Tonight’s webinar was a great presentation but then I’m a huge fan of Dr. Brad Boeve so it’s hard for me to be objective. I enjoyed learning about all the correlations between brain anatomy and symptoms. The webinar’s question-and-answer session, organized by CurePSP, was not so good.
Did any of you pick up new things? What Dr. Boeve had to say about experimental DBS (deep brain stimulation) was new to me. He indicated that it is showing some promise in PSP and for some CBS patients with dystonia.
There’s one important aspect of tonight’s webinar I’m still not sold on. Though I’ve read a lot of articles about the clinical overlap in the four disorders discussed on the webinar (PSP, CBD, bvFTD, and PPA) and though I’ve attended an FTD caregiver education conference (when it was in SF several years ago), I don’t get the point of a PSP/CBD audience sitting through a Q&A that was nearly all about FTD.
What follows are the notes I took from Dr. Boeve’s presentation, the nearly-100%-focused-on-FTD Q&A, and a bit about Janet Edmunson’s presentation on CurePSP and Sharon Denny’s presentation on AFTD. CurePSP and AFTD were the co-hosts of the webinar.
[Editor’s Note: The archived webinar recording is no longer available on the CurePSP website.]
Topic: Cognitive & Behavioral Issues in PSP, CBD, FTD and PPA
Speaker: Dr. Brad Boeve, Neurologist, Mayo Rochester (MN)
4/29/10 Webinar Hosted by CurePSP and AFTD
PSP = progressive supranuclear palsy
CBD = corticobasal degeneration
CBS = corticobasal syndrome
FTD = frontotemporal dementia
bvFTD = behavioral variant frontotemporal dementia
PPA = primary progressive aphasia
FTLD = frontotemporal lobar degenerations
PSP and CBD have classically been considered parkinsonian disorders. For many people, cognitive and behavioral symptoms do evolve. On the flip side, FTD and PPA begins with cognitive and behavioral symptoms and, for many, parkinsonian symptoms evolve. There is a lot of overlap.
PSP: initially characterized in the 1960s
CBD: initially characterized in the late 1960s; 20 years of no publications
PPA: initially characterized in 1982; nonfluent variant and semantic variant
FTD: coin termed in 1994
These four disorders have been classically considered to be distinct and separate. But there’s growing evidence that these are strikingly similar, with one of the primary distinctions being what parts of the
brain are maximally affected.
* Frontal lobe (especially dorsolateral prefrontal cortex): planning; judgment; insight; executive functions; problem-solving; multi-tasking
* Orbital medial part of brain: socially-appropriate behavior (knowing what to say and when to say it); theory of mind; social cognition
* Left perisylvian region (frontotemporal, parietal regions): language; verbal aspects of language
* Right perisylvian region (frontotemporal, parietal regions): prosody
* Hippocampi: memory (short-term memory, upcoming plans); severely affected in AD; we don’t see dense memory impairment
* Amygdala: emotional valence; ex – seeing trash in the park vs. seeing someone sleeping in the park; memory traces of emotional events
* Anterior cingulate region: motivation; spontaneity
* Right temporal occipital region: visual recognition (ability to recognize objects and people)
* Bottom part of brain: social disinhibition; loss of empathy and insight; change in food preferences (usually towards sweets); hoarding of food (especially stuffing food in mouth faster than it
can be swallowed); utilization behavior
A few more terms:
Poor verbal expression vs. Poor naming: these are different regions
Aprosodia (monotone voice)
Visual agnosia (inability to recognize objects and people)
We don’t often seen atrophy on brain scans, but there can still be problems. The symptoms come up because the networks are affected.
PSP – Clinical Features: primarily subcortical parts of brain and the substantia nigra (SN is also affected in PD)
* Symmetric rigidity and bradykinesia: axial > appendicular; levodopa unresponsive
* Postural/gait instability
* Extraocular movement dysfunction (saccadic pursuits: delayed, slowed saccades; supranuclear gaze palsy, particularly downgaze)
* Apathy (or lack of motivation is the term he prefers), bradyphrenia (the wheels are working but the gears are slow)
CBS is a clinical diagnosis. CBD is a pathological diagnosis. He prefers the term CBS.
