Category Archives: MSA

The Eye in PSP/Atypical Parkinson’s – lecture notes

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At last week’s atypical parkinsonsim support group meeting at UC Irvine, a neuro-ophthalmologist spoke about eye problems in parkinsonism. The talk wasn’t specific to PSP, CBD, or MSA. Vera James is the facilitator of this PSP/CBD/MSA support group. Here are Vera’s notes, which she posted to one of the MSA-related online support groups last week.

Orange County Atypical PD+ Support Group (PSP, CBD, MSA)
UC Irvine
Meeting date: Wed, Jan 6, 2010
Notes by: Vera James, support group leader [with a few grammatical fixes by Robin]

Guest speaker: Swaraj Bose, MD, a neuro-ophthalmologist at the Gavin Herbert Eye Institute, UCI

His main reason for speaking with us was to give us a fair idea of the eye problems and why do the eyes behave in the way they do in Parkinson’s/PSP/Atypical Parkinson’s and what the caregiver can do.

The eye movement comes from the brain (head computer). We have two eyeballs that are in an orbit/socket. Each eye has 6 muscle that moves the eye left to right or up and down for the visual field. The vision comes from the back of the brain at the cortex, the middle brain, neurons of the pons. These nerve cells and area are what causes the problems.

Dr. Bose gave us a handout called “The Eye in PSP/Atypical Parkinson’s.” The information will all be in this message along with some notes I made when he made remark about some of the common things in Parkinson’s/ PSP/Atypical Parkinson’s. Some information is vision problems in PSP like the down-gaze that is common with PSP patients but some suggestion you may find will help the MSA patients also. I am also putting those in because we know that some patients may be misdiagnosef and may have these same eye issues.

Common eye complaints:

#1 – Related to disturbance of down-gaze PSP.

– Difficulty in coordinating eye movements while reading even if their vision is normal, especially through their bifocal glasses.

– Difficulty in eating because they cannot look down at their food on the plate.

– Difficulty in going downstairs and stepping off curbs.

#2 – Related to lack of convergence/fast and slow tracking- Parkinson/PSP/Atypical PD.
(Note: Convergence means to bring the eyes together)

– Difficulty in focusing, words run into each other.

– Hard to shift down to the beginning of the next line automatically after reaching the end of the first line.

– Inability to quickly move eyes up or down.

– Inability to track moving objects or maintain eye contact.

Dr. Bose said that most patients with any of these illnesses will have problems maintaining eye contact, and in tracking objects. He said this is where the problem comes in with driving and the reason that a patient shouldn’t be driving. He gave an example saying that if you are driving and a child run out in front of you 150 ft away, you will catch them going the one way, but with the slow tracking the eyes are doing, the child could be back in front of you before your tracking would get the eyes to the other side to view where the child would be. By then you could have hit the child.

– Double vision.

One eye sees one thing, the other eye sees another and the brain brings them together. Kind of the way 3D glasses do. When you have double vision, the brain isn’t bringing the eyes together to get the one vision.

#3 – Related to vision disturbances-Parkinson/PSP/Atypical PD.

– Difficulty in focusing/blurry vision/visual hallucinations.

Visual hallucinations can be in all of these illness. Some visual hallucinations can be from to much medication, but it can also be from a lack of dopamine in the cortex where the signal is fallen and gives false images and causes these visual hallucinations also. So not all visual hallucinations are psychotic. Other things that can also cause visual hallucinations are benadryl and OTC cold meds. They can also cause spasm.

– Changes of reading glasses at a quicker intervals.

– Decreased in contrast sensitivity (difficulty in distinguishing shades of gray) and color perception.

#4 – Eyelid abnormality

– Difficulty in voluntarily opening their eyes (apraxia)

– Forceful eyelid closing (blepharospasm). This is treated with botox.

– Decrease in the rate of blinking (3-4/min vs. 20/min)

#5 – Dry eyes

– Burning sensation, redness, watering, itching, excessive tearing, rubbing of eyes, blurry vision.

– Double vision with one eye. Usually results in ‘ghosting’ of images or shadowing of images.

Treatment — A multi-disciplinary approach:

Diagnosis of the movement disorder is important. This will determine the course, manifestations and outcome.

Communication with neurologist, neuro-ophthalmologist, rehabilitation personnel, nurses, therapists, care giver, neuro-psychiatrists amd primary care physicians is VITAL.

