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.)
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.
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
* 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
* 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.
* first and worse with thin liquids
* aspiration common
* large piece of food in windpipe is not usually the problem
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
* 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?
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.
* 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.]
* 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]
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?
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]
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)
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]
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.
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.