Review of CBD (Mayo)

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Mayo researchers just published an article on CBD. The abstract is a mix of clinical information and pathological information. If you are like me, you’ll want to skip past the pathological terminology!

The clinical information in the abstract leads me to believe that the article’s content is very similar to Dr. Irene Litvan’s webinar several months ago on CBD. You can find my notes on that webinar here:

http://forum.psp.org/viewtopic.php?t=8575

The abstract mentions the term “Richardson syndrome.” This refers to the most common form of PSP (progressive supranuclear palsy); one of the symptoms of this form is cognitive impairment.

Robin

Nature Reviews. Neurology. 2011 Apr 12. [Epub ahead of print]

Corticobasal degeneration: a pathologically distinct 4R tauopathy.

Kouri N, Whitwell JL, Josephs KA, Rademakers R, Dickson DW.
Department of Neuroscience Mayo Clinic, Jacksonville, FL.

Abstract
Corticobasal degeneration (CBD) is a rare, progressive neurodegenerative disorder with onset in the 5(th) to 7(th) decade of life. It is associated with heterogeneous motor, sensory, behavioral and cognitive symptoms, which make its diagnosis difficult in a living patient.

The etiology of CBD is unknown; however, neuropathological and genetic evidence supports a pathogenetic role for microtubule-associated protein tau.

CBD pathology is characterized by circumscribed cortical atrophy with spongiosis and ballooned neurons; the distribution of these changes dictates the patient’s clinical presentation. Neuronal and glial tau pathology is extensive in gray and white matter of the cortex, basal ganglia, diencephalon and rostral brainstem. Abnormal tau accumulation within astrocytes forms pathognomonic astrocytic plaques.

The classic clinical presentation, termed corticobasal syndrome (CBS), comprises asymmetric progressive rigidity and apraxia with limb dystonia and myoclonus. CBS also occurs in conjunction with other diseases, including Alzheimer disease and progressive supranuclear palsy.

Moreover, the pathology of CBD is associated with clinical presentations other than CBS, including Richardson syndrome, behavioral variant frontotemporal dementia, primary progressive aphasia and posterior cortical syndrome.

Progress in biomarker development to differentiate CBD from other disorders has been slow, but is essential in improving diagnosis and in development of disease-modifying therapies.

PubMed ID#: 21487420 (see pubmed.gov for this abstract only)

Adjusting to the diagnosis – 4/6/11 webinar notes

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If anyone else attended this webinar today, I’d be interested in receiving your comments and any notes you took (especially in places where I missed things). I thought the middle part of the webinar was especially good. If you missed it, here are my notes. And CurePSP staff indicated that the recording of this webinar should be available online (psp.org) by 4/8/11.

Early Stages of Diagnosis: A Family Guide for PSP, CBD & MSA — the process of adjusting to the diagnosis, and important steps for patients and families to take during the early stages of the diseases

Webinar Speaker: Trish Caruana, MSW, VP of Programs and Education at CurePSP

4/6/11 (rescheduled to this day from 3/30)

Objectives
* Provide a brief overview of PSP, CBD, and MSA
* Discuss the process of being diagnosed
* Review the initial adjustment to the diagnosis
* Outline the steps to take to ensure the best overall care
* Develop a framework to maintain health

What is PSP?
* Rare neurodegenerative brain disease (5-6 per 100K – “incidence.” Robin’s note: she means “prevalence”)
* Problems with stiffness, balance and vision, speech and swallowing
* Changes in personality
* Cognitive changes

What is CBD?
* Similar to PSP (balance, vision, speech and swallowing)
* Rare: estimated 2K-3K in the US
* Difficulty generating and articulating speech
* Stiffness, jerkiness, slowness, and clumsiness either in the upper or lower extremities
* Asymmetric onset of symptoms
* Memory or behavior problems
* Many of these symptoms may not be appearing now, if you are in the early diagnosis phase

What is MSA:
* Also an atypical parkinsonian disease
* Involuntary functions are affected such as blood pressure, heart rate, actions of the intestines and bladder and breathing activity
* OH
* Urinary incontinence and constipation
* Impaired speech and swallowing
* Inability to sweat
* Sleep apnea and sleep disturbance
* Waving hand movements and staggering gait

Someone initially given this info is going to be taking in a lot of info and trying to figure out how their lives will change.

