Saliva testing of amyloid-β42 (Aβ42) levels may contribute to the prevention of Alzheimer’s disease (AD) by determining AD risk and guidance on the use of prophylactic nonsteroidal anti-inflammatory drugs (NSAIDs), new research suggests.
Canadian investigators used a salivary ELISA test to measure Aβ42 levels in saliva. They found that elevations in Aβ42 levels in persons at risk for developing AD were similar to levels in individuals who already had AD.
Given that AD is a neuroinflammatory process that begins as early as 10 years prior to the onset of cognitive deficits, the researchers suggest that NSAIDs, initiated a decade prior to the typical age of AD onset, may be effective in staving off these inflammatory effects in people whose Aβ42 concentrations are found to be high.
“We have known since the 1990s that people taking anti-inflammatory drugs are spared from getting AD, but what we didn’t know then and know now is how soon before the disease you have to start taking these medications and roughly how much you need,” lead author Patrick McGeer, MD, PhD, professor emeritus, Department of Psychiatry, University of British Columbia, Vancouver, Canada, told Medscape Medical News.
“The answers have been very slow in coming, but the knowledge that you can learn a lot from measuring saliva has provided the missing link,” he said.
The report was published online March 13 in the Journal of Alzheimer’s Disease.
Beyond the Brain
In the brains of patients with AD, activated microglia express HLA-DR (human leukocyte antigen–antigen D related), an immunologic marker that has been thought to be exclusively associated with peripheral leukocytes, the authors write.
These findings suggest that the brain does not enjoy “immunologic privilege” from inflammation originating elsewhere in the body.
Recent research has pointed to the role of neuroinflammation in the development of AD, and epidemiologic data have suggested that patients using anti-inflammatory drugs are “spared” from AD, the authors write.
They cite an earlier meta-analysis of 17 studies that they conducted that demonstrates that patients with rheumatoid arthritis who were treated with these agents had a lower risk of developing AD than those who were not using them.
“There was one consistent caveat in these epidemiological studies,” the authors warn: “The NSAIDs need to have been started at least 6 months and preferably as long as 5 years before the clinical diagnosis of AD.”
Positron-emission tomography deepened understanding of this phenomenon by revealing buildup of Aβ in the brain, and cerebrospinal fluid (CSF) testing revealed its concomitant reduction in CSF.
These studies, together with further imaging that established loss of brain tissue in AD, indicated that AD onset “commences more than a decade before clinical signs develop,” the authors state.
This discovery “explains the epidemiological data in which NSAIDs must be commenced years before clinical detection [of AD],” the authors state.
The question still remained “how to establish who might be at risk for this Aβ buildup and subsequent cognitive decline,” McGeer said.
Contrary to previous hypotheses implicating the brain as the exclusive organ that secretes Aβ42, recent research suggests that Aβ42 is secreted in all tissues of the body, and its secretion in saliva is a “reflection of its production by submandibular glands,” the authors state.
“These genes are expressed all day and every day throughout the body, and saliva tests have been shown to provide information about Aβ42 levels in various organs,” said McGeer.
Window of Opportunity
The authors summarize their previous study that demonstrated that individuals not at risk for AD secreted Aβ42 at levels close to 20 pg/mL (19 – 25 pg/mL), regardless of age or sex, with constant and unvarying production day by day and over time.
By contrast, for individuals who secreted high levels (41 – 60 pg/mL), those levels were comparable to the levels found in patients with AD.
“Significantly, there were no overlapping cases,” the authors report.
Elevated secretion levels were found in normal control persons as young as 48 or 50 years.
The authors propose a “theoretical 6-phase construct” of AD development. The opportunity for therapeutic intervention decreases with each progressive phrase.
Phase 1 begins at age 55 years, roughly 10 years prior to AD onset (which typically occurs at age 65).
Without intervention, the prevalence doubles every 5 years. The process starts with Aβ deposition in the brain and reduced levels of Aβ in the CSF.
“Therapeutic opportunities at this initial stage are the highest,” the authors note, adding, “any strategy which limits Aβ production, enhances its clearance, or prevents its aggregation should be disease-modifying.”
As the disease progresses in phase 2, Aβ brain concentrations continue to increase, while CSF levels continue to decrease. This process is accompanied by cortical tau aggregation in the brain.
In phase 3, cortical tangle and thread development occur. In phase 4, mild cognitive impairment is detectable.
AD can be clinically diagnosed in phase 5, and cognitive deficits progress from mild to severe in phase 6.
Although therapeutic opportunities in phase 6 are “minimal,” it is “in this phase that most clinical trials have been conducted,” the authors observe.
Intervention with prophylactic NSAIDs, such as ibuprofen, should take place during the early stages, prior to tau aggregation, to counter the inflammatory process, they emphasize.
“Given the enormous potential of salivary testing measuring Aβ levels, people at risk, such as people with family history, should be tested to determine if they should be taking ibuprofen during the window of opportunity,” McGeer said.
Saliva is “easy to get through a noninvasive test and provides a clean set of data derived from the production of a single isolated gland,” he pointed out.
He added that there are some concerns about gastric bleeding and other risks associated with NSAIDs, although such events “occur rarely, the risks are low, and the benefits are high.”
Is Inflammation Good or Bad?
Commenting on the report for Medscape Medical News, Keith Fargo, PhD, director of scientific programs and uutreach at the Alzheimer’s Association, who was not involved with the research, observed that epidemiologic studies have drawbacks because they “have confounding variables.”
These studies “look at people who took NSAIDs vs those who did not, but people treated with NSAIDs took them for a reason, such as pain or an inflammatory condition,” he pointed out.
“You can look at a study like this and make an argument that it is actually the inflammation that is protective, rather than the NSAIDs, and that NSAIDs may even be harmful, as was demonstrated in one RCT [randomized controlled trial].”
He noted that neuroinflammation is a “huge area of research now in AD, and most people expect that we will find out that inflammation plays an enormous role, but we just don’t know yet what that role is — positive, negative, or both.”
Although it is “tempting” to say that “inflammation is bad, it could be that the inflammation in AD is a reaction to some other factor that is truly causative and that inflammation may be the immune system’s attempt to protect against that other factor.”
He noted that the development of a “widely deployable, inexpensive biomarker test,” including blood tests, has become the “holy grail” of AD research.
A saliva test that asseses amyloid levels has “some real potential advantages, and clearly the Alzheimer’s Association is supportive of continued development of biomarkers,” he said.
“What we need to do now is to see that laboratories are established all around the world that can carry out these tests,” McGeer emphasized.
He added, “This is a good start, and once they’re functioning, we can use salivary biomarker testing for a whole host of other conditions, not just Alzheimer’s.”
The study was conducted at Aurin Biotech, Inc. Dr McGeer owns shares in Aurin Biotech, Inc. The other authors’ disclosures are available online. Dr Fargo has disclosed no relevant financial relationships.
J Alzheimers Dis. Published online March 13, 2018. Abstract
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