I was very intrigued by the information in this article (previous post), and think it applicable to your remarks, John. Just need a way to measure these misfolded proteins...and then a method to correct the mis folding.

http://phenomena.nationalgeographic....of-parkinsons/

... every case of Parkinson’s boils down to a protein called alpha-synuclein. Think of a protein as a sculpture made by folding up a long chain of beads. If alpha-synuclein folds correctly, it helps the neurons in our brain to send messages to one another. If it folds incorrectly, it becomes rowdy and sociable, gathering in large destructive clumps that wreck neurons.

How could this common cause lead to such variation in symptoms?

... alpha-synuclein can actually misfold in two different ways, creating two distinct strains. They’re chemically identical, but subtle differences in their shape imbue them with distinct traits.

Strain A is quick and dirty. When added to neurons, it rapidly produces toxic clumps of alpha-synuclein that kill many cells within a few weeks. Strain B is a slow-burner. It forms clumps more at a more leisurely pace, and didn’t kill any neurons over the course of the experiment.

However, strain B can force another protein called tau to gather into tangled clumps—a hallmark of Alzheimer’s disease. This might explain why these two diseases sometimes show up in the same unfortunate brain. More than half of people with Alzheimer’s have clumps of alpha-synuclein in their brains, while many Parkinson’s patients are riddled with tau tangles...

http://medicalxpress.com/news/2013-0...n-origami.html

...found that the human protein prefoldin can change the way these misfolded protein aggregates form and potentially reduce their toxic impact on the brains of Alzheimer's patients.


The formation of insoluble fibril aggregates of the protein amyloid- has been identified as a key mechanism responsible for memory loss in Alzheimer's patients. These fibrils are toxic to neurons, and finding a means of preventing their formation represents a key strategy in the development of a therapy for the disease. Recent studies suggest methods that alter the mechanism of amyloid- aggregates could offer a promising approach.
Prefoldin is a molecular chaperone involved in preventing the clumping of misfolded proteins and helping misfolded proteins return to their normal shape. The researchers found that amyloid-molecules incubated with even just a small amount of human prefoldin underwent a change in aggregation behavior—they instead formed into small, soluble oligomer clumps. The observations suggest that human prefoldin interacts with amyloid-molecules to alter their binding properties.
As in the brain, amyloid fibrils also kill neurons in cell culture. Using neurons from the brains of mice, the researchers showed that the amyloid- oligomers formed in the presence of human prefoldin induced less neuron death than amyloid- fibrils. Prefoldin expression actually increases in the brains of mice with high levels of amyloid- (Fig. 1), suggesting that the upregulation of prefoldin expression might be a response mechanism used by the brain to protect itself from the toxic effects of amyloid- fibrils.
... Increasing the expression of human prefoldin in the brain may therefore increase the proportion of less toxic amyloid- aggregates, presenting a potential means of fighting the disease.
"Our findings may also apply to various other neurological diseases caused by protein misfolding, such as prion disease, Huntington's disease and Parkinson's disease," explains Tamotsu Zako from the research team.
Explore further: New Alzheimer's research suggests possible cause: The interaction of proteins in the brain
More information: Sörgjerd, K. et al. Human prefoldin inhibits amyloid- (A) fibrillation and contributes to formation of non-toxic A aggregates. Biochemistry 52, 3532–3542 (2013). dx.doi.org/10.1021/bi301705c

Thank you for your replies.

soccertese,

You are right to point out the confounding impact of the placebo effect on conventional trials. However, my proposal for individual trials finesses this out: we measure the combined impact of the placebo and the actual therapy on an individual. For instance, suppose that taking drug X by person A was followed by them walking 10% faster. We cannot say that the drug, per se, caused the response. I propose that we call it a "therebo" - a contraction of THERapy and placEBO.

Tupelo3,

There's no need to apologize - covering old ground is bound to happen and is, anyway, useful.

You write: "We need clinical trials with sub-samples that are more homogenous in their genetic traits and environmental factors." I agree. Without knowing the environmental toxins that play a part in the aetiology of PD it is difficult to select homogenous groups with respect to environmental factors. Restricting intake to limited geographical areas is the best way I can think of.

olsen,

Alpha-synuclein appears to play a key role in PD. How many ways can alpha-synuclein fold?

John

Ferreira et al. using a n-of-1 trial design report [1] that coffee keeps some PwP awake. (!!!)

Wikipedia's article [2] on "Single subject design" highlights the importance of:
- continuous assessment;
- baseline assessment.

Sometimes a fictional example can throw some light on a problem.

Consider a PwP, A, who on successive days walks a mile in this number of minutes:
before treatment: 19, 20, 20, 19, 19
during treatment: 18, 17, 17, 18, 19

Assuming that the therapy is known to be safe, would you advise A to continue with the therapy?

Consider another PwP, B, who on successive days walks a mile in this number of minutes:
before treatment: 31, 32, 32
during treatment: 34, 35

Would you advise B to continue with the therapy? And now that B's results are available, would you change your advice to A?

References:

[1] "Espresso Coffee for the Treatment of Somnolence in Parkinson’s Disease: Results of n-of-1 Trials"
Joaquim J. Ferreira,1,2,* Tiago Mestre,1 Leonor Correia Guedes,1 Miguel Coelho,1 Mário M. Rosa,1,2 Ana T. Santos,1 Márcio Barra,1 Cristina Sampaio,1,2 and Olivier Rascol
Front Neurol, 2016
Espresso Coffee for the Treatment of Somnolence in Parkinson’s Disease: Results of n-of-1 Trials

[2] Single-subject design - Wikipedia

John