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 Treatment of LBD with Cholinesterase Inhibitors (Lit review) 
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Joined: Fri Aug 11, 2006 1:46 pm
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Location: SF Bay Area (Northern CA)
Post Treatment of LBD with Cholinesterase Inhibitors (Lit review)
This abstract was recently made available on pubmed.gov:

Dementia and Geriatric Cognitive Disorders. 2007 Mar 26;23(6):251-267

Treatment of Dementia in Parkinsonian Syndromes with Cholinesterase Inhibitors.

Liepelt I, Maetzler W, Blaicher HP, Gasser T, Berg D.
Hertie Institute for Clinical Brain Research, University of Tubingen, Tubingen, Germany.

In Parkinsonian syndromes behavioural symptoms and dementia can be even more debilitating than motor symptoms and are an important predictor for nursing home placement and mortality. Neuropathologically, dementia seems to be primarily related to cortical changes rather than to subcortical alterations. Concerning neurotransmitter systems, the cholinergic system has been proposed to play a key role in cognitive disturbances. Based on studies with patients with Alzheimer disease, the application of cholinesterase inhibitors is vividly discussed also for dementia associated with parkinsonian syndromes. This review focuses on the specific symptoms of dementia in different parkinsonian syndromes and critically questions the effect of cholinergic treatment on cognitive functions in patients with extrapyramidal syndromes and dementia. There is evidence that medication with some cholinesterase inhibitors can enhance cognition as well as activities of daily living in dementia with Parkinson's disease and seems to reduce behavioural disturbances in both dementia with Parkinson's disease and dementia with Lewy bodies. The effect of treatment with cholinesterase inhibitors in progressive supranuclear palsy and corticobasal degeneration warrants carefully designed studies including a sufficient number of patients and symptom-adopted dementia scales. Copyright (c) 2007 S. Karger AG, Basel.

PubMed ID#: 17389795

Some excerpts related to DLB are:

"...Initial studies indicate that treatment with ChEIs might
be more beneficial for patients with PDD and DLB than for
patients with AD."

"...(A)dditional AD pathology is much more frequent in
DLB than in PDD, and LBs are more pronounced in the
temporal cortex in DLB."

"Although there are some hints that the neuropsychological
test profile may differ between DLB and AD, DLB can be
suspected but not diagnosed with certainty on the basis
of a cognitive profile alone."

"Compared to AD, hippocampal and medial temporal
lobe atrophy are less pronounced in DLB. However,
the global rate of brain atrophy is similar in patients with
DLB and patients with other aetiologies of dementia.
...As we know from DaT-SCAN SPECT, the
nigrostriatal dopaminergic function is more severely
impaired in patients with DLB compared to patients with
AD but does not differ from patients with PD."

"DLB patients have a pronounced dysfunction of the
cholinergic neurotransmitter system which is even greater
than that seen in patients with AD. Cholinergic
activity is lower in DLB patients with compared to those
without hallucinations, which suggests that also
hallucinations might be reduced after therapeutic
intervention with cholinergic agents."

"McKeith et al. carried out a randomized doubleblind
multicenter study with a representative sample size
(n = 120). Although the slight improvement in the MMSE
score of patients treated with rivastigmine compared to
the placebo group did not reach significance, there was
a significant reduction in some behavioural domains
of the NPI, e.g. apathy, indifference, anxiety or delusions."
(NPI = neuropsychiatric inventory)

"Beversdorf et al. designed a double-blind, double-
crossover study...with the ChEI donepezil
in a small group of 7 patients. In spite of the short
treatment phase (4 weeks), MMSE and ADAScog scores
were significantly more improved after donepezil than
after placebo medication, about 2 points each. Functional
ability did not improve, neither did achievement of
verbal fluency or visuospatial functions."
(MMSE = mini-mental state exam. ADAScog =
Alzheimer’s Disease Assessment Scale, cognition
subscale.)

"Another class III study compared the performance
of patients with PDD and DLB. ...(T)he MMSE score
increased by about 4 points after 20 weeks of treatment
with donepezil."

"(One) open-label study that investigated the treatment
effect of galantamine reported a significant improvement
in the MMSE and in 4 subscales of the NPI (delusion,
hallucination, apathy and depression) after 12 weeks
of medication."

