Category Archives: CBD

Atypical Parkinsonism – Breakout session notes (3/12/09)

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On Thursday 3/12/09 at the Victory Summit (Symposium for People Living with Parkinson’s Disease) in San Jose, there was a one-hour breakout session on “Atypical Parkinson’s Disease.” There were two presenters:
* Grace Liang, MD, Neurologist/Movement Disorder Specialist, The Parkinson’s Institute
* Amy Manning-Bog, PhD, Researchers, The Parkinson’s Institute

In a one-hour period, I thought they gave a great summary of the clinical picture of the four atypical parkinsonism disorders, and of the basic research underway that pertains to these disorders with particular attention to MSA. The Q&A was especially good; there were many in the audience who grasped even the challenging research update. I shared the draft of my notes with Dr. Manning-Bog, and she kindly corrected them and expanded the explanation in a few places. Also, support group member Helen added many points I had missed. Here are our combined notes from the presentations and the Q&A…

Notes from Dr. Liang’s Presentation

In order to know what “atypical PD” is, we must first review what “typical PD” is. Typical PD:
* usually starts on one side
* usually has a resting tremor
* includes Lewy body pathology
* slow progression (several decades)
* responds to medications

Common parkinsonian motor signs include:
* bradykinesia (slowed movements)
* tremor
* rigidity
* balance difficulty/gait instability

Other motor signs of PD include:
* hypophonia
* freezing
* stooped posture
* decreased facial expression

There are many non-motor symptoms of PD:
* constipation
* sleep disorders
* depression

These additional non-motor symptoms are prominent in atypical PD:
* blood pressure fluctuations
* swallowing difficulties
* urinary symptoms
* change in thinking and memory abilities

Parkinsonism can include the following diagnoses:
* Drug-induced Parkinsonism: may be caused by dopamine blocking drugs (examples – Haldol, Reglan, Risperdal, Depakote); reversible to some extent; these medications should be avoided by those with PD or parkinsonism
* Vascular Parkinsonism: caused by loss of blood flow to certain regions of the brain; minimal response to medication

NPH (normal pressure hydrocephalus):
* symptoms include shuffling gait, urinary incontinence, and dementia
* very rare
* not easy to diagnose
* treated with surgery but not that the surgical results are variable

DLB (dementia with Lewy bodies):
* second most common dementia (after AD)
* early notable cognitive changes (can be before or after motor symptoms start; the “time course” determines whether we call this PDD or DLB)
* visual hallucinations are common and are made worse by medication
* fluctuating mental alertness
* delusions

DLB – treatment:
* there is a balance between motor and cognitive symptoms
* dementia drugs can be helpful (examples – Aricept, Exelon, Razadyne, Namenda)
* minimize factors that can increase confusion and hallucinations
* use antipsychotics sparingly for delusions and hallucinations. Note the FDA black-box warning on antipsychotics. The care team must balance the patient’s (and caregiver’s) quality of life with the risks of this type of medication.

MSA (multiple system atrophy):
* often called “Parkinson’s Plus”
* autonomic dysfunction (orthostatic hypotension or low blood pressure upon standing, urinary incontinence, erectile dysfunction)
* there is also a cerebellar form (where balance is a problem)

MSA – treatment:
* there is not usually a strong or prolonged response to PD medication
* to support blood pressure: increase fluid intake, increase salt intake, wear support stockings
* muscle exercises to improve tone and circulation (this can be something as simple as keeping the feet moving throughout the day)
* balance exercises
* evaluate whether there are sleep problems

PSP (progressive supranuclear palsy):
* named for eye movement problem: it’s hard to look up and down
* early balance problems (falls) and gait freezing
* swallowing difficulties
* speech changes
* impulsive behavior

PSP – treatment:
* PD meds may not improve symptoms (and can make balance worse)
* evaluate for speech and swallowing problems
* physical therapy and fall precautions
* dystonia and contractures might be treatable with botox injections

CBD (corticobasal degeneration):
* rare
* usually starts with loss of function of one limb
* apraxia (examples: forgotten how to put clothes on correctly; forgotten how to brush teeth correctly)
* dystonia (involuntary muscle contractions) may occur
* cognitive changes (decreased ability to interpret visual or sensory signs; language difficulty) (example of a sensory sign: the patient can’t tell if he/she is holding a dime or a nickel)

CBD – treatment:
* variable results
* might try dementia medication (Namenda or AChEIs such as Aricept, Exelon, and Razadyne)
* physical therapy is important
* speech therapy is important

“Helpers” or Important resources:
* grab bars
* walker (actually, people can become *more* mobile by using a walker)
* shower seat
* reacher (pick-up stick)
* special eating utensils with big grips and bendable metal
* gait belt
* thickener (example: ThickIt)