The process of being diagnosed
Buddhist saying: “If you are facing the right direction, all you need to do is keep walking.”
Getting a diagnosis affects everyone psychologically

Misconceptions about diagnosis
Our simplistic view: Symptoms + Evaluation = Diagnosis

Finding out what’s really going wrong
Medical response: Evaluation; treating symptoms; referrals to other specialists; new and worsening symtoms; no diagnosis given; some diagnosis given; correct diagnosis
Patient and family reactions: Hope for answers; poor response to treatments; frustration; fear; confusion; the power of “naming”; disbelief; panic (what can we do? what info is there? assumption is often that there is one thing that can be done)

Initial adjustments to the diagnosis on the part of the patient and family:
* intellectual (making sense of info; paring down the info)
* physical (probably the patient has already made physical adjustments to the falls, for example)
* psychological (our sense of who we are)
* emotional (people feel that the illness defines them)
* social (people may drop out of activities they enjoy due to fatigue or depression)
* financial (healthcare costs, job, career, retirement)
* life plans (what were my future plans? time for reassessment of these plans)
* spiritual/religious

It’s natural for patients to think about many of these things on their own. We hope they have a good support system.

It’s natural for people to question the diagnosis.

After diagnosis: denial, anger, bargaining, depression, acceptance
These are the five stages of grief (and dealing with loss) by Elizabeth Kubler-Ross

The most important thing about acceptance is that it can lead to taking action. Taking action has four components:
1- Education: disease; current treatment; research; organizations; experts. (“Can’t take action until you know these things.”)
2- Medical: neurologist; movement disorder specialists (“usually this is a neurologist but sometimes it can be a psychologist or nurse practitioner.” Robin’s note – a psychologist cannot be a movement disorder specialist!); primary care physician (who can “synthesize info”); rehab specialists; study sites
3- Resources (“information in the community that may be helpful”): organizations (including Parkinson’s Disease support groups); adaptive equipment; home health; transportation
4- Social Supports: family; extended family; friends; colleagues; church/synagogue; support groups

Creating a framework for maintaining the best health possible for yourself and your family

Continuing to move forward if you have the disease:
* Ask for help from medical providers. Come prepared to appointments with your questions.
* Acknowledge and accept your own thoughts and feelings
* Share your concerns and emotions with someone close to you
* Consider professional counseling/group support
* Ask for help from your family and friends
* Stay in touch with people you love and help them understand the disease
* Remember what helped you cope with other difficult situations in your life and draw from those experiences
* Maintain daily routines as much as possible
* Enjoy the simple things
* Focus on what you can control
* Find courage and direction in your faith or belief system

If your loved one has the disease:
* Recognize it’s normal to feel a variety of emotions
* Maintain and/or start new routines that promote your physical and mental health. Don’t get out of balance by spending 7×24 with your family member with the disease.
* Create a support system
* Continue to learn as much as you can — connect with others going through the challenges of the disease and share ideas
* Accept that you are human

CurePSP can help
* Visit our website
* Request or download our educational materials
* Read our newsletters (Robin’s note: I have not seen a CurePSP newsletter in perhaps a year. Even the old issues are no longer posted on the CurePSP website.)
* Listen to our ongoing webinars
* Attend our family conferences
* Contact us

Question & Answer Period: (all answers are given by Trish)

Robin’s Comment: The #s are prevalence numbers, not incidence #s.

Trish’s Reply: We don’t have good numbers on these diseases. Hopefully our numbers will improve with research.

Robin’s Comment: Perhaps you can address denial. Many caregivers comment that their family members are in denial. Is this a problem?

Trish’s Reply: It’s a defense mechanism. It can serve a good purpose. It can be seen as a stubbornness to stay involved in life. But it can also lead people to think that they don’t need help, and they aren’t open to talking.