CBS/CBD – Clinical Features:
* Progressive course
* Asymmetric findings
* Limb rigidity
* Limb apraxia
bvFTD – Clinical Features:
* Personality/behavioral changes
* Loss of empathy/sympathy
* Loss of insight
* Social disinhibition
* Change in food preferences
* Poor judgment and planning
We see the frontal-type behaviors in some with PSP and CBD. This is because the same brain networks are effected.
PPA – Types and Associated Clinical Features:
Nonfluent: changes in speech/language production
Semantic: uncommon; loss of nouns and word meaning
Logopenic variant of PPA is almost always AD, with an atypical
presentation. It won’t be covered tonight.
Some people with PSP present with florid FTD or PPA features. Same thing with FTD. Considerable overlap. Many times the diagnosis changes or another possible diagnosis gets added. This is typical. Other symptoms evolve as other parts of the brain are affected.
FTLD = frontotemporal lobar degenerations
Management – Goals:
* Pharmacotherapy: improve symptoms; manage behaviors; decrease injury risk (to patients – due to falls; to family members – due to behaviors)
* Non-Pharmacotherapy: improve symptoms; manage behaviors; decrease injury risk; improve caregiving strategies
There are clearly ways to improve quality of life
Approach: ask patients and caregivers to list and then rank which symptoms/problems are most bothersome, which allows the clinicians to tailor the management plan. We try to focus on 3 issues to manage initially.
Problem list: what are the most significant in these categories?
Management through Pharmacotherapy:
* No FDA-approved medications specifically develop to impact these disorders.
* There are a few well-designed studies that have shown that any medication improves symptoms in any of these disorders.
* There is considerable debate among clinicians whether any medications are worth using in patients with any of these disorders.
* Most of these medications are expensive and there are side effects.
Does your clinician’s approach fit with your approach? (conservative, aggressive, etc) No right or wrong way.
Non-medication management is more important that medication at the present time. This will change in the future.
Education/Counseling/Behavioral Management of Cognitive Symptoms:
* Stay physically fit, mentally active, and socially active. There is some evidence supporting this now. If you are fortifying the brain networks by being active, more changes need to happen in the
brain for symptoms to worsen. In theory, maximizing activity certainly can’t hurt and there is some evidence that it helps.
* Establish and maintain a daily routine
* Religious use of a daily planner (even for those who have memory problems!). Mayo has a whole program on teaching people how to use daily planners. It’s not just a matter of picking up a daily planner. You need training.
Medication Management of Executive Dysfunction and Memory Impairment: (Cognitive Symptoms)
* carbidopa/levodopa, dopamine agonists (Sinemet, Mirapex, Requip)
* cholinesterase inhibitors (Aricept, Exelon, Razadyne): designed for people with Alzheimer’s; some experts will tell you that these should not be used; some clinicians think these medications are okay
* psychostimulants (Provigil, Nuvigil, Ritalin, Adderall, Desoxyn): more controversial; some of the same circuits are involved with narcolepsy; expensive and have side effects
* Namenda: used frequently in some of these syndromes. Note that there is a placebo-controlled clinical trial of Namenda in the US in FTD and PPA.
Education/Counseling/Behavioral Management of Neuropsychiatric Symptoms:
* Develop tolerance and choose your battles!
