Advanced MRI Techniques to Diagnose PSP

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Philipps University in Marburg, Germany is very active in PSP research. This is a good review article of various advanced MRI techniques being used to help in the diagnosis of PSP. Many of the studies reviewed are related to a differential diagnosis between PSP, CBD, and MSA. MSA-P is described as the “most relevant clinical differential diagnosis” for PSP.

I learned a few things from this article:

1. For every study that shows good results from a technique, there is typically a later study showing not-as-good results.

2. All of the PSP imaging studies include patients with the Richardsons’s syndrome form of PSP. The clinical diagnostic criteria is based upon this “classic” form of PSP. So, these imaging studies really only apply to those with RS (or PSP-RS). Nearly half of those with PSP are excluded from these studies!

3. The “humming bird sign” (also known as the “penguin-silhouette sign”) for PSP on conventional MRI is described as “controversial.”

4. Voxel-based morphometry seems to be a good technique for differentiating PSP and CBD.

Robin

Journal of Neurology. 2010 Dec 22. [Epub ahead of print]

Magnetic resonance imaging in progressive supranuclear palsy.

Stamelou M, Knake S, Oertel WH, Höglinger GU.
Department of Neurology, Philipps University, Marburg, Germany.

Abstract
Progressive supranuclear palsy (PSP) is a tauopathy, presenting clinically most often with a symmetrical akinetic-rigid syndrome, postural instability, supranuclear gaze palsy and frontal dementia.

In the absence of reliably validated biomarkers, the diagnosis of PSP in vivo is presently based on clinical criteria, which to date do not include supporting imaging findings, as is accepted for other neurodegenerative diseases.

However, data from conventional magnetic resonance imaging (MRI) and various advanced MRI techniques including magnetic resonance volumetry, voxel-based morphometry, diffusion-weighted and diffusion-tensor imaging, magnetization transfer imaging and proton resonance spectroscopy suggest that MRI can contribute valuable information for the differential diagnosis of PSP.

We review here the presently published literature concerning MRI in PSP and discuss the potential role of MRI in differentiating PSP from other parkinsonian syndromes.

PubMed ID#: 21181185 (see pubmed.gov for this abstract only)

Autonomic dysfunction in PSP (a few excerpts)

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This sentence from the article summarizes what is known about dysautonomia and PSP: “Although autonomic dysfunction is accepted to be an important clinical symptom in MSA and PD patients, the role of autonomic dysfunction in progressive supranuclear palsy (PSP) patients is still quite unclear because of contradictory data on this issue.”

Here’s the abstract of an article and the (few) PSP-related excerpts.

Robin

Therapeutic Advances in Neurological Disorders. 2010 Jan;3(1):53-67.

Treatment of dysautonomia in extrapyramidal disorders.

Ziemssen T, Reichmann H.
ANF Laboratory, Department of Neurology, University Clinic Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.

Abstract
Although extrapyramidal diseases are commonly thought to solely affect the extrapyramidal motor system, nonmotor symptoms such as behavioural abnormalities, dysautonomia, sleep disturbances and sensory dysfunctions are also frequently observed.

Autonomic dysfunction as an important clinical component of extrapyramidal disease (idiopathic Parkinson’s disease, multiple system atrophy, progressive supranuclear palsy, dementia with Lewy bodies) is often not formally assessed and thus frequently misdiagnosed.

Symptoms of autonomic dysfunction in general impact more on quality of life than motor symptoms. Appropriate symptom-oriented diagnosis and symptomatic treatment as part of an interdisciplinary approach can greatly benefit the patient.

Unfortunately, double-blind, randomized, controlled studies are scarce with the consequence that most recommendations are not based on the highest level of evidence.

This review elaborates a limited overview on the treatment of cardiovascular, gastrointestinal, urogenital and sudomotor autonomic dysfunction in various extrapyramidal syndromes.

PubMed ID#: 21180636 (see pubmed.gov for this abstract only)

Here are excerpts:

“As we have recently shown, 71% of PSP patients presented with pathologically small pupils in darkness at least in one eye in comparison to 32% MSA, 16% PD patients and 7% healthy controls. In an additional study, we could demonstrate that PSP patients frequently present with significant autonomic dysfunction. The parasympathetic cardiovascular system seems to be involved to a similar extent in PD and PSP patients, whereas sympathetic cardiovascular dysfunction is more frequent and severe in PD patients, but can also be found in PSP patients.”

