Drugs that tamp down inflammation in the brain could slow or even reverse the cognitive decline that comes with age.
In a publication appearing today in the journal Science Translational Medicine, University of California, Berkeley, and Ben-Gurion University scientists report that senile mice given one such drug had fewer signs of brain inflammation and were better able to learn new tasks, becoming almost as adept as mice half their age.
“We tend to think about the aged brain in the same way we think about neurodegeneration: Age involves loss of function and dead cells. But our new data tell a different story about why the aged brain is not functioning well:
It is because of this “fog” of inflammatory load,” said Daniela Kaufer, a UC Berkeley professor of integrative biology and a senior author, along with Alon Friedman of Ben-Gurion University of the Negev in Israel and Dalhousie University in Canada. “But when you remove that inflammatory fog, within days the aged brain acts like a young brain.
It is a really, really optimistic finding, in terms of the capacity for plasticity that exists in the brain. We can reverse brain aging.”
The successful treatment in mice supports a radical new view of what causes the confusion and dementia that often accompany aging. More and more research shows that, with age, the filtration system that prevents molecules or infectious organisms in the blood from leaking into the brain — the so-called blood-brain barrier — becomes leaky, letting in chemicals that cause inflammation and a cascade of cell death.
After age 70, nearly 60% of adults have leaky blood- brain barriers, according to Friedman’s magnetic resonance imaging (MRI) studies.
An accompanying paper by the two researchers and Dan Milikovsky of Ben-Gurion University shows that the inflammatory fog induced by a leaky blood-brain barrier alters the mouse brain’s normal rhythms, causing microseizure-like events — momentary lapses in the normal rhythm within the hippocampus — that could produce some of the symptoms seen in degenerative brain diseases like Alzheimer’s disease.
Electroencephalograms (EEGs) revealed similar brain wave disruption, or paroxysmal slow wave events, in humans with epilepsy and with cognitive dysfunction, including Alzheimer’s and mild cognitive impairment (MCI).
Together, the papers give doctors two biomarkers — leaky barriers detectable by MRI and abnormal brain rhythms detectable by EEG — that can be used to flag people with blood-brain barrier problems, as well as a potential drug to slow or reverse the consequences.
“We now have two biomarkers that tell you exactly where the blood-brain barrier is leaking, so you can select patients for treatment and make decisions about how long you give the drug,” said Kaufer, a member of UC Berkeley’s Helen Wills Neuroscience Institute. “You can follow them, and when the blood-brain barrier is healed, you no longer need the drug.”
Blood-brain barrier
Scientists have long suspected that a leaky blood-brain barrier causes at least some of the tissue damage after brain injury and some of the mental decline that comes with age. But no one knew how.
In 2007, however, Friedman and Kaufer linked these problems to a blood protein, albumin. In 2009, they showed that when albumin leaks into the brain after trauma, it binds to the TGF-β (TGF-beta) receptor in brain cells called astrocytes.
This triggers a cascade of inflammatory responses that damage other brain cells and neural circuits, leading to decreased inhibition and increased excitation of neurons and a propensity toward seizures.
They also showed in mice that blocking the receptor with an antihypertension drug, losartan, prevented the development of epilepsy after brain trauma. Epilepsy is a frequent consequence of concussions like those sustained by soldiers from roadside bombs.
Subsequent studies revealed leakiness in the barrier after stroke, traumatic brain injury and football concussions, solidly linking albumin and an overexcited TGF-β receptor to the damage resulting from these traumas.
In their new studies, Kaufer and Friedman showed that introducing albumin into the brain can, within a week, make the brains of young mice look like those of old mice, in terms of hyperexcitability and their susceptibility to seizures. These albumin-treated mice also navigated a maze as poorly as aged mice.
“When we infused albumin into the brains of young mice, we recapitulated aging of the brain: the gene expression, the inflammatory response, resilience to induced seizures and mortality after seizures, performance in a maze.
And when we recorded their brain activity, we found these paroxysmal slow wave events,” Kaufer said. “And all were specific to the site we infused. So, doing this is sufficient to get an aged phenotype of this very young brain.”
