Targeting Alzheimer's
(appeared on 6th Nov 2013)

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A new method, using an unusual optical effect, to detect Alzheimer’s disease is reported, says S.Ananthanarayanan.

Alzheimer’s is the most common form of dementia, or loss of cognitive ability, which rapidly gets worse and as yet has no cure. The disease is known to arise from plaque formation in the cells of the brain but there is not even a proven preventive. Even clear diagnosis, for what it is worth, is possible only with examination of brain tissue and chemical agents that could be used to strike at the plaques are toxic. Parkinson’s is another disease which affects movement and can progress to dementia, where there is similar loss of nerve tissue in the brain, and elsewhere. In this case also it is the accumulation of protein matter at diseased nerve cells that is implicated, with similar difficulty of treatment.

In the context, the report of a group at Chalmers University of Technology in Sweden and at the Wroclaw University of Technology in Poland, in the journal, Nature, that the kind of tissue that causes disease in Alzheimer’s, Parkinson’s and some other conditions can be detected by a non-invasive method, is news indeed. And the method used is not the familiar X Ray scan or MRI or spectroscopy or scattering or any methods usually employed, but one where a phenomenon called multiple photon absorption, of an intense laser beam in the Infra Red region when it passes through a diseased tissue, is detected.

Amyloid deposit

Proteins are complex molecules which have a characteristic way of packing, or folding, into a low energy shape. Sometimes, usually because of some genetic defect, the folding goes wrong and the same protein would show different properties. Amyloids are lumps of insoluble fibres arising from a group of such inappropriately folded proteins and their accumulation at neurons has been associated with a number of diseases, particularly the degeneration of nerves. There is much evidence that amyloid formation has a role in the onset and progress of Alzheimer’s and Parkinson’s disease as also some other conditions that arise from damage to nerve tissue.

The amyloid structure is the less encountered ‘twisted pleated sheet’ structure, a stack of sheets which can be many microns long, as opposed to the more frequent, coiled or helix, in 3-dimensional forms of proteins. Sometimes both forms are present and the material could show great strength when extended or resistance to shear. The amyloid structure, like some others, also affects a beam of light differently according to the planes in which when the electric and magnetic vibrations in the light are oriented. But the clear identification is by actually verifying the ‘pleating of the sheets’ by their effect on an X Ray beam passed through a sample. But the effect now discovered by Piotr Hanczyc, Marek Samoc and Bengt Norden, the authors of the paper in Nature, could enable detection and imaging of amyloid fibres by sensing the effect of absorption of laser radiation, in the less harmful, Infra Red region, selectively by these structures.

Non-linear optics

The optical effects that the group worked with belong to the field of non-linear optics, or where effects on a beam of light passing through a medium do not get uniformly stronger as the beam gets stronger, but get tremendously stronger. The reason for this response is that the effect the medium has on the beam is itself a result of the incident beam. Specifically, as light waves consist of undulating electric and magnetic effects, it is the electric part that affects the scattering or absorbing medium – and the effect is really discernable only when the electric effect is very strong, like it is at the inter-atomic level. Non-linear effects are hence better observed radiation is created by an intense source, like the pulsed laser.

One kind of non-linear effect is when two photons that enter the medium combine to form a single photon of double the energy, and hence twice the frequency. Another kind is when the two photons are absorbed, to knock the electronic system in the medium to a state that is higher by the energy of the two photons. This is an effect that is different from absorption of the photons separately, which is linear, and is a case of non linear absorption.

Such two photon absorption or generation of light of twice the frequency is made use of in very high resolution microscopy, where only the material that shows this kind of behavior gets detected. The tissue, collagen, the structural protein in animals is one such material and two photon generation is used for microscopy of the cornea and nerve fibres of the optic nerve exit. Generation at twice the frequency, or the harmonic, is also used for generation of ‘green laser’, for use in pointers, for instance. In these cases, it is necessary to filter out the intense infra-red source light, to avoid damage to the users’ eyes!

The method used for measuring the two-photon absorption was the z-scan technique. In this method, the incident laser beam, is first split into two. One beam is the source monitor, to correct the results of the scan for variations in the source. The second beam is focused through a lens and a thin sliver of the sample is placed at the point of focus. The light coming through is then detected, as shown in the picture. The Sample is then moved along the axis of the beam, the ‘z’ axis, over a short length, related to the wavelength of the light used. At the correct position, there is a dip in the intensity of the transmitted beam, which yields the level of absorption.

Use with amyloids

The researchers worked with three kinds of fibre forming proteins and measured the level of multi-photon absorption both with native protein and also with amyloid fibres. It was found that the amyloid structure gives rise to marked multi-photon absorption. While there is uncertainty about the reasons, whether interactions within the molecule or between molecules are responsible,

the result is one which promises a way of targeting just the amyloid protein molecules in the lumps that form on diseased nerve tissue. The ability at least opens the door to seeking curative procedures. There are problem, of course, one being that collagen tissue would also show up in multiple photon absorption scans, which pinpoints what work needs to be done.

"Nobody has talked about using only light to treat these diseases until now. This is a totally new approach and we believe that this might become a breakthrough in the research of diseases such as Alzheimer's, Parkinson's and Creutzfeldt-Jakob disease. We have found a totally new way of discovering these structures using just laser light", says Piotr Hanczyc at Chalmers University of Technology." This research also suggests that protein based materials may leverage multi-photon absorption for specific applications in nanotechnology, photonics and opto-electronics, say the authors of the paper

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