“In PSP, significant pathologies in autonomic brainstem centres of PSP patients have already been demonstrated.”

Case Report of CBDer with Alien Hand Syndrome

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This article on alien hand syndrome is available at no charge online. See:

http://www.plosone.org/article/info%3Ad … ne.0015010

It contains an interesting case report of someone diagnosed clinically with CBD on the basis of alien hand syndrome and declining response to levodopa (Sinemet). The case report describes in great detail how the features of this patient’s alien hand.

I’ve copied the (understandable) introduction and case report below. Further down is the abstract.

Robin

Here are excerpts:

“The alien hand syndrome (AHS) is a very rare movement disorder. Patients with AHS experience one of their limbs as alien, which acts autonomously and performs meaningful movements without being guided by the intention of the patient. The patients find themselves unable to stop the alien hand from reaching and grabbing objects without using their other hand. Patients are aware that the limb is still part of their body, but they report the feeling as if an external agent is controlling the limb. Consequently, they often describe it in the third person.”

“The phenomenon of AHS is complex and has various clinical manifestations, possibly related to different lesion sites. … The neural mechanisms of this movement disorder still remain unclear. It has been proposed that unwanted movements may arise because of a release of the primary motor cortex (M1) from conscious control by intentional planning systems.”

“Here we report data of a patient diagnosed with corticobasal degeneration and left hand AHS. His left hand showed relatively preserved volitional motor functions. Although there were spontaneous movements of the alien hand, we also had the possibility to elicit alien movements of the hand in a controlled way. We were able to evoke movements of the hand by slightly pushing the hand away from the patient’s body, which then resulted in a small movement into the opposite direction. This behavior is also known as “Gegenarbeiten”, meaning counteracting or working against. Using this reliable behavioural effect we conducted a functional magnetic resonance imaging (fMRI) study to further examine the neural correlates of unconscious or alien movements.”

“The study consisted out of two fMRI experiments. We first examined unwanted movements the way described above. The second experiment was a motor localizer scan to assess brain areas associated with conscious movements.”

Case report
“The 75-year-old right-handed gentleman (WH) was diagnosed with Parkinson’s syndrome five years ago. Within the last six months he reported a rapid loss of control of his left hand. It became much more stiffed and lost fine motor skills. When he walked down a stair he was not able to release the railway voluntary. Playing table tennis became awful. He was not able to serve because the left hand did not loose the grip of the ball. Dopaminergic medication was not as efficient as it used to be at the beginning of disease.”

“Clinically we saw an uplifted arm and reduced arm swing on the left side, strongly left sided rigidity and intermitted irregular myoclonus of the left arm. There were no signs of sensory deficit; reflexes were obtained symmetrical. Tracer studies (DAT Scan and IBZM Spect) revealed loss of presynaptic dopamine as well as a reduction of the post-synaptic dopaminergic receptor state. Structural MRI showed increased and asymmetrical ventricles. Based on the clinic and imaging we diagnosed an atypical Parkinsonian syndrome by possible corticobasal degeneration.”

“After increasing of dopaminergic medication rigidity improved but by now WH reported attacks of his left hand toward his body: the hand grabbed into his face and he could not loose the grip voluntary. When he used his right hand to release the left hand from his face the grip of the left hand became even stronger and he got scratched. He then controlled his hand during night covering up the left arm and keeping the bedside lamp turned on. Neuropsychological testing revealed intermanual conflict (the left hand did not let go objects), transitive dyspraxia using an object (i.e. hole-puncher), only slightly reduced tactile sensory, and tonic grasping. No mirror movements or synkinesis was observed.”

Here’s the abstract:

PLoS One. 2010 Dec 13;5(12):e15010.

Alien Hand Syndrome: Neural Correlates of Movements without Conscious Will.

Schaefer M, Heinze HJ, Galazky I.
Department of Neurology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.

Abstract
BACKGROUND: The alien hand syndrome is a striking phenomenon characterized by purposeful and autonomous movements that are not voluntarily initiated. This study aimed to examine neural correlates of this rare neurological disorder in a patient with corticobasal degeneration and alien hand syndrome of the left hand.

