CSF Aβ42 predicts early-onset dementia in Parkinson disease.
Neurology. 2014 Apr 18. [Epub ahead of print]
Alves G, Lange J, Blennow K, Zetterberg H, Andreasson U, Førland MG, Tysnes OB, Larsen JP, Pedersen KF.


Abstract


OBJECTIVE:
To test in vivo the proposal from clinicopathologic studies that β-amyloid (Aβ) pathology shortens the time to dementia in Parkinson disease (PD), and to explore the utility of CSF Aβ and related measures as early prognostic biomarkers of dementia in an incident PD cohort.


METHODS:
We assessed a population-based incident cohort of 104 patients with PD who underwent lumbar puncture at diagnosis. We analyzed CSF concentrations of Aβ42, Aβ40, and Aβ38 using a multiplexed immunoassay with electrochemiluminescence (ECL) detection and levels of Aβ42, total tau, and phosphorylated tau using ELISA. Patients were followed prospectively for 5 years. Dementia was diagnosed according to published criteria.


RESULTS:
CSF levels of Aβ42 were significantly decreased in patients who developed dementia (n = 20, 19.2%) compared to those who did not (n = 84, 80.8%), as measured by ECL (-33%, p = 0.006) as well as ELISA (-36%, p < 0.001). No differences were observed for other markers. Low Aβ42 values predicted a substantially increased risk for subsequent dementia at high sensitivity (≥85%), with hazard ratios of 9.9 (95% confidence interval 2.3-43.5, p = 0.002) for Aβ42ECL <376 pg/mL and 7.6 (2.2-26.4, p = 0.001) for Aβ42ELISA <443 pg/mL, after adjustment for baseline age and PD-mild cognitive impairment (MCI) status. Aβ42 reductions tended to precede the onset of PD-MCI that progressed to dementia.


CONCLUSIONS:


These in vivo data support the role of Aβ pathology in the etiology and highlight the potential utility of CSF Aβ42 as an early prognostic biomarker of dementia associated with PD.

http://en.wikipedia.org/wiki/Beta_amyloid

Intervention strategies

Researchers in Alzheimer's disease have identified five strategies as possible interventions against amyloid:[53]

β-Secretase inhibitors. These work to block the first cleavage of APP outside of the cell.
γ-Secretase inhibitors (e. g. semagacestat). These work to block the second cleavage of APP in the cell membrane and would then stop the subsequent formation of Aβ and its toxic fragments.
Selective Aβ42 lowering agents (e. g. tarenflurbil). These modulate γ-secretase to reduce Aβ42 production in favor of other (shorter) Aβ versions.

β- and y-secretase are responsible for the generation of Aβ from the release of the intracellular domain of APP, meaning that compounds that can partially inhibit the activity of either β- and y-secretase are highly sought after. In order to initiate partial inhibition of β- and y-secretase, a compound is needed that can block the large active site of aspartyl proteases while still being capable of bypassing the blood-brain barrier. To date, human testing has been avoided due to concern that it might interfere with signaling via Notch proteins and other cell surface receptors.

Immunotherapy. This stimulates the host immune system to recognize and attack Aβ, or provide antibodies that either prevent plaque deposition or enhance clearance of plaques or Aβ oligomers. Oligomerization is a chemical process that converts individual molecules into a chain consisting of a finite number of molecules. Prevention of oligomerization of Aβ has been exemplified by active or passive Aβ immunization. In this process antibodies to Aβ are used to decrease cerebral plaque levels. This is accomplished by promoting microglial clearance and/or redistributing the peptide from the brain to systemic circulation. One such beta-amyloid vaccine that is currently in clinical trials is CAD106.[54] Immunization with synthetic Aβ1-42 has been shown to be beneficial in mice and displays low toxicity; however human trials have shown no significant differences. Thus, it is not yet effective in humans and requires further research. Specific findings show that the 20 amino acid SDPM1 protein binds tetramer forms of Aβ(1-40)- and Aβ(1-42)-amyloids and blocks subsequent Aβ amyloid aggregation. It is important to note that this study was done in mice and that while it prevents further development of neuropathology it did not result in an improvement in cognitive performance. Lastly, Aβ42 immunization resulted in the clearance of amyloid plaques in patients with Alzheimer's disease but did not prevent progressive neurodegeneration.[55]

Anti-aggregation agents[56] such as apomorphine. These prevent Aβ fragments from aggregating or clear aggregates once they are formed.[57] Studies comparing synthetic to recombinant Aβ42 in assays measuring rate of fibrillation, fibril homogeneity, and cellular toxicity showed that recombinant Aβ42 had a faster fibrillation rate and greater toxicity than synthetic Amyloid beta 1-42 peptide.[58] This observation combined with the irreproducibility of certain Aβ42 experimental studies has been suggested to be responsible for the lack of progress in Alzheimer’s research.[59] Consequently, there has been renewed efforts to manufacture Aβ42 and other amyloid peptides at unprecedented (>99%) purity[60]

There is some indication that supplementation of the hormone melatonin may be effective against amyloid. Melatonin interacts with amyloid beta and inhibits its aggregation[61][62][63] This anti-aggregatory activity occurs only through an interaction with dimers of the soluble amyloid beta peptide. Melatonin does not reverse fibril formation or oligomers of amyloid beta once they are formed. This is supported by experiments in transgenic mice which suggest that melatonin has the potential to prevent amyloid deposition if administered early in life, but it may not be efficacious to revert amyloid deposition or treat Alzheimer's disease.