* Acknowledge and redirect; refrain from arguing
* Employ therapeutic fibs: sometimes the outcome is more important than the process; lies are appropriate in some circumstances
* Support group involvement (local support groups, even local PD and AD support groups; CurePSP; AFTD; sometimes even Huntington’s Disease support groups, if you are dealing with an inherited disorder)
* Work with local psychologists and psychiatrists: not many are knowledgeable about these disorders
Medication Management of Disinhibition, Socially Inappropriate Behavior, Delusions: (Neuropsychiatric Symptoms)
* SSRIs (Celexa, Lexapro, Paxil, Prozac, Prozac, Zoloft)
* atypical neuroleptics (including Seroquel, Risperdal, Zyprexa): have gotten a lot of bad press but we feel that they have a role
* anticonvulsants (Depakote, Neurontin, Tegretol): they do have side effects
* beta-blockers (Inderal)
Medication Management of Apathy: caregivers view this as a big deal; clinicians don’t tend to view this as a big deal
* carbidopa/levodopa, dopamine agonists
* cholinesterase inhibitors
Management of Parkinsonism: (Motor Symptoms)
* carbidopa/levodopa, dopamine agonists: not very responsive to our standard agents; being aggressive with Sinemet is worthwhile
* DBS (deep brain stimulation): this is experimental; it is showing some promise in PSP; in select cases with dystonia in CBS, DBS has provided a benefit with effects lasting for a year or two (so it’s
Management of Gait Impairment and Falls (especially in PSP): (Motor Symptoms)
* gait assistance devices and PT: we need to do a better job counseling patients; Deena J. is a PT with considerable expertise in this area
* power-operated vehicle: work with Medicare or other insurance
Management of Dysarthria/Nonfluent Aphasia/Apraxia of Speech:
* speech therapy: can be helpful in some individuals; worth trying, particularly in nonfluent aphasia
* carbidopa/levodopa, dopamine agonists: not usually helpful
Management of Dysphagia:
* swallowing study
* Thick-It, pureed food, PEG tube (no right or wrong answer)
Sleep issues can include:
* Daytime hypersomnia
* Obstructive sleep apnea
* Central sleep apnea
* PLMS (periodic limb movements during sleep)
Management of Sleep Issues:
* Discuss with primary MD
* Consider formal sleep medicine evaluation and formal sleep study, in select cases
* This is a quality of life issue. There are many sleep disorders; almost all are treatable. Don’t overlook them.
Two primary groups of disorders:
* Tauopathies: Alzheimer’s Disease, Pick’s Disease; CBD, PSP, AGD; FTDP-17MAPT
* TDP-43opathies: FTLD with MND; FTLD with ubiquitin/TDP-43-positive inclusions; FTDP-17PGRN
A huge percentage of those with AD also have TDP-43. So any research into AD will help all these disorders.
Proteins found upon brain autopsy:
clinical PSP: nearly all have tau; some have TDP-43
clinical CBD: 60% have tau; a small percentage have TDP-43; 10-20% actually have atypical AD (amyloid)
clinical FTD: roughly half tau; roughly half TDP-43; a few have AD (amyloid)
clinical PPA: 60% have tau; a small percentage have TDP-43; 10-20% have atypical AD (amyloid). NFA is more often a TDP-43 problem.
[Robin’s comment on the PSP data: but what about the people diagnosed with PSP who actually have MSA, DLB, or AD upon brain autopsy?]
[Robin’s note: I may’ve posted here on 4/11/10 or so a recent UCSF article on the overlap in PSP, CBD, and FTLD-type disorders. The article is useful if you want to drill further into what types of
protein-opathies those clinically diagnosed with PSP, CBD, FTD, and a few other disorders actually have upon brain autopsy.]
The challenge is we don’t have a test now that reflects the underlying protein. In PSP, it’s less of an issue because most people have a tau disorder. But it’s a problem for the other disorders. We need to develop better biomarkers (MRI, PET, blood test, spinal fluid test, etc) so we can treat individual patients with the right therapies. We don’t want to give a medication to someone that turns out to be toxic if they have a certain protein.
Tauopathy therapies being studied: (short list; there are many others)
* microtubule stabilizers
* tau kinase inhibitors such as GSK3-beta enzymes
* Hsp90 inhibitors
* tau aggregation inhibitors such as Davunetide and a Rember-derivative: clinical trials in these two over the next 1-2 years. Davunetide trial is international.
[Robin’s notes: One of the GSK-3 beta enzymes is Nypta. The Nypta trial has already started in Europe. Hopefully it will start by June at various US sites. Regarding Davunetide, which is also called NAP or AL-108, there’s a small 12-person pilot trial of this in PSP and CBD at UCSF now. Hopefully the full clinical trial will begin in September.]