When they genetically engineered mice so that they could knock out the TGF-β receptor in astrocytes after they’d reached old age, the senile mouse brains looked young again. The mice were as resistant to induced seizures as a young mouse, and they learned a maze like a young mouse.
Serendipitously, a Palo Alto, California, medicinal chemist, Barry Hart, offered to synthesize a small-molecule drug that blocks the TGF-β receptor in astrocytes only, and that could traverse the blood-brain barrier.
When they gave the drug, called IPW, to mice in doses that lowered the receptor activity level to that found in young mice, the brains of the aged mice looked younger, too. They showed young brain-like gene expression, reduced inflammation and improved rhythms — that is, reduced paroxysmal slow wave events — as well as reduced seizure susceptibility. They also navigated a maze or learned a spatial task like a young mouse.
UC Berkeley scientists propose a radical new theory that the memory loss and cognitive dysfunction of aging is due to a leaky barrier between the blood stream and the brain. Image is adapted from the UC Berkeley news release.
In analyzing brain tissue from humans, Kaufer found evidence of albumin in aged brains and increased neuroinflammation and TGF-β production with age. Friedman developed a special type of MRI imaging — dynamic contrast-enhanced (DCE) imaging — to detect leakage in the blood-brain barrier and found more leakage in people with greater cognitive dysfunction.
Altogether, the evidence points to a dysfunction in the brain’s blood filtration system as one of the earliest triggers of neurological aging, Kaufer said.
Kaufer, Friedman and Hart have started a company to develop a drug to heal the blood-brain barrier for clinical treatment and hope that the drug will help reduce brain inflammation — and, thus, permanent damage — after stroke, concussion or traumatic brain injury, and eventually help older adults with dementia or Alzheimer’s disease who have demonstrated leakage of the blood-brain barrier.
“We got to this through this back door; we started with questions about plasticity having to do with the blood-brain barrier, traumatic brain injury and how epilepsy develops,” Kaufer said. “But after we’d learned a lot about the mechanisms, we started thinking that maybe in aging it is the same story. This is new biology, a completely new angle on why neurological function deteriorates as the brain ages.”
Funding: This work was supported by the National Institutes of Health (R01NS066005, R56NS066005), European Union’s Seventh Framework Program, Israel Science Foundation and United States-Israel Binational Science Foundation.
The earliest clinical trials to identify the role of NSAIDs in slowing down the progression of or preventing AD were conducted in the late 1990s. The most initial clinical indication about the possible role of anti-inflammatory drugs in AD came from a review of 17 epidemiologic studies, conducted to find out an association between arthritis, anti-inflammatory medications, and AD [10].
A clinical trial by Rogers et al., reviewing the impact of indomethacin in the progression of AD, revealed that 100-150 mg/day of indomethacin appeared to offer a protective role against cognitive decline in patients with mild-to-moderate AD when measured against a placebo group.
The double-blind study, conducted over a duration of six months, assessed the efficacy of indomethacin by measuring percent change in cognitive behavior from the baseline, which was determined by several cognitive tests such as the Mini-Mental State Examination (MMSE), AD Assessment Scale (ADAS), Boston Naming Test (BNT), and Token Test (TK).
Despite positive results, the study was limited by small sample size, as well as the short duration of time to fully recognize the spectrum of changes that can occur with AD [11].
However, a double-blind, placebo-controlled RCT of diclofenac/misoprostol in AD patients failed to reveal any beneficial effects in slowing progression or improving cognitive decline [12].
A larger, multicenter RCT, conducted over one year was also unable to show any positive impact on cognitive function by either naproxen or rofecoxib, indicating that patients with mild-to-moderate AD do not benefit from these NSAIDs compared to the placebo group [13].
The ADAPT (AD Anti-inflammatory Prevention Trial) study, conducted in a multicenter setting, was a placebo-controlled RCT to investigate the efficacy of NSAIDs in primary prevention of AD. Held over three years, after which the treatments were terminated following concerns over cardiovascular safety, the trial failed to show any benefit from celecoxib or naproxen in terms of prevention of AD over this duration.
