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Diagnosing Alzheimer’s: The eyes may have it


 

Technique is critical, he added. "It took us years to perfect our technique for the lens. It’s very difficult to work with lens, harder to work with old lens, and extremely hard to work with old, sick lens."

Instead of relying solely on Congo red or other staining techniques, Dr. Goldstein’s team confirmed their findings using a combination of biochemical analyses, immunogold electron microscopy, and two different types of mass spectrometry – methods he said are irrefutably accurate. "You can’t argue with this unless you are willing to argue with the very concept of mass spectrometry. It’s the gold standard," he said.

Confirmation in transgenic mice and Down syndrome patients strengthens the hypothesis, he said, as do the conclusions of his most recent paper. It looked at data from 1,249 people included in the Framingham Eye Study, and found a genetic link between a specific type of midlife cataracts (consistent with those previously found in Alzheimer’s) and later cognitive and brain structural changes associated with Alzheimer’s (PLoS ONE 2012;7:e43728) .

The culprit appeared to be a mutation of a gene that codes for delta-catenin, which Dr. Goldstein postulated may normally help suppress Abeta production. The altered form, however, appears to affect neuronal structure and is instead associated with an increase in Abeta-42 production in cell culture. The malformed delta-catenin protein was also found throughout the lenses of study subjects with Alzheimer’s, but not in control lenses.

Screening patients in the future?

Dr. Goldstein said he envisions a future in which annual lens exams might guide risk assessment and treatment initiation. But physicians who might someday screen patients certainly won’t have a mass spectrometer in the back room.

He has invented two devices, he said, that will fill that need. The most recent is a laser scanning ophthalmoscope that uses dynamic light scattering to detect the tiniest amyloid particles in the lens – particles less than 30 nm. This is the device he’s using in the ongoing Boston University/Boston Children’s Hospital study of lens amyloid in children with Down syndrome.

The second device combines optical imaging with aftobetin, a fluorescent amyloid ligand. Dr. Goldstein holds a patent on this device, which he invented in partnership with Cognoptix (formerly Neuroptix), a company he cofounded in 2001, although he is no longer operationally affiliated with it.

Cognoptix has developed the SAPPHIRE II system, a combination drug/device that detects amyloid in the lens using aftobetin. The company licensed aftobetin from the University of California, San Diego. It’s formulated into an ophthalmic ointment administered prior to scanning with the SAPPHIRE II system. The procedure uses fluorescent ligand scanning to detect amyloid aggregates in the lens, said Paul Hartung, president and chief executive officer of the Acton, Mass., company.

"We use an eye-safe laser tuned to pick up the fluorescence. It doesn’t require dilation of the pupil, and it has the capability of actually registering itself in the correct location in the eye," he said in an interview.

SAPPHIRE II has had a busy year, including a proof of concept study published in May and reported at the Alzheimer’s Association International Conference. In this study, the system successfully differentiated five Alzheimer’s patients from five controls (Front. Neurol. 2013 May 27 [doi:10.3389/fneur.2013.00062]).

Cognoptix has begun a second study testing the system against PET amyloid brain imaging in 20 patients with probable Alzheimer’s and 20 controls, Mr. Hartung said.

A third planned study is a pivotal phase III trial that will enroll 400 subjects, all of whom will undergo both the eye exam and PET amyloid imaging. It’s designed to support premarketing approval, Mr. Hartung said. Currently SAPPHIRE II has an investigational device exemption from the Food and Drug Administration’s Center for Devices and Radiological Health.

"Our end goal is to get this into the general practitioner’s office, where about 40% of Alzheimer’s drug prescriptions are written by general practitioners who really have no data on hand. Right now, based on cognitive assessments, they have only a 50-50 chance of getting the right diagnosis," Mr. Hartung said.

Dr. Goldstein and Mr. Hartung hold financial interests in devices to measure lens amyloid. Dr. Ralph Michael listed no financial disclosures. Dr. Charles Eberhart said he had no relevant financial disclosures.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

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