau becomes modified (hyperphosphorylated), making it sticky. This clumps. Accumulates in brain cells called neurons and other cells; these accumulations or clumps are called “tangles.” Tau loses its usual beneficial effect of strengthening the neuron. These accumulations lead to cell death.

One reason protein accumulation in the brain occurs is because the machinery to dispose of the garbage protein is dysfunctional. Autophagy does not occur.

Downstream consequences:
* Loss of cellular energy supplies due to the generation of free radicals (or oxidants) that attack the mitochondria, making it dysfunctional. (The free radicals are generated in reaction to the clumped protein.) With dysfunctional mitochondria, the cells cannot keep up its energy supplies.
* Neuroinflammation. Microglial cells are indicators of inflammation.
* Eventual cell death.

ANIMAL MODELS

Animal model research:
* Animal models increase our understanding of the causes of disease: genes, toxins and pathways are identified
* Screen for possible treatments: pre-clinical trials
* PSP and CBD: expression of tau mutation in mice
* MSA: over-expression of alpha-synuclein in mice. There is even a model that specifically allows over-expression of alpha-synuclein in oligodendroglial cells (the support cells).
* We don’t have adequate biomarkers of these diseases, which is why we need animal models.

BIOMARKERS

Biomarkers: biological characteristics that are objectively measured that indicate the pathogenic cause of a disease or a pharmacological process (treatment of disease). Examples: lab tests, brain imaging. These lead to earlier disease detection. They are a “window into the brain.” Ideally, biomarkers can serve as a substitute for a clinically meaningful endpoint that delays or stops disease and will predict clinical benefit. Biomarkers would optimize clinical trials: trials would be shorter (weeks/months rather than months/years) and more effective.

Brain MRI is an effective biomarker. Brain MRI can possibly reveal focal brainstem atrophy (volume loss) in atypical parkinsonism syndromes. The MRI examples shown were for PD, PSP, and MSA. (Oba, et al, Neurology 2005)

[Robin’s note: the Oba 2005 abstract is one of the first I ever circulated to online support groups. You can find the abstract on pubmed.gov, for free, using PubMed ID# 15985570. The authors’ conclusion was: “The area of the midbrain on mid-sagittal MRI can differentiate PSP from PD, MSA-P, and normal aging.”]

Another biomarker: measuring MRI focal atrophy over time. The NNIPPS study found that the rate of midbrain atrophy in PSP is 7x faster than controls while the rate of pontine atrophy in MSA is 20x faster than controls.

[Robin’s note: This data comes from a 2007 article published by Pavouir, et al.]

Another biomarker: PET (positron emission tomography) scans. PET scans allow for functional imaging; they show how the brain works (metabolism). In the CBD PET scan shown, one side of the frontal lobe and one side of the parietal lobe have decreased functioning. The asymmetric nature of CBD is clear.

[All of this biomarker data, plus some additional biomarker info Dr. Bordelon didn’t review, is nicely summarized in a March 2009 medical journal article. You can find the abstract on pubmed.gov using PubMed ID# 19364361.]

Future research into the use of blood and spinal fluid measures as biomarkers. Can we measure the proteins that are accumulating or other downstream consequences? Example: lots of studies of spinal fluid in Alzheimer’s Disease are being replicated in the atypical parkinsonism community.

Future research into the use of imaging biomarkers to label protein accumulation in the brain. Example: amyloid ligands for PET scanning. (Ligands are agents that serve as markers.) The PET scan image shown is of an MSA patient with markers for protein accumulation lit up in the basal ganglia of the brain. [Dr. Bordelon described amyloid as a general term meaning protein accumulation in the brain. Robin’s note: this is confusing because I thought amyloid was a specific type of protein.]

TREATMENT – NEUROPROTECTIVE

Three treatment categories: Neuroprotective, Restorative, Symptomatic

Neuroprotective approaches: the goal is to modify, slow, or stop disease progression over time. Currently, we can make a diagnosis after symptoms develop.

Four examples of neuroprotective studies that are underway: (ten years ago we couldn’t say that we were trying to modify the course of these disorders)

#3 PSP – Pyruvate, Creatine and Niacinamide: Dr. Litvan, Univ of Louisville; acts on energy supply pathway in brain

[This trial is not currently recruiting. See http://clinicaltrials.gov/ct2/show/NCT00605930 In this study, those receiving the supplements will get “A bar of 2 gm of pyruvate and 1 gm of creatine, and a pill of 1 gm of niacinamide once a day for 24 weeks.”]