The study selected patients older than 70 years, with at least one first-degree relative with AD, and the outcome was determined as the diagnosis of AD in the selected patient, made by various tests for Dementia Evaluation (DE), laboratory testing as well as neuroimaging [14].
While this trial suggested that other NSAIDs, particularly the selective A-β-42 lowering agents (SALA) may be more beneficial in reducing the risk of AD, this was disproven by a pooled dataset from six prospective cohort studies, which showed that although NSAIDs use lowered the risk of AD, there was no significant difference between the SALA and the non-SALA groups [15]. An extended follow up of the patients included in the ADAPT study, conducted over almost two years, with subsequent collection and analysis of cerebrospinal fluid (CSF) from the participants, suggested that NSAIDs might even contribute to AD pathogenesis in its later stages.
This seemed to occur more in patients with pre-existing AD pathology at the time of enrollment in the original ADAPT study, which, despite no clinical manifestations, influenced the impact of NSAIDs on AD pathogenesis. The study also hypothesized, in agreement with previously conducted observational studies, that NSAIDs may be protective against AD but only after two to three years of use. CSF biomarker results also supported the viewpoint that naproxen can be neuroprotective against cognitive deterioration in previously cognitively healthy individuals [16].
A follow-up trial, the Anti-inflammatory Prevention Trial followup study (ADAPT-FS), screened 1537 participants of the original ADAPT study by telephone assessment battery (TAB) as well as clinical examinations conducted at Dementia-evaluation visits (DEVs) seven years after the termination of the original research. The purpose of the trial was to examine the hypothesis suggested by the extended follow up of ADAPT study–whether the trend towards the decreased risk of AD with NSAIDs was sustained or not. The primary outcome in ADAPT-FS was the time to develop AD after enrollment in ADAPT. The trial diagnosed 89 cases of AD in addition to those diagnosed after ADAPT, taking the total toll to 161 AD patients.
Combined data analysis from both studies failed to support the priorly reported decrease in AD incidence with naproxen over two to three years after use. An increased risk of death compared to the placebo group was also shown for celecoxib. The trial concluded that NSAIDs use could not be supported for AD prevention in the elderly, a result contrasting with evidence from epidemiological studies [17].
Certain theories have been propounded regarding the diverging relationship of NSAIDs with AD predicted by observational studies and RCTs. One holds that the results of observational studies may be spurious, arising due to some confounding or bias.
Another suggests that the negative consequences in RCTs may be due to the notion that NSAIDs need to be taken for several years before the onset of AD to have a protective effect. As outlined above, the ADAPT and the ADAPT-FS trial do not support this claim; other RCTs, such as the Cache County study, reported a beneficial effect of NSAIDs only in certain groups, and after a certain period of use. Decreased incidence, as well as the prevalence of AD, occurred with NSAIDs use longer than two years; below this, no benefit occurred.
The study also reported a link between the age of consumption and apolipoprotein E (APOE) E4 genotype: those who started at age less than 65 and were APOE E4 carriers derived more benefit from NSAID use [18]. The findings seemed to suggest that a window period exists after starting NSAIDs during which they do not impact the conversion risk to AD. While this is corroborated by the Rotterdam study [19], the ADAPT-FS trial does not agree with this presumption [20].
Some systematic reviews have also been carried out to compare the pre-existing data on NSAIDs use in AD. A meta-analysis of available RCTs carried out by Gupta et al. [21], compared seven placebo-controlled, double-blind trials, in which patients were evaluated using the MMSE or ADAS-cognitive (ADAS-Cog) scale. Both parameters failed to show any significant advantage of the use of NSAIDs over placebo for AD. The meta-analysis was limited by the short duration over which the RCTs were conducted (mostly <12 months), as well as defined sample size. It suggested that the relationship between NSAIDs and AD was inconclusive as of yet, and required further corroboration by larger, long-term RCTs [21].
