What a shame that this CurePSP webinar with such an expert as Dr. Irene Litvan was held at 6:30am California time with very little advance notice. I was able to get up in time and noticed one other local support group member on the call. There was a ten-minute delay in getting started (due to technical problems). Judging by the few questions that were asked, I don’t think that many people participated in the webinar.
My key takeaway from today’s webinar with Dr. Litvan is that there are three common clinical presentations of CBD:
- corticobasal syndrome
- frontotemporal dementia presentation
- progressive aphasia
Here are the details Dr. Litvan shared on the three presentations:
#1 – corticobasal syndrome: symptoms are unilateral; parkinsonism (slowness, stiffness); ideomotor apraxia (ie, difficulty using a limb not due to motor of sensory problems); myoclonus (jerky movements); dystonic posture (abnormal posture/contracture); alien limb syndrome (feeling of limb as alien); levitation (uncontrolled elevation of limb); sensory neglect (unaware of sensation only when there is double stimulation).
If presentation #1 includes bilateral parkinsonism, rather than unilateral parkinsonism (which is more common), then the survival time is shorter.
#2 – frontotemporal dementia (FTD) presentation: the primary symptom is frontal dementia (executive, frontal behavioral and language disturbances). May or may not have bilateral parkinsonism.
Presentation #2 has a shorter survival time.
#3 – progressive aphasia: language problems.
Unfortunately, Dr. Litvan did not describe the third presentation at all nor did she give the percentage prevalence of these three common forms. (Or, if she did, I missed it!) You’ll have to refer to the notes from Dr. Boeve’s presentation for that. PPA (primary progressive aphasia) was one of the four disorders Dr. Boeve addressed in his webinar.
One other item mentioned briefly was the use of transcranial ultrasound in Europe (but not in the US) for aiding in the diagnosis of CBD.
In some ways, Dr. Litvan’s presentation was an excerpt of Dr. Boeve’s webinar from several months ago.
If you listened to today’s webinar, please let me know your key takeaways and if your understanding of the three clinical presentations is different from mine (described above).
My notes from Dr. Litvan’s presentation and the very short Q&A follow. [Editor’s Note: The webinar recording is no longer on the CurePSP website.]
Hosted by CurePSP
Challenges in CBD Management
Irene Litvan, MD, Director, Division of Movement Disorders, University of Louisville, Louisville, KY
Topics addressed in today’s presentation
* Diagnostic Challenges
* Pathogenesis (Cause/s)
CBD Diagnostic Challenges:
* Varied clinical presentations
* No markers for the disease (no blood test)
* Clinical presentations do not always correspond to underlying CBD brain lesions
Early and accurate diagnosis is important for:
* appropriate management
* clinical research
CBD Epidemiologic Aspects
* Underdiagnosed (25-48%). Fewer than half who have the disease are diagnosed as having it during life.
* Diagnosis: at half course of the disease
* There are no epidemiologic studies
* Togasaki & Tanner estimated that
(a) 4-6% of patients with parkinsonism have CBD
(b) incidence: 0.6 – 0.9 new patients per 100,000 each year
(c) prevalence: 4.9 – 7.3 per 100,000
* Sources: Litvan et al, 1996; Wenning et al 1998; Litvan et al 2000; Togasaki and Tanner, 2000
CBD usually has a combination of:
* cognitive features (such as language) and/or
* motor features (such as dystonia or parkinsonism)
* underlying brain lesions of aggregated tau protein. (This protein is a problem in AD and PSP.)
Classically, CBD presents with the corticobasal syndrome unilaterally:
* parkinsonism (slowness, stiffness)
* ideomotor apraxia (ie, difficulty using a limb not due to motor of sensory problems)
* myoclonus (jerky movements)
* dystonic posture (abnormal posture/contracture)
* alien limb syndrome (feeling of limb as alien)
* levitation (uncontrolled elevation of limb)
* sensory neglect (unaware of sensation only when there is double stimulation)
Underlying brain lesions are heterogeneous in the corticobasal syndrome (CBS):
* 36 people presented with CBS while only 18 had CBD. 6 had PSP; 4 had AD; 3 had CJD; 3 had non-specific changes; 1 had Pick, 1 had Pick/AD.