Fall prevention:
* remove throw rugs and clutter on floor
* don’t use a step stool
* put things at eye level rather than reaching up for things
* hold onto hand rails and don’t carry a load of things while using stairs

Key points:
* be observant
* control the environment
* protect your brain — reduce risk factors
* nutrition: consider vitamin B, fish oil, Mediterranean diet, CoQ10?, creatine. (Both CoQ10 and creatine are being studied in PD and atypical PD.)
* exercise, exercise, exercise. This is great for the mind, body, and spirit
* do something you enjoy each day

Organizational resources:
LBDA.org
curepsp.org
shy-drager.org
ppsg.org
wemove.org
caregiver.org
nfacares.org
pdtrials.org
atypical parkinsonism support group organized by Robin Riddle

Notes from Dr. Manning-Bog’s presentation:

Changes in brain tissue overlap between the atypical diseases:
* loss of dopaminergic neurons
* depletion
* presence of cytosolic inclusions

A “Lewy body inclusion” is an abnormal deposit of protein. Many proteins are included but it’s mostly alpha-synuclein.

Alpha-synucleinopathies (PD, MSA, LBD) can either be familial or sporadic.

There are modifiers:
* genetics
* environment
* aging

Alpha-synuclein comprises up to 2% of total brain protein in normal brains.

Alpha-synuclein can self-aggregate or bind itself to form multimers of the protein and even alpha-synuclein fibrils.

Alpha-synuclein aggregation (or clumping) could be due to:
* increased expression
* decreased degradation (ie, the cell doesn’t get rid of the protein)
* exposure to toxicants that can stimulate alpha-synuclein to bind itself

In the last few years, a transgenic mouse model was developed for MSA (by Eliezer Masliah’s group at UC San Diego). This is an exciting tool because researchers can isolate and manipulate the alpha-synuclein gene! Now that Dr. Masliah has generated these MSA mice, there is a tool that we can use to study mechanisms to disaggregate and clear alpha-synuclein from cells (i.e. neurons in PD and oligodendroglia in MSA). We can use this tool to test therapeutics in a pre-clinical environment.

Images were shown of alpha-synuclein fibrils in test tubes. This research was done at UC Santa Cruz. This research is promising. Researchers could disintegrate the fibrils (although not always completely) and may leave some toxic synuclein species.

Eliezer Masliah’s group at UC San Diego tried to target the aggregation of synuclein and increase the degradation of synuclein by giving the drug rifampicin to MSA mice. This partially worked. Results were promising — less cell death and alpha-synuclein deposition were apparent in mice treated with rifampicin.

Dr. Manning-Bog’s research approach is to deliver alpha-synuclein to where it needs to go. The goal is to restore alpha-synuclein trafficking via the lipid raft.

If researchers find a mechanism that prevents alpha-synuclein build-up in cells, these agents can be tested in animal models of other diseases that involve alpha-synuclein (including the MSA model or a mouse model of alpha-syn build-up in neurons).

>From this standpoint, any work that is done on these aspects of alpha-synuclein is important to any PD form that has alpha-synuclein pathology. (For example, the alpha-synuclein trafficking arm of my research program, for example, is relevant to any PD form with alpha-synuclein pathology.)

[I asked Dr. Manning-Bog why she talked about the MSA mouse model during her presentation. She replied: “While putting together my talk for the symposium, I asked Dr. Brandabur what types of Atypical PD were most commonly treated at the Institute. She informed me that MSA is one of the more predominant Atypical PD forms of the Institute’s patient population. For this reason, I focused on the research of other labs, because it would be so directly relevant to many patients. Patients with atypical PD are starved for information, so I thought that I should try to tailor the presentation to their interests.”]

Dr. Manning-Bog is also at step one of some tau research. (She has an intern working on this.) She’s seen toxic tau protein changes in DJ1 transgenic mice. This may be a good model for researching Parkinson’s Disease Dementia. This is a first step.

[Robin’s note: PD, DLB and MSA are disorders of alpha-synuclein. They are called alpha-synucleinopathies. Any of the alpha-synuclein research should help these disorders. Of these, only PD and DLB are Lewy body diseases. AD, PSP and CBD are disorders of tau. They are called tauopathies. Any of the tau research should help these disorders. Because DLB typically appears with Alzheimer’s pathology – the so-called “Lewy body variant of Alzheimer’s disease” – tau research may help the DLB community as well.]

Notes from the Q&A:

Q: Can you have the other symptoms of PSP without having the eye movement problem?
A by Dr. Liang: Yes.

Q: What’s the story about statins?
A by Dr. Manning-Bog: Statins have been studied in a few models and seem to be neuroprotective. (See note 1 below.)
A by Dr. Liang: Statins can effect muscle tissue. The atypical PD disorders are neurological disorders, not muscular disorders, so statins are not implicated in the decline seen in these disorders.

