Scientists at the Blanchette Rockefeller Neurosciences Institute (BRNI; Morgantown, West Virginia), affiliated with West Virginia University (also Morgantown), have isolated a substance in skin cells that may provide doctors with a quick and accurate yes-or-no answer when they suspect a patient is showing early signs of the disease – perhaps putting them on the road toward developing a skin test for Alzheimer's disease (AD), as well as the road to personalized medicine as they attempt to gain partners for the development of a diagnostic and drug for AD.

The test could be "performed easily" by a nurse or medical technician in a doctor's office or outpatient clinic, BRNI said.

In an article that was published online the week of Aug. 14 in the Proceedings of the National Academy of Sciences (PNAS), researchers at BRNI describe a biomarker that can accurately distinguish between Alzheimer's disease and other forms of dementia during the first one to two years of the disease's progression.

Daniel Alkon, MD, scientific director of BRNI and co-author of the study, told Diagnostics & Imaging Week how quickly a commercial diagnostic could be developed "really depends on two things: first of all, how quickly we can organize a network of patients that we can test for a period of a couple of years with hospital and pharma partners. And we really need both, particularly pharma partners, because we need to scale up from about the 160 people that we've now tested up to a couple thousand at least before it could be made available generally to the public."

Alkon continued, "In terms of implementation, I don't think there is any problem – there's nothing standing in the way." And BRNI is actively seeking partnerships with pharma companies and hospitals to help fund and organize such studies.

The BRNI biomarker showed high accuracy when tested with human skin cells from a tissue bank, as well as for samples obtained in a previous, unpublished study of patients with autopsy-confirmed diagnoses. The bio-marker also could potentially be used with blood samples.

"When it begins, Alzheimer's disease is often difficult to distinguish from other dementias or mild cognitive impairment," said Alkon, who co-authored the study with Tapan Khan, PhD, assistant professor. "Potential treatments of Alzheimer's, however, are likely to have their greatest efficacy before the devastating and widespread impairment of brain function that inevitably develops after four or more years."

Many scientists have concluded in recent years that Alzheimer's effects are found throughout the body, not just in the brain.

"Recent evidence in human patients and animal models supports the hypothesis that early dysfunction in the brains of Alzheimer's disease patients involves inflammatory signaling pathways," according to the study.

The study also said that the "neurodegenerative processes responsible for AD may begin well before the disease can be detected by current clinical and/or imaging diagnostic criteria."

"Therefore, a biological marker to predict or confirm AD would be invaluable for initiating early therapeutic regimens," the study says. "Although definitive diagnosis of AD requires both clinically demonstrated dementia and amyloid plaques and tangles [in the brain] at autopsy, a molecular marker in peripheral tissue (e.g., skin, blood and saliva) with high sensitivity and specificity, detectable soon after the onset of symptoms, could be important for enhancing the accuracy of clinical diagnosis and screening AD drug therapies."

By testing for signs of Alzheimer's-related inflammation in skin cells called fibroblasts, the BRNI team has located a biomarker for the disease that can be tested without the invasive tests previously required, such as a lumbar tap.

Alzheimer's disease stimulates a change in the en-zyme, MAP Kinase Erk 1/2. When fibroblasts are tested by exposing them to Bradykinin, a common inflammatory signal, the Erk 1/2 response in skin cells of Alzheimer's patients was sharply distinguished from the results in cells from age-matched controls. It also was differentiated from the skin cells from patients with non-Alzheimer's dementias, such as Parkinson's disease, multiple infarct dementia and Huntington's chorea.

Khan and Alkon have created an Alzheimer's Index that may contribute greatly to physicians' evaluations of patients with dementia. The index is a mathematical formula that allows the scientists to convert the test results for each patient to a single number.

"The results demonstrate that when the Alzheimer's Index agrees with the clinical diagnosis of the presence of Alzheimer's, there is a high probability of accurate diagnosis," Alkon said.

Results of the researchers' tests "show promising specificity and sensitivity that could offer reliable confirmation of the clinical diagnosis of AD vs. other dementias," the study said.

There are important aspects associated with the development of a diagnostic for AD, Alcon told D&IW.

"One is that the diagnostic itself could be, I think, commercially quite valuable, as well as clinically valuable in its own right. But I also think, if you look at the industry that is developing drugs for Alzheimer's disease and other dementias, really billions of dollars are being invested today. And unfortunately, they are being invested without certainty as to which of the people actually have Alzheimer's," he said.

Unfortunately, AD can only be determined after a patient has had it for five to six years – "too late" for the therapies being developed to be of any use, Alcon said.

Not coincidentally, the molecular pathway measured by the BRNI biomarker includes the same enzyme, PKC, which is targeted by the drug Bryostatin, a drug originally studied to combat cancer but failed in that intended use. BRNI is currently seeking approval from the FDA to begin clinical trials of Bryostatin to determine if it is useful in treating both the symptoms and neurodegeneration of Alzheimer's disease.

Alcon said that BRNI expects initial trials of Bryostatin for AD to begin in the next few months.

At least one other company has sought FDA approval for a test that it says can aid in the diagnosis of AD. Nymox Pharmaceutical (Gaithersburg, Maryland) was turned down by the FDA, for the second time, in a vote of 5-2 in July 2005 in the company's quest to have its urine test, AlzheimAlert, approved.

Alcon and Khan's article, "An Internally Controlled Peripheral Biomarker for Alzheimer's Disease: Erk1 and Erk2 Responses to the Inflammatory Signal Bradykinin," appears on the PNAS web site.

BRNI is an independent research center, affiliated with West Virginia University, which seeks to accelerate the transfer of basic neuroscience discoveries into practical treatments for patients suffering from Alzheimer's disease and other memory disorders.

U.S. Sen. Jay Rockefeller founded the institute in memory of his mother, who died of Alzheimer's disease.