This connection with melatonin, which regulates sleep, is strengthened by the recent research showing that the wakefulness inducing hormone orexin influences amyloid beta (see below).[64] Interestingly, animal experiments show that melatonin may also correct mild elevations of cholesterol which is also an early risk factor for amyloid formation.

The cannabinoid HU-210 has been shown to prevent amyloid beta-promoted inflammation.[65] The endocannabinoids anandamide and noladin ether have also been shown to be neuroprotective against amyloid beta in vitro.[66]

It has been shown that high-cholesterol diets tend to increase Aβ pathology in animals. Modulating cholesterol homeostasis has yielded results that show that chronic use of cholesterol-lowering drugs, such as the statins, is associated with a lower incidence of AD. In APP genetically modified mice, cholesterol-lowering drugs have been shown to reduce overall pathology. While the mechanism is poorly understood it appears that cholesterol-lowering drugs have a direct effect on APP processing.[67]

Chelation therapy, which involves the removal of heavy metals from the body, has also been shown to be beneficial in lowering amyloid plaque levels. This is because Aβ aggregation is somewhat dependent on the metal ions copper and zinc. Zinc in synaptic vesicles, which is under the control of the zinc transporter ZnT3, plays a major role in Aβ formation. The expression of the ZnT3 is significantly lower in Alzheimer’s patients compared to healthy patients. Mice without ZnT3 were found to have much lower plaque formation. Further promoting this concept, Aβ deposition was impeded in APP transgenic mice treated with the antibiotic clioquinol, a known copper/zinc chelator.[67]

Drug therapy has been another approach to treatment. Memantine is an Alzheimer’s drug which has received widespread approval. It is a non-competitive N-methyl-D-aspartate (NMDA) channel blocker. By binding to the NMDA receptor with a higher affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions, particularly from extrasynaptic receptors, which forms the basis of neuronal excitotoxicity. It is an option for the management of patients with moderate to severe Alzheimer's Disease (modest effect). The study showed that 20 mg/day improved cognition, functional ability and behavioural symptoms in patient population.[68]

Another drug that is currently under research is victoza, which is typically used as a diabetes drug. Treatment with victoza yielded cognitive benefits that included improved object and spatial recognition. Additionally victoza enhances induction and maintenance of long term potentiation (LTP) and paired-pulse facilitation (PPF) in both APP/PS1 and non-genetically altered mice. Other histological benefits include a reduced inflammatory response and an increase in the number of young neurons in the dentate gyrus. The β-amyloid level was also found to be significantly reduced.[69]

There are many different ways to measure Amyloid beta. It can be measured semi-quantitatively with immunostaining, which also allows one to determine location. Amyloid beta may be primarily vascular, as in cerebral amyloid angiopathy, or in senile plaques and vascular.

One highly sensitive method is ELISA which is an immunosorbent assay which utilizes a pair of antibodies that recognize Amyloid beta.[71][72]

Imaging compounds, notably Pittsburgh compound B, (6-OH-BTA-1, a thioflavin), can selectively bind to amyloid beta in vitro and in vivo. This technique, combined with PET imaging, has been used to image areas of plaque deposits in Alzheimer's patients.

Atomic force microscopy, which can visualize nanoscale molecular surfaces, can be used to determine the aggregation state of Amyloid beta in vitro.[73]

Dual polarisation interferometry is an optical technique which can measure the very earliest stages of aggregration and inhibition by measuring the molecular size and densities as the fibrils elongate.[74][75] These aggregate processes can also be studied on lipid bilayer constructs.[76]

about the formation and metabolism of beta protein:

https://www.google.com/search?q=C.+P...sm=93&ie=UTF-8

But we were unable to find a small molecule that worked in vivo to prevent the plaques and tangles that are seen in the histopathology of the Alzheimer brain. Alpha, beta and gamma secretase enzyme cleavage of the transmembrane precursor protein, is thought to produce a protein that misfolds, and clumps together causing neuronal death, basically choking the supply of nutrients and other factors to cortical neurons.

If the same thing is happening with alpha-synuclein to produce Lewy bodies which are just a marker of damage done via the inhibitory effect of alpha synuclein on complex 1 activity of mitochondrial respiratory chain(see Wikipedia for a detailed explanation), and the eventual death of motor neurons, then we are on the right track, to explain the root cause of "synucleopathy", and thus parkinsonism. At the present time this is all just theory, but at least we have a theory to build on, one which may not cure PD but help to prevent it.