#4 PSP and CBD – Coenzyme Q10: Dr. Apuertenova, Lahey Clinic (Boston); acts on energy supply pathway in brain

[This trial is currently recruiting. See http://clinicaltrials.gov/ct2/show/NCT00382824 The last time I talked to Stephanie Scala at Lahey Clinic about this, the dose given was 2400mg/day and they were using the Vitaline brand. A fair amount has been posted about CoQ10 and this Lahey Clinic study on the PSP Forum: http://forum.psp.org/viewtopic.php?t=3042]

[Stephanie Scala at Lahey Clinic also told me that CoQ10 was being studied in MSA with a dose of 1200mg/day. This study wasn’t listed on clinicaltrials.gov.]

#5 PSP and CBD – Lithium: NIH-sponsored, multi-site; acts on tau phosphorylation-GSK-3 specifically; no longer recruiting due to toxicity issues

[In late August, local support group member Phil told us that NIH had cancelled the lithium trial. His wife Jackie, participating in the trial at Oregon Health & Science University in Portland, had experienced severe side effects. See dosing and titration info at http://www.clinicaltrials.gov/ct2/show/NCT00703677]

#6 MSA – Intravenous Immunoglobulin: Dr. Peter Novak, Univ of MA; acts on neuro-inflammation pathway in brain.

[This IVIg trial is currently recruiting. See http://clinicaltrials.gov/ct2/show/NCT00750867]

Two neuroprotective clinical trials will start in 2010:

#7 PSP – TAUROS (which stands for “Tau Restoration in PSP”): using a new drug called Nypta, developed by Noscira (based in Madrid). Acts on tau phosphorylation (“the stickiness”) and GSK-3. Researchers are hoping this drug will not have the problematic toxicity of lithium. Both lithium and Nypta are acting on the enzyme GSK-3 but Nypta is a more specific inhibitor of GSK-3. Nypta is a more pure inhibitor of this phosphorylation mechanism than lithium.

This is a phase II (safety/tolerability), double-blind, placebo-controlled study. Participants will be randomized to receive 600mg Nypta, 800mg Nypta, or a placebo for 52 weeks. Biomarkers: MRI at some of the European sites; an optional spinal fluid test will be available at all sites.

Multi-center study in Spain, UK, Germany, and US. US sites participating include: UCLA, Robert Wood Johnson Medical School (New Brunswick, NJ), Univ of Louisville (KY), Univ of South Florida, Univ of Colorado, Mayo Clinic (Jacksonville, FL), and Parkinson’s and Movement Disorders Institute (Fountain Valley, CA).

There was a big investigators meeting this week. The study will enroll in early 2010.

[Dr. Bordelon said the “University of Maryland in New Jersey in New Brunswick” is participating. I think this is a misreading of “UMDNJ.” UMDNJ = University of Medicine & Dentistry of NJ. The Robert Wood Johnson Medical School is one of the schools of UMDNJ. Dr. Lawrence Golbe is based at RWJMS.]

[Noscira is a unit of the company Zeltia. Here’s a short Reuters news story from 11/3/09 about Zeltia’s drug Nypta receiving orphan drug status in the US and Europe: http://www.reuters.com/article/rbssIndu … 1320091103]

[There is a short bit of info about PSP on the manufacturer’s website: http://www.noscira.com/investigacion.cfm?mS=226&mSS=555 This says nothing about Nypta.]

[Update on 11/9/09: Mayo Jax has asked one of its PSP patients to come in for an evaluation appointment in February 2010, presumably for this study. Just because Mayo Jax is participating in this study does NOT mean that Mayo Rochester or Mayo Phoenix is participating.]

#8 PSP – Davunetide, a new drug developed by Allon Therapeutics. This drug also acts on tau phosphorylation but through a different mechanism. It also enhances cell survival (a second mechanism).

This is a phase II (safety/tolerability), double-blind, placebo-controlled study. Participants will be randomized to receive Davunetide (intranasal) or a placebo for 52 weeks. Biomarkers: MRI and spinal fluid.

