Is it truly Alzheimer's disease (AD) or only one of the many look-alike senile dementias?
A skilled neurologist or psychiatrist can make this differential diagnosis with 90 percent-plus accuracy. But a 100 percent AD verdict calls for a postmortem examination of the patient's brain cells. Those telltale neurons reveal the sinister evidence in their amyloid-beta (A-beta) peptides - senile neuritic plaques - wrapped around a bonafide AD cell.
Those stubby A-beta molecules come in two sizes - 40 or 42 amino acids. The 42 length is a toxic feature of AD; 40 is somewhat milder. Both of those peptides hive off from a far lengthier parent enzyme called amyloid precursor protein (APP), which runs from 681 to 782 amino acids long. APP inhabits every cell of the human body and cleaves away A-beta when Alzheimer's disease kicks in. Its signs and symptoms feature, in particular, memory loss and progression of cognitive decline.
"Development, testing and effective implementation of any new anti-Alzheimer's therapy," observed research psychiatrist Lee Goldstein at Harvard-affiliated Massachusetts General Hospital (MGH), "requires a safe and effective means of diagnosing and monitoring disease progression. If patients at risk of developing the disease could be identified early and accurately, ideally before cognitive symptoms emerge, therapeutic interventions can be instituted before the onset of irreparable damage to the brain."
Goldstein is lead author of an article in the current Lancet, dated April 12, 2003. Its title: "Cytosolic-amyloid deposition and supranuclear cataracts in [ocular] lenses from people with Alzheimer's disease." Its co-senior authors are ophthalmologist Leo Chylack Jr. at Brigham & Womens Hospital and oxidation biologist Ashley Bush at MGH.
"There are a couple of findings relevant to this paper," Goldstein told BioWorld Today. "One is that we have discovered a novel potential or putative biomarker for Alzheimer's disease. We've identified for the first time in the human lens A-beta, including the toxic 1-to-42 species."
Maverick Cataract Occurs In Alzheimer's
"We've also identified it," he continued, "in the aqueous humor, which is the fluid in the anterior chamber of the eyeball. It's analogous to cerebrospinal fluid in the brain. It's the fluid in the anterior chamber of the eye. In addition, the most exciting piece of this work is that we have defined the true amyloid pathology in the lens that seems to be associated with AD. We detected a very unusual cataract in the peripheral region of the lenses of AD patients. We didn't see this in other postmortem lenses from folks with other neurodegenerative disorders.
"We actually saw," Goldstein continued, "A-beta for the first time in the cytosol of the lens cells. That's the first time it's ever been found in the lens-cell cytosol itself. All inside the lens and in the fluid right outside.
"The reason all this is so exciting for us and everybody," he went on, "is that if the pathology or the disease process going on in the AD brain is also occurring in the lens, we have a very nifty way to quantitatively and noninvasively detect this process in patients. Not only have we made all these neat A-beta findings, we now have access to a compartment in the body where we might be able - very easily, very early - hopefully to pick up the disease process as a diagnostic and monitoring marker for Alzheimer's disease."
Goldstein recounted how he came upon his discovery: "I'd been doing some cataract research as well at the Brigham & Womens Hospital, and it occurred to me that A-beta might be in ocular structures. No one had looked at it in humans. We started acquiring lenses from nine patients with confirmed AD at autopsy. In the very first case we found a very unusual cataract. It was very different from common garden-variety, age-related cataracts. People write me that I have cataracts. Does that mean I'm going to get Alzheimer's?' It's not the same thing. The common type of age-related cataracts this is not.
"It's in the peripheral part of the lens. You can't even see it unless you widely dilate the pupil. It's behind the iris so you can't really see it. It doesn't impair vision; it's a nothing for our biomarker purposes. But as far as eyesight is concerned, this particular pathology is clinically inconsequential, because it won't bring you to an ophthalmologist, who'll never notice it. It doesn't do anything really. Usual age-related cataracts are more centrally located, they're very common and they're ultimately blinding. We found the uncommon ones in all nine postmortem cases. In addition, when we looked at some of those cases, we found the cytosol-like A-beta in the same region where we see those unique cataracts."
Authors Launch Neuroptix Corp. To License Patent
"We really are sitting on a great wealth of research going back three to 3.5 years," Goldstein observed. "This is the first in a series of papers that we're working on, looking at A-beta in the lens. Once proven, diagnosing AD by examining the eyes is something an ordinary ophthalmologist will be able to do. There are ways to very accurately dissect aggregation in the lens, and we have harnessed some of those technologies in the context of clinically useful ophthalmological instruments. There are really two prongs to this. One is to see whether we can use such devices to aid in the diagnosis of the disease. The second prong is to monitor the effects of drugs that are being researched to treat AD.
"There's great interest in the pharmaceutical industry to find a way to measure the effectiveness of the drugs. Right now the tools for doing that are rather limited. They necessitate using very large numbers of patients one at a time and so are very costly both in money and effort. So industry is very interested in techniques that might enable them to bring drugs to market more quickly.
"Leo Chylack and I have created a biotech venture we call Neuroptix Corp. We are board members, consultants and shareholders, as well as co-inventors with Ashley Bush for a pending MGH patent filing. It's titled A method for noninvasive diagnosis and tracking of AD,' and is licensed to Neuroptix."