Record a thorough history.

Set realistic goals.

A thorough eye examination should include:
– Best correction for distance/near vision
– Color vision
– Visual field examination
– Detailed record of eye movements in all directions
– Prism measurement and correction. Prism lenses or prism overlays take some getting used to.
– Evaluation of eye surface including dry eyes
– Eyelid evaluation
– Convergence estimation.
– Retina and optic nerve evaluation
– Prescribe glasses for distance and near
– Optimize eye movement problems by exercises, prisms and rehabilitation
– Treat dry eyes and other associated eye conditions

Alter/Redesign equipment for reading (lighting, position), position of book and food (at eye level), devices/support for walking and stepping down stairs to prevent falls (safety).

Take medication regularly and watch for side effects.

Living and seeing well:

Safety begins at home:
– Rooms/hallways free of clutter
– Remove cords/rugs from floor
– All rooms well lit, night lights along hallways
– Install grab bars in shower, stairs to prevent falls
– Cane, walker, wheel chair

Proper reading lights (from left and behind)

Reading material (books/newspapers) at eye level. Use a piano reading stand.

Place food at patient’s eye level, raise table, small platform. Suggestion: bed or TV tray placed on the table to raise the plate higher for the PSP patient to view food. This would also be helpful for all patients who are still feeding themselves so they don’t have to work as hard to bring the food up to their mouths.

Get correct glasses prescription filled

Use separate glasses for reading and distance

Use lubricating eye drops like Systane or Refresh during the day and a gel (Genteal gel ointment) at bed time.

Regular eye exercises (when prescribed). Body and breathing exercises.

Take medications regularly

Visual hallucinations can be a side effect of medications or a lack of dopamine in the cortex.

Driving can be tricky. Speak with your eye doctor.

Keep yourself engaged with some creative activities/projects

Regular follow-up with neurologist and neuro-ophthalmologist

Join a support group

Summary:

* Visual disturbances and eye changes including problems with eye movements are commonly seen in patients with Parkinson’s/PSP/Atypical Parkinson’s

* Visual complaints are usually distortion or blurry vision, near vision problems, color vision abnormalities and even visual hallucinations

* Eye movement abnormalities include difficulty in convergence (bringing the eyes together while reading), lack of vertical movement of eyes (upward/downward gaze abnormality) and eye movement asymmetry

* Other problems include a decrease in blinking of eyelids, difficulty in opening the eyelids, dry eyes and lack of facial expression

* These eye conditions, if diagnosed early in the course of the disease, can be treated and managed by an ophthalmologist or a neuro-ophthalmologist

* Simple measures used in visual rehabilitation and medications given by the movement disorders neurologist and supportive care can significantly alter the quality of life of patients with these conditions.

FDG-PET for differentiating PD, PSP, and MSA

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This article on the use of FDG-PET in differentiating PD, MSA, and PSP was published today in The Lancet Neurology. I haven’t had a chance to wade through all of the article yet but it seems to be one of the better articles we’ve seen lately on PSP and MSA. 167 patients in the NY area participated in the study. Only 9 of these patients have died and donated brain tissue thus far. So I’m not sure how “real” the diagnostic accuracy percentages are. And the diagnosis of CBD was not part of the study.

Below, I’ve copied a HealthImaging.com article on this research as well as the abstract.

Robin

The Lancet Neurology, Early Online Publication, 11 January 2010.

Differential diagnosis of parkinsonism: a metabolic imaging study using pattern analysis

Chris C Tang MD, Kathleen L Poston MD, Thomas Eckert MD, Andrew Feigin MD, Steven Frucht MD, Mark Gudesblatt MD, Vijay Dhawan PhD, Martin Lesser PhD, Jean-Paul Vonsattel MD, Stanley Fahn MD, David Eidelberg MD

Summary

Background
Idiopathic Parkinson’s disease can present with symptoms similar to those of multiple system atrophy or progressive supranuclear palsy. We aimed to assess whether metabolic brain imaging combined with spatial covariance analysis could accurately discriminate patients with parkinsonism who had different underlying disorders.