She believes there will be sites in Spain, Germany, UK and US, but these sites are not confirmed yet. This study will likely start in spring or summer of 2010.

[Dr. Bordelon described Allon Therapeutics as being a US company. It’s a Canadian company, based in Vancouver. You can find some info on this experimental drug from http://allontherapeutics.com/]

[Davunetide is also called NAP (AL-108). My assumption is that the US sites will be UCSF (lead site), Mayo Rochester, and UPenn, as these were the sites planning to study NAP in 2009 through a CurePSP grant. That CurePSP grant was to study NAP in both CBD and PSP. Dr. Bordelon only mentioned PSP, and she didn’t mention this history with the CurePSP-funded NAP study being led by UCSF.]

RESEARCH TARGETS

Basic mechanisms and animal models are being used in the lab. The hope is that this lab research now in the pipeline will turn into neuroprotective clinical trials. This lab research targets:
* prevention of protein misfolding
* acceleration of clearance of protein aggregates
* stabilization of brain cell function. How do we stabilize tau and the microtubules that it supports? Or how do we stimulate growth factors for the overall health of the cell?
* enhancement of cell energy production through free radical scavengers (antioxidants)

TREATMENT – RESTORATIVE

Restorative treatment: stem cell treatment. California Institute for Regenerative Medicine has funded two studies of stem cell treatments — in PD and Huntington disease. Once optimized, these findings can be applied to other diseases, including atypical parkinsonism disorders. These CIRM-funded studies, now underway, are looking at:
* the type of stem cells that can be best used, including iPS
* delivery system: direct surgical implantation (which is our current system) and blood delivery to target the right area of the brain (which is under development)
* prevention of rejection of cells
* keeping stem cells healthy
* directing stem cells to develop neurons

Another restorative treatments under investigation: delivery of Growth Factors to damaged areas of brain. Growth Factors are signals to neurons to grow and repair. GFs are in very high abundance during brain development, in the embryonic stage. How can we re-activate the GFs once the brain has begun to degenerate? There are currently clinical trials for this in Parkinson’s Disease and other disorders.

Another restorative treatments under investigation: activating the brain’s own stem cells to grow into the damaged areas. We didn’t know until recently that the brain has its own supply of stem cells in the area where CSF is contained. This is a rich source.

Another restorative treatments under investigation: working at the genetic level to turn off genes that cause disease. The technique is called RNAi. (i=interference) RNA is part of the genetic code. Significant progress for neurological diseases has been made in this area.

TREATMENT – SYMPTOMATIC

Symptomatic treatment. This area needs more and better study as we still don’t have great treatments for these problems:
* treating movement and cognitive problems
* gait and balance problems
* speech and swallowing
* incontinence and low BP

#9 PSP – DBS (deep brain stimulation), which is brain surgery. Research going on to use a novel target, the PPN (pedunculopontine nucleus), in PSP. The target in the brain (PPN) is very small. Only very experienced neurosurgeons could conduct this surgery. Dr. Lozano in Toronto is the lead investigator. This is CurePSP-funded.

[General info on this Canadian DBS study in PSP is here: http://forum.psp.org/viewtopic.php?t=7733]

#10 PSP and CBD – TMS (transcranial magnetic stimulation), which is a non-invasive therapy. The study includes three visits, each lasting three hours. These three visits can be accomplished in a one-week period, if necessary. Three different treatments are given: TMS for mood, TMS for movement, and one placebo (to rule out the placebo effect). Dr. Allan Wu at UCLA is the lead investigator. This is an active clinical trial that is currently recruiting patients; the contact at UCLA is phone 310/206-3356. This is CurePSP-funded.

[General info on this TMS study in PSP and CBD at UCLA is here: http://forum.psp.org/viewtopic.php?t=7732 I emailed the local support group on 8/24/09 to say that one member of our group participated in this treatment and saw “no results.” That email also indicated that there are some small studies of TMS going on in Parkinson’s Disease.]

#11 MSA – rasagiline (Azilect), a medication. There will be a trial in 2010. It is being organized by Teva Pharmaceutical, the manufacturer of Azilect. It is not yet enrolling. It will likely be a large, multi-center trial. This drug is currently being studied in PD for symptom control and neuroprotection.