* Source: Boeve paper
Alzheimer Disease presenting with CBD:
* visuomotor disturbances
* ideomotor apraxia
* intermanual conflict
* action myoclonus
* left dystonia
* left alien limb syndrome
* aphasia (including difficulty naming objects)
* clock drawing shows hemi-neglect on the right side (of the brain). So nearly all 12 numbers are on the right side of the clock. Usually hemi-neglect is on the left side.
* brain autopsy showed: AD with lesions on one side; this is a rare presentation of AD
* Source: Chand et al 2006
CBS with underlying TDP-43 proteinopathy with progranulin mutations
* Described by: Guerreiro et al 2008; Le Ber et al 2008; Lopez de Munain et al 2008; Kelley et al 2007; Spina et al 2007
We need to know the underlying disease in order to find treatments
Clinical diagnoses in 32 consecutive autopsied cases at the Mayo Clinic with brain CBD pathology:
* Initial Clinical Diagnosis: 10 CBD (31%); 6 atypical PD; 2 PSP; 4 Primary progressive aphasia; 6 dementia/AD; 1 DLB; 1 Marchiafava-Bignami disease; 1 Multiple sclerosis; 1 Stroke
* Final Clinical Diagnosis: 18 CBD (50%); 7 PSP (22%); 4 Primary progressive aphasia; 1 AD; 1 DLB; 1 Marchiafava-Bignami disease
* Source: Boeve et al 2000
CBD with a frontotemporal dementia (FTD) presentation:
* dementia (executive, frontal behavioral and language disturbances)
* may or may not have bilateral parkinsonism
* Sources: Bergeron et al 1998; Wenning et al 1998; Litvan et al 1999; Grimes et al 1999
Chart from Murray et al, Neurology 2007;6k:1274-1283 (UPenn study):
Only a few had the final clinical diagnosis of CBD yet the chief complaints were classic CBD (unilateral problems)
CBD presentation matters because survival is different for each presentation. Shorter survival in CBD when presenting with dementia and/or bilateral parkinsonism.
In summary, diagnostic challenges are:
* No diagnostic biological markers. Diagnosis still relies on clinical features, confirmed by pathology.
* CBD presents with various clinical presentations including CBS, FTD, and primary progressive aphasia
* The underlying brain lesions of the CBS vary and include CBD, PSP, Alzheimer Disease, FTD, progranulin mutations and Creutzfeld-Jakob Disease
Lab tests that can help some with diagnosis:
* brain MRI in CBD: might be able to see unilateral atrophy
* transcranial ultrasound: used in Europe; might help with diagnosis
What goes wrong in the brains of those with CBD?
* Tau aggregates in neurons and glia.
* Astrocytic plaque is indicative of CBD.
* Some key terms: NFT, tufted astrocyte; threads; coiled body; astrocytic plaque.
Tau is important for the brain cell structure. In CBD, tau collects in insoluble forms.
What triggers tau to change in CBD?
We don’t really know but question whether the following factors may play a role — genetics; mitochondrial abnormalities (oxidative stress); dietary/environmental toxicants; inflammation; gene/environment combination
What do we know about genetics?
* CBD is very weakly hereditary
* No highly penetrant tau mutations are found
* CBD is associated with H1 haplotypes and H1 hyplotype variants. Also true in PSP.
* ? Genetic predisposition CBD
From looking at H1/H1, H1/H2, and H2/H2 at PSP, CBD, and in controls, we conclude:
* H1/H1 genotype is (nearly) necessary but far from sufficient for CBD or PSP to develop
H1/H1: 88% of PSP; 84% of CBD; 60% of controls
* Predisposition triggered by other factors of relative rare mutation with low penetrance?
