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 Boeve paper (Brain '07) on REM sleep behavior disorder 
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Post Boeve paper (Brain '07) on REM sleep behavior disorder
There are three items in this post, all relating to recent research into RBD by Dr. Boeve: Mayo Rochester press release about the Brain '07 journal article, abstract of the article, and excerpts of the article.

The Mayo Rochester press release says the research "led to the findings that patients with the violent rapid eye movement sleep (REM) behavior disorder (RBD) have a high probability of later developing Lewy body dementia, Parkinson's disease or multiple system atrophy (a Parkinson's-like disorder), because all of these conditions appear to stem from a similar neurodegenerative origin." LBD, PD, and MSA are all synucleinopathies. (PSP and CBD are tauopathies.)

Mentioned in the online version of the news release is a short video of a 70-year-old man with "severe RBD": (video only - no audio)
http://www.medicaledge.org/media-files/ ... leblur.mpg


Mayo Clinic in Rochester
Wednesday, May 16, 2007

Violent Sleep Disorder Linked to a Form of Dementia
Early indicator of neurologic disorder risk

Mayo Clinic researchers and a group of international collaborators have discovered a correlation between an extreme form of sleep disorder and eventual onset of parkinsonism or dementia. The findings appear in the current issue of the journal Brain.

Clinical observations and pathology studies, as well as research in animal models, led to the findings that patients with the violent rapid eye movement sleep (REM) behavior disorder (RBD) have a high probability of later developing Lewy body dementia, Parkinson's disease or multiple system atrophy (a Parkinson's-like disorder), because all of these conditions appear to stem from a similar neurodegenerative origin.

"Our data suggest that many patients with idiopathic (not associated with any other neurologic symptoms) RBD may be exhibiting early signs of an evolving neurodegenerative disease, which in most cases appear to be caused by some mishap of the synuclein protein," says Bradley Boeve, M.D., Mayo Clinic neurologist and lead author of the study. Synuclein proteins are associated with synapses in the brain, and clumps of abnormal alpha-synuclein protein are present in some forms of dementia. "The problem does not seem to be present in the synuclein gene itself, but it's something that happens to the protein following gene expression. Just what happens to it to cause the conditions isn't clear."

The result, however, is quite clear. The patients -- usually older males -- strike out violently, often yelling, when they enter REM sleep (see video). Mayo researchers following these individuals over many years saw many of them develop symptoms of dementia. Postmortems showed they all had developed Lewy bodies but not the pathology of Alzheimer's disease. Earlier studies by two of the co-authors on this paper (from the University of Minnesota) had described this sleep disorder and associated it with eventual onset of Parkinson's disease or Parkinson's disease-like disorder in some patients. This Mayo study builds on that work and makes the connection to onset of a non-Alzheimer's dementia.

Dr. Boeve says many cases may go unreported because the individual sleeps alone, the activity is tolerated or the condition is misdiagnosed. Violent movements during sleep do not always mean someone has this condition. Sometimes the behavior is due to untreated sleep apnea and the condition resolves with regular sleep apnea treatment -- use of a CPAP breathing machine. In those cases, the cause is sleep apnea. It's the idiopathic RBD findings on sleep studies that may precede dementia or parkinsonism by years or decades -- underscoring the need for patients with suspected RBD to undergo a sleep study.

"This association may provide one of the earliest indicators thus far of eventual dementia or parkinsonism," says Dr. Boeve. "While some patients don't ever exhibit symptoms of dementia or parkinsonism, all patients studied thus far with RBD do develop pathology in the brainstem." This is both good news and bad news. While Lewy body dementia and Parkinson's disease have no cure, they can be treated. Medications can restore cognitive function for many with Lewy body dementia, often much more impressive improvement in cognition than what these drugs do in patients with Alzheimer's disease. The quandary facing physicians is whether to inform patients that they have an increased risk of developing dementia or parkinsonism, when symptoms may not appear for years or may never appear at all.