[See: http://clinicaltrials.gov/ct2/show/NCT00977665]

SUMMARY

There have been significant advances in our understanding of the causes of these 3 disorders.

Treatments are being designed, and are entering clinical trials.

The most likely treatment approach will be multi-pronged. (Example: using aggregation inhibitors, anti-oxidants, etc)

Studies underway:
[See #1 to #11 above]
Visit clinicaltrials.gov, a portal for finding out about active research studies. Plug in keywords or a disease name.
Brain donation: one of the most significant contributions someone can make

QUESTIONS AND ANSWERS: (all answers are by Dr. Bordelon)

RESEARCH

Question: What are the benefits of participating in a clinical trial? I have early-stage PSP.

Answer: Clinical trials are the only way of determining if a medication is effective. An example is the CoQ10 clinical trial. It’s our only way of determining if CoQ10 is effective.

Clinical trials can be helpful in understanding risk factors for diseases.

The drug or treatment being studied may have direct benefit or improvement of symptoms. For example, both DBS and TMS offer the possibility of improvement of symptoms to trial participants.

In a trial of experimental medication, some participants will be taking a placebo. Depending on the regulatory agency, those participants taking a placebo may be able to access an “open-label extension,” if the drug is determined to be safe. This means they would have access to the experimental medication.

The risk of a drug trial is that the drug might not work or might worsen the disease.

In summary, why participate? Because it might benefit you and increases the chance that effective treatments may be found. And participation increases our knowledge about these diseases. It may have a beneficial effect for others who may be affected with these disorders.

Question: How can we contribute (time, effort, and money) towards a research program that might discover some treatment or a cure? We are dealing with MSA.

Answer: Directly participating in a clinical study has a significant contribution.

Educating people around you about the disorder you are facing is helpful and important. This increases awareness in the community.

Advocacy to members of congress in US is helpful and important. Congress controls the budget of the NIH, which is key to neuroscience research in the US. Another example: there is a bill currently going through Congress about a Parkinson’s Disease Registry. Such a registry may have benefit for atypical parkinsonism disorders as well.

Brain donation is one of the most significant contributions anyone can make. This establishes a diagnosis and helps research studies that are underway to determine causes.

Fundraising is important.

Question: What are the benefits of brain donation to future generations?

Answer: This is one of the greatest gifts someone can make towards research.

MDs are uncomfortable asking about this.

See psp.org for info. [http://psp.org/page/braindonation]

Speak with your MD about this.

Incorporate brain donation into your living will.

Question: Has any of the research led to a medication or a surgical treatment?

Answer: We are hopeful that in time this will happen.

TREATMENTS

Question: What over-the-counter (OTC) treatments are available or what treatments are available that don’t require participating in a clinical trial? I have either PSP or MSA.

Related Question: What is CoQ10 used for?

Answer: CoQ10 and creatine are available OTC, considered generally safe, and are well-tolerated. They can be added to a medication regimen. Discuss this with your neurologist or general practitioner. If you have liver problems, be cautious with creatine.

CoQ10 dosing should be 1200 mg/day (taken as: 400mg 3x/day, or 600mg 2x/day).

Creatine dosing should be 5 grams 2x/day.

Neither CoQ10 nor creatine have been studied in atypical parkinsonism disorders. None of the trials in Parkinson’s Disease clearly shows these supplements work but the data are intriguing such that that these supplements continue to be studied. An early study of CoQ10 in PD showed it may have mild benefit for symptoms.

With these supplements, you are not looking for symptom control. You are looking for neuroprotection (slowing down disease). This means you may not see a direct benefit. Don’t stop the drug if you don’t see direct benefit because these supplements don’t work that way.

Question: What are the effects of exercise? Are any types of exercise recommended?

Answer: Exercise is incredibly important. It should be emphasized as much as medications, if not more. It must be done in a safe fashion. Optimally, you should exercise daily. Select an exercise that is enjoyable and that you would want to do every day.

Good types of exercise promote flexibility, mobility, and keeping muscles in shape. Yoga and tai-chi can be helpful and important for balance and postural strengthening.

We think exercise is beneficial for the brain — that it’s neuroprotective. Exercise increases the release of Growth Factors in the brain.

Consultation with a PT can be helpful in determining an exercise regimen.

She has had patients whose balance has improved in PSP with exercise!

