Category Archives: LBD

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

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