Q: When do you get Lewy bodies?
A by Dr. Manning-Bog: Lewy bodies develop throughout the brain predominantly in disease conditions.
A by Dr. Liang: But it could be that Lewy bodies are part of normal aging. We don’t know.
A by Dr. Manning-Bog: We don’t know yet if Lewy bodies are toxic. Currently, we don’t think they cause the disease. They may serve to sequester toxic synuclein. It may be that when synuclein is not sequestered into a Lewy body, it’s toxic.
A by Dr. Manning-Bog: In PD, Lewy bodies start in the brain stem and progress to midbrain, then cortex. In DLB, there are Lewy bodies in the brain’s cortex.

Q: Can imaging see Lewy bodies?
A: No, Lewy bodies are only detectable upon autopsy.

Q: What’s the prevalence of dementia in these disorders?
A by Dr. Liang: The studies vary between 30% and 80% of those with PD getting dementia. It depends on what tests are given to research participants and the definition of “dementia.”

[Answer by Robin:
DLB: 100% of those with DLB have dementia; “progressive dementia” is a “central feature” of DLB (according to the diagnostic criteria)
MSA: none of those with MSA have dementia; according to the diagnostic criteria, dementia is an exclusionary criterion for MSA
PSP: according to the latest clinicopathological correlations, 54% to 62% of those with PSP had dementia as a primary symptom
CBD: there have been no studies on this; my impression is that the percentage for CBD is roughly the same as for PSP; however, it seems from Dr. Liang’s presentation that the percentage may be higher]

Q: What about stem cell research?
A by Dr. Manning-Bog: In research using iPS (induced pluripotent stem cells) to create dopmainergic neurons, the yield is only two percent! This means that iPS isn’t an efficient means of treatment currently. But iPS offers a great way to study the disease mechanism. Before any iPS cells are transplanted into patients, we need to study teratomas, the tumors that can grow.

Q: Are you hopeful about the research?
A by Dr. Manning-Bog: Yes, I’m hopeful!

Note 1:
Dr. Manning-Bog provided two references on statin studies. You can look up the abstracts on pubmed.gov by using the PubMed ID#.

1. The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor lovastatin reduces severity of L-DOPA-induced abnormal involuntary movements in experimental Parkinson’s disease.
Schuster S, Nadjar A, Guo JT, Li Q, Ittrich C, Hengerer B, Bezard E.
J Neurosci. 2008 Apr 23;28(17):4311-6.
PubMed ID#: 18434508

2. Simvastatin is associated with a reduced incidence of dementia and Parkinson’s disease.
Wolozin B, Wang SW, Li NC, Lee A, Lee TA, Kazis LE.
BMC Med. 2007 Jul 19;5:20.
PubMed ID#: 17640385

New book by Parkinson’s Plus Patient Dan Brooks

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Dan Brooks started a blog about his life with Parkinson’s Plus in December 2006. (Ru posted about this on The Back Porch.) The blog — at http://wewillgoon.blogspot.com/ — has grown into a book, which has just been published! The book, “I Will Go On: Living with a Movement Disorder,” is available online through Amazon* for $16. Here’s some info from amazon.com about the book:

“Dan was a 50-year-old husband, father and district-level administrator in a public school system, when he first noticed pronounced tremors, speech difficulties and walking problems developing. In this book, Daniel chronicles his life with a Parkinson’s Plus syndrome and explains how he dealt with the neurological decline that resulted. Read a user-friendly, patient’s explanation of the defining symptoms of these atypical Parkinsonism disorders and find out how this neurodegenerative disease progressed in Dan’s case. This book addresses the many facets of neurodegenerative diseases, while primarily focusing on Atypical Parkinsonian disorders, namely PSP, MSA, and CBD. Parkinson’s Disease is also discussed in depth. Dan tells a compelling and inspirational story of how he maintained his faith in God, while courageously facing life with a movement disorder.”

Dan’s goal is to encourage and inspire patients or caregivers as they face the challenges posed by neurodegenerative illness. He wrote to me: “Sometimes this medical condition is overwhelming, as you know, but I have adjusted and learned to accept what is happening. There is still a lot of life to live and I am very energized right now by this book project. … I am very pleased to have finished [the book]. My hope is that patients and caregivers will appreciate the patient’s viewpoint from which I write. … If I help one person with this book, it will have been worth the effort.”

You can read an overview about the book and learn more about Dan at his blog http://wewillgoon.blogspot.com/ I’m sure you will agree that he’s a remarkable person! Many of us count ourselves lucky that our paths have crossed with his.

