Can olfactory bulb biopsy distinguish PSP – MSA – PD?

The last line of this abstract caught my eye: “It is suggested that olfactory bulb biopsy be considered to confirm the diagnosis in PD subjects being assessed for surgical therapy.” In the article, the authors indicate that one of their concerns is that MSAers, misdiagnosed as having PD, will get deep brain stimulation and will be harmed by that. They say:

“It has been reported that patients with multiple system atrophy (MSA) misdiagnosed as PD have undergone placement of deep brain stimulators and have not had a lasting benefit. As the characteristic glial cytoplasmic synuclein-immunoreactive inclusions of MSA are also present and diagnostic in the olfactory bulb, as reported by Kovacs et al. (we have confirmed this finding in five MSA cases), olfactory bulb biopsy would differentiate between PD and MSA. Olfactory bulb biopsy might therefore be useful for the evaluation of candidates for surgical therapy of PD, where the risks of biopsy might be justified if it would spare non-PD subjects the greater risks associated with pallidotomy, thalamotomy, deep brain stimulation or neural transplantation.”

In one of the response letters, scientists asked specifically about PSP and MSA. The authors of the main article reply:

“The authors question whether olfactory bulb biopsy could distinguish PD from MSA or PSP, especially since Lewy bodies may be present in sparse numbers in both of the latter two conditions. We have utilized olfactory bulb alpha-synuclein stains in six MSA cases, and found all had numerous and characteristic flame-shaped glial cytoplasmic inclusions, unambiguously identifying these as MSA. It may be more difficult to distinguish PD from PSP. Our data show that 15 of 45 PSP cases had olfactory bulb Lewy bodies. Of these 15, the majority also had Lewy bodies in the brainstem and limbic region, suggesting that these subjects had both PD and PSP. Whether or not these subjects would differ in surgical outcome from those with pure PD or pure PSP is not known at this time. We are currently testing methods for detecting glial tauopathy to determine whether these might positively identify PSP subjects from olfactory bulb material.”

So an olfactory bulb biopsy — which is a relatively minor surgical procedure done while someone is alive — would differentiate PD from MSA but not PD from PSP. To increase the success rate of deep brain stimulation going forward, it sounds like researchers may require an olfactory bulb biopsy to weed out the MSAers.

And I thought the part about “testing methods for detecting glial tauopathy to determine whether these might positively identify PSP subjects from olfactory bulb material” was interesting too.

Probably not many of you will want to read the abstract (or the full paper). But if you do and you pick up a different facet, please share!

Robin

Acta Neuropatholpgica. 2009 Feb;117(2):169-74. Epub 2008 Nov 4.

Olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders.

Beach TG, White CL 3rd, Hladik CL, Sabbagh MN, Connor DJ, Shill HA, Sue LI, Sasse J, Bachalakuri J, Henry-Watson J, Akiyama H, Adler CH; Arizona Parkinson’s Disease Consortium.
Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ.

Involvement of the olfactory bulb by Lewy-type alpha-synucleinopathy (LTS) is known to occur at an early stage of Parkinson’s disease (PD) and Lewy body disorders and is therefore of potential usefulness diagnostically. An accurate estimate of the specificity and sensitivity of this change has not previously been available. We performed immunohistochemical alpha-synuclein staining of the olfactory bulb in 328 deceased individuals. All cases had received an initial neuropathological examination that included alpha-synuclein immunohistochemical staining on sections from brainstem, limbic and neocortical regions, but excluded olfactory bulb. These cases had been classified based on their clinical characteristics and brain regional distribution and density of LTS, as PD, dementia with Lewy bodies (DLB), Alzheimer’s disease with LTS (ADLS), Alzheimer’s disease without LTS (ADNLS), incidental Lewy body disease (ILBD) and elderly control subjects. The numbers of cases found to be positive and negative, respectively, for olfactory bulb LTS were: PD 55/3; DLB 34/1; ADLS 37/5; ADNLS 19/84; ILBD 14/7; elderly control subjects 5/64. The sensitivities and specificities were, respectively: 95 and 91% for PD versus elderly control; 97 and 91% for DLB versus elderly control; 88 and 91% for ADLS versus elderly control; 88 and 81% for ADLS versus ADNLS; 67 and 91% for ILBD versus elderly control. Olfactory bulb synucleinopathy density scores correlated significantly with synucleinopathy scores in all other brain regions (Spearman R values between 0.46 and 0.78) as well as with scores on the Mini-Mental State Examination and Part 3 of the Unified Parkinson’s Disease Rating Scale (Spearman R -0.27, 0.35, respectively). It is concluded that olfactory bulb LTS accurately predicts the presence of LTS in other brain regions. It is suggested that olfactory bulb biopsy be considered to confirm the diagnosis in PD subjects being assessed for surgical therapy.