Methods
Between January, 1998, and December, 2006, patients from the New York area who had parkinsonian features but uncertain clinical diagnosis had fluorine-18-labelled-fluorodeoxyglucose-PET at The Feinstein Institute for Medical Research. We developed an automated image-based classification procedure to differentiate individual patients with idiopathic Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. For each patient, the likelihood of having each of the three diseases was calculated by use of multiple disease-related patterns with logistic regression and leave-one-out cross-validation. Each patient was classified according to criteria defined by receiver-operating-characteristic analysis. After imaging, patients were assessed by blinded movement disorders specialists for a mean of 2·6 years before a final clinical diagnosis was made. The accuracy of the initial image-based classification was assessed by comparison with the final clinical diagnosis.

Findings
167 patients were assessed. Image-based classification for idiopathic Parkinson’s disease had 84% sensitivity, 97% specificity, 98% positive predictive value (PPV), and 82% negative predictive value (NPV). Imaging classifications were also accurate for multiple system atrophy (85% sensitivity, 96% specificity, 97% PPV, and 83% NPV) and progressive supranuclear palsy (88% sensitivity, 94% specificity, 91% PPV, and 92% NPV).

Interpretation
Automated image-based classification has high specificity in distinguishing between parkinsonian disorders and could help in selecting treatment for early-stage patients and identifying participants for clinical trials.

Funding
National Institutes of Health and General Clinical Research Center at The Feinstein Institute for Medical Research.

http://www.healthimaging.com/index.php? … e&id=20154

TOP STORIES
Lancet: FDG-PET could distinguish between Parkinsonian disorders
Written by Editorial Staff, HealthImaging.com
January 11, 2010

FDG-PET imaging-based classification has high specificity to differentiate individual patients with idiopathic Parkinson’s disease, multiple system atrophy and progressive supranuclear palsy and could help in selecting treatment for early-stage patients and identifying participants for clinical trials, according to research published online Jan. 11 in Lancet Neurology.

David Eidelberg, MD, director of the center for neurosciences at the Feinstein Institute for Medical Research in Manhasset, N.Y., and colleagues assessed whether metabolic brain imaging combined with spatial covariance analysis could accurately differentiate between patients with Parkinsonism who had different underlying disorders.

In the study, 167 patients who had Parkinsonian features but uncertain clinical diagnosis had an 18F-FDG PET scan. The researchers developed an automated image-based classification procedure to differentiate individual patients with Parkinsonian disorders and the accuracy was assessed by comparison with the final clinical diagnosis.

Eidelberg said that out of the 167 patients assessed, image-based classification for idiopathic Parkinson’s disease had 84 percent sensitivity, 97 percent specificity, 98 percent positive predictive value (PPV) and 82 percent negative predictive value (NPV).

Eidelberg and colleagues found that imaging classifications were also accurate for multiple system atrophy (85 percent sensitivity, 96 percent specificity, 97 percent PPV, and 83 percent NPV) and progressive supranuclear palsy (88 percent sensitivity, 94 percent specificity, 91 percent PPV and 92 percent NPV).

In an accompanying commentary, Angelo Antonini, MD, at IRCCS San Camillo, Venice and Parkinson Institute in Milan, Italy, wrote that the “clinical and research relevance of these findings should not be underestimated. Neuroprotective and disease-modifying drug research is intensifying and results mostly rely on accurate early diagnosis.”

“The excellent specificity and PPV of the imaging classification makes this test suitable for diagnostic use rather than as a screening tool,” Eidelberg noted.

“Although imaging might be cost effective for early diagnosis, I expect that these procedures will find their natural application in the identification of suitable candidates for drug trials or complex surgical procedures (example, deep brain stimulation, stem-cell transplantation or fetal tissue transplantation). However, additional blinded, prospective, multicenter studies will first be needed to confirm the accuracy of this pattern-based categorization procedure,” Antonini concluded.

Last updated on January 11, 2010 at 12:48 pm EST

DAT-SPECT: useful for DLBvAD, not useful for MSA, PSP, CBD

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This recently-published article touches upon the four disorders in our group.

It’s a review article is about the use of DAT-SPECT — dopamine transporter SPECT scans — in diagnosing movement disorders. The authors have done a great job in reviewing all the data and then presenting understandable one-sentence conclusions, which I will now share…

For MSA, PSP, and CBD, the authors conclude: In “clinical practice, DAT-SPECTs are not useful in differentiating between PD and atypical parkinsonian syndromes (MSA, PSP, CBD).”

