Category Archives: Parkinson’s

Progression of dysarthria + dysphagia in PSP, CBD, etc

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I’ve posted some of the info in this article previously and the PubMed ID# but have never posted these excerpts.

This 2001 study is of dysarthria and dysphagia in autopsy-confirmed cases of DLB, CBD, MSA, PSP, and PD. According to the article, all atypical parkinsonism patients develop either dysarthria or dysphagia within one year of disease onset. (I thought dysarthria meant slurred speech. But, according to this article, it can also mean hypophonic speech or monotonic speech.)

Here’s the citation and abstract:

Archives of Neurology. 2001 Feb;58(2):259-64.

Progression of dysarthria and dysphagia in postmortem-confirmed parkinsonian disorders.

Muller J, Wenning GK, Verny M, McKee A, Chaudhuri KR, Jellinger K, Poewe W, Litvan I.
Cognitive Neuropharmacology Unit, Bethesda, MD

BACKGROUND: Dysarthria and dysphagia are known to occur in parkinsonian syndromes such as Parkinson disease (PD), dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). Differences in the evolution of these symptoms have not been studied systematically in postmortem-confirmed cases.

OBJECTIVE: To study differences in the evolution of dysarthria and dysphagia in postmortem-confirmed parkinsonian disorders.

PATIENTS AND METHODS: Eighty-three pathologically confirmed cases (PD, n = 17; MSA, n = 15; DLB, n = 14; PSP, n = 24; and CBD, n = 13) formed the basis for a multicenter clinicopathological study organized by the National Institute of Neurological Disorders and Stroke, Bethesda, Md. Cases with enough clinicopathological documentation for the purpose of the study were selected from research and neuropathological files of 7 medical centers in 4 countries (Austria, France, England, and the United States).

RESULTS: Median dysarthria latencies were short in PSP and MSA (24 months each), intermediate in CBD and DLB (40 and 42 months), and long in PD (84 months). Median dysphagia latencies were intermediate in PSP (42 months), DLB (43 months), CBD (64 months), and MSA (67 months), and long in PD (130 months). Dysarthria or dysphagia within 1 year of disease onset was a distinguishing feature for atypical parkinsonian disorders (APDs) (specificity, 100%) but failed to further distinguish among the APDs. Survival time after onset of a complaint of dysphagia was similar in PD, MSA, and PSP (15 to 24 months, P =.7) and latency to a complaint of dysphagia was highly correlated with total survival time (rho = 0.88; P<.001) in all disorders.

CONCLUSIONS: Latency to onset of dysarthria and dysphagia clearly differentiated PD from the APDs, but did not help distinguish different APDs. Survival after onset of dysphagia was similarly poor among all parkinsonian disorders. Evaluation and adequate treatment of patients with PD who complain of dysphagia might prevent or delay complications such as aspiration pneumonia, which in turn may improve quality of life and increase survival time.

PubMed ID#: 11176964

These results were the most interesting (and depressing):

“Dysarthria or dysphagia within 1 year of disease onset was a distinguishing feature for atypical parkinsonian disorders (APDs).”

“Median dysarthria latencies were short in PSP and MSA (24 months each), intermediate in CBD and DLB (40 and 42 months), and long in PD (84 months).”

“Median dysphagia latencies were intermediate in PSP (42 months), DLB (43 months), CBD (64 months), and MSA (67 months), and long in PD (130 months).”

“Survival time after onset of a complaint of dysphagia was similar in PD, MSA, and PSP (15 to 24 months).”

On this last point, here are the CBD and PSP data from the article:

Survival Time After Onset of Dysphagia, months
CBD 49 (25-89…..including a single patient with dysphagia but without dysarthria)
PSP 18 (6-96)

Here are some excerpts from the article’s Comment section:

“(Early) dysarthria and perceived swallowing dysfunction are not features of PD.”

“Dysarthria) as a presenting symptom has been described in clinical series of CBD, MSA, and PSP. In PD and DLB, hypphonic/monotonous speech represented the most frequent type of dysarthria, whereas imprecise or slurred articulation predominated in CBD, MSA, and PSP.”