"It's an ethical dilemma," says Dr. Boeve. "We know that many patients with RBD will develop dementia or parkinsonism, but we can't positively predict what will happen in each individual case. Some physicians choose to tell very little of this to their patients. I try to explain this, but also emphasize the positive -- that some people never show any symptoms and live a normal life. There are documented cases of patients who have had RBD for decades and die from heart disease, stroke or cancer, and never show any signs of dementia or parkinsonism."

Neurology researchers from Mayo Clinic's campuses in Minnesota, Florida and Arizona, researchers in Mayo's Sleep Disorder Center, along with scientists from Harvard, the University of Minnesota and J. W. Goethe University in Germany, combined years of separate studies to reach these findings. This paper represents a collaborative effort by all of these scientists.

Co-authors include M. H. Silber, M.B.Ch.B.; T. J. Ferman, Ph.D.; D. W. Dickson, M.D.; J. E. Parisi, M.D.; E. E. Benarroch, M.D.; J. E. Ahlskog, M.D., Ph.D.; G. E. Smith, Ph.D.; R. C. Caselli, M.D.; M. Tippmann-Peikert, M.D.; E. J. Olson, M.D.; S-C. Lin, M.D.; T. Young, M.D.; and Z. Wszolek, M.D., all of Mayo Clinic; C. B. Saper, M.D., Ph.D. of Harvard Medical School; C. H. Schenk, M.D.; M. W. Mahowald, M.D.; and P. R. Castillo, M.D., of the University of Minnesota; and K. Del Tredici, M.D., and H. Braak, M.D., of J. W. Goethe University, Frankfurt am Mein, Germany. Support for the study came from the National Institutes of Health, the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program at Mayo Clinic, and by a grant from the German Research Council.
###


And here's the abstract:

Brain. 2007 Apr 5; [Epub ahead of print]

Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease.

Boeve BF, Silber MH, Saper CB, Ferman TJ, Dickson DW, Parisi JE, Benarroch EE, Ahlskog JE, Smith GE, Caselli RC, Tippman-Peikert M, Olson EJ, Lin SC, Young T, Wszolek Z, Schenck CH, Mahowald MW, Castillo PR, Del Tredici K, Braak H.

Department of Neurology, Department of Psychology and Psychiatry, Laboratory Medicine and Pathology, Sleep Disorders Center and Neuropathology Laboratory, Mayo Clinic College of Medicine, Rochester, MN, Mayo Clinic College of Medicine, Jacksonville, FL, Mayo Clinic College of Medicine, Scottsdale, AZ, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Minnesota Regional Sleep Disorders Center, University of Minnesota, Minneapolis, MN, USA and Institute for Clinical Neuroanatomy, J.W. Goethe University, Frankfurt/Main, Germany.

REM sleep behaviour disorder (RBD) is a parasomnia characterized by the loss of normal skeletal muscle atonia during REM sleep with prominent motor activity accompanying dreaming. The terminology relating to RBD, and mechanisms underlying REM sleep without atonia and RBD based on data in cat and rat are presented. Neuroimaging data from the few published human cases with RBD associated with structural lesions in the brainstem are presented, in which the dorsal midbrain and pons are implicated. Pharmacological manipulations which alter RBD frequency and severity are reviewed, and the data from human neuropathological studies are presented. An anatomic framework and new schema for the pathophysiology of RBD are proposed based on recent data in rat regarding the putative flip-flop switch for REM sleep control. The structure in man analogous to the subcoeruleus region in cat and sublaterodorsal nucleus in rat is proposed as the nucleus (and its associated efferent and afferent pathways) crucial to RBD pathophysiology. The association of RBD with neurological disease ('secondary RBD') is presented, with emphasis on RBD associated with neurodegenerative disease, particularly the synucleinopathies. The hypothesized pathophysiology of RBD is presented in relation to the Braak staging system for Parkinson's disease, in which the topography and temporal sequence of synuclein pathology in the brain could explain the evolution of parkinsonism and/or dementia well after the onset of RBD. These data suggest that many patients with 'idiopathic' RBD are actually exhibiting an early clinical manifestation of an evolving neurodegenerative disorder. Such patients may be appropriate for future drug therapies that affect synuclein pathophysiology, in which the development of parkinsonism and/or dementia could be delayed or prevented. We suggest that additional clinicopathological studies be performed in patients with dementia or parkinsonism, with and without RBD, as well as in patients with idiopathic RBD, to further elucidate the pathophysiology and also characterize the clinical and pathophysiological relevance of RBD in neurodegenerative disease. Furthermore, longitudinal studies in patients with idiopathic RBD are warranted to characterize the natural history of such patients and prepare for future therapeutic trials.

