[paula_w]

This study compared amyloid load in dementia with lewey bodies [DLB], a very malignant illness, with parkinson's disease w/ dementia [PDD] and normal brains.


J Neurol Neurosurg Psychiatry 2008;79:1331-1338 doi:10.1136/jnnp.2007.127878

• Research paper

Amyloid load in Parkinson’s disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography

1. P Edison1,
2. C C Rowe2,
3. J O Rinne3,
4. S Ng2,
5. I Ahmed1,
6. N Kemppainen3,
7. V L Villemagne2,
8. G O’Keefe2,
9. K Någren3,
10. K R Chaudhury4,
11. C L Masters2,
12. D J Brooks1,5

Results: The DLB cohort showed a significant increase in mean brain [11C]PIB uptake and individually 11 of the 13 subjects with DLB had a significantly increased amyloid load. In contrast, mean [11C]PIB uptake was normal for the PDD group although two of 12 patients with PDD individually showed a raised amyloid load. Where significant increases in [11C]PIB uptake were found, it was increased in cortical association areas, cingulate and striatum. None of the subjects with PD showed significantly raised cortical [11C]PIB uptake.


Conclusion: This study suggests that amyloid load is significantly raised in over 80% of subjects with DLB, while amyloid pathology is infrequent in PDD. These in vivo PET findings suggest that the presence of amyloid in DLB could contribute to the rapid progression of dementia in this condition and that anti-amyloid strategies may be relevant.

http://jnnp.bmj.com/content/79/12/1331.abstract

[paula_w]

it's harder to understand and there is no abstract. it is current tho so we need to try to get a copy . there doesn't seem to be much research on PDD.

I know there are some who have relatives with pd or maybe you personally who have been helped by Alzheimers drugs. would you please share your experience? i don't want to keep a drug that works away from anyone.

but with the track record of the drug industry......... they could be trying to lump the dementias together and create a dementia, gait and postural instability market.

they have been working on a DBS for PPN but i just received a pipeline email saying they don't work.

when are the patients going to be utilized at the research tables? the right patients, who know a bit about it all? how bad does it have to get?

do we have to investigate pd nursing home deaths or near deaths following the addition of AD drugs ? shouldn't all doctors and nursing homes be aware that you just can't prescribe these drugs because they are FDA approved. That whole process needs to be investigated. I'm only one person.

we need a friendly medical researcher or movement disorder specialist to come in and talk to us about this. too logical? too easy? too beneath any doctors? too hard and no one knows? the latter i can accept.....

the irony is so glaringly evident.....it takes 15 years to get FDA approval for a drug that might help us but quiet approval of a drug that could kill us happened quickly ad globally.

what gives? I would love to hear personal experiences with AD drugs and pd patients. we may need something like AD med at the end, but not all of us and certainly not without dementia.

the article posted by olsen about anticholinergics causing cognitive decline......amantadine is not a major anticholinergic, but two things stick out with that article:

1. it may cause reversible mental fog, they do that because they are lowering acetycholine....too low and you have alzheimers - so it makes sense to say they cause cognitive decline but was there any proof that this isn't a reversible situation...gone with the discontinuing of the med? isn't amantadine an NMDA agonist or antagonist? that last question is a guess and over my head, working from memory...uh oh, lol.
2. the article could be part of a trend to sway public uninformed opinion that people with parkinson's need cholinesterase inhibitors. yes that was saying they are lying, or they don't know but it sounds logical- dementia is dementia....

we have to get to the bottom of this,,,,i'm not going to stop until i do. if you want to send me a private message and fill me in confidentially, i will ask why of course but if it's necessary, i'll keep the information private.

thanks,
paula

http://www.springerlink.com/content/...ext.pdf?page=1

[lindylanka]

Paula,
I know these are difficult topics for an open forum, but I really think that there must be a clear definition of the different types of dementias out there, that would clarify a lot. If there are people who do know more about this, especially professional people, please post....