"First results in DLB show only slight improvement of
cognitive dysfunction due to treatment with rivastigmine.
However, ChEIs are probably effective in the reduction of
behavioural disturbances. Only one third of all studies
focused on safety analysis. There, adverse side events
tended to be more frequent in patients treated with
rivastigmine than with placebo. In addition, treatment
with ChEIs can cause hypersalivation, hypertension
and falls in patients with DLB. Worsening of parkinsonian
symptoms did not occur after 20 weeks of blinded
drug treatment, which is supported by most of the
open-label trials."

"In all the discussed disorders, PDD, DLB, PSP and
CBD, the cholinergic system is affected. However, the
benefit of ChEIs on dementia might differ between the
different entities."

"...At present, there are only some hints of the
beneficial effect of cholinergic treatment on cognition
in DLB. However, behavioural aspects might be positively
affected, which may increase the quality of the patient’s
life and reduce caregiver distress. Heterogeneity of patient
samples is likely to be one reason for the lack of evidence
of effects of treatment with ChEIs on cognition in DLB.
The definition may include various subgroups of patients,
e.g. patients with and without additional Alzheimer
pathological cortical changes, which differ in severity and
progression of the disease. Identification of clinical
characteristics of patients and definition of subgroups that
will respond well to ChEIs medication are needed."


Mon Apr 02, 2007 2:27 am
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Joined: Fri Aug 11, 2006 1:46 pm
Posts: 4811
Location: SF Bay Area (Northern CA)
Post Razadyne study
RE: the article below on "Treatment of Dementia in Parkinsonian Syndromes with Cholinesterase Inhibitors" in the March '07 issue of the journal Dementia and Geriatric Cognitive Disorders. In that article, studies "in human subjects (with LBD) up to February 2006, which used at least 1 of the following ChEIs, were reviewed: rivastigmine, donepezil, galantamine..." In particular, that article described a galantamine study in this way:

"(One) open-label study that investigated the treatment effect of galantamine reported a significant improvement in the MMSE and in 4 subscales of the NPI (delusion, hallucination, apathy and depression) after 12 weeks of medication."

Galantamine is now sold under the brand name Razadyne but used to be sold under the brand name of Reminyl.

A month later in the same journal researchers report on a new 24-week open-label study of galantamine. I've copied below the citation and abstract for that new article.

Robin



Dementia and Geriatric Cognitive Disorders. 2007 Apr 3;23(6):301-305 [Epub ahead of print]

Efficacy and Safety of Galantamine in Patients with Dementia with Lewy Bodies: A 24-Week Open-Label Study.

Edwards K, Royall D, Hershey L, Lichter D, Hake A, Farlow M, Pasquier F, Johnson S.
Alzheimer's Diagnostic and Treatment Center, Bennington, Vt., USA.

Background: Dementia with Lewy bodies (DLB) is a common dementia of the elderly. A significant cholinergic deficit has been demonstrated that may be responsive to treatment by cholinesterase inhibitors (ChEIs).

Methods: A 24-week, open-label study was designed to assess the efficacy and safety of a ChEI, galantamine, in 50 patients with DLB.

Results: This study showed beneficial effects with galantamine in 2 of the 3 primary efficacy parameters. The scores on the Neuropsychiatric Inventory (NPI-12) improved by 8.24 points from baseline (p = 0.01) especially in visual hallucinations and nighttime behaviors (p = 0.004). The scores on the Clinician's Global Impression of Change improved by 0.5 points from baseline (p = 0.01). The third primary efficacy parameter, the Cognitive Drug Research Computerized Cognitive Assessment System, was unchanged from baseline. Adverse events were generally mild and transient.

Conclusion: Galantamine appears to be an effective and safe therapy for patients with DLB.

PubMed ID#: 17409748


Mon Apr 09, 2007 8:37 pm
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Joined: Fri Aug 11, 2006 1:46 pm
Posts: 4811
Location: SF Bay Area (Northern CA)
Post Autopsy study of ChEIs' effect on the brain
And here's info on a small autopsy study, published earlier this year.

This very short abstract is about UK research just published in the journal Neurology. The key sentence is: "In the first human autopsy study examining the impact of ChEI treatment on brain pathology, we compared treated patients with DLB with matched untreated patients..." The DLB patients who received ChEIs (such as Aricept*) had less beta-amyloid deposits in the brain. Presumably this is a good thing.

*ChEIs include donepezil (Aricept), rivastigmine (Exelon), and galantamine (now called Razadyne). They are also called AChEIs - acetycholinesterase inhibitors.