Never advisable to take someone’s defense mechanism away unless you have something equally effective to substitute for it.

Question: To what extent are medical students exposed to these diseases?

Answer: When PD is mentioned in the curriculum, it gets short shrift. Therefore, one can imagine that these diseases, as a subset, are not well-covered. It would be hard to find people to interview with the disease.

Comment: PT is helpful.

Trish’s Comment: CurePSP is doing some advocacy to help insure that PT is covered over the course of the disease.

Question: Husband with CBD has depression but isn’t taking anti-depressant.

Answer: Medication can make symptoms worse and can have side effects. Even a positive reaction can be short-lived. Hopefully a decision about taking an anti-depressant is made with a neurologist or psychiatrist. There are many kinds of anti-depressants. Raise this issue with the care provider. Perhaps ask for a psychiatry referral.

Question: What about erratic behaviors?

Answer: People can be impulsive. Example: someone with gait problems but they get up to walk on their own. No one way to help with these impulsive behaviors.

Try to assess whether there are times that make these behaviors worse. Then come up with a plan for the person.

Behavioral changes in PSP correlate with brain atrophy

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This abstract is a bit hard to understand because it uses anatomical terminology. The Mayo Rochester authors attempt to determine whether brain atrophy (“gray matter loss”) correlates with severity of behavioral changes in PSP.

Some of the behavioral changes mentioned in the article include apathy (experienced by 83% of the 18 probable PSP patients), logopenia (being less talkative), severe behavioral dyscontrol, asponteneity, and disinhibition. The authors note that “behavioral changes in probable PSP subjects are far less severe than behavioral changes in bvFTD, at least early in the disease course.” [bvFTD = behavioral variant of Frontotemporal Dementia]

This point is interesting: “Although this suggests that behavioral changes in PSP are not reflecting cognitive severity, it is also important to recognize that cognitive impairment in PSP is usually mild and due to processing speech or executive function, neither of which are adequately captured by the MMSE.”

Robin

Here’s the abstract:

Movement Disorders. 2011 Feb 15;26(3):493-8. doi: 10.1002/mds.23471. Epub 2011 Jan 12.

Gray matter correlates of behavioral severity in progressive supranuclear palsy.

Josephs KA, Whitwell JL, Eggers SD, Senjem ML, Jack CR Jr.
Department of Neurology, Mayo Clinic, Rochester, Minnesota

Abstract
Background: Behavioral changes occur in progressive supranuclear palsy. This study aimed to identify the anatomic correlate of behavioral severity in progressive supranuclear palsy.

Methods: We performed standardized tests of behavioral severity (Frontal Behavioral Inventory), cognitive severity (Mini-Mental State Examination), motor severity (Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale Part III), and a 3.0-T volumetric head magnetic resonance imaging scan in 18 prospectively recruited subjects meeting National Institute of Neurological Diseases and Stroke-Society of Progressive Supranuclear Palsy criteria for probable progressive supranuclear palsy.

Atlas-based parcellation was utilized to obtain regional gray matter volumes of frontal, temporal, and parietal lobe, and caudate and putamen, and voxel-based morphometry was used to assess voxel-level gray matter loss.

We performed correlation analyses between total Frontal Behavioral Inventory score and gray matter volume, as well as assessed gray matter volume across three groups defined according to behavioral severity (mild, moderate, and severe) based on total Frontal Behavioral Inventory score.

Results: Specific behaviors, with the exception of apathy that occurred in 83% of the subjects, were relatively infrequent. There was no association between Frontal Behavioral Inventory and cognitive or motor severity.

Regions of the frontal lobe, particularly, the lateral posterior frontal cortex, significantly correlated with the total Frontal Behavioral Inventory score when using both regional volume and voxel-level analyses.

The groupwise analyses also supported these findings.

The presence of apathy correlated with atrophy of the putamen.

Discussion: Behavioral severity in progressive supranuclear palsy appears to be associated with volume loss of frontostriatal regions, in particular, lateral posterior frontal lobe and putamen.