Completely by chance and anecdotally I once came across a story of an elderly PD patient who was being treated with Mirapex who was described as having dementia, and his family was 'having a game' dealing with him. He was displaying some of the obsessive compulsive behaviours we know so well in younger patients, along with night-time restlessness and 'fighting' in his sleep. From all accounts he was completely bewildered by it, it was out of character, and otherwise he was intellectually sound - but by then he was in a home and his treatment was out of his families control. Needless to say I have often wondered whether that really was dementia or not.......


The potential for problems of over-, under-, and improper medication in disempowered groups of people is a problem that is not going to go away easily - in fact it is only time and a fresh generation of empowered patients that will make a difference, plus some really enlightened medical thinking....

[paula_w]

so very well written lindy, and it encompasses everything.....that is a sad story.

keep your intuition and experiences coming. we need just that.

paula

[ZucchiniFlower]

This is interesting, too:
May 27, 2009

Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET

H. Shimada, MD, S. Hirano, MD, PhD, H. Shinotoh, MD, PhD,

Objective: To characterize brain cholinergic deficits in Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB).

Methods: Participants included 18 patients with PD, 21 patients with PDD/DLB, and 26 healthy controls. The PD group consisted of nine patients with early PD, each with a disease duration of less than 3 years, five of whom were de novo PD patients, and nine patients with advanced PD, each with a disease duration greater than or equal to 3 years. The PDD/DLB group consisted of 10 patients with PDD and 11 patients with DLB. All subjects underwent PET scans with N-[11C]-methyl-4-piperidyl acetate to measure brain acetylcholinesterase (AChE) activity. Brain AChE activity levels were estimated voxel-by-voxel in a three-compartment analysis using the arterial input function, and compared among our subject groups through both voxel-based analysis using the statistical parametric mapping software SPM5 and volume-of-interest analysis.

Results: Among patients with PD, AChE activity was significantly decreased in the cerebral cortex and especially in the medial occipital cortex (% reduction compared with the normal mean = –12%) (false discovery rate–corrected p value <0.01). Patients with PDD/DLB, however, had even lower AChE activity in the cerebral cortex (% reduction = –27%) (p < 0.01). There was no significant difference between early PD and advanced PD groups or between DLB and PDD groups in the amount by which regional AChE activity in the brain was reduced.

Conclusions: Brain cholinergic dysfunction occurs in the cerebral cortex, especially in the medial occipital cortex. It begins in early Parkinson disease, and is more widespread and profound in both Parkinson disease with dementia and dementia with Lewy bodies.
**********************

Cholinergic denervation occurs early in Parkinson disease
Nicolaas I. Bohnen and Roger L. Albin

Published online before print June 17, 2009
There's no abstract. An earlier article:

Cognitive correlates of cortical cholinergic denervation in Parkinson’s disease and parkinsonian dementia
Journal Journal of Neurology
Publisher Steinkopff
ISSN 0340-5354 (Print) 1432-1459 (Online)
Issue Volume 253, Number 2 / February, 2006

Abstract

We recently reported findings that loss of cortical acetylcholinesterase (AChE) activity is greater in parkinsonian dementia than in Alzheimer’s disease (AD). In this study we determined cognitive correlates of in vivo cortical AChE activity in patients with parkinsonian dementia (PDem, n = 11), Parkinson’s disease without dementia (PD, n = 13), and in normal controls (NC, n = 14) using N–[11C]methyl–piperidin–4–yl propionate ([11C]PMP) AChE positron emission tomography (PET). Cortical AChE activity was significantly reduced in the PDem (–20.9%) and PD (–12.7 %) subjects (P < 0.001) when compared with the control subjects. Analysis of the cognitive data within the patient groups demonstrated that scores on the WAIS-III Digit Span, a test of working memory and attention, had most robust correlation with cortical AChE activity (R = 0.61, p < 0.005).