Neurology. 2007 May 15;68(20):1726-9.

Cholinesterase inhibitors reduce cortical Abeta in dementia with Lewy bodies.

Ballard CG, Chalmers KA, Todd C, McKeith IG, O'Brien JT, Wilcock G, Love S, Perry EK.
Wolfson Centre for Age Related Diseases, Kings College London, London, UK.

Cholinesterase inhibitors (ChEIs) are effective symptomatic treatments in dementia with Lewy bodies (DLB), although effects on pathologic mechanisms are unknown. In the first human autopsy study examining the impact of ChEI treatment on brain pathology, we compared treated patients with DLB with matched untreated patients for cortical beta-amyloid (Abeta) and tau pathologies. Treated patients with DLB had significantly less parenchymal Abeta deposition, which is relevant to disease management and treatment of dementia patients using ChEI.

PubMed ID#: 17502555


I did track down this full article at the Stanford Medical Library. Fortunately it's short and, except for the last paragraph, relatively understandable! The hardest thing to remember is that Abeta stands for "beta-amyloid"! (Why isn't it abbreviated as betaA??)

The autopsy study included 24 patients all diagnosed clinically with DLB and verified pathologically. Twelve of these patients had received treatment with a ChEI in placebo-controlled clinical trials. On average, they received 24 months of ChEIs (6 donepezil, 4 rivastigamine, 1 tacrine, 1 galantamine). Twelve of these patients had received no ChEI treatment because they had DLB before ChEIs were available The two groups were matched for age, initial severity, and duration of dementia.

In the Results section, the authors state that "Parenchymal Abeta deposits in the cortex...were 70% lower in DLB patients receiving cholinesterase treatment vs. those who were untreated. ... In secondary analyses, there were no significant differences between the treated and untreated groups with respect to phosphorylated tau. The mean change in MMSE from baseline was 27% less in the treated vs untreated group."

Here are a few excerpts from the Discussion section: "Ninety percent or more of patients with DLB have sufficient plaque pathology to meet...criteria for probable or definite AD; hence Abeta deposition is a major pathologic feature in most individuals. ... The current data suggest that in addition to the symptomatic benefits of cholinesterase therapy in people with DLB, there is also significant impact upon this key disease substrate..."

And: "Experimental model data support the concept of neuroprotective effects of enhanced cholinergic transmission. One or more ChEIs (tacrine, donepezil, galantamine, rivastigmine, or huperzine A) protect neurons from toxic (eg, glutamate, Abeta peptide) or ischemic (oxygen or glucose deprivation) induced cell death in cell culture models. Other possible mechanisms by which ChEIs could influence AD pathology include direct effects of nicotinic or muscarinic receptor stimulation on the promotion of nonamyloidogenic APP processing, interruption of ChEI-induced pathology related to the abnormal expression of ChEIs in plaques, direct effects on Abeta fibril formation, or anti-inflammatory action."

One question I have after reading the full article is whether the 24 in the study also had AD pathology. And are the results as good in those with "pure" DLB and no AD pathology?


Sat May 26, 2007 3:14 pm
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Joined: Mon Feb 05, 2007 3:43 am
Posts: 215
Location: Seattle, WA
Post 
Robin:

I've seen this same paper, and I'm flummoxed by it; it has to be one of the first to show an actual reduction in Abeta from a ChEI.

The whole topic leads me to more questions than answers - it's obvious that there's an immediate behavioral benefit to treatment with a ChEI, properly titrated. Studies keep showing the class is safe in people with DLB. There's now suspicion that it reduces neuronal death and Abeta formation. . .

So, it's obvious to me that the class, as a whole, is a Good Thing, and early treatment is key. Clearly what is needed is a study that directly compares the three US-marketed ChEIs against each other, and possibly including Huperzine A, which I'm warming up to, albeit slowly. Patients, caregivers and clinicians should be able to know if in vitro differences between the ChEIs translate into meaningful differences in the real world. Does taking the once-a-day, lower-side effect route really result in less benefit than the stuff that takes a 300 calorie 'snack'? Are the western products more effective than the traditional Chinese approach? By using different outcome measures, it's a crapshoot to try to compare one to the other. I think everybody's got some religion about it, but I don't think anybody's belief set is entirely provable.

As an aside, I'm not so sure that there's *anything* such as "pure DLB" - I seem to recall that something like 80% of people have Abeta deposits by age 85.

_________________
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 May 27, 2007 1:43 am
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