Copyright © 2010 Movement Disorder Society.

PubMed ID#: 21462261 (see pubmed.gov for this abstract only)

Four new genes found that play a role in AD

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This news article on Alzheimer’s genetic discoveries may be of interest here. About 30% of PSP co-occurs with Alzheimer’s pathology.

Given the sharply falling costs of genetics technology, it’s possible to do large-scale genome-wide association studies for not too much money. This article talks about a US study involving genes from 54K people with Alzheimer’s Disease and age-matched controls. The lead investigator is Dr. Gerard Schellenberg, who is the lead investigator of an important GWAS done in PSP. The Schellenberg-led team discovered four new genes with a role in AD. Previously researchers had known about six genes, including APOE4, which was discovered in 1995. “APOE, a cholesterol metabolism gene that can increase risk by 400 percent if a person inherits one copy and 1,000 percent if a person inherits a copy from each parent. In contrast, each of the new genes increases risk by no more than 10 to 15 percent.”

“Meanwhile, [a] European group, led by Dr. Julie Williams of the School of Medicine at Cardiff University, was engaged in a similar effort. The two groups compared their results and were reassured, Dr. Schellenberg says, that they were pretty much finding the same genes.”

The next step is for the American team and the European team to collaborate, increasing the sample size. Dr. Schellenberg is sure that they will find more genes.

Note that this research is only made possible through brain donations.

I’ve copied a link to the article below.

Robin

http://www.nytimes.com/2011/04/04/healt … eimer.html

New Studies on Alzheimer’s Uncover Genetic Links
By Gina Kolata
Published: April 3, 2011
New York Times

Things one caregiver learned along the way

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Ann Harrison lives in Boston.  Her father died in March from pneumonia.  Her father participated in dementia research studies at Mass General, and his brain was donated there upon his death.  (It’s the only way she will learn which progressive dementia he had.)  This week, Ann posted to an LBD-related online support group a list of things she learned along the way that helped her father.  She gave me permission to share her list, and two subsequent email exchanges about one item on the list (the 24-hour clock) and one item not on the list (brain donation).

– Robin

Posted by:  Ann Harrison
Date:  3/31/11

Here are some things, large and small that I learned [that helped my father.]

Find a neurologist you trust. The disease changes over time and the medications to make the patient most comfortable also change. We saw a “geriatric specialist” first, who put Dad on five or six different medications all at once. Some were good, some were not, but adding them all at once was bad. Then we saw a highly regarded geriatric neurologist who did all the right tests and was slow about adding medications, but who constantly broke appointments and was hard to reach. Then I took [a local support group leader’s] recommendation and saw Dr. Gomperts at MGH. He never decided which of the untreatable progressive dementias Dad had, but was always available within a few hours and worked with me to balance medications as Dad’s parkinsonianism and fears got worse.

Second, watch all medications. Dad’s serious problems started after he was put on vesicare by his urologist. Who would guess that medications for urinary frequency could have terrible effects on cognition? If I had known about this [online support group], Dad might have had another year or eighteen months of slowly declining normality, instead of a rapid decline into dependency. Later, he had a bad reaction to Benedryl – something you can give to babies.

At first, Dad’s worst problems were confusing times of day. Even before he was in serious trouble, he would show up for PT in the middle of the night. We started with caregivers from breakfast until afternoon nap, then from dinner time to bed time, leaving him alone while he normally slept. If he awoke, he had no way to orient himself in time. I built him a 24 hour, single-handed clock that showed when he should go back to sleep and when he should expect someone to be there. Here are the instructions:

pragmaticcaregiver.blogspot.com/2007/05/id-like-to-buy-clue-part-1.html

[Robin’s note:  In an email exchange with Ann, I noted that probably once a month I recommend the 24-hour clock from the pragmatic caregiver to people in the local support group.  I think it’s a great idea but I’ve never heard from anyone other than the “pragmatic caregiver” that it worked.  I asked Ann if the clock addressed her father’s confusion.] [The 24-hour clock] helped some.  We also put a big cardboard box in hall with a sign saying “It’s night time, go back to bed!”  Sometimes he would call me at 1 or 2 AM and I’d tell him to look at the clock to and see that no-one was supposed to be there.  So, yes, I think it helped, for a while.  Then he needed 24 hour care …

Dad’s temporal disorientation lead to his calling me at all times of the day and night, which got to be a problem as he forgot phone numbers and called other people by mistake. I got him a memory phone without number buttons. He was able to read long after he was able to talk coherently, so I just put names on the buttons rather than pictures.