PubMed ID#: 18982334

The comments are:

Acta Neuropathologica. 2009 Feb;117(2):213-4; author reply 217-8. Epub 2008 Nov 25.
Can olfactory bulb biopsy be justified for the diagnosis of Parkinson’s disease?
Parkkinen L, Silveira-Moriyama L, Holton JL, Lees AJ, Revesz T.
Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
PubMed ID#: 19031077

Acta Neuropathologica. 2009 Feb;117(2):215-6; author reply 217-8. Epub 2008 Nov 5.
Olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders.
Jellinger KA.
Institute of Clinical Neurobiology, Vienna, Austria.
PubMed ID#: 18985364

Improvement of gaze control after training/exercises

This is a neat little study out of the Univ of Minnesota where 19 people with possible or probable PSP were part of a randomized controlled trial. Some received “balance training complemented with eye movement and visual awareness exercises” and others received balance training alone. Gaze control was assessed after week 1 and week 5. Gaze control significantly improved for the first group (who received the balance training and eye movement exercises). Presumably the goal is to combat downward gaze palsy that many with PSP have. An improvement in eye movement perhaps could lead to safer walking, easier reading, and an easier time finding food on one’s plate.
Robin

Archives of Physical Medicine & Rehabilitation. 2009 Feb;90(2):263-70.

Improvement of gaze control after balance and eye movement training in patients with progressive supranuclear palsy: a quasi-randomized controlled trial.

Zampieri C, Di Fabio RP.
Department of Physical Medicine and Rehabilitation, University of Minnesota, Minneapolis, MN.

OBJECTIVE: One of the main oculomotor findings in progressive supranuclear palsy (PSP) is the inability to saccade downward. In addition, people with PSP have difficulty suppressing fixation, which may contribute to vertical gaze palsy. The objective was to investigate the effectiveness of a rehabilitation intervention tailored to enhance suppression of fixation and gaze shift in participants with PSP.

DESIGN: Controlled trial with a quasi-randomized design. Measures occurred at week 1 and 5. Researchers assessing participants were blind to the group assignments.

SETTING: Movement disorders assessment laboratory.

PARTICIPANTS: Nineteen adults with possible or probable PSP who were ambulatory for short distances and had far visual acuity of 20/80 and a Folstein Mini-Mental State score of more than 23.

INTERVENTIONS: Balance training complemented with eye movement and visual awareness exercises was compared with balance training alone.

MAIN OUTCOME MEASURES: Gaze control was assessed using a vertical Gaze Fixation Score and a Gaze Error Index.

RESULTS: Gaze control after the balance plus eye exercise significantly improved, whereas no significant improvement was observed for the group that received balance training alone.

CONCLUSIONS: These preliminary findings support the use of balance and eye movement exercises to improve gaze control in PSP.

PubMed ID#: 19236979

Improvement in gaze control after training/exercises in PSP

This is a neat little study out of the University of Minnesota where 19 people with possible or probable progressive supranuclear palsy (PSP) were part of a randomized controlled trial.  Some received “balance training complemented with eye movement and visual awareness exercises” and others received balance training alone.  Gaze control was assessed after week 1 and week 5.  Gaze control significantly improved for the first group (who received the balance training and eye movement exercises).  Presumably the goal is to combat downward gaze palsy that many with PSP have.  An improvement in eye movement perhaps could lead to safer walking, easier reading, and an easier time finding food on one’s plate.
The abstract is copied below.
Robin
————————————–

Archives of Physical Medicine & Rehabilitation. 2009 Feb;90(2):263-70.

Improvement of gaze control after balance and eye movement training in patients with progressive supranuclear palsy: a quasi-randomized controlled trial.

Zampieri C, Di Fabio RP.
Department of Physical Medicine and Rehabilitation, University of Minnesota, Minneapolis, MN.