Robin

* Link to amazon.com for “I Will Go On: Living with a Movement Disorder”
http://www.amazon.com/Will-Go-Living-Mo … 597&sr=8-1

“Speech, Swallowing, and Mealtime” – Notes from 2/18/09 Webinar

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CurePSP (psp.org) hosted a webinar today on the topic of “Speech, Swallowing and Mealtime Questions.”  The speaker was expert speech therapist Laura Purcell Verdun.

Though many of the slides shown during today’s webinar are specifically about PSP and CBD, most of the slides were not limited to these two disorders. In addition, speech and swallowing problems occur in all the atypical parkinsonism disorders.

Here are the notes I took during the web-based conference call.  Please share your notes as you may have picked up different points than I did.

Robin

Robin’s Notes from

Speech, Swallowing and Mealtime Questions
CurePSP Webinar
February 18, 2009
Presenter:  Laura Purcell Verdun, SLP-CCC
([email protected], 703/573-7600 ext 1414)

Definitions:
Dysphagia:  difficulty swallowing
Aspiration:  food or liquid going into the lungs
Silent aspiration:  aspiration without clinical indication (cough, choke)

PSP swallowing difficulties:
difficulty looking down at plate of food
mouth stuffing or rapid drinking (frontal lobe problems)
poor self-feeding due to tremor or rigidity
restricted head and neck posture
hyperextension of head is especially a problem in PSP (food/liquids can go straight down to the lungs)
impaired coordination between swallowing, breathing, and eating
lack of awareness of swallowing

CBD swallowing difficulties:
slow or impaired chewing
apraxia
slowed swallowing movements

Swallowing management:
early evaluation of swallow
frequent monitoring of swallowing function
what are the patient’s goals?  (caloric intake, enjoyment, etc)

Swallowing evaluation:
patient/family should bring to meeting info on swallowing/feeding history

Common clinical questions:
do you have trouble swallowing?
do you have excess saliva in your mouth?
do meals take longer to eat?
does food stick to roof of mouth?
do you cough or clear your throat when you drink water or other liquid?
do you have trouble taking medication (pills)?

Warning signs:
drooling
food collecting in mouth
increased effort in swallowing
trouble talking
coughing and choking with a red face (showing it’s a stressful event)
wet voice (gurgly, sounds like someone is talking underwater) – the concern is that saliva is sitting on vocal cords
key:  do you cough or choke during mealtimes than during other times of the day?

VFSS = MBSS
Videofluroscopic Swallowing Study = Modified Barium Swallow Study
xray video of swallowing mechanism
important:  needs to replicate home feeding environment  (example: does patient hold cup at home?)
identify safe swallowing strategies

Oral hygiene – one treatment option:
need scrupulous dental care to get bacteria out of mouth
avoid alcohol, caffeine, and smoking
use club soda or sparkling water to help cut through secretions
Biotene (biotene.com) and Oasis – two good over-the-counter product lines
Plak-Vac oral suction toothbrush  (800/325-9044)

Drooling
use prescription anticholinergics such as Scopolamine patch, Robinul, atropine drops
speak with MD about botox injections.  Find an MD with experience doing these injections as there is a chance that the injections can worsen the swallow mechanism.

How will swallowing strategies impact the caregiver or family?  There can be changes to meal preparation.

Mealtime strategies:
sit upright
limit distractions
clear secretions from mouth prior to eating
put food plate in line of vision
experiment with different plates, utensils, straws, cups, etc.  (Sometimes straws can be useful.)
keep chin down
slow, steady rate of ingestion:  small bite followed by a swallow
alternate liquid and food swallows
take liquids by teaspoons
no Jello
be sure everyone knows the Heimlich maneuver
supervision during mealtimes
find other ways to nurture person with PSP/CBD

Diet modifications:
stick with moist, tender foods (eg, dark meat chicken, fish, casserole)
blend multiple consistency items
avoid textured, particulate, and dry foods (eg, nuts, cereal)
thickening liquids to slow rate of transit.  Problems:  may lead to reduced fluid intake; may be harder for lungs to tolerate thickening agents if aspirated

Thickening agents:
commercial thickeners
tofu
potato flakes

VitalStim:
clinical efficacy and utility of this therapy is unproven

Possible indications for alternate nutrition

Things to consider regarding a feeding tube:
discussions should take place sooner rather than later
don’t wait for a crisis!
discussions should be repeated
gastric contents and saliva can be aspirated
no clinical trials to know if feeding tubes are beneficial

Speech:
Change in speech may occur earlier in PSP than CBD
People with PSP and CBD may lose the ability to speak in late stages

Speech terms:
Dysarthria:  trouble pronouncing sounds; consistent articulation errors
Dysphonia:  difficulty generating a clear, strong voice
Apraxia:  inconsistency of errors; speech disorder
Oral apraxia:  the inability to perform a task upon command
Progressive non-fluent aphasia (PNFA):  simplified formation of sentences