METHODOLOGY/PRINCIPAL FINDINGS: We employed functional magnetic resonance imaging to investigate brain responses associated with unwanted movements in a case study. Results revealed that alien hand movements involved a network of brain activations including the primary motor cortex, premotor cortex, precuneus, and right inferior frontal gyrus. Conscious and voluntary movements of the alien hand elicited a similar network of brain responses but lacked an activation of the inferior frontal gyrus. The results demonstrate that alien and unwanted movements may engage similar brain networks than voluntary movements, but also imply different functional contributions of prefrontal areas. Since the inferior frontal gyrus was uniquely activated during alien movements, the results provide further support for a specific role of this brain region in inhibitory control over involuntary motor responses.

CONCLUSIONS/SIGNIFICANCE: We discuss the outcome of this study as providing evidence for a distributed neural network associated with unwanted movements in alien hand syndrome, including brain regions known to be related to movement execution and planning as well as areas that have been linked to inhibition control (inferior frontal gyrus) and experience of agency (precuneus).

PMID: 21179436

Primary Progressive Aphasia- Notes from Weintraub Talk

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There was a conference call today for support group leaders put on by the Association for Frontotemporal Dementias. (PSP and CBS/CBD fall into the “movement disorders” type of FTDs, which is how/why I’m invited to attend.) The topic of the call was Primary Progressive Aphasia, and the speaker was Sandy Weintraub, PhD, of Northwestern, one of the centers in the US studying PPA (and all FTDs).

My notes are below.

Robin

FYI – PPA has been addressed briefly in two webinars this year:

Boeve Webinar: Dr. Weintraub’s presentation is an expansion of the PPA topic within Dr. Brad Boeve’s recent webinar on cognitive and behavioral aspects in FTDs. Dr. Boeve said taht 60% of those with a clinical diagnosis of PPA end up being diagnosed with a tauopathy (such as PSP, CBD, or AD) upon brain autopsy.

I posted my notes on Dr. Boeve’s webinar back in April 2010:
http://forum.psp.org/viewtopic.php?t=8410

Litvan Webinar: As we learned in Dr. Irene Litvan’s presentation, one of the three clinical presentations of CBS is PPA. In my notes on Dr. Litvan’s presentation, I had complained that she hadn’t covered the “progressive aphasia” presentation at all. Well, today’s conference call certainly supplied the missing pieces.

I posted my notes on Dr. Litvan’s webinar back in October 2010:
http://forum.psp.org/viewtopic.php?t=8575

FTD Support Group Leaders’ Conference Call
Organizer: Association for Frontotemporal Dementias (ftd-picks.org)
12/20/10

Topic: Primary Progressive Aphasia: Understanding language presentations and approaches to care

Speaker: Sandra Weintraub, PhD
Northwestern University’s CNADC (Cognitive Neurology and Alzheimer’s Disease Center)
Chicago, IL
www.brain.northwestern.edu/ppa/

The FTD class of disorders is ever-widening.

Three main types of FTD disorders, depending on early symptoms:
* change in behavior, personality, and emotions: bvFTD
* decline in language (speaking, understanding, reading, writing): PPA
* change in motor function and movement: PSP, CBS, MND

“Early” = first 2 years. These years are critical for families. And critical for clinicians to understand the underlying pathology.

PSP, CBS, and MND often have cognitive symptoms associated with them as they progress.

All FTD disorders are progressive.

What is aphasia?
1. A disorder of language: inability to link words to thoughts for communication
2. Caused by brain damage: usually associated with a sudden loss of language function, caused by a stroke but in PPA is slowly progressive because the cause is neurodegenerative disease
3. Affects all aspects of language usage, not just speech output. A disorder of speech alone without language
impairment is “dysarthria” and it does not prevent the individual from communicating their thoughts since they can
still write normally. Asking the patient to write is one way to distinguish aphasia and dysarthria.

Early Symptoms of PPA (Primary Progressive Aphasia)
1. Gradual loss of language (aphasia): word-finding, speaking in full sentences, understanding conversation and/or written words, writing.

Subtypes include: Agrammatic, Logopenic, Semantic. Subtype depends on what the language disorder is.
Agrammatic: They say “water” rather than “I want water now.”
Logopenic: Slow output and groping for words.
Semantic: What is “salt”? Single-word comprehension deficit. (Called “Semantic Dementia”.)