“In a clinical study of CBD, Rinne et al described dysarthria as one of the initial symptoms in 11% of the patients, which is close to our findings. At follow-up, on average 5.2 years, dysarthria was diagnosed in 70% of the patients… According to our findings, dysarthria occurred in almost every patient with CBD.”

“In both PSP and MSA, progressive dysarthria is believed to represent a manifestation of brainstem and cerebellar involvement. In fact, PET studies revealed marked hypometabolism in the cerebellum and brainstem of patients with MSA, which correlated with dysarthria.”

“In our study, dysphagia was associated with concomitant dysarthria in all parkinsonian patients except one. This sequence of dysphagia following dysarthria has also been reported in clinical studies of PD, MSA, and PSP.”

“…Golbe et al reported dysphagia after a median of 1 year after the onset of dysarthria in PSP.”

In all these disorders, “bronchopneumonia has been reported as a leading cause of death, which may be subsequent to silent aspiration resulting from dysphagia.”

“Most of our patients with MSA and PSP complained of a swallowing dysfunction, in contrast to patients with PD, CBD, and DLB… Impaired lingual proprioception is hypothesized to contribute to the unawareness of swallowing difficulties in PD and might in part explain significantly longer latencies to dysphagia in our PD cases. In contrast, patients with PSP were reported to be keenly aware of swallowing problems, including those with cognitive impairment.”

“(The) similarly short remaining survival time in PD and PSP after the onset of perceived dysphagia suggests that this symptom represents a reliable marker for the onset of functionally relevant swallowing abnormalities in both disorders.”

Robin

MRI and MRS in PSP, MSA-P, PD (Brazilian study)

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This small Brazilian study looked at 11 patients with PSP, 7 patients with MSA-P, 12 patients with PD, and 10 controls. Everyone was studied with magnetic resonance imaging (MRI) and spectroscopy by MRI (MRS).

The authors concluded:
“(1) Patients with PSP and MSA-P presented increased motor and cognitive impairment in the scales used, correlating with decrease in NAA/Cr in lentiform nucleus and NAA/Cho in midbrain in the PSP group;
(2) Cerebral and cerebellar atrophy were more prevalent and severe in PSP and MSA-P groups;
(3) Linear hypersignal in the lateral portion of the putamen, hypersignal in midbrain and in pons, all suggest the diagnosis of PSP or MSA-P;
(4) Midbrain or pons atrophy suggests atypical parkinsonism, the former PSP, and the latter MSA-P;
(5) Comparing the two methods, MRI and MRS, the former had better applicability.”

The abstract and lots of excerpts follow. The English-language article is available for free online here:
http://www.scielo.br/pdf/anp/v67n1/a02v67n1.pdf –> PDF form
http://www.scielo.br/scielo.php?script= … so&tlng=en –> HTML form

For me, the most interesting parts of this article were the three figures with captions, indicating what percentage of the patient groups had particular MRI or MRS findings, including the hot cross bun sign in MSA. (You’ll have to go online to see the figures.) And the Discussion section was worthwhile reading.

Robin

Arqivos de Neuropsiquiatria. 2009 Mar;67(1):1-6.

Neuroimaging in Parkinsonism: a study with magnetic resonance and spectroscopy as tools in the differential diagnosis.

Vasconcellos LF, Novis SA, Moreira DM, Rosso AL, Leite AC.
Hospital dos Servidores do Estado, Rio de Janeiro, RJ, Brazil.

The differential diagnosis of Parkinsonism based on clinical features, sometimes may be difficult. Diagnostic tests in these cases might be useful, especially magnetic resonance imaging, a noninvasive exam, not as expensive as positron emission tomography, and provides a good basis for anatomical analysis. The magnetic resonance spectroscopy analyzes cerebral metabolism, yielding inconsistent results in parkinsonian disorders.

We selected 40 individuals for magnetic resonance imaging and spectroscopy analysis, 12 with Parkinson’s disease, 11 with progressive supranuclear palsy, 7 with multiple system atrophy (parkinsonian type), and 10 individuals without any psychiatric or neurological disorders (controls). Clinical scales included Hoenh and Yahr, unified Parkinson’s disease rating scale and mini mental status examination.

The results showed that patients with Parkinson’s disease and controls presented the same aspects on neuroimaging, with few or absence of abnormalities, and supranuclear progressive palsy and multiple system atrophy showed abnormalities, some of which statistically significant. Thus, magnetic resonance imaging and spectroscopy could be useful as a tool in differential diagnosis of Parkinsonism.