PSP speech:
hypokinetic, spastic dysarthria
palilalia  (repeat your own words)

CBD speech:
apraxia of speech and oral apraxia
hypokinetic, spastic dysarthria
often has a component of PNFA
yes-no reversal

PSP speech strategies:
take a good breath before starting to speak
speak up and be deliberate
keep sentences short
repeat entire sentence if necessary, not just one word
use gestures
say one sentence at a time without immediate repetition
LSVT may help  (lsvt.org)

CBD speech strategies:
short phrases and simpler language
it may help to use written communication
use gestures
investigate using communication board

Strategies for the listener to utilize:
eliminate distractions, including background noise
face the speaker
keep questions and comments brief
ask one question at a time
stick with one topic at a time
provide choices to ease decision-making  (eg, ask “do you want coffee or tea?” vs. “what do you want to drink?”)

Robin’s note about resources:  I didn’t take these down because they are largely the same as appeared in a 2008 article authored by Laura Purcell Verdun.

Questions and Answers:

No medication can help with swallowing.

Laura personally does not use VitalStim for any patient population.  There is no research on VitalStim in treating neurodegenerative diseases (PD, PSP, etc).  Make sure your expectations aren’t misplaced.  VitalStim doesn’t address either of Laura’s two priorities in treatment.

Her priorities in treatment are oral hygiene and mealtime management.

Personal voice amplifiers can work if the voice is quiet but the speech is still clear.  Could even use a portable Karaoke machine.  Other machines:  Spokesman, Chattervox (more expensive).  [Robin’s note:  I couldn’t find the Spokesman or Spoke Man device any place on the web.  Hopefully someone can find it.  I will email Laura about the correct name.]

Augmentative or assisted communication device.  These are machines that are used to communicate for someone.  Most devices are computer-based or electronic.  How will you access this device?  Pointer, eye piece, etc.  Are there cognitive problems precluding the use of such devices?

Swallowing problems may occur later in CBD than PSP.  Hard to say.

Question:  Litvan published a paper in ’01 that showed that on average those with PSP died 18 months after the onset of dysphagia while those with CBD died 49 months after the onset of dysphagia.  Is this roughly your experience with survival time as well?
Laura’s answer:  those with PSP have dysphagia problems sooner than those with CBD but survival time is probably longer than 18 months for PSP.  She hasn’t kept track of survival time.

As soon as a person is diagnosed with one of these disorders, there should be a conversation about whether a feeding tube is desired in the future.  This is a very personal decision.  Not all MDs are comfortable bringing up this topic.  What does the person hope to accomplish in placing a feeding tube?  This conversation needs to be repeated later.

A soft, cervical collar may help keep the head up.

Exercises can be of benefit.  Apraxia can be aided in speech tasks (repeating words) and in non-speech tasks (blowing out candle, sticking out tongue).  She said that apraxia is especially a problem in PSP.  (I think she misspoke; she meant to say CBD.)

 

PSP/CBD Update – Diagnosis, Genetics, Treatment (Litvan ’07)

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Larry in southern California (whose wife has PSP) emailed several of the Yahoo!Groups yesterday about this August ’07 Irene Litvan article, asking if anyone knew anything about “transcranial sonography (TCS),” which is a diagnostic method mentioned in the article. Turns out that only a short paragraph of the Litvan article was on TCS. Dr. Irene Litvan is one of the top experts in the world on PSP. She’s written quite a bit on CBD and MSA as well.

This review article is an update for neurologists as to what advancements have been made in the area of diagnostic tools, genetics, and treatments for PSP, CBD, and MSA. The rest of this post is a summary of what I learned from the article. If you want more details, read the abstracts of the articles on PubMed (pubmed.gov – enter in the ID#). (A few of the full articles are available online for free. It’s mostly the harder-to-comprehend papers that are free!)

Dr. Litvan, writing in August ’07, concludes the article by saying that the field of atypical Parkinsonian disorders — diagnostic tools, genetics, and treatment — has “significantly advanced over the past year.” From a patient/family perspective, it is hard to agree with her.