Learning to adapt to his condition was really hard – from the moment when a shoe-store clerk suggested shoes with velcro closing that I thought he would hate, but the person he’d become found them fascinating and wonderful, to the moment when I realized that he really didn’t need his partial plate – nobody cared if he had front teeth or not … a whole series of letting-go incidents. But so many voices on the [online support group] kept saying that we the caregivers need to move into the world our loved ones now inhabit because they can’t come back to ours … and I learned to live with it. There were bad times when other people had to remind me that he couldn’t come into my world, even if it was Christmas and I just wanted him to go downstairs for dinner.

The voices on this [online support group] also helped me understand that the hospice doctor’s recommendation for a stair lift was good, even though I thought climbing stairs kept him strong and he had never fallen there. Safety is more important than strength when you’ve got a disease that’s going to be fatal.

The [online support group] also helped with legal issues. Before his serious decline, Dad had given me power of attorney, added my name to his bank accounts, and made me his health care proxy. It was on this [online support group] that I learned about what Massachusetts calls the “Comfort Care / Do Not Resuscitate” form. I signed them during hospitalizations in the first few years, but those forms were only binding during the hospital stay. The official form had to be signed by his regular physician. I also got a letter from that doctor saying that he was incompetent due to dementia, which I needed once or twice to get a bank to accept my power of attorney.

After he got so unstable on his feet that he shouldn’t try to walk alone, I found a motion sensor alarm for his bed. His caregivers added a baby monitor, so they could go downstairs to make meals without worrying that he would try to get up and fall.

And then there was Capgras. His problem was more about being in a house that looked like his house than thinking that people were not themselves. By the time that symptom arose, he had great difficulty getting out of the house, so driving him around the block wasn’t a good solution. Generally, talking about the pictures of his parents, my mother, and his boat would convince him that if he wasn’t at home, he was still in a good place.

And all the bathroom stuff – the toilet seat booster, the booster with arms, depends, commode… constantly letting go of who he was, and adapting to who he was becoming. One non-toilet related bathroom accessory was a long shower bench that he could sit on outside the tub, then slide across into the tub and swing his legs in. Even with grab bars all around, the step into the tub was frightening – to him and to his caregivers. The long bench solved that problem without having to redo the bathroom.

Some messages I took selectively, deciding that the quality of Dad’s life mattered more than keeping him completely safe. So he ate whatever he wanted because texture is a lot of the pleasure of food and food was something he enjoyed to the last day of his life. No thickened liquids, no pureed diet. Maybe his pneumonia was caused by aspiration, maybe he would have lived long enough to be completely bedridden, sucking on a bottle if I hadn’t been stubborn about food, but I can live with my decision there.

And hospice and staying at home to the end. He didn’t go to a doctor’s office for the last eighteen months of his life. Regular visits from the hospice nurse kept minor problems from flaring up, and knowing that we had a doctor who would come to the house if something went wrong was a huge relief – to him and to all of us.

Sincerely,
Ann

Robin’s note:  I asked Ann why she hadn’t added “brain donation” to her list, as this was something she had learned about along the way.  She replied that her father was not part of the decision to donate his brain and therefore it was not something that benefited him directly.  She said that there are lots of benefits to her, but were none to her father.  I know that when individuals donating their brains are involved in that decision, they feel that something good is coming out of something bad.  And they are often proud for making such a decision.  This doesn’t work for every family (as many wait until the family member is on his/her death bed before making the decision) but, when it does, it can be a point of pride for the entire family.