2. Other cognitive functions are normal or relatively so. Hard to test someone’s memory if they can’t speak.

3. Daily living activities are affected mostly by aphasia in early stages. This is because short term memory and personality are intact.

4. Aware of symptoms and can become depressed due to this awareness.

5. Symptoms progress over time and other problems develop.

Boston Naming Test is used in diagnosis.

Example – Pictures of objects. The patient is asked to name the object.

Example – Test of single word comprehension – nouns and verbs. “Show me the picture where someone is laughing.” Someone with Semantic subtype cannot do.

Example – Color name comprehension. “Show me the color blue.”

Example – Body part name comprehension. “Show me the nose.”

“My sister like to have wheat bread. She will puts the mayo, cheese, turkey and lettuce. She will take a knife to cut the sandwich. The sandwich will put on the plate, My sister will have milk in a glass.”

–> This is agrammatic

“Get whatever type of bread you would like. Then add cheese, with different types. Then add liquid on the bread. Then leados, vegitables, chicken or turkey or other different ones. Then you have a good one!”

–> Fewer nouns here. The patient is having difficulty coming up with the right words. Could be agrammatic, logopenic or semantic! Lots of overlap! She thinks it is a logopenic patient. (I think “leados” is “lettuce.”)

MRI scan on the left. (Taken as if you were standing above the patient’s head.) PET scan on the right. The left side of the images are the right side of the brain.

Later Symptoms:
1. Mutism. Usually this is a late symptom. In rare cases, someone can be mute for 3-4 years.
2. Severe difficulty understanding what others are saying even though hearing is normal
3. Personality changes
4. Memory loss
5. Daily living activities severely limited

Early PPA vs. bvFTD:
PPA patients have aphasia but no other symptoms.
bvFTD patients have personality change, concentration problem, and social-interpersonal problems.
Motor symptoms may be present in both.

Late PPA vs. bvFTD:
PPA patients have aphasia and concentration problem. They may or may not have memory loss, visual disorder, personality change, and social-interpersonal.
bvFTD patients have personality change, concentration problem, and social-interpersonal problems. They may or may not have aphasia, memory loss, and visual disorder.
Motor symptoms may be present in both.

Visual disorder = your brain can’t see.

bvFTD and PPA
* Psychosocial and treatment strategies differ vastly from memory loss dementia.
* Need specialized education, support services, community resources.

Northwestern’s PPA/FTD Program
* website: brain.northwestern.edu/ppa/
* semi-annual newsletters to NWU patients and families
* monthly caregiver support groups. They’ve been asked to split these into two — PPA and bvFTD.
* one conference per year (caregivers and patients)

In the new FTD booklet, there’s a section on PPA:
www.nia.nih.gov/Alzheimers/Publications/FTLD/

Strategies for families in managing symptoms of aphasia:
* Speak in simple sentences to patients — simpler words and simple forms of construction. Don’t use the word “or”!
* Construct a communication notebook for patients. Have a page devoted to “my favorite grocery items.” Take pictures and label them with words. iPhone application says words aloud.
* Devise a strategy for emergency situations bypassing the need to use the telephone
* Seek treatment from a speech-language pathologist
* Provide patient with identifying information, Example – MedicAlert bracelets.
* These are from: Weintraub S, Morhardt DJ: Treatment, education and resources for non Alzheimer dementia: One size does not fit all. Alzheimer’s Care Quarterly, July/September: 201-214, 2005. They are summarized in one of the handouts we received.

Question & Answer:

Q: What about the patient who lives alone?

A: Though some of these patients can’t speak, they may still be highly functional. Need to assess how this person can react to an emergency.

Q: What about depression?

A: This can be a serious problem. Medications can be very helpful. Families should be on the look-out for this.

Talking therapy is not always the best thing!

Comment by audience member: There can be profound loneliness in PPA.

Q: Any learnings from your patient support group?

A: Keep gatherings small. More like one-on-one or two-on-one. Any more people gets confusing for the patient.

Q: How does your patient support group work?

A: The patients demanded their own support group. Over time, the amount of talking has declined. Group leaders now insert activities when there isn’t much talking.

Q: What percentage of PPA patients end up having personality involvement?