PubMed ID#: 19330200

Here are excerpts from the full article:

“Magnetic resonance imaging (MRI) and spectroscopy by MRI (MRS) are noninvasive tools helping the physician to establish a more accurate diagnosis. MRI offers an adequate analysis of abnormalities in the basal nuclei, midbrain, pons, medulla, and cerebellum, which are impaired in atypical” parkinsonism.

“Method
We designed a prospective, case-control, double-blind, 24 months study. The MRI was performed in a GE machine, 1.5 Tesla Sigma Horizon model, the sequences analyzed were T 1, T 2, flair, diffusion, axial-oblique in T 2 in Fast Spin-Echo (FSE) and Proton Density (PD) and T 2 in Spin-Echo (SE). In addition to 5 mm slices, we included 3 mm slices in the lentiform nucleus. The MRS was single voxel (8 cc), PRESS technique (TR/TE=1500/50) bilaterally in lentiform nucleus, midbrain, white matter of frontal lobe and hippocampus.” …

“Forty individuals were included in this study (age range: 50 to 85 years), 30 with Parkinsonian syndrome and 10 without any neurological or psychiatric disorders.”

“All individuals were examined by the same neurologist, and 26 patients met the criteria for probable Parkinson’s disease (PD) [n=10], (Gelb et al.), progressive supranuclear palsy (PSP) [n=10], (Tolosa et al.), and multiple system atrophy-parkinsonian type (MSA-P) [n=6], (Gilman et al.). For clinical assessment, the scales adopted were Hoehn-Yahr stage, unified Parkinson’s disease rating scale (UPDRS) Part III and mini-mental status examination (MMSE). The patients performed the Tilt Table test for evaluation of dysautonomia.”

“Results …
Dysautonomia was documented in 20% of PD and 100% of MSA-P.

In the motor scales (UPDRS and Hoehn and Yahr), the results showed higher scores in PSP and MSA-P than in PD. There was statistical significance in PD versus MSA-P, and a trend to statistical significance in PD and PSP.

Patients with PSP presented lower scores in MMSE, followed by MSA-P and PD, and there was statistical significance in the three groups comparing to controls (Table 1).

Image variables demonstrated cerebral atrophy in all cases of PSP and MSA-P, having statistical significance in PD versus PSP, PD versus MSA-P, controls versus PSP, and controls versus MSA-P. Cerebellar atrophy was more common in MSA-P and PSP, with statistical significance in PD versus MSA-P, controls versus PSP and controls versus MSA-P. We observed a higher prevalence of white matter alterations in atypical [parkinsonism] with no statistical significance. Signal change in the lentiform nucleus was observed more commonly in MSA-P and PSP, but no statistical significance was documented (Figs 1­3).”

Fig 1. Hyposignal in the lentiform nucleus (found in 67% of MSA-P group), and hypersignal in the pons (found in 33% of the MSA-P group) and the midbrain on T2, flair or DP sequences (found in 70% of PSP group).

Fig 2. Posterolateral linear hypersignal in the lentiform nucleus with asymmetric symptoms, T2 sequence (found in 50% in MSA-P group).

Fig 3. Transverse signal (“hot cross bun sign”) in the pons, T2 sequence (found in 33% of MSA-P group).” …

“DISCUSSION
…Parkinsonian signs may be seen in different medical conditions, having variable course, treatment and prognosis so it is important to determine an accurate diagnosis as soon as possible. Based only in clinical data, especially in the early stages of the disease, physicians may not establish a correct diagnosis.

… One study conducted in a movement disorders specialized center, showed that the positive predictive value of PD was 98.6%, and to atypical parkinsonism 71.4%, confirming that the diagnosis of atypical [parkinsonism], even in specialized centers, is sometimes difficult to establish.

… We included the three [parkinsonism syndromes] that most frequently lead to misdiagnosis: PD, MSA-P, and PSP, all compared to control group. …

We used three clinical scales: motor part of UPDRS, Hoehn and Yahr and MMSE. These scales showed increased motor impairment (higher scores in UPDRS and Hoehn-Yahr) in the MSA-P, followed by PSP, and increased cognitive impairment (lower scores of MMSE) in PSP, followed by MSA-P. We did not observe a correlation between the duration of the symptoms with MRS abnormalities, but with the clinical diagnosis of patient.