For DLB, the authors conclude: “DAT-SPECT cannot discriminate between PD/PD-dementia and DLB but can be very useful in the differential diagnosis between DLB and Alzheimer disease and can also be of some value in the differential diagnosis between DLB and vascular dementia.”

I remember learning back in 2008 that there was some type of legal issue with bringing SPECT scans to the US, though they are already widely used in Europe. SPECT imaging is important for some disorders (such as DLB) so it’s been frustrating that SPECT imaging is not approved for use in the US except in a few research settings. In 2008, there was a Q&A with Dr. Mark Stacy from Duke about this:

“Question: Why are SPECT scans not available in the US?
Answer: Because of corporate changes. GE bought Amersham (sp?). Amersham wanted to bring another type of SPECT agent to market. It’s been found that the drug that GE started to bring to market in Europe is easier to use. So it got slowed down bringing this agent to the US. GE is talking to the FDA about using European trial data.”

Recently, I asked Dr. Hubert Fernandez (on NPF’s “Ask the Doctor” Forum) about the status of bringing DAT-SPECT scans to the US. He first explained what a DAT ligand is and then answered the question:

“DAT (dopamine transporter) is a type of ligand (vehicle or medium) to conduct the SPECT scan. [It] ‘tags’ dopamine. It is important that the medium used is the correct one. Good examples are altropane or B-CIT….these are ligands that are used for SPECT scans to evaluate for PD.

Yes, for now, they DAT SPECT scans are not commercially available….but soon they they will be. One of the companies that manufactures a DAT ligand has received an ‘approvable letter’ from the FDA.”

OK, that’s probably all any of you want to know about DAT-SPECT imaging.

I’ve copied the article’s abstract and a few excerpts below, if any of you want to go further…

Robin

Journal of Neurology, Neurosurgery & Psychiatry. 2010 Jan;81(1):5-12.

The role of DAT-SPECT in movement disorders.

Kägi G, Bhatia KP, Tolosa E.
Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, National Hospital for Neurology and Neurosurgery, London, UK.

Dopamine transporter (DAT) imaging is a sensitive method to detect presynaptic dopamine neuronal dysfunction, which is a hallmark of neurodegenerative parkinsonism. DAT imaging can therefore assist the differentiation between conditions with and without presynaptic dopaminergic deficit.

Diagnosis of Parkinson disease or tremor disorders can be achieved with high degrees of accuracy in cases with full expression of classical clinical features; however, diagnosis can be difficult, since there is a substantial clinical overlap especially in monosymptomatic tremor (dystonic tremor, essential tremor, Parkinson tremor).

The use of DAT-SPECT can prove or excludes with high sensitivity nigrostriatal dysfunction in those cases and facilitates early and accurate diagnosis.

Furthermore, a normal DAT-SPECT is helpful in supporting a diagnosis of drug-induced-, psychogenic- and vascular parkinsonism by excluding underlying true nigrostriatal dysfunction.

This review addresses the value of DAT-SPECT and its impact on diagnostic accuracy in movement disorders presenting with tremor and/or parkinsonism.

PubMed ID#: 20019219 (see pubmed.gov for abstract only)

———-

Excerpts (in case you didn’t get enough already):

“Atypical parkinsonism (MSA, PSP, CBD)
The differentiation of atypical parkinsonian disorders from PD and between each other can raise considerable difficulties, particularly in early disease stages. This difficulty is reflected in clinicopathological studies where atypical parkinsonism accounts for a large part of misdiagnosis in PD. MSA, especially the parkinsonian subtype (MSA-P), can initially be very difficult to distinguish from PD before more specific symptoms like pronounced autonomic involvement, laryngeal stridor or lack of response to dopaminergic therapy occur. The same is true for the parkinsonian type of PSP (PSP-P) in which the more disease-specific signs and symptoms such as supranuclear vertical gaze palsy and imbalance with falls occur. Also, corticobasal degeneration (CBD) can initially easily be mistaken as PD because of its marked asymmetrical akinetic-rigid syndrome before apraxia, myoclonus and cognitive problems occur. A faster disease progression and a poor responsiveness to levodopa are common features in atypical forms and is explained by the pre- and postsynaptic dopaminergic degeneration. However,
some responsiveness to levodopa is not uncommon in early MSA-P or PSP-P. Previously, several studies have been carried out to establish the value of DAT-SPECT for the differentiation between PD and atypical PD. It has been shown that DAT-SPECT is sensitive in detecting presynaptic nigrostriatal degeneration in PD and atypical PD but not useful in the differential diagnosis of PD and atypical PD.”