There were also significant correlations between cortical AChE activity and other tests of attentional and executive functions, such as the Trail Making and Stroop Color Word tests. There was no significant correlation between cortical AChE activity and duration of motor disease (R = –0.01, ns) or severity of parkinsonian motor symptoms (R = 0.14, ns).

We conclude that cortical cholinergic denervation in PD and parkinsonian dementia is associated with decreased performance on tests of attentional and executive functioning.

[ZucchiniFlower]

Our problems are much more complicated than a lack of dopamine...

History of falls in Parkinson disease is associated with reduced cholinergic but not nigrostriatal dopaminergic activity

N Bohnen, K Frey, M Muller, R Koeppe, M … - Society of Nuclear …, 2009 - Soc Nuclear Med
J Nucl Med. 2009; 50 (Supplement 2):1235
Nicolaas Bohnen1, Kirk Frey1, Martijn Muller1, Robert Koeppe1, Michael Kilbourn1 and Roger Albin2

Conclusions:

These data indicate that unlike nigrostriatal dopaminergic denervation, cholinergic hypofunction contributes to increased fall risk in PD. Thalamic AChE activity also had a significant inverse relationship with the absolute number of falls. In this respect, thalamic AChE activity in part represents the cholinergic output or projection area of the brainstem pedunculopontine nucleus (PPN), which is a locomotor nucleus involved in gait control.

http://jnumedmtg.snmjournals.org/cgi...Abstracts/1235

[ZucchiniFlower]

J Nucl Med. 2009; 50 (Supplement 2):129

Neurosciences: Neurology
Movement Disorders


Heterogeneity of neurodegeneration in Parkinson disease: Variable degree of dopaminergic versus cholinergic denervation

Nicolaas Bohnen1, Martijn Muller1, Robert Koeppe1, Michael Kilbourn1, Roger Albin2 and Kirk Frey1
1 University of Michigan, Department of Radiology, Ann Arbor, MI 2 University of Michigan, Department of Neurology, Ann Arbor, MI

129

Objectives: To investigate the relationship between the degree of nigrostriatal dopaminergic denervation and cortical acetylcholinesterase (AChE) activity in patients with Parkinson disease (PD).

Methods: PD patients (Hoehn and Yahr stages I-III, n=47; mean age 69.4±9.5 years; range 51-83; 11F/36M) underwent [C-11]methyl-4-pi*peri*dinyl propionate (PMP) acetylcholinesterase (AChE) and [C11]dihydrotetrabenazine (DTBZ) VMAT2 brain PET imaging. Patients on dopaminergic drugs were examined in the clinically defined "off" state.

Results: There was an overall significant but modest correlation between striatal DTBZ and cortical AChE activity (R=0.32, P=0.03 for the putamen & R=0.49, P=0.003 for the caudate nucleus). However, visual inspection of the data plot demonstrated 9 outliers outside the primary linear regression area (R=0.64, P<0.001 for the putamen & R=0.61, P<0.001 for the caudate nucleus) corresponding to subjects with low striatal DTBZ but preserved cortical AChE activity.

Conclusions: Although the majority of patients with PD have evidence of a robust parallel decline in striatal dopaminergic and cortical cholinergic activity, there is a subgroup (19.1%) of patients with decreased dopaminergic but preserved cholinergic activity.

Research Support: Supported by the Michael J. Fox Foundation and the Department of Veterans Affairs.

[ZucchiniFlower]

I'm in a rush but here's the link to a fascinating article:

Virtues and woes of AChE alternative splicing in stress-related neuropathologies

http://www.sciencedirect.com/science...25f70cce712e7c

[paula_w]

i appreciate your contributions ZF and you were the first one that pointed out what anticholinergic drugs are for and why pwp take them. I have questions - just barely comprehending the point of each abstract, i'll try to ask them in a way that would take a brief answer if possible. starting with your first post:

Results: Among patients with PD, AChE activity was significantly decreased in the cerebral cortex and especially in the medial occipital cortex (% reduction compared with the normal mean = –12%) (false discovery rate–corrected p value <0.01). Patients with PDD/DLB, however, had even lower AChE activity in the cerebral cortex (% reduction = –27%) (p < 0.01). There was no significant difference between early PD and advanced PD groups or between DLB and PDD groups in the amount by which regional AChE activity in the brain was reduced.