Question: MDs outside the US are making claims of cures for brain disorders. Should we seek out this treatment?

Answer: It depends on the claims. If the treatment is expensive, be cautious.

She asks her patients to run these claims by her (or an MD) as she’s concerned about harm.

Question: Is there any validation to the stem cell treatments in China, Russia, and Ukraine?

Answer: As yet, no studies show that stem cell treatments work. Be cautious. These are situations where we don’t know exactly what is going on.

Studies under investigation as to what stem cells should be used. Regimented research is needed. Clinical trials are needed.

She talked about the case of a Huntington Disease patient. After overseas stem cell treatment, the patient got signfiicantly worse. They were unable to get medical records from India as to what was given to this patient.

Run-away dyskinesias have been seen in some cases. We need to wait for studies into this to be sure these treatments are safe.

Currently stem cell treatments are not safe. Be cautious, especially given the high cost and no scientific evidence. These treatments might cause harm. Talk to your physician about this.

GENETICS

Question: What are the chances of passing down the atypical parkinsonian disorder to children or grandchildren?

Answer: Very rare. Only isolated families have passed this disorder along. In contrast: 10% of PD may be passed among family members.

NEXT WEBINARS

11/19 – Golbe
12/3 – Jerome Lisk and panel

Expert update on PSP/CBD genetics study

Thursday’s CurePSP webinar included an update by researcher extraordinaire Dr. Gerard Schellenberg of UPenn on the PSP and CBD Genetics Program. It was great to get this update from the expert. (I thought it warranted its own short webinar.)

What follows are my notes on Dr. Schellenberg’s presentation, a short comment made by neurologist Dr. Yvette Bordelon on the study’s findings, and some of my own comments.

See also my blog post on October 1st with a short update and some general background on the genetics study.  Paul Freeman (CurePSP board member) told us in September 2009 at a local support group meeting that four new genetic mutations associated with PSP have been discovered through this brain research — made possible through brain donation.

Robin


 

Presenter – Gerard Schellenberg, PhD
Univ of Pennsylvania School of Medicine

Topic – Charles D. Peebler Jr. PSP and CBD Genetics Program

What does it take to get PSP or CBD (at least in terms of the genetic components)?

* The bad form of one gene is very rarely the cause of PSP or CBD. What this means is that if you have a family member with PSP or CBD, your chances of developing the disease is pretty remote. In contrast: there are diseases, such as Huntington’s Disease and some forms of ALS, where a single gene is involved, and if you inherit the bad form of that gene you will get the disease. This type of genetics — “single gene inheritance” — tracks very strongly in families.

* Most cases are caused by the bad form of 5 to 10 genes. For each bad copy inherited, risk is increased. If you develop the good form of each of these genes, your chance of developing PSP or CBD is very low.

* We think there also might be some environmental insult involved. We don’t really have a good handle on what the environmental input is.

Goal: identify ALL the genes that contribute to PSP/CBD. They aren’t focusing on one gene, as this is rare. Put another way: they are focused NOT on the genes that cause PSP and CBD but rather on the genes that contribute to the risk of PSP and CBD.

This genetics study requires:

* DNA from a large number of autopsy-confirmed cases of PSP and CBD

* DNA from a large number of cases of those who do not have PSP or CBD. This is compared to the DNA from those who do have PSP or CBD.

* Genetic technology to study all regions of all chromosomes (across the genome or genetic material)

* A statistical analysis team

This is an international effort:

Germany (Dr. Muller, Dr. Hoglinger)

US: Mayo Jax (Dr. Dennis Dickson)

UK: Queen’s Square (Dr. Andrew Lees – one of the international experts on PSP and CBD, Dr. Rohan Silva)

Brains collected by the German team:
Munich – 8 CBD, 21 PSP
Wurzburg – 2 PSP
Barcelona – 3 CBD, 17 PSP
Netherlands Brain Bank – 23 PSP
London Brain Bank – 2 CBD, 8 PSP
Saskatchewan, Canada – 37 PSP
Wilrijk, Belgium – 2 PSP
Australian Brain Bank – 1 CBD, 9 PSP
Pamplona, Spain – 1 PSP
Subtotal – 14 CBD, 125 PSP