* in a genetic form of the disorder, too little PGRN (progranulin) leads to too much TDP-43
Plea: please consider participating in research! When we get any of these medicines (such as Davunetide), how are we going to prove or disprove the medicines are working? These studies are typically free. They are funded by our tax dollars, private foundations, and organizations (such as CurePSP).
What if we had a disease-modifying agent? Even better is a slowed progression of symptoms with disease-altering therapy!
* Increase awareness among the public and healthcare professionals that these disorders exist, are recognizable disorders, and can be diagnosed and managed
* Develop networks of patients, families, friends, and healthcare professionals to improve managing the day-to-day aspects of these disorders
* Increase federal and private funding for research, education and counseling. This is where you can help! If anyone has ties to foundations or other funding sources, let them know of your interest in research funding for medication and non-medication approaches. Lots of people are having fundraisers. Anything that can be done for research is a positive advance.
* Refine the clinical, genetic, neuropsychological, radiologic, and pathologic characterization of these disorders
* Improve our understanding of tau and TDP-43 protein physiology and pathophysiology so promising therapies can be developed and tested
* Identify and develop clinical, laboratory, neuropsychological, and radiologic measures for future therapeutic drug trials
We want to ultimately prevent, delay the onset, and slow the progression of the disorders that cause PSP, CBD, FTD, and PPA!
www.brain.northwestern.edu/ppa/index.html –> best website anywhere on PPA
Questions & Answers: (all answers were by Dr. Boeve, unless indicated)
[Robin’s note: I’ve grouped these by topic and re-ordered them]
Q by Janet Edmunson: Can someone have a diagnosis of PSP, CBD, and FTD?
A: It is possible to have all three features. Very uncommon would
be to have features of all four disorders (including PPA).
Some clinicians give the diagnosis of the predominant disorder.
Q by Janet Edmunson: How do you deal with sexual behavior?
A: This sort of behavior sometimes leads to people being dismissed
from a care facility, and they have to be placed in a psychiatric facility.
Consider SSRIs, atypical neuroleptics, sometimes even
anti-convulsive/seizure medications. In on case of a gentleman with
these behaviors, hormone medication (estrogen) is being tried.
A by Janet: Seroquel worked for Charles.
Have to remind yourself that it’s the disease talking and not the person.
A by Dr. Boeve: There was just an announcement about the
manufacturer of Seroquel having to settle a huge dispute with the government.
I use this medication frequently myself.
Yes, direct the anger at the illness, not the patient.
Q: I have had PSP since 2004 and will be 80 in June. Is this a form
of Parkinson’s? Are all these diseases a form of PD? What research
is being done and has there been any progress in finding a cause or
cure for PSP?
A: Because the parts of the brain overlap with the parts affected in
PD, there can be overlap. But PD and PSP are different, distinct
disorders. PD is a Lewy body disorder. PSP is a tau protein disorder.
If you are near a center that is participating in the Davunetide
trial, please participate!
Q: Are you familiar with research on neuroplasticity? Has any
research been done on neuroplasticity and FTD-type disorders?
A: This refers to the ability of the brain to make up for problems
in another part of the brain. Example: a stroke patient may re-gain
use of a paralyzed limb over time by virtue of one part of the brain
helping other parts. We need more research in this area!
Dr. Bruce Miller and UCSF researchers have found some rare
individuals with a particular neurodegenerative disorder who
developed artist talent after developing the disorder. This
demonstrates neuroplasticity. [Robin’s note: I think Dr. Boeve said
semantic dementia was the disorder but I’m not sure. SD is another
subtype of FTD.]
Q: My brother was diagnosed with FTD at the age of 55. He hasn’t
been able to talk for 18 months. I suspect he now only understands
simple sentences. What do we know about the way these patients
think? Do they keep, at least for some time, the ability to think
with words? Do they “lose” words in their minds as they “lose” words
in their mouth?
A: Usually the speech production part of the brain is affected more
than the speech understanding part of the brain. People seem to
understand far more than you would anticipate on the basis of their
spontaneous speech. In advanced stages, it’s harder to know.
It’s a learning test for clinicians and family members.
Q: Are there any alternative medications or supplements that might
enhance cognitive function in FTD?