DIAGNOSIS. From the article, I learned about recent studies of four diagnostic methods using “ancillary tools”:

1. TCS (transcranial sonography): TCS may help distinguish PD vs. atypicals, PD vs. MSA/PSP, MSA/PSP vs. CBD, and perhaps PSP vs. CBD, if I’m reading this correctly. PSP can be differentiated from CBD because the dilation of the third ventricule of the brain has so far only been described in PSP. This TCS study was done in Europe. TCS cannot be performed in up to 20% of patients. The study had nothing to say about LBD or about differentiating MSA from PSP. Of all the papers referenced in her review article, this is the only one labeled as “of outstanding interest” by Dr. Litvan. (PubMed ID#17189043)

2. Diffusion-weighted MRI: This method may help distinguish PSP and MSA-P. (PubMed ID#17089396)

3. T2-weighted MRI: This method may help differentiate MSA and PD. (PubMed ID#17361340)

4. Saccade tasks: This sort of diagnostic test (of saccade latencies and directional errors) would be performed by a neuro-ophthalmologist. This test may help distinguish PSP vs. CBD/PD. (PubMed ID#17124191)

GENETICS. From the article, I learned some things about genetics that I was unaware of:

* The location of a second genetic risk for PSP was identified in 2007. (This utilized brain tissue at the Mayo Jax PSP Brain Bank. PubMed ID#17357082; very challenging reading)

* The LRRK2 genetic mutation, which can be a factor in PD and DLB, is “not associated with MSA or with sporadic PSP.” (This is the genetic mutation that was discussed in the Frontline program last week on PD, “My Father, My Brother, and Me.”)

TREATMENT. And here’s what I learned about treatment:

* Because of the success (“significant gait and postural balance benefits”) of an Italian study of DBS in two locations of the brain in advanced PD patients, Dr. Litvan believes that DBS of the pedunculopontine nucleus (PPN) “may be useful in treating the balance and gait disorder in the atypical parkinsonian disorders, particularly in patients with PSP and MSA.” In fact, CurePSP is funding a study of DBS of the PPN in those with PSP in Toronto. (PubMed ID#17251240)

* Mayo Rochester is studying respiratory dysfunction in MSA. (PubMed ID#17235127; very challenging reading)

* Transgenic mice models are being developed for PSP, CBD, and MSA.

What follows are the abstract of the article.

Robin

Current Opinion in Neurology. 2007 Aug;20(4):434-7.

Update of atypical Parkinsonian disorders.

Litvan I.
Department of Neurology, University of Louisville, Louisville, Kentucky.

PURPOSE OF REVIEW: This timely update discusses novel diagnostic approaches, recently identified genes, and innovative experimental symptomatic treatments for these devastating disorders.

RECENT FINDINGS: Differential patterns in the basal ganglia transcranial sonography, magnetic resonance diffusion-weighted imaging regional apparent diffusion coefficients in the brainstem, basal ganglia T2-weighted gradient echo sequences combined with fluid attenuated inversion recovery, or saccades error rates in single and mixed-task blocks could help differentiate the various parkinsonian disorders. In addition to the familial tauopathies (frontotemporal dementia associated with chromosome 17) presenting with an atypical parkinsonian phenotype, ‘TDP-43opathies’ and ‘tataboxbinding or ataxinopathies’, depending on the protein deposited in the brain, widen the scope of the familial atypical parkinsonian disorders. Recent identification of novel deep brain stimulation targets such as the pedunculopontine nucleus may help treat the balance and gait disorder in atypical parkinsonian disorders in the near future.

SUMMARY: These new findings are important for diagnosis, help better understanding of the nosology of these disorders, and will likely in the near future impact our clinical practice.

PubMed ID#: 17620879 (see pubmed.gov for abstract only)

Siblings/children of PSPers have motor+other deficits(’01)

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(I did a search and couldn’t find any previous post about this 2001 study.)

Remember how we’ve been told that PSP doesn’t run in families except in rare cases…. I learned about this disturbing 2001 article during the October ’08 PSP/CBD webinar presented by Dr. Golbe, an expert in PSP. Another MD (Timothy Hain) described this article as follows: “Relatives of patients with PSP tend to score more abnormally on screening tests for Parkinsonism (Baker and Montgomery, 2001), supporting either a genetic factor or exposure to a common environmental toxin.”

Note that fewer than 1% of those diagnosed with PSP have a family member with PSP. The percentage for PD is much higher: 20-25%. (Those numbers are also from the Golbe webinar. I’ve posted my notes to Golbe’s webinar here on the Forum.)

So maybe first-degree relatives don’t get PSP but have some sort of motor, olfactory, and affective deficits….? (FDRs = siblings and children) The 2001 article states: “In any case, what is clear is that many of the FDR testing in the abnormal range in the current study are unlikely to go on to develop PSP, suggesting that the PD Battery may be detecting an asymptomatic carrier state or subclinical form of the disease.”

After you’ve had a chance to read over the rest of this post, please let me know if you have a different take on things or if you’ve understood more of it than I have!

Here’s the abstract of the 2001 article:

Neurology. 2001 Jan 9;56(1):25-30.
Performance on the PD test battery by relatives of patients with progressive supranuclear palsy.
Baker KB, Montgomery EB Jr.
Departments of Neurology and Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, OH.

OBJECTIVE: To determine whether there is a greater prevalence of asymptomatic first-degree relatives (FDR) of patients with progressive supranuclear palsy (PSP) performing abnormally on the PD test battery (PD Battery) compared to sex- and age-matched normal control (NC) individuals. The PD Battery incorporates tests of motor function, olfaction, and mood. It has high specificity and sensitivity in distinguishing mildly affected PD patients from NC individuals in previous studies.

METHODS: This test battery and regression analysis-derived scoring equations were applied to asymptomatic FDR.

RESULTS: Twenty-three FDR and 23 NC individuals were tested. Of the FDR, 39% scored in the abnormal range, whereas none of the NC individuals achieved abnormal scores. This difference was significant. Further analysis demonstrated that the two groups differed significantly on a measure of simple reaction time.

CONCLUSIONS: The proportion of FDR who demonstrated abnormal performance on the PD Battery was greater than NC individuals. Thus, the PD Battery may detect the asymptomatic carrier state or risk for PSP or a subclinical effect of a shared environmental exposure.

PubMed ID#: 11148231 (see pubmed.gov for abstract only)

Dr. Golbe had one slide on this paper in his presentation: (the info wasn’t presented in this way but the facts are correct)

Performance on the PD test battery by [asymptomatic] relatives of patients with [sporadic] progressive supranuclear palsy

FDR of patients with PSP
23 studied (7 sons, 13 daughters, 1 brother, 2 sisters)
Mean age = 43.5 years
Abnormal score on battery of motor, olfactory and affective test = 9 people (39.1%)
Median reaction time on a reaction time task = 380 ms

Controls
23 gender-matched individuals
Mean age = 44.3 years
Abnormal score on battery of motor, olfactory and affective test = 0
Median reaction time on a reaction time task = 305 ms

I exchanged email with the lead author Dr. Baker. I asked if this study had been reproduced since 2001. He said: “Unfortunately, I have no follow-up information to what is published in that report as we were unable to get funding for a larger scale project and our research has since been directed elsewhere.”

The remainder of this email is the Discussion section of the 2001 article, which I acquired.

Robin

Some abbreviations used in this excerpt from the article:
FDR = first-degree relatives
NC = normal controls
BDI = Beck Depression Inventory

“Discussion. The FDR of patients with PSP had a significantly higher prevalence of abnormalities on the PD Battery than did NC subjects without a family history of movement disorders. Consistent with this was the finding that the performance of the two groups was significantly different across all three subtests of the battery. It is impossible to know at this point which, if any, of the FDR might go on to develop PSP at some point in the future. The increasing number of familial cases being reported in the literature suggests that there may be some increase in risk, but just how much is not clear. There was no family history of PSP beyond the single index case for each of the FDR participating in this study. In any case, what is clear is that many of the FDR testing in the abnormal range in the current study are unlikely to go on to develop PSP, suggesting that the PD Battery may be detecting an asymptomatic carrier state or subclinical form of the disease.”

“Investigations into the factors responsible for PSP, whether focused on genetics or environmental toxins, are complicated by the late onset and rarity of the disease as well as the limited reliability of historical information from families. Moreover, similar to what has been observed in PD, there may be a familial form of PSP that differs genetically from the more typical and seemingly sporadic form of the disease. Indeed, the pattern of inheritance suggested by reports in the literature has been mixed, with both recessive and dominant patterns observed. Other familial case reports are not sufficiently complete to allow a confident determination to be made. However, a recent investigation examining the frequency of tau polymorphisms in PSP patients with no family history of the disease showed evidence of linkage disequilibrium between PSP and the tau marker using a recessive as opposed to a dominant model of inheritance. Although certainly complicated by the factors mentioned previously, this study provides some evidence that the more sporadic variety of PSP may be recessively inherited with variable penetrance.”

“If we assume an autosomal recessive mode of transmission, then 25% or approximately 6 of the 23 FDR tested in the current study would be expected to carry the putative gene or be at risk. Alternatively, an autosomal dominant pattern suggests that 50% or approximately 12 of the 23 subjects should be at risk. The actual prevalence of abnormalities in the FDR tested was 39% or 9 of 23, a figure that falls about midway between the different models. The absence of false positives in the matched NC group, although worthy of note, does not bear a significant impact on this finding. Within the larger database of 120 NC individuals from which the matched subjects were selected, the total false positive rate is 9%. Although there is no correlation between age and PD score in that group, the false positive rate for individuals under 52 years of age is only 3.1%. Given that 20 of the 23 FDR of PSP patients were 51 years of age or younger, it is not surprising that the NC sample should be without false positives. Even if we were to allow for a 9% false positive rate in NC individuals, this would predict that only 1 of the 11 FDR without the gene would have a false positive abnormality using the dominant model or 2 of 17 using the recessive model. Thus, the PD Battery would have accurately identified 66% (8 of 12) under the autosomal dominant model and 42% (7 of 17) using the autosomal recessive model—much higher than the rather conservative 9% false positive rate in the NC sample. Finally, a sex-linked inheritance pattern does not seem likely; however, the power of the performed test was insufficient to completely rule out such a pattern in this small sample.”