PubMed ID#: 17412731


It seems like we've heard this before (also from Dr. Boeve); so I went to the full article to see what was new. It's one of the best articles I've read on RBD (REM sleep behavior disorder)...and there are a few new things.

In the article, Boeve addresses "idiopathic RBD," which is the term given for RBD when there is no known cause for it (ie, there is no neurological disorder present). Decades after participating in a study on RBD, those with RBD were re-contacted and it was discovered that many of them had been diagnosed in the intervening years with LBD, PD, etc. Boeve suggests that the term "idiopathic RBD" is incorrect. He says: "(M)any patients with 'idiopathic' RBD are actually exhibiting an early clinical manifestation of an evolving neurodegenerative disorder. Such patients may be appropriate for future drug therapies that affect synuclein pathophysiology, in which the development of parkinsonism and/or dementia could be delayed or prevented." Boeve argues that no "truly promising treatments for synuceinopathies have been developed to date, due in part to the prolonged focus on the motor aspects of PD, and on the cognitive and neuropsychiatric aspects of DLB, in the waking state."

Here are some other excerpts I found interesting:

"Among the non-synucleinopathy disorders associated with RBD (eg PSP, SCA-3 and AD), patients have tended to have RBD evolve in concert with or after the onset of parkinsonism, whereas RBD typically begins years before the onset of cognitive and motors features of PD, DLB, MSA and PAF. Hence, RBD preceding the motor and cognitive features of a neurodegenerative disorder may be particularly specific for synucleinopathies." (Synucleinopathies include PD, LBD, MSA, and PAF. PAF = pure autonomic failure.)

"The association of RBD with PD, DLB, MSA, PAF and other disorders with Lewy body pathology is therefore clearly established. In fact, RBD is now considered a suggestive feature in the clinical diagnostic criteria for DLB. ... The frequency of RBD is about 33-60% in PD patients, 50-80% in DLB patients, and 80-95% of MSA patients, but these frequencies are based on convenience samples of patients with these disorders evaluated at specialized centres. ... (Determining) the true frequency of...RBD in the various neurodegenerative disorders will indeed be challenging."

"RBD has been reported in two cases of clinically suspected sporadic PSP and in (13%) of a group of PSP subjects. ... There are no published reports of RBD associated with Pick's disease," FTD, argyrophilic grain disease, etc. Others "have observed sparse cases of RBD associated with clinically probable AD..."

"Despite evaluating over 200 patients with clinically diagnosed (PSP) also over the past 10 years, and pathologically characterizing well over 400 PSP brains as part of the Society for PSP Brain Bank, a history of recurrent dream enactment behaviour in clinically and/or pathologically diagnosed PSP is extremely uncommon in our experience."

"The one patient we followed longitudinally with the corticobasal syndrome who had a long history of dream enactment behaviour was ultimately found to have mixed" LBD/AD pathology.

97% of Mayo's RBD cases had a synucleinopathy, as seen from this table:

"Updated clinicopathological experience at Mayo Clinic from January 1990 to December 2006 of REM sleep behavior disorder associated with dementia and/or parkinsonism:
Pathological diagnoses N
Lewy body disease 31 (12 also met criteria
for intermediate or high likelihood of Alzheimer's disease)
Multiple system atrophy 4
Progressive supranuclear palsy 1 (coexisting vascular
and Alzheimer pathology was present)
Total 36"

"Several reports over the past few years have led to the appreciation that RBD is frequently associated with the synucleinopathies and less frequently with the non-synucleinopathy neurodegenerative disorders. ... (This) supports the concept of selective vulnerability occurring in key brainstem neuronal networks in the synucleinopathies, and such neuronal networks are likely to be less dysfunctional or normal in the tauopathies and other neurodegenerative disorders."

"Typical clinical features of RBD:
Male gender predilection
Mean onset age 50-65 years (range childhood - 80 years)
Vocalizations, swearing, screaming
Motor activity varies from simple limb jerks to complex motor behavior, with injuries to patient or bedpartner
Dream often involve chases or attacks by animals or humans
Exhibited behaviors mirror dream content
Behaviors tend to occur in latter half of the sleep period
When associated with neurodegenerative disease, RBD often precedes dementia and/or parkinsonism by years or decades"

"No randomized, double-blind, placebo-controlled study has ever been reported for any drug treatment for RBD. Yet, numerous medications have been tried over the past 20 years to reduce the frequency and severity of RBD, with clonazepam being the most successful agent, and melatonin also showing efficacy alone or in combination with clonazepam. ... (These) two agents may affect different aspects of the pathophysiological circuitry of RBD. Levodopa and pramipexole reduce the clinical manifestations of RBD, but may do this via suppression of REM sleep. Other drugs with inconsistent effects include carbamazepine, donepezil and quetiapine. Many other drugs, such as benziodiazepines (other than clonazepam), tricyclic antidepressants and antiepileptic agents, have been tried with generally poor response. There is growing evidence implicating the newer generation antidepressant agents, particularly venlafaxine and mirtazapine, are frequent precipitators or aggravators of RBD. Chocolate and caffeine consumed in excess have also been implicated with RBD."

If I'm understanding the article correctly, there have not been any autopsy studies of those with polysomnography-proven RBD where the pathological diagnosis with DLB, MSA, or PD.

"(R)ecent experimental evidence...indicates that cholinergic mechanisms may have a modulatory role in REM-related phenomena..."

"RBD is a dream disorder almost as much as a REM motor disorder, and the tendency for the dream content to involve an aggressive, attacking or chasing theme is well-known but poorly understood."

"(A)nimals deprived of REM sleep die; however, the precise benefit of sleep and particularly REM sleep is unknown."

"This temporal sequence of pathology could explain why RBD precedes parkinsonism and dementia in many patients with Lewy body pathology. ... Yet, if this staging scheme is accurate, why do a significant minority of patients with PD +/- dementia and DLB never exhibit dream enactment behaviour, and why do some DLB patients never exhibit parkinsonism? One explanation is that RBD may not be expressed until sufficient degeneration in the relevant nuclei has occurred, and parkinsonism may not be expressed until sufficient degeneration (typically thought to be at least 80% neuronal loss) in the substantia nigra has taken place."

"Almost 40% of patients with idiopathic RBD in one series were subsequently found to have developed a parkinsonian disorder, and with continued longitudinal follow-up, over 65% of the original cohort has developed parkinsonism and/or dementia. ... Symptoms of RBD preceded dementia and/or parkinsonism in 67% of another series."

"In a recent study...the patients with dream enactment behaviour had reduced cerebral metabolic rate for glucose in regions preferentially affects in patients with...DLB."


Sat May 26, 2007 6:10 pm
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Joined: Tue Feb 06, 2007 8:35 pm
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Thanks, Robin. We've surmised this for a while. Dr. Boeve is really on the forefront. Any drug trials developed for RBD? Too busy to do my own research :oops:

thx again,
dale

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Dale
[My dear, Mom, Beatrice, (born in 1929) was diagnosed with LBD in Dec 2006. She passed away peacefully on July 12, 2013 at Embassy Hall, Shannex, Quispamsis, N.B.]


Sun Jun 03, 2007 1:58 am
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RBD is most successfully treated with klonopin - I believe there are published papers confirming success with EEG verification.

Eric

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Cal is not the real name of a real 84 year old with DLB. I don't speak for LBDA, nor do I have clever initials behind my name, so information is provided without warranty. Caveat everybody. I blog at http://PragmaticCaregiver.blogspot.com


Sun Jun 03, 2007 5:38 am
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Robin,

Very interesting to say the least. My LO had huge sleep disorders for many years prior to Dx...in fact he still has them at times, although the physical enactment part has diminished markedly. He certainly can verbalize eloquently though. :)

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Dianne C.


Sun Feb 15, 2009 11:46 am
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