A: We don’t know. All of the research has been with small series of patients.

Some studies show that the Semantic patients end up with more emotional/behavioral disturbances. This may be due to frontal lobe involvement.

Q: Is Namenda helpful in PPA?

A: Namenda didn’t help with PPA in a trial they did (3-6 months). There was no short-term benefit. So they assumed there was no long-term benefit.

Comment by audience member: Namenda helped his wife for several years.

Q: What portion of FTDs are PPA?

A: We don’t know. Northwestern sees a huge number of PPA patients.

Q: What do we know about genetic patterns with PPA?

A: There are only two PPA families we know of where it seems to be inherited.

In families, where someone has PPA, other family members (first degree relatives) may have early learning disorders (eg, dyslexia).

We haven’t followed those with early learning/language disorders to find out if they develop neurodegenerative diseases later.

Q: What are the pathological diagnoses for PPA?

A: We do have data on this:

60% of all PPA have some form of FTLD pathology (whether it’s tauopathy, FTDP43, CBD, PSP, etc).

40% have Alzheimer’s pathology.

If you have the logopenic form of PPA, you are more likely to have the Alzheimer’s form.

If you have the grammar form of PPA, you are more likely to have a tauopathy.

Cortical atrophy differentiates RS from PSP-P

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These Australian researchers looked at the brains of 24 pathologically confirmed PSP cases. 17 cases had PSP-Richardson’s Syndrome and 7 cases had PSP-Parkinsonism — the two most common forms of PSP.

They found:

* “Cortical atrophy was more severe in PSP-RS than PSP-P and affected more frontal lobe regions.”

* “Additionally, atrophy of the internal globus pallidus, amygdala, and thalamus was more severe in PSP-RS.”

* “As expected, more severe frontal lobe tau pathology differentiated PSP-RS from PSP-P.”

And, most interestingly, they found:

* “No correlations were found between the degree of atrophy and severity of tau pathology in any region assessed…”

* No correlations “between the severity of atrophy or tau pathology and the presence or absence of cardinal PSP symptoms.”

* “Our study shows that thalamocortical atrophy is a defining feature of PSP-RS, but this atrophy does not correlate with the presence of any specific cardinal clinical feature.”

Robin

Movement Disorders. 2010 Dec 13. [Epub ahead of print]

Cortical atrophy differentiates Richardson’s syndrome from the parkinsonian form of progressive supranuclear palsy.

Schofield EC, Hodges JR, Macdonald V, Cordato NJ, Kril JJ, Halliday GM.
Neuroscience Research Australia and the University of New South Wales, Sydney, New South Wales, Australia.

Abstract
To determine whether brain atrophy differs between the two subtypes of progressive supranuclear palsy (PSP), Richardson’s syndrome (PSP-RS), and PSP parkinsonism (PSP-P), and whether such atrophy directly relates to clinical deficits and the severity of tau deposition.

We compared 24 pathologically confirmed PSP cases (17 PSP-RS and 7 PSP-P) with 22 controls from a Sydney brain donor program.

Volume loss was analyzed in 29 anatomically discrete brain regions using a validated point-counting technique, and tau-immunoreactive neurons, astrocytes and oligodendrocytes/threads semiquantified.

Correlations between the two pathological measures and the presence or absence of cardinal PSP symptoms were investigated.

Cortical atrophy was more severe in PSP-RS than PSP-P and affected more frontal lobe regions (frontal pole, inferior frontal gyrus). The supramarginal gyrus was atrophic in both subtypes. Additionally, atrophy of the internal globus pallidus, amygdala, and thalamus was more severe in PSP-RS.

As expected, more severe frontal lobe tau pathology differentiated PSP-RS from PSP-P. No correlations were found between the degree of atrophy and severity of tau pathology in any region assessed, or between the severity of atrophy or tau pathology and the presence or absence of cardinal PSP symptoms.

Our study shows that thalamocortical atrophy is a defining feature of PSP-RS, but this atrophy does not correlate with the presence of any specific cardinal clinical feature.

Interestingly, there is a disassociation between tau pathology and atrophy in the brain regions affected in PSP-RS that requires further investigation.

© 2010 Movement Disorder Society.

PubMed ID#: 21154980 (see pubmed.gov for this abstract only)