“The observed difference in olfactory function between the two groups is of interest given the lack of olfactory findings in patients with PSP. Reports in the literature have shown that the odor identification ability of patients with PSP is comparable to normal control subjects and significantly better than patients with idiopathic PD. However, in reviewing both reports it is clear that there is a marked trend toward reduced olfactory function in the patients with PSP. Neither set of authors reported the results of subsequent power analysis, leaving open the possibility of a type II error in their results. That is to say, the possibility exists that the null hypothesis, which in this case would state that there is no difference between the groups, may have been falsely accepted. The higher rate of smoking in the FDR group is of some concern given the potential impact of smoking on the sense of smell. However, the PDscore reflects performance on all three subtests and abnormal performance on any single subtest of the battery will not result in an abnormal score. The observed difference on the BDI is not surprising, given previous reports of psychiatric symptoms, including depression-like symptoms, in patients with PSP.”

“Reaction time was observed to be significantly longer in the FDR group as compared to the NC group across all tasks. If we assume the possibility of a subclinical disease state or an asymptomatic carrier state in PSP, there is both theoretical and empirical evidence that coincides with this finding. Previous studies have suggested that motor initiation utilizes physiologic mechanisms separate from those underlying motor execution. These studies have suggested that the anterior striatum, consisting of the head of the caudate nucleus and the anterior putamen, may be more involved in motor initiation, whereas the posterior striatum is more involved in motor execution. PET and SPECT have shown preservation of dopamine in the anterior striatum relative to posterior striatum of PD compared to PSP patients. Several groups have demonstrated that reaction time is delayed in patients with PSP, even in those with relatively mild disease. All of this suggests that reaction time may be of some value in further improving the identification of PSP as well as the asymptomatic carrier state or subclinical form of the disease.”

“There was an observed trend in the current study for extension movements to be more affected than flexion movements in the FDR group. This is consistent with observations in experimental animal studies. Denny­Brown showed that nonhuman primates became immobile in a flexed posture following large lesions of the globus pallidus. Similarly, injections of muscimol, a gamma-aminobutyric acid (GABA) agonist that inactivates the globus pallidus, have been shown to produce a greater slowing of extension movements compared to flexion movements on a wrist flexion and extension task similar to that used in the current study. Finally, recordings of neuronal activity changes made in nonhuman primates and correlated with wrist flexion and extension movements before and following induction of parkinsonism using n-methyl-4-phenyl-1,2,3,6-tetrahyrdopyridine (MPTP) showed that greater changes in neuronal activity following MPTP were associated with the wrist extension task than with the flexion task.”

“One possible explanation for the greater impairment of extension movements may be that there is a greater representation or dedication of neurons to flexion motor control in the basal ganglia. This greater representation could explain the predominance of flexion after stimulation and may convey increased resistance to degradation of performance
of flexion movements. Thus, flexion is relatively well preserved, resulting in a flexor bias such as flexed posture. Also, there would be greater impairment of extension movements with disease.”

“The results of the current study are of considerable interest regardless of whether the pathogenesis of PSP involves genetic or environmental factors. In either case, the PD Battery, either in its present form or with the addition of reaction time data, could help advance research into the cause of PSP. If the cause is genetic, then the PD Battery may be able to detect the asymptomatic carrier state or risk. Comparing the genetic makeup of the FDR scoring in the abnormal range with that of the unaffected parents or siblings who score in the normal range could lead to the identification of a shared genetic makeup that could cause or facilitate PSP. Likewise, if the cause is environmental, the PD Battery may be able to detect preclinical or subclinical involvement. As such, comparing the environmental exposure of FDR who score in the abnormal range with those who do not may help to identify potential causative agents. Further, the presumably earlier detection would be closer to the time of exposure, thereby facilitating the discovery of causative environmental factors.”

Here’s some info on the “PD Battery” and the “PDscore”:

“PD Battery. The PD Battery incorporates tests of motor function, olfaction, and mood, and has been described previously. Briefly, the motor task consists of rapid wrist flexion and extension movements made to one of two types of targets in response to an auditory “go” signal. Olfactory function was measured by the University of Pennsylvania Smell Identification Test (UPSIT, Sensonics, Inc. Haddonfield, NJ). Finally, mood state was assessed using the BDI. Results from the test battery were combined in a logistic regression analysis into an equation that yielded a score (PDscore) between 0 and 1.0 for each individual.”