OBJECTIVE: One of the main oculomotor findings in progressive supranuclear palsy (PSP) is the inability to saccade downward. In addition, people with PSP have difficulty suppressing fixation, which may contribute to vertical gaze palsy. The objective was to investigate the effectiveness of a rehabilitation intervention tailored to enhance suppression of fixation and gaze shift in participants with PSP.

DESIGN: Controlled trial with a quasi-randomized design. Measures occurred at week 1 and 5. Researchers assessing participants were blind to the group assignments.

SETTING: Movement disorders assessment laboratory.

PARTICIPANTS: Nineteen adults with possible or probable PSP who were ambulatory for short distances and had far visual acuity of 20/80 and a Folstein Mini-Mental State score of more than 23.

INTERVENTIONS: Balance training complemented with eye movement and visual awareness exercises was compared with balance training alone.

MAIN OUTCOME MEASURES: Gaze control was assessed using a vertical Gaze Fixation Score and a Gaze Error Index.

RESULTS: Gaze control after the balance plus eye exercise significantly improved, whereas no significant improvement was observed for the group that received balance training alone.

CONCLUSIONS: These preliminary findings support the use of balance and eye movement exercises to improve gaze control in PSP.

PubMed ID#: 19236979  (see pubmed.gov for the abstract only)

“Core body temperature rhythm is altered” in PSP

I don’t think this is a surprise to anyone. With the autonomic dysfunction that can come with PSP, body temperature regulation can malfunction as well. This research is out of Japan; the Japanese are world-class researchers of autonomic dysfunction.
Robin

Clinical Autonomic Research. 2009 Feb;19(1):65-68.

The core body temperature rhythm is altered in progressive supranuclear palsy.

Suzuki K, Miyamoto T, Miyamoto M, Hirata K.
Dept. of Neurology, Dokkyo Medical University, Tochigi, Japan.

We measured circadian rhythmicity in rectal temperature change and found that the amplitude of body temperature was significantly reduced in patients with progressive supranuclear palsy compared to those with Parkinson disease.

PubMed ID#: 19224326 (see pubmed.gov for this short abstract)

Using eye saccade velocity to distinguish PSP-P and PD

This interesting research out of Germany looked at 12 cases of the RS (Richardson’s Syndrome) form of PSP, 5 cases of the PSP-P (PSP-Parkinsonism) form, 27 cases of Parkinson’s Disease, and 23 healthy controls. (It was just published on PubMed though the journal is dated Dec ’08 and the epub is dated 1/14/09.)

At the bottom of this post I’ve copied an abstract of an ’05 journal article explaining the terms RS and PSP-P. In short, “Cases of RS syndrome [make] up 54% of all cases, and [are] characterized by the early onset of postural instability and falls, supranuclear vertical gaze palsy and cognitive dysfunction.” “A second group of [32% are] characterized by asymmetric onset, tremor, a moderate initial therapeutic response to levodopa and were frequently confused with Parkinson’s disease (PSP-P).”

Because PSP-P and PD are so similar in symptoms, clinicians need a way to differentiate the two disorders. The German researchers conclude that video-oculography (VOG) can be used because of the “clear-cut separation between PSP-P and [PD] obtained by measuring saccade velocity.” Typically, a neuro-ophthalmologist has the equipment to conduct a VOG.

It should be noted that none of the patients had pathologically-confirmed diagnoses, so the results may change based upon that.

Robin

Journal of Neurology. 2008 Dec;255(12):1916-1925. Epub 2009 Jan 14.

Differential diagnostic value of eye movement recording in PSP-parkinsonism, Richardson’s syndrome, and idiopathic Parkinson’s disease.

Pinkhardt EH, Jürgens R, Becker W, Valdarno F, Ludolph AC, Kassubek J.
Dept. of Neurology, University of Ulm, Ulm, Germany.

Vertical gaze palsy is a highly relevant clinical sign in parkinsonian syndromes. As the eponymous sign of progressive supranuclear palsy (PSP), it is one of the core features in the diagnosis of this disease.

Recent studies have suggested a further differentiation of PSP in Richardson’s syndrome (RS) and PSP-parkinsonism (PSPP).

The aim of this study was to search for oculomotor abnormalities in the PSP-P subset of a sample of PSP patients and to compare these findings with those of (i) RS patients, (ii) patients with idiopathic Parkinson’s disease (IPD), and (iii) a control group. Twelve cases of RS, 5 cases of PSP-P, and 27 cases of IPD were examined by use of video-oculography (VOG) and compared to 23 healthy normal controls.