“The amount and pattern of reduced striatal DAT binding in MSA have been shown to be in the range of PD with a more pronounced loss of DAT binding in the posterior putamen compared with the caudate to be typical for both. Asymmetry of DAT binding loss tends to be more pronounced in PD, and progression is faster in MSA compared with PD. PET and DAT-SPECT studies have shown that even clinically pure forms of MSA-C have some decrease in DAT binding but less compared with MSA-P or PD. This finding could be of some diagnostic impact in the differential diagnosis of MSA-C to idiopathic late-onset cerebellar ataxia (ILOCA). For separating MSA from PD,
other techniques such as voxelwise analysis of DAT-SPECT combined DAT/D2 receptor SPECT (IBZM, Epidepride,
Iodolisuride and IBF) or D2 PET (raclopride) can provide more information, although D2 receptor binding imaging methods are influenced by dopaminergic therapy and are therefore most useful in drug-naive patients. In drug-naive PD, D2 binding exceeds normal levels because of D2 receptor upregulation, whereas D2 binding is reduced in MSA early on because of postsynaptic degeneration. PET studies may contribute in the differential diagnosis of these entities. Striatal metabolic studies using FDG have shown to be of value in the differential diagnosis of atypical parkinsonism with hypermetoablism in the dorsolateral putamen in PD, bilateral hypometabolism in the putamen in MSA and hypometabolism of the brainstem and the middle frontal cortex in PSP. In CBD, unlike PSP or PD,
unilateral balanced (caudate/putamen) reduction in tracer uptake has been observed. In addition, cardiac imaging with MIBG has shown changes consistent with heart denervation in patients with PD which are not present in patients with MSA or PSP.”

“DAT-SPECT is also of limited value in the differential between PD and PSP, although PSP seem to have a more
symmetrical and profound DAT loss in the whole striatum, whereas in PD the posterior part of the putamen shows more loss of DAT density compared with the anterior part and the caudate.”

“DAT loss in CBD is in the same range as it is in PD and atypical PD, although DAT loss is much more asymmetrical and less pronounced than that seen in MSA and PSP. D2 SPECT seems to be of less value compared with MSA and PSP because D2 binding in CBD is more often in normal range than it is in MSA and PSP.”

“In conclusion, DAT-SPECT imaging does not help to differentiate between the neurodegenerative parkinsonian disorders. Hence, in clinical practice, DAT-SPECTs are not useful in differentiating between PD and atypical parkinsonian syndromes (MSA, PSP, CBD).”

“Dementia with Lewy bodies
In dementia with Lewy bodies (DLB), the extent of DAT loss in the striatum is in the range of PD and therefore not useful in the differential of PD and atypical PD. Neuropathological data suggest that 50­60% of dementia in people aged 65 or older is due to Alzheimer disease, with a further 10­20% each attributable to DLB or vascular cognitive impairment. Operationalised clinical diagnostic criteria have been agreed for all of these syndromes, but even in specialist research settings, they have limited accuracy when compared with neuropathological autopsy findings. Distinguishing Alzheimer disease from DLB is clinically relevant in terms of prognosis and appropriate treatment. A striking biological difference between DLB and Alzheimer disease is the severe nigrostriatal degeneration and consequent DAT loss that occurs in DLB, but not to any significant extent in Alzheimer disease. Several imaging
studies have shown that DAT imaging improves diagnostic accuracy with a sensitivity of 78% and a specificity of up to 94% in the separation between DLB and AD. Most of these studies have used clinical diagnosis as the gold standard, and the results have to be taken with some caution. One study with 20 cases with pathologically proven dementias (DLB/non-DLB) and with an FP-CIT SPECT at initial clinical workup showed that the DAT imaging substantially enhanced the accuracy of diagnosis of DLB by comparison with clinical criteria alone. Abnormal DAT imaging has therefore also been included as a suggestive feature in the DLB consensus criteria in 2005.”

“In conclusion, DAT-SPECT cannot discriminate between PD/PD-dementia and DLB but can be very useful in the differential diagnosis between DLB and Alzheimer disease and can also be of some value in the differential diagnosis between DLB and vascular dementia.”

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

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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)

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

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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