Another systematic review and meta-analysis of 18 observational studies and an RCT, exploring the relationship between both NSAIDs (aspirin and non-aspirin) and steroids with AD, suggested that NSAIDs use provided an incident risk reduction of 28% for AD [3]. More extended NSAID use was linked with greater benefit, while no significant advantage was recorded for steroids.
As with previous studies, there existed a discrepancy between the RCTs and the observational studies; however, this systematic review offered some explanations for the difference. According to this review, NSAIDs use is beneficial only for longer durations; the 15 months of NSAID use in the ADAPT trial due to risk-based interruption could have been insufficient to produce a sustained protective effect in the participants.
Furthermore, the ADAPT trial faced a reduction in statistical power during its course, because the estimated incidence of 2.5% for AD upon which the hypothesis was based was greater than the actual prevalence of 1.1%. The review also suggested that since RCTs have not been conducted in specific populations with the APOE E4 genotype, results from RCTs cannot be considered the final word in determining the relationship between NSAIDs and AD [3].
The review recommends that NSAIDs, including aspirin if used over longer durations, can significantly lower the incident risk of AD. Since the review includes observational studies fulfilling at least five of eight Newcastle-Ottawa Scale (NOS) criteria and included newer studies, it was found to be statistically robust by sensitivity analyses.
A systematic review by Miguel-Alvarez et al., while not underscoring the role of NSAIDs in prevention of AD, suggested that NSAIDs have no role in the treatment of AD and should not be used as a therapeutic option. The review included seven carefully selected RCTs, based on MMSE, ADAS-Cog, and CDR-SOB (Clinical Dementia Rating Scale sum-of-boxes) parameters of evaluation.
There was extensive heterogeneity among the studies included, not only in terms of NSAIDs administered, but also regarding dose, administration time, and follow-up duration. However, the lack of publication bias among the included studies strengthens the result of the review.
The review concluded that there was no beneficial effect of NSAIDs on either cognition or overall disease severity [22]. Similar results were also reported by a Cochrane review of NSAIDs, aspirin, and steroids for treatment of AD, which included 14 RCTs. This review also reported a higher incidence of side effects, as well as a higher death rate among patients treated with NSAIDs, particularly COX-2 inhibitors [23].
While chronic NSAID use has been reportedly preferred over short-term use for prevention of AD [3], one review of both epidemiological and clinical trial studies hypothesizes that such usage might only be beneficial in the very early stages of AD pathogenesis, coincident with initial A-β deposition, microglial activation, and release of pro-inflammatory cytokines.
Once the process of A-β deposition has started, NSAIDs are not useful; instead, a detrimental effect can occur owing to their inhibitory activity on already activated microglial cells. This hypothesis might in part explain why SALAs were more successful than non-SALAs, and why specific trials such as ADAPT failed to show an effect on AD prevention [24].
Conclusions
A thorough review of the literature suggests conflicting opinions for the use of NSAIDs in AD. While observational and epidemiological studies have stressed on a beneficial role of NSAIDs in reducing the risk of AD or its progression, RCTs and meta-analyses thereof have failed to corroborate this significantly. No RCTs have been conducted to date in populations with APOE E4 genotype.
For people with existing cognitive decline, as well as diagnosed AD, NSAIDs should not be administered, as no clinical evidence has been demonstrated regarding their benefit. The authors also recommend that further RCTs should be conducted over longer durations with larger samples to clarify the role of NSAIDs in the treatment of AD in selected populations.
Source:
UC Berkeley
Media Contacts:
Robert Sanders – UC Berkeley
Image Source:
The image is adapted from the UC Berkeley news release.
Original Research: Closed access
“Blood-brain barrier dysfunction in aging induces hyperactivation of TGFβ signaling and chronic yet reversible neural dysfunction”. Vladimir V. Senatorov Jr. et al.
Science Translational Medicine doi:10.1126/scitranslmed.aaw8283.
Closed access
“Paroxysmal slow cortical activity in Alzheimer’s disease and epilepsy is associated with blood-brain barrier dysfunction”. Dan Z. Milikovsky et al.
Science Translational Medicine doi:10.1126/scitranslmed.aaw8954.