Both groups of PSP patients (RS, PSP-P) had significantly slower saccades than either IPD patients or controls, whereas no differences in saccadic eye peak velocity were found between the two PSP groups or in the comparison of IPD with controls.

RS and PSP-P were also similar to each other with regard to smooth pursuit eye movements (SPEM), with both groups having significantly lower gain than controls (except for downward pursuit); however, SPEM gain exhibited no consistent difference between PSP and IPD.

A correlation between eye movement data and clinical data (Hoehn & Yahr scale or disease duration) could not be observed.

As PSP-P patients were still in an early stage of the disease when a differentiation from IPD is difficult on clinical grounds, the clear-cut separation between PSP-P and IPD obtained by measuring saccade velocity suggests that VOG could contribute to the early differentiation between these patient groups.

PubMed ID#: 19224319 (see pubmed.gov for this same abstract)

Here’s an abstract of an important paper on PSP in 2005 that introduced the terminology RS and PSP-P:

Brain. 2005 Jun;128(Pt 6):1247-58. Epub 2005 Mar 23.

Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson’s syndrome and PSP-parkinsonism.

Williams DR, de Silva R, Paviour DC, Pittman A, Watt HC, Kilford L, Holton JL, Revesz T, Lees AJ.
The Queen Square Brain Bank for Neurological Disorders, University College London, UK.

The clinical diagnosis of progressive supranuclear palsy (PSP) relies on the identification of characteristic signs and symptoms. A proportion of pathologically diagnosed cases do not develop these classic features, prove difficult to diagnose during life and are considered as atypical PSP. The aim of this study was to examine the apparent clinical dichotomy between typical and atypical PSP, and to compare the biochemical and genetic characteristics of these groups. In 103 consecutive cases of pathologically confirmed PSP, we have identified two clinical phenotypes by factor analysis which we have named Richardson’s syndrome (RS) and PSP-parkinsonism (PSP-P). Cases of RS syndrome made up 54% of all cases, and were characterized by the early onset of postural instability and falls, supranuclear vertical gaze palsy and cognitive dysfunction. A second group of 33 (32%) were characterized by asymmetric onset, tremor, a moderate initial therapeutic response to levodopa and were frequently confused with Parkinson’s disease (PSP-P). Fourteen cases (14%) could not be separated according to these criteria. In RS, two-thirds of cases were men, whereas the sex distribution in PSP-P was even. Disease duration in RS was significantly shorter (5.9 versus 9.1 years, P < 0.001) and age at death earlier (72.1 versus 75.5 years, P = 0.01) than in PSP-P. The isoform composition of insoluble tangle-tau isolated from the basal pons also differed significantly. In RS, the mean four-repeat:three-repeat tau ratio was 2.84 and in PSP-P it was 1.63 (P < 0.003). The effect of the H1,H1 PSP susceptibility genotype appeared stronger in RS than in PSP-P (odds ratio 13.2 versus 4.5). The difference in genotype frequencies between the clinical subgroups was not significant. There were no differences in apolipoprotein E genotypes. The classic clinical description of PSP, which includes supranuclear gaze palsy, early falls and dementia, does not adequately describe one-third of cases in this series of pathologically confirmed cases. We propose that PSP-P represents a second discrete clinical phenotype that needs to be clinically distinguished from classical PSP (RS). The different tau isoform deposition in the basal pons suggests that this may ultimately prove to be a discrete nosological entity.

PubMed ID#: 15788542 (see pubmed.gov for abstract only)

If you want to read the full paper published in Brain ’05, it’s available online for free here:
http://brain.oxfordjournals.org/cgi/reprint/128/6/1247
I have found that articles that are available for free are not always left online for free access. So if you want to save a copy of this article on your hard drive, do so now.

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

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

CurePSP Webinar
Speech, Swallowing and Mealtime Questions
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)

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)

(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.”

Bak article on cognitive profiles – AD, PSP, CBD, MSA, DLB

Thomas Bak from the UK wrote a great article in Nov/Dec ’06 providing the cognitive profiles of those with AD, PSP, CBD, MSA, and DLB, based upon the subtests of ACE (Addenbrooke’s Cognitive Examination).