MRI variables demonstrated that some are helpful to differentiated [parkinsonism] syndromes, as the presence of cerebral and cerebellar atrophy and signal enhancement of some encephalic structures (lentiform nucleus, midbrain and pons), more common in atypical [parkinsonism].

The decreased signal enhancement in the lentiform nucleus may be observed in normal aging, so in our study we only considered it as ‘abnormal’ if the hypointensity was moderate to severe. Our data showed that moderate to severe decrease hypointensity in lentiform nucleus was observed more frequently in MSA and PSP, with no difference between PD and control groups and when it was associated with posterolateral linear hypersignal in putamen, suggested the diagnosis of atypical [parkinsonism] (more frequently in MSA group).

The most useful measurement of encephalic diameter in our study was the midbrain, as it had been shown by Warmutth et al. Values below 15 mm in the midbrain suggested PSP or MSA-P, with lower values seen in PSP.

Some values of MRS had statistical significance, the most useful were from the lentiform nucleus, hippocampus, and midbrain, depending on the diagnosis, indicating a severe neuronal impairment (neuronal death). There are few studies in which the brainstem is evaluated by MRS, due to technical difficulties (bone proximity). In our study we demonstrated that it is feasible, but we had to repeat the exam, in some cases several times, to achieve a consistent chart. The study done by Watanabe et al. demonstrated the usefulness of MRS of the pons in MSA patients. As the midbrain is the most affected area in PSP, we analyzed it by MRS. We have found NAA/Cho decrease in midbrain of PSP group with statistical significance, indicating neuronal loss.

Based on our data we concluded that:
(1) Patients with PSP and MSA-P presented increased motor and cognitive impairment in the scales used, correlating with decrease in NAA/Cr in lentiform nucleus and NAA/Cho in midbrain in the PSP group;
(2) Cerebral and cerebellar atrophy were more prevalent and severe in PSP and MSA-P groups;
(3) Linear hypersignal in the lateral portion of the putamen, hypersignal in midbrain and in pons, all suggest the diagnosis of PSP or MSA-P;
(4) Midbrain or pons atrophy suggests atypical parkinsonism, the former PSP, and the latter MSA-P;
(5) Comparing the two methods, MRI and MRS, the former had better applicability.

Our study showed that anatomical analysis through MRI and MRS of some areas could be useful in the differential diagnosis of PD and atypical [parkinsonism], helping physicians to establish a more accurate diagnosis of [parkinsonian syndromes].”

Book recommendation: “AfterShock”

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This book recommendation came around again to me recently and I thought I’d pass along the title here. The recommended book is:
“AfterShock: What To Do When The Doctor Gives You – Or Someone You Love – a Devastating Diagnosis”
by Jessie Gruman, PhD
$12 new or $1 used on amazon.com
www.aftershockbook.com

On Friday, someone on an online MSA support group noted that Dr. Gruman was on the Martha Stewart show on Friday 3/27. I dug around on marthastewart.com but couldn’t find any segments from that Friday show available online. (Maybe the segment with Dr. Gruman will be posted later.) The Martha Stewart website did have some additional info on “Dealing with a Devastating Medical Diagnosis”:

“What would you do if you were diagnosed with a life-threatening illness? How would you handle this news? While shock, fear, and even hysteria might be normal reactions, it’s helpful to have a guide for what’s often a very tumultuous road ahead.

When you’re given the news that you have cancer, HIV, or another serious diagnosis, it may feel as if your world has shattered and all of your plans for the future have vanished in a flash. You feel fear, despair, anger, sadness — often all at once. It’s understandable; a serious diagnosis is a crisis, and you should treat it as one. Don’t force yourself to go to work or make big decisions while you’re really upset. Give yourself time to pull it together: Spend time with loved ones; don’t forget to eat; nap if you can; cry if you feel like it. There are no rewards for being tough. It’s a tribute to human resilience that as you learn more and adjust to the shock, you’ll find you regain some focus and are able to take the important next steps.