* ? H2/H2 is protective
H2/H2: 0% in PSP; CBD of CBD
Defined tau mutations give rise to tauopathies presenting with PSP/CBD clinical and pathological phenotype. Example: PPND (FTDP-17 with N279-K mutation). Seen in Mr. Wszolek, a Mayo patient.
What do we know about mitochondrial abnormalities and oxidative injury?
* Impaired activity of Complex I of the mitochondrial respiratory chain
* Oxidative stress in CBD. Cells die.
What do we know about inflammation?
* Activated microglia in the brain in CBD. Can see this in people who have died and in living people.
* Sources: Ishizawa and Dickson 2001; Gerhard et al 2004; Henkel et al 2004)
Hypothesized pathways to cell death in CBD and PSP:
* H1 haplotype variants: do these lead to tau dysfunction?
* Inflammation: does this lead to tau inclusions, which causes cell death, which leads to more inflammation
CBD Treatment Challenges:
* Difficulties in accurately diagnosing patients during life
* Difficulty in slowing disease progression when the cause is unknown
* Symptomatic treatments have limited efficacy. We can improve the quality of life.
Dystonia (limbs) — botox
Dystonia (neck) — botox (avoid when antecollis)
Speech problems — speech therapy; communication aids
Myoclonus — clonazepam, piracetam, valproate
Belpharospasm — botox
Walking — PT; weighted walker
Patient and family support — social services; laymen associations; support RX
* CBD has various clinical presentations: CBS, progressive aphasia (language problem), frontal dementia
* The underlying brain lesions corresponding to these presentations are not always CBD
* Telltale signs (such as focal signs) are present in mid-phase of the disease
* More research is needed to identify:
(a) better ways to diagnose CBD during life;
(b) causes contributing to development;
(c) specific ways to slow the progression of the disease
Questions & Answers: (all questions were answered by Dr. Litvan)
In response to someone noting that they’ve made arrangements for brain donation and to someone else to donated her mother’s brain upon death, Dr. Litvan said: “Thank you for donating your brain!”
Q: What are some centers that are studying this disease?
A: Mayo, UPenn, UCSF
Q: Are there any known causes?
A: There is a genetic susceptibility for those with the H1 genotype. There is a study going on in PSP as to the causes, but not in CBD. We aren’t studying this in CBD due to the diagnostic challenges.
Q: Any hope on the horizon for developing biomarkers?
A: There are multiple groups trying to search for this. One group is trying to label the protein tau with a PET scan. This would help with the diagnosis and at least to differentiate from other disorders. There are a lot of researchers involved. Of course we want more researchers to be involved and more money.
ABOUT THE THREE PRESENTATIONS AND SYMPTOMS
Q: Are there typical symptoms to expect as disease progresses?
A: It depends on the form of the disease. If the disease presents in a unilateral way, the disease may affect the other side of the body. If the disease presents with dementia, the disease may affect both sides of the body.
Usually memory is not a major issue in this disease.
Q: Will dementia appear?
A: It can happen that dementia never appears.
Q: Alien limb.
A: Usually the arms are more effected than the legs.
Q: My sister has language problems. What guess can you make about her survival time?
A: Forms that have speech problems progress slowly. Those with CBS have a survival time of 5-8 years.
Q: In PSP, there are two common forms. Do you guess that the same two forms appear in CBD?
A: Yes, this is exactly what I said. There are three forms in CBD.
Q: Are itching and constipation part of CBD?
A: Itching is not part of CBD. Constipation is part of many neurodegenerative diseases.
Q: If CBD presents as AD, can AD drugs help?
A: We don’t have AD drugs that can help with CBD symptoms.
Q: Would CBD patients benefit from DBS (deep brain stimulation)?
A: No. People with PD who get DBS do improve because they respond to dopamine medication. If you don’t respond to levodopa/carbidopa, then you won’t respond to DBS.