You can find it for free online here:
http://www.acnr.co.uk/NO06/ND06_review_cog.pdf

In that article, he says:

“There are two serious problems connected with the use of MMSE in this patient group [with parkinsonian syndromes]. Firstly, MMSE has been demonstrated to be particularly insensitive to frontal-executive dysfunction, which, as will be shown below, constitutes the most common cognitive deficit in basal ganglia diseases. Secondly, based on the unitary concept of dementia, it does not examine different cognitive domains but confines itself to one global ‘dementia score’. It is, therefore, unable to determine qualitative differences between diseases.”

He advocates the use of other tests besides or in addition to the MMSE. In particular, he likes Addenbrooke’s Cognitive Examination (ACE) test, which includes verbal fluency among other cognitive batteries. He says this test “has been validated in PSP, CBD
and MSA.”

Check out Figure 1 of his short, two-page article. Figure 1 shows the impairment levels of those with (clinical diagnoses of) AD, PSP, CBD, MSA, and DLB on the various ACE subtests of Orientation, Attention, Memory, Verbal Fluencies, Language, and Visuospatial functions.

I have referred to this article in other posts but I think it deserves it’s own topic!

Phosphate (including creatine) depletion in PSP

This abstract was published yesterday on PubMed. It’s about a German study of “cerebral depletion in high-energy phosphates” in PSP. It’s challenging reading because many of the terms and concepts are new to me. One of the authors, Dr. Hoglinger, is one of the stars of PSP research. I will email him regarding the implications of this research (or perhaps Ed can?).

One implication *might* be that PSP patients could benefit from taking creatine. The NIH has been studying whether creatine provides a neuroprotective effect in Parkinson’s Disease. Creatine is used by body builders to build muscle.

Local group member Sam gave his partner Eva creatine on a daily basis. He had this to say a few years ago: “Supposedly 10 grams a day of creatine is helpful; that’s about a teaspoonful. We found that straight Creatine powder–no additives chemicals– dissolves poorly in liquid, and settles sludge-like at the bottom, so we stopped using it. But recently we started adding Maximum Crea-Gain (800/808-8800 or www.energienutrition.com) to the morning juice and it mixes well. It has a dab of artificial flavor, which I don’t like, but is better than other creatine blends which are loaded with dyes and flavor chemicals.” After Eva died, I asked Sam about use of creatine; he said: “Yes, I continued squeezing CoQ10 and mixing creatine with her food to the end, and would keep doing that. They were easy additives and possibly of benefit. No reason to stop them.”

That’s about all I know regarding creatine…. If anyone understands the abstract below, please share!

Robin

Journal of Cerebral Blood Flow & Metabolism. 2009 Feb 4. [Epub ahead of print]

In vivo evidence for cerebral depletion in high-energy phosphates in progressive supranuclear palsy.

Stamelou M, Pilatus U, Reuss A, Magerkurth J, Eggert KM, Knake S, Ruberg M, Schade-Brittinger C, Oertel WH, Höglinger GU.
Department of Neurology, Philipps University, Marburg, Germany.

Indirect evidence from laboratory studies suggests that mitochondrial energy metabolism is impaired in progressive supranuclear palsy (PSP), but brain energy metabolism has not yet been studied directly in vivo in a comprehensive manner in patients.

We have used combined phosphorus and proton magnetic resonance spectroscopy to measure adenosine-triphosphate (ATP), adenosine-diphosphate (ADP), phosphorylated creatine, unphosphorylated creatine, inorganic phosphate and lactate in the basal ganglia and the frontal and occipital lobes of clinically probable patients (N=21; PSP stages II to III) and healthy controls (N=9).

In the basal ganglia, which are severely affected creatine in PSP patients, the concentrations of high-energy phosphates (=ATP+phosphorylated creatine) and inorganic phosphate, but not low-energy phosphates (=ADP+unphosphorylated creatine), were decreased. The decrease probably does not reflect neuronal death, as the neuronal marker N-acetylaspartate was not yet significantly reduced in the early-stage patients examined.

The frontal lobe, also prone to neurodegeneration in PSP, showed similar alterations, whereas the occipital lobe, typically unaffected, showed less pronounced alterations.

The levels of lactate, a product of anaerobic glycolysis, were elevated in 35% of the patients.

The observed changes in the levels of cerebral energy metabolites in PSP are consistent with a functionally relevant impairment of oxidative phosphorylation.

PubMed ID: 19190655 (see pubmed.gov for this abstract only)