Monthly Archives: November 2009

Checklist on Family Matters

Date
Posted by

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)

Date
Posted by

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

Date
Posted by
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

Date
Posted by

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

Date
Posted by

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.