Finding a good doctor is really important — begin by looking for a specialist who has extensive experience treating the exact disease you have. Finding that person can be a puzzle. There are many referral sources, and none of them will tell you everything you need to know. The tried and true way is to ask a physician you know and like to refer you to another physician that he or she has worked with before. …

Often, friends, family members, and co-workers don’t know how to respond. They should begin by acknowledging the difficult situation. People say they’re uncomfortable raising the topic with someone who is sick and that they don’t want to remind the sick person of it or make them cry, but saying nothing is far more damaging. Say this: “I hear you’ve had some bad news. I’m so very sorry. I hope everything goes OK.” It means so much.

Also, don’t talk about a friend or family member’s illness without his or her permission, even to other family members. Ask what information can be shared and with whom. And then listen — many people with a serious illness swing between hope and fear.

When it comes to health care, you have to force yourself to act like a consumer. Things have changed a lot in health care in the past decade. Advances in surgery and drugs and diagnostics mean it’s now possible to live long and well with diseases that were a death sentence as recently as 10 years ago. But we will only benefit from these advances if we are involved. We have to decide which doctors to visit, get the tests, take the pills, and seek help when we can’t manage on our own. Patients have a critical role in the success of our health care.”

That’s from:
http://www.marthastewart.com/article/de … ewart-show
There’s a list of online resources available.

This page on Dr. Gruman’s website gives a great description of the book:
http://www.aftershockbook.com/book_inde … troduction

Below is an email I sent out in June ’07 to the local support group in which a social worker recommended “AfterShock” and gave some additional ideas for self management of long-term conditions.

Robin

Date: Mon, 18 Jun 2007 17:34:47 -0700
To: [email protected]
From: Robin Riddle <[email protected]>
Subject: “Self Mgmt of Long-term Conditions” (Meeting Notes)

I attended the Palo Alto Parkinson’s Disease support group meeting last week where I picked up one book suggestion and a few general suggestions that I thought I’d pass along. The speaker was Kate Lorig, Patient Education at Stanford Hospital. The topic was Self Management of Long Term Conditions.

Here’s some general information on Stanford’s workshops and programs to help people live with long-term health problems: http://patienteducation.stanford.edu/programs/
Some programs are meeting-based and others internet-based.

This particular support group is mixed with caregivers and those with Parkinson’s Disease. The speaker asked those with PD “what are the biggest challenges of living with PD?” and, for the caregivers, “what are the biggest challenges of living with someone who has PD?” Then the group voted on the top challenges, which were:

* living with ever-diminishing hopes
* sense of loss
* comparing how things used to be (“the good ole days”) to how things are now
* balance/coordination/muscle weakness

On the psychological issues of ever-diminishing hopes and a sense of loss, the speaker said that once you have a chronic condition, death is a reality. She highly recommends a new book called “After Shock” by Dr. Jessie Gruman. (You can find info on this book at http://www.aftershockbook.com/. You might listen to some interviews with Dr. Gruman before purchasing the book.) None of your family and friends know how to deal with the “new you.”

The speaker recommends planning at least one thing every day that the patient and caregiver can still enjoy — such as having an ice cream cone, watching the news, or travelling. She thinks it would be best to have several small things every day planned.

She emphasized that it’s the patient’s job to tell other people exactly what they can do to help. Again, she thinks that having something small planned is worthwhile, such as telling someone “you can invite me to a movie once a month.”

The speaker believes that doing volunteer work is useful: “helping others will help you.” A meeting attendee recommended the website dosomething.org for volunteer activities of any time duration.

The speaker says that most people with chronic conditions and most people caregiving for those with chronic conditions are depressed — some sub-clinically (ie, not needing therapy) and some clinically. She recommends that everyone have a specific thing to do or think about if they perceive they are having negative thoughts. A specific thing to do might include going to the movies, exercising, or baking. A specific thing to think about might include polar bears or penguins. (These were her examples!)

The speaker addressed the challenge of balance/coordination/muscle weakness by saying that these issues can be addressed through exercise. She recommended that everyone with a chronic health problem get exercise that doesn’t hurt. In particular she likes tai chi, and recommends the tai chi tapes of Paul Lam (see taichiproductions.com) and Jon Kabat-Zinn. JKZ also has mindfulness training tapes.