Other brains contributed:
Mayo Clinic Brain Bank – 78 CBD, 599 PSP

Other brains contributed:
Queen’s Square Brain Bank (London) – 144 PSP

Brains collected by Dr. Schellenberg from US-based institutions:
Emory Univ – 13 CBD, 6 PSP
McLean Brain Bank – 8 CBD, 64 PSP
Indiana – 12 CBD, 31 PSP
Los Angeles VA/UCLA – 1 CBD, 14 PSP
Massachusetts General – 34 PSP
NY Brain Bank – 6 CBD, 22 PSP
Rancho Los Amigos Medical Center – 3 PSP
Sun Health Research Institute – 38 PSP
Univ of Michigan – 23 PSP
UPenn CDNR – 30 CBD, 51 PSP
Univ of Washington – 4 PSP
Univ of Southern California – 2 PSP
UCSD – 10 PSP
Univ of Texas Southwestern – 6 CBD, 14 PSP
Johns Hopkins – 27 PSP
Subtotal – 75 CBD, 343 PSP

Total brains (or samples) contributed over the last two years:
CBD: 168
PSP: 1212
total autopsy-documented cases: 1380

In addition to the 1380 PSP/CBD samples, they have DNA from 3000 controls. These controls are healthy children who have come into the Children’s Hospital of Philadelphia for routine check-ups.

The genetic technology being used tests 660,000 sites across the human genome (all the inherited material or all of the inherited DNA). We can pretty much test everywhere in the human genome for change related to PSP and CBD.

What we learned through this study, after the statistical analysis: we learned about four new genes that are involved in one’s risk of developing PSP or CBD. We didn’t previously know about genes on chromosomes on 1, 3, 11 and 12. We knew about the tau genetic mutation on chromosome 17. This knowledge about four new genes is the exciting pay-off from two years of very hard work. Each of these genes tells us something about the mechanism or the pathway for how PSP or CBD develops.

Next:
* explore how each of these genes plugs into the disease. This knowledge is critical to understanding what causes it and what causes it to progress to the point where symptoms start to appear.
* explore how genetics and the environment interact

A lot of pharmaceutical discovery is based in part on genes found through these methods. This has been particularly true in Alzheimer’s Disease. Genetics findings are really driving a lot of the pharmaceutical discovery efforts by the big companies.

Next specific steps in this study:

* analyze tau in more detail. How does the bad form of tau contribute to risk? Is it simply making more tau protein or something more complicated?

* replication studies to verify these are not statistical artifacts. We are collecting 1000 more PSP cases to look at these four genes and tau. [Robin’s question: are they collecting more CBD brains as well?]

* identify additional genes with the additional samples

Summary:

* The genetic experiment worked! And it worked spectacularly!

* 4 new genes previously not implicated in PSP or CBD

* potential for identifying new genes (which gives us insight into the disease process)

* potential for new leads for therapeutics to treat or prevent PSP or CBD

Thank you:

* families that contributed DNA. These contributions are absolutely essential.

* CurePSP that took a risk and put up a large amount of money for this study

* donors to CurePSP to make this research possible, particularly the Charles Peebler Jr. family

Comment by Dr. Yvette Bordelon on Dr. Schellenberg’s presentation:

This is spectacular! These are very exciting results for PSP and CBD.

These genome-wide screens have been attempted in other disorders, and haven’t been nearly as successful. In PD several attempts have been made, none of which have shown clear correlations.

Robin’s notes:

In a recent letter to a brain donor’s family, Mayo Jax confirmed the PSP diagnosis and indicated that it had 730 PSP brains in its brain bank. Dr. Schellenberg reported above that 599 PSP brains were included in the original group. Presumably the additional 131 brains collected thus far at Mayo Jax will be part of the goal of collecting 1000 more brains.

If your loved one has donated tissue to an institution not listed above (such as UCSF or the Univ of NM, to name two that I know have PSP or CBD brains), please contact the neuropathologist to find out if samples can be provided to Dr. Schellenberg to reach the goal of 1000 more brains.

I’m proud to report that I’ve played a role in having 15 path-confirmed PSP or CBD brains donated to institutions listed above as study participants. Most of these donations have been to Mayo Jax. (I’ve played a role in many more brains being donated to Mayo Jax for other disorders, and to other institutions not yet participating in the PSP/CBD study.