Conclusions: Brain cholinergic dysfunction occurs in the cerebral cortex, especially in the medial occipital cortex. It begins in early Parkinson disease, and is more widespread and profound in both Parkinson disease with dementia and dementia with Lewy bodies.

Does that mean our acetylcholinesterase, or AChE is dysfunctional ?[recalling here that pesticide toxins bind to AChE and damage them] thus causing a build up of too much acetylcholine because the inhibitor isn't breaking it down?

Is that what they mean by "regional AChE activity in the brain was reduced. '?

Is brain cholinergic dysfuction a term that can be applied interchangeably to a lack of AChE inhibition and break down of acetylcholine as well as a need for more acetylcholine because....??? the AChE is defective,? gone? we take too much artane? what causes the lack of acetylcholine? would that solve alzheimers and is it a question that can't be answered yet?

we take anticholinergic drugs. does that mean cholinergic enhances acetylcholine and anticholinergic works to break it down?


next post:
We recently reported findings that loss of cortical acetylcholinesterase (AChE) activity is greater in parkinsonian dementia than in Alzheimer’s disease (AD).

If we are losing the inhibitor AChE that breaks acetylcholine down, why would we take cholinergic drugs like aricept that would inhibit the breakdown of acetylcholine even more?

Fox post:
Conclusions: Although the majority of patients with PD have evidence of a robust parallel decline in striatal dopaminergic and cortical cholinergic activity, there is a subgroup (19.1%) of patients with decreased dopaminergic but preserved cholinergic activity.

What isn't working in "cortical cholinergic activity"? Does this mean as we progress, we inhibit and break down acetylcholine less? Is too much acetylcholine working against the dopamine because the AChE activity declines and there is no breakdown of acetylcholine?

I keep going back to Ron's saying 'one pushes and the other pull." not when one isn't working....then could they both push or pull....it certainly sounds like a struggle to maintain our balance.


last post:
The ACh hydrolyzing enzyme acetylcholinesterase (AChE) is a combinatorial series of proteins with variant N and C termini generated from alternate promoter usage and 3′ alternative splicing. Neuronal AChE variants show indistinguishable enzymatic activity yet differ in their expression, multimeric assembly and membrane-association patterns.

Differentially induced under stress, they show distinct non-hydrolytic properties and interact with different protein partners. Recent findings suggest that transcriptional and post-transcriptional regulation of AChE pre-mRNA is a neuroprotection strategy but might involve long-term damage.

Specifically, variant-specific causal involvement of AChE in the progression of both neurodegenerative diseases (e.g. Alzheimer's and Parkinson's diseases) and neuromuscular syndromes (e.g. myasthenia gravis) raises the possibility that future therapeutic drugs might target specific AChE variant(s) or the corresponding RNA transcripts.

Not sure i understand this one. what is post -transcriptional regulation of AChE and is it actually saying that neuroprotective strategies can cause long term damage?

hmmm.....is it me?

adding after more thought. is it basically saying that here is some evidence that stress causes brain damage - in this case by releasing too much AChE inhibitor? again---in waay over my head and this is a question.

thanks ZF,
paula

[ZucchiniFlower]

Paula, I don't have time to respond to your questions today. Hopefully, tomorrow!

I'm wondering if Artane is contributing to my poor balance. I may stop taking it. I'm down to 1/2 pill a day (1 mg), for the last few days, half my usual dose. I may try Zandopa instead.

Oh, this is a cool post number: 777!