If you fall, don’t ask someone to lift you as they probably don’t know what they are doing and will hurt themselves or you. Instruct any helper to get others to help, particularly others who are trained in helping get people up off the floor.

She said that everyone using a cane, walker, or wheelchair needed lessons on using these tools properly.

That’s it!
Robin

Atypical Parkinsonism – Breakout session notes (3/12/09)

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On Thursday 3/12/09 at the Victory Summit (Symposium for People Living with Parkinson’s Disease) in San Jose, there was a one-hour breakout session on “Atypical Parkinson’s Disease.” There were two presenters:
* Grace Liang, MD, Neurologist/Movement Disorder Specialist, The Parkinson’s Institute
* Amy Manning-Bog, PhD, Researchers, The Parkinson’s Institute

In a one-hour period, I thought they gave a great summary of the clinical picture of the four atypical parkinsonism disorders, and of the basic research underway that pertains to these disorders with particular attention to MSA. The Q&A was especially good; there were many in the audience who grasped even the challenging research update. I shared the draft of my notes with Dr. Manning-Bog, and she kindly corrected them and expanded the explanation in a few places. Also, support group member Helen added many points I had missed. Here are our combined notes from the presentations and the Q&A…

Notes from Dr. Liang’s Presentation

In order to know what “atypical PD” is, we must first review what “typical PD” is. Typical PD:
* usually starts on one side
* usually has a resting tremor
* includes Lewy body pathology
* slow progression (several decades)
* responds to medications

Common parkinsonian motor signs include:
* bradykinesia (slowed movements)
* tremor
* rigidity
* balance difficulty/gait instability

Other motor signs of PD include:
* hypophonia
* freezing
* stooped posture
* decreased facial expression

There are many non-motor symptoms of PD:
* constipation
* sleep disorders
* depression

These additional non-motor symptoms are prominent in atypical PD:
* blood pressure fluctuations
* swallowing difficulties
* urinary symptoms
* change in thinking and memory abilities

Parkinsonism can include the following diagnoses:
* Drug-induced Parkinsonism: may be caused by dopamine blocking drugs (examples – Haldol, Reglan, Risperdal, Depakote); reversible to some extent; these medications should be avoided by those with PD or parkinsonism
* Vascular Parkinsonism: caused by loss of blood flow to certain regions of the brain; minimal response to medication

NPH (normal pressure hydrocephalus):
* symptoms include shuffling gait, urinary incontinence, and dementia
* very rare
* not easy to diagnose
* treated with surgery but not that the surgical results are variable

DLB (dementia with Lewy bodies):
* second most common dementia (after AD)
* early notable cognitive changes (can be before or after motor symptoms start; the “time course” determines whether we call this PDD or DLB)
* visual hallucinations are common and are made worse by medication
* fluctuating mental alertness
* delusions

DLB – treatment:
* there is a balance between motor and cognitive symptoms
* dementia drugs can be helpful (examples – Aricept, Exelon, Razadyne, Namenda)
* minimize factors that can increase confusion and hallucinations
* use antipsychotics sparingly for delusions and hallucinations. Note the FDA black-box warning on antipsychotics. The care team must balance the patient’s (and caregiver’s) quality of life with the risks of this type of medication.

MSA (multiple system atrophy):
* often called “Parkinson’s Plus”
* autonomic dysfunction (orthostatic hypotension or low blood pressure upon standing, urinary incontinence, erectile dysfunction)
* there is also a cerebellar form (where balance is a problem)

MSA – treatment:
* there is not usually a strong or prolonged response to PD medication
* to support blood pressure: increase fluid intake, increase salt intake, wear support stockings
* muscle exercises to improve tone and circulation (this can be something as simple as keeping the feet moving throughout the day)
* balance exercises
* evaluate whether there are sleep problems

PSP (progressive supranuclear palsy):
* named for eye movement problem: it’s hard to look up and down
* early balance problems (falls) and gait freezing
* swallowing difficulties
* speech changes
* impulsive behavior

PSP – treatment:
* PD meds may not improve symptoms (and can make balance worse)
* evaluate for speech and swallowing problems
* physical therapy and fall precautions
* dystonia and contractures might be treatable with botox injections

CBD (corticobasal degeneration):
* rare
* usually starts with loss of function of one limb
* apraxia (examples: forgotten how to put clothes on correctly; forgotten how to brush teeth correctly)
* dystonia (involuntary muscle contractions) may occur
* cognitive changes (decreased ability to interpret visual or sensory signs; language difficulty) (example of a sensory sign: the patient can’t tell if he/she is holding a dime or a nickel)

CBD – treatment:
* variable results
* might try dementia medication (Namenda or AChEIs such as Aricept, Exelon, and Razadyne)
* physical therapy is important
* speech therapy is important

“Helpers” or Important resources:
* grab bars
* walker (actually, people can become *more* mobile by using a walker)
* shower seat
* reacher (pick-up stick)
* special eating utensils with big grips and bendable metal
* gait belt
* thickener (example: ThickIt)

Fall prevention:
* remove throw rugs and clutter on floor
* don’t use a step stool
* put things at eye level rather than reaching up for things
* hold onto hand rails and don’t carry a load of things while using stairs

Key points:
* be observant
* control the environment
* protect your brain — reduce risk factors
* nutrition: consider vitamin B, fish oil, Mediterranean diet, CoQ10?, creatine. (Both CoQ10 and creatine are being studied in PD and atypical PD.)
* exercise, exercise, exercise. This is great for the mind, body, and spirit
* do something you enjoy each day

Organizational resources:
LBDA.org
curepsp.org
shy-drager.org
ppsg.org
wemove.org
caregiver.org
nfacares.org
pdtrials.org
atypical parkinsonism support group organized by Robin Riddle

Notes from Dr. Manning-Bog’s presentation:

Changes in brain tissue overlap between the atypical diseases:
* loss of dopaminergic neurons
* depletion
* presence of cytosolic inclusions

A “Lewy body inclusion” is an abnormal deposit of protein. Many proteins are included but it’s mostly alpha-synuclein.

Alpha-synucleinopathies (PD, MSA, LBD) can either be familial or sporadic.

There are modifiers:
* genetics
* environment
* aging

Alpha-synuclein comprises up to 2% of total brain protein in normal brains.

Alpha-synuclein can self-aggregate or bind itself to form multimers of the protein and even alpha-synuclein fibrils.

Alpha-synuclein aggregation (or clumping) could be due to:
* increased expression
* decreased degradation (ie, the cell doesn’t get rid of the protein)
* exposure to toxicants that can stimulate alpha-synuclein to bind itself

In the last few years, a transgenic mouse model was developed for MSA (by Eliezer Masliah’s group at UC San Diego). This is an exciting tool because researchers can isolate and manipulate the alpha-synuclein gene! Now that Dr. Masliah has generated these MSA mice, there is a tool that we can use to study mechanisms to disaggregate and clear alpha-synuclein from cells (i.e. neurons in PD and oligodendroglia in MSA). We can use this tool to test therapeutics in a pre-clinical environment.

Images were shown of alpha-synuclein fibrils in test tubes. This research was done at UC Santa Cruz. This research is promising. Researchers could disintegrate the fibrils (although not always completely) and may leave some toxic synuclein species.

Eliezer Masliah’s group at UC San Diego tried to target the aggregation of synuclein and increase the degradation of synuclein by giving the drug rifampicin to MSA mice. This partially worked. Results were promising — less cell death and alpha-synuclein deposition were apparent in mice treated with rifampicin.

Dr. Manning-Bog’s research approach is to deliver alpha-synuclein to where it needs to go. The goal is to restore alpha-synuclein trafficking via the lipid raft.

If researchers find a mechanism that prevents alpha-synuclein build-up in cells, these agents can be tested in animal models of other diseases that involve alpha-synuclein (including the MSA model or a mouse model of alpha-syn build-up in neurons).

>From this standpoint, any work that is done on these aspects of alpha-synuclein is important to any PD form that has alpha-synuclein pathology. (For example, the alpha-synuclein trafficking arm of my research program, for example, is relevant to any PD form with alpha-synuclein pathology.)

[I asked Dr. Manning-Bog why she talked about the MSA mouse model during her presentation. She replied: “While putting together my talk for the symposium, I asked Dr. Brandabur what types of Atypical PD were most commonly treated at the Institute. She informed me that MSA is one of the more predominant Atypical PD forms of the Institute’s patient population. For this reason, I focused on the research of other labs, because it would be so directly relevant to many patients. Patients with atypical PD are starved for information, so I thought that I should try to tailor the presentation to their interests.”]

Dr. Manning-Bog is also at step one of some tau research. (She has an intern working on this.) She’s seen toxic tau protein changes in DJ1 transgenic mice. This may be a good model for researching Parkinson’s Disease Dementia. This is a first step.

[Robin’s note: PD, DLB and MSA are disorders of alpha-synuclein. They are called alpha-synucleinopathies. Any of the alpha-synuclein research should help these disorders. Of these, only PD and DLB are Lewy body diseases. AD, PSP and CBD are disorders of tau. They are called tauopathies. Any of the tau research should help these disorders. Because DLB typically appears with Alzheimer’s pathology – the so-called “Lewy body variant of Alzheimer’s disease” – tau research may help the DLB community as well.]

Notes from the Q&A:

Q: Can you have the other symptoms of PSP without having the eye movement problem?
A by Dr. Liang: Yes.

Q: What’s the story about statins?
A by Dr. Manning-Bog: Statins have been studied in a few models and seem to be neuroprotective. (See note 1 below.)
A by Dr. Liang: Statins can effect muscle tissue. The atypical PD disorders are neurological disorders, not muscular disorders, so statins are not implicated in the decline seen in these disorders.

Q: When do you get Lewy bodies?
A by Dr. Manning-Bog: Lewy bodies develop throughout the brain predominantly in disease conditions.
A by Dr. Liang: But it could be that Lewy bodies are part of normal aging. We don’t know.
A by Dr. Manning-Bog: We don’t know yet if Lewy bodies are toxic. Currently, we don’t think they cause the disease. They may serve to sequester toxic synuclein. It may be that when synuclein is not sequestered into a Lewy body, it’s toxic.
A by Dr. Manning-Bog: In PD, Lewy bodies start in the brain stem and progress to midbrain, then cortex. In DLB, there are Lewy bodies in the brain’s cortex.

Q: Can imaging see Lewy bodies?
A: No, Lewy bodies are only detectable upon autopsy.

Q: What’s the prevalence of dementia in these disorders?
A by Dr. Liang: The studies vary between 30% and 80% of those with PD getting dementia. It depends on what tests are given to research participants and the definition of “dementia.”

[Answer by Robin:
DLB: 100% of those with DLB have dementia; “progressive dementia” is a “central feature” of DLB (according to the diagnostic criteria)
MSA: none of those with MSA have dementia; according to the diagnostic criteria, dementia is an exclusionary criterion for MSA
PSP: according to the latest clinicopathological correlations, 54% to 62% of those with PSP had dementia as a primary symptom
CBD: there have been no studies on this; my impression is that the percentage for CBD is roughly the same as for PSP; however, it seems from Dr. Liang’s presentation that the percentage may be higher]

Q: What about stem cell research?
A by Dr. Manning-Bog: In research using iPS (induced pluripotent stem cells) to create dopmainergic neurons, the yield is only two percent! This means that iPS isn’t an efficient means of treatment currently. But iPS offers a great way to study the disease mechanism. Before any iPS cells are transplanted into patients, we need to study teratomas, the tumors that can grow.

Q: Are you hopeful about the research?
A by Dr. Manning-Bog: Yes, I’m hopeful!

Note 1:
Dr. Manning-Bog provided two references on statin studies. You can look up the abstracts on pubmed.gov by using the PubMed ID#.

1. The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor lovastatin reduces severity of L-DOPA-induced abnormal involuntary movements in experimental Parkinson’s disease.
Schuster S, Nadjar A, Guo JT, Li Q, Ittrich C, Hengerer B, Bezard E.
J Neurosci. 2008 Apr 23;28(17):4311-6.
PubMed ID#: 18434508

2. Simvastatin is associated with a reduced incidence of dementia and Parkinson’s disease.
Wolozin B, Wang SW, Li NC, Lee A, Lee TA, Kazis LE.
BMC Med. 2007 Jul 19;5:20.
PubMed ID#: 17640385

Can olfactory bulb biopsy distinguish PSP – MSA – PD?

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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