A: We don’t have any evidence. Some believe in fish oil, CoQ10,
various vitamin preparations, blueberries, green tea, curry,
etc. These dietary and supplementary agents…on a theroretical
level, we don’t know how they impact tau. They might not hurt and
they might help. Be cautious of expensive items. There are some scams.
Q: I have heard that Namenda may be harmful to the cognitive
function of those with FTD. Is there any validity to this?
A: All medications have side effects. All side effects should be
reversible. Not aware of any evidence of permanent side
effects. It’s variable.
We are doing a Namenda study in FTD.
Q by Sharon Denny: Is Aricept the same type of agent as Namenda?
A: No. They act on different neurochemical systems. They can have
a role together because of this.
There is some early evidence supporting the use of Namenda in FTD,
but we just don’t know. There needs to be a larger trial.
Q: Any meds to control verbal outbursts often seen in patients with FTD?
A: Most clinicians would consider the SSRIs. Because of their
activity of serotonin and norepinepherine and because they are
well-tolerated, the SSRIs are tried. Next, some clinicians will
consider atypical neuroleptics.
Physically aggressive behavior, hallucinations, and delusions can be
treated with atypical neuroleptics.
Q: As the fulltime caregiver for my brother (age 53, Pick’s
Disease), one of the issues we are currently dealing with is his
disruptive mealtime behavior. What are your suggestions on how to
deal with this?
A: Hard to tell without more details. Probably manners are not
being practiced. There may be hoarding. There may be inappropriate
statements said at the dinner table.
Honestly, this is very difficult. This is difficult both in the home
and in restaurants. Medicines tend not to work well. This
circumstance probably requires tolerance by the family, as
frustrating as this may sound.
If there’s a chance of choking (due to hoarding), it’s important to
teach all caregivers the Heimlich maneuver. Please learn it if you
don’t know it!
Q: Are there techniques for diverting or minimizing behaviors
associated with FTD?
A: This takes a real talent. If there’s any way to work with social
workers, psychologists, and neuropsychologists, that is helpful
because these people are trained in re-directing.
For many, this disruptive behavior expresses something. Try to
figure out what the person is expressing. “I understand you are
upset. Can you describe this more?” Acknowledge it, and then re-direct.
Re-direct by saying “let’s go watch TV,” for example.
Q: My wife was diagnosed with FTD and also has COPD. She does have
difficulty breathing, but is fixated on the phrase “I can’t
breathe.” She repeats this over and over again no matter what the
level of exertion and the actual being out of breath. How can I
divert this behavior? This seems to be more pronounced when I am present.
A: Phrases can be repeated over and over. There can be
humming. There is often a restricted repertoire of verbal output.
This is hard to curb. Any verbal expression or aggressive behavior
is a form of communication. It may be that this person is trying to
indicate that she’s distressed or in pain. The medicines don’t tend
to be helpful. A lot of it comes down to what the person is trying
to communicate. Can the individual write?
Q: Is there a national list of neurologists who specialize or have a
particular interest in FTD?
A: On the AFTD’s website, there’s a regional list of academic centers.
Chair, Board of Directors, CurePSP (psp.org)
Vision: cure and prevent PSP, CBD, and related brain diseases
Genetics consortium: announcing that they’ve discovered 6 new genes
that are related to PSP and CBD.
There are three upcoming webinars: (registration required)
5/13/10 with Laura Purcell Verdun, speech therapist, on “Speech &
Swallowing Therapy: Q&A Session”
Email Laura with your questions at [email protected]
6/24/10 with Chris Debrelle (sp?) on “Tips for Caregivers”
7/15/10 with Dr. Irene Litvan on “Symptoms, Treatments, and Resources
Available for CBD”
About AFTD (Association for Frontotemporal Dementias)
Program Director, AFTD (ftd-picks.org)
FTD = cluster of progressive disorders caused by degeneration of the
frontal and temporal lobes of the brain (bvFTD, PPA, SD, PSP, CBD)
Vision: a world where FTD is understood, effectively diagnosed, and
5/21: Caregiver Education Conference and AFTD’s Annual Meeting in
Fort Worth, TX
If you have questions about FTD or PPA, contact the AFTD. Contact info: