Solanezumab Selected for Alzheimer’s A4 Prevention Trial

18 Jan 2013

Today at the 7th Annual Human Amyloid Imaging conference held in Miami, Florida, researchers announced the selection of Lilly’s monoclonal antibody solanezumab as the first therapeutic drug to be evaluated in the Anti-amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) prevention clinical trial. This is the first time investigators will test an Aβ-clearing drug in older people thought to be in the pre-symptomatic stage of Alzheimer’s. The trial will enroll 1,000 people 70 and older with evidence of amyloid in their brains, but who do not show clinical symptoms of the disease.

“We carefully considered a number of promising anti-amyloid treatments for the A4 trial over the past six months,” said Reisa Sperling, Brigham and Women’s Hospital, who is principal investigator for the A4 trial. “Our committee ultimately reached the decision that solanezumab was the best choice for this first trial in asymptomatic people at high risk for cognitive decline.”

The A4 trial has been highly anticipated by the field at large. Intended to bridge the gap between trials for autosomal-dominant and sporadic AD, it complements the otherwise similar DIAN and API secondary prevention initiatives in people who are genetically destined to develop AD. A4 will not select for people who are at elevated genetic risk, but will enroll people who have the same preclinical biomarker changes observed in longitudinal studies of genetic and sporadic preclinical populations. The trial is funded by the National Institutes of Health and by private sector contributions.

“This trial is going to be incredibly important,” said Gil Rabinovici, University of California, San Francisco. “The preventive trials in autosomal-dominant AD are interesting as proof of concept, but even if the results are positive, the question will remain open about how generalizable the results are to sporadic AD. A4 is going to target the much more common population—older amyloid-positive people who we think are at risk for cognitive decline."

Earlier this week, the National Institute on Aging announced partial funding for the three-year A4 trial as part of its funding of the Alzheimer’s Disease Cooperative Study (ADCS) renewal grant (see ARF related news story). Led by Paul Aisen at the University of California, San Diego, the ADCS will facilitate the A4 trial, and the NIA will fund part of its cost.

Why solanezumab? “It has a good safety profile, which is a big deal when giving a drug to clinically normal people," said Sperling, who directs the Harvard Aging Brain Study at the Massachusetts General Hospital and BWH. Sperling was also encouraged by the evidence of a modest clinical benefit in the mild Alzheimer’s disease dementia patients in the Phase 3 trials (see ARF related news story). "Our confidence level in solanezumab grew after the results were confirmed through an independent, academic analysis by the ADCS released in early October,” she told Alzforum. “We hope that starting treatment much earlier in the disease, before symptoms are present, as well as treating for a longer period of time, will slow cognitive decline and ultimately prevent Alzheimer’s disease dementia.” William Jagust, University of California, Berkeley, agreed. “It suggests that if you moved to asymptomatic individuals, you might have an even greater effect,” he said.

The A4 researchers will use florbetapir (Amyvid®) as the PET amyloid tracer to select participants for the trial. Florbetapir is FDA approved for detecting the presence of amyloid in the brains of patients with cognitive impairment who are being evaluated for Alzheimer’s disease and other causes of cognitive decline. Academic centers, including those that will participate in A4, are already set up to use it. Both solanezumab and florbetapir are also being used in an upcoming DIAN treatment trial. Keith Johnson, Massachusetts General Hospital, will lead the PET amyloid imaging aspects of the A4 trial.

“The academic community probably has more experience now with florbetapir than with any other F18 agent,” said Jagust. “There’s also a wealth of data in the academic community using this tracer.”

Christopher Rowe, University of Melbourne, Australia, agreed. “Other tracers are under development that may have higher uptake in amyloid plaques, but they’re not ready for widespread use at this time,” he told Alzforum. “Whether [high uptake] is important for detecting change in amyloid with therapy is not clear, but theoretically, you would expect those [tracers] to be slightly more sensitive at detecting a therapeutic effect on amyloid load," he said.

The solanezumab decision was made a bit easier as researchers have come to acknowledge the A4 trial as the first in a series of preventative trials that may include different anti-amyloid therapies, said Sperling. “We have evolved from thinking of A4 as a single trial to thinking of it as a platform from which we will be able to test multiple drugs over time,” she said. Each trial will inform researchers about how to recruit subjects, conduct studies, and who best responds to treatments. “All of this will inform future trials,” Sperling said.—Gabrielle Strobel and Gwyneth Dickey Zakaib.

References

News Citations

Other Citations

HAI—Spotlight on Tau Tracers at Human Amyloid Imaging Meeting

25 Jan 2013

Just outside the Miami Conference Center in Florida, green ocean waves lapped at a sandy beach spotted with chunks of brain coral. It was perhaps an appropriate locale for a gathering of 250 scientists who met 16-18 January 2013 at the 7th Human Amyloid Imaging (HAI) meeting to share the most up-to-date research on brain imaging.

At this year's meeting, organized by Keith Johnson of Massachusetts General Hospital, William Jagust of the University of California, Berkeley, and William Klunk and Chet Mathi at the University of Pittsburgh Medical School, Pennsylvania, researchers took a hard look at new data on amyloid-β’s relationship to Alzheimer’s disease (AD). Experts discussed how Aβ plaque relates to other biomarkers, such as tau. Going against perceived wisdom, they asked whether tau tangles precede Aβ deposition? Long-awaited tau tracers are getting off the ground to help answer this question, and as they are being tested in humans, hints are emerging that some tracers may bind a specific form of tau found only in AD patients. Researchers also addressed how data generated from a slew of upcoming Aβ tracers might be compared. In addition, they debuted new guidelines that will advise how amyloid imaging should be used, and for whom. For more on these questions, see subsequent parts of this series. While the conference showed the field has come a long way since amyloid imaging was first introduced in 2002 (see ARF related news story), it also revealed that a lot of work lies ahead.

Tau Imaging Agents on the Horizon
Human data about upcoming tau tracers created the greatest buzz at HAI. Several ligands are in development for use in positron emission tomography, and some have reached the clinical research stage. Hartmuth Kolb of Siemens Inc., in Culver City, California, and Victor Villemagne, University of Melbourne, Australia, both presented human data for candidate tau ligands. All tracers seem to specifically label tau, as previously shown in preclinical studies. This stands in contrast to the first reported tau agent, FDDNP (e.g., see Small et al., 2013). “In-vivo detection of tau is crucial to understanding the mechanism of Alzheimer’s disease,” said Charles Duyckaerts, University of Paris, who was not involved in the development of these compounds.

Last year at the HAI meeting, Kolb presented data for in-vivo mouse and postmortem human tissue binding of 18F-T807 and T808, which were developed by screening with tau-laden human brain slices (see ARF related news story). This year in Miami, Kolb presented the first human data, detailing results of two initial studies evaluating the safety and kinetics of both tracers. Kolb proffered six human scans for each tracer; half the subjects had AD or MCI and the other half were healthy controls.

Both ligands appeared to bind specifically to tau. Healthy participants showed no binding in the brain, while the brains of the dementia patients did. Binding correlated with dementia severity, and the distribution appeared to follow Braak staging. Neither compound bound white matter in either healthy or demented participants, which has been a problem with other tracers. Furthermore, both compounds entered and left the brain quickly. Kolb said both seemed safe for human use.

Human Tau Imaging: People with AD retain more T807 in the brain. Image courtesy of Siemens Healthcare

Looking at the data, one scientist asked why the compounds seemed to continue to accumulate in the cortex relative to the cerebellum in AD patients, rather than leveling off or decreasing. Another researcher wondered about T808’s high binding in the striatum, since that region does not contain tau deposits in AD. Kolb said that further studies will hopefully pinpoint the reason for these observations. The jury is still out on whether T807 or T808 is more useful. "Both are still in the game at this point,” said Kolb. The next possible steps with these tracers will be to validate tau binding with postmortem brain tissue and to submit Investigational New Drug applications to the FDA so larger Phase 1 and Phase 2 studies can be conducted. If those trials indicate that the compounds are indeed binding tau, one will be advanced for use in research settings, Kolb said.

Villemagne also presented updated human data on a tau ligand developed by researchers at Tohoku University School of Medicine, Sendai, Japan (see ARF related news story). Last year, he showed data on the first eight humans who underwent PET scans with this ligand, called 18F-THK523, and this year he refreshed that dataset with 15 more people, bringing the total to 23. Ten are healthy controls, 10 patients have AD, and three people are diagnosed with semantic dementia, a form of frontotemporal lobar degeneration without Aβ or tau deposition.

Overall, THK523 selectively bound tau and did not bind to Aβ, as seen by comparing THK523 PET scans to those carried out in the same participants using the Aβ ligand Pittsburgh compound B. Most researchers believe specific tracers for both Aβ and tau are needed. Cortices of people with AD retained 40 percent more THK523 than those without AD, and the binding followed the known distribution of tau deposition in the brain (see Braak and Braak, 1991). Importantly, greater retention correlated with shrinking hippocampal volume and worsening cognition. Overall, the results suggest that the ligand was binding tau deposits. The team plans to corroborate these findings with histopathological studies as postmortem tissue becomes available, Villemagne said.

Interestingly, cognitively normal people with Aβ deposition showed hippocampal THK523 uptake on par with that in AD patients, said Villemagne. AD patients, on the other hand, had additional tracer retention in the cortex. This suggests that a patient becomes demented at the same time as tau aggregates reach cortical areas, Villemagne told Alzforum, though he emphasized that correlation does not prove causation.

Curiously, THK523 does not bind all kinds of tau aggregates. Villemagne and colleagues scanned one person with behavioral FTD, another with progressive nonfluent aphasia, and a third with progressive supranuclear palsy—all tauopathies known to involve different forms of the aggregated protein (see Delacourte, 2005). THK523 did not detect tau in any of these cases in vivo, but tau aggregates did show up with immunohistochemical staining in brain tissue of the PSP patient postmortem. Villemagne explained that tau can assume different shapes in different pathologies, and since ligand binding depends on shape, THK523 may not bind all forms of tau in neurodegenerative disease. Though very preliminary, this finding raises the possibility that THK523 could be a specific marker for tau in AD, said Stephen Salloway, Brown University, Providence, Rhode Island. “Having tau tracers that bind specifically to neurofibrillary tangles would be a major advance for our field,” Salloway told Alzforum. “We’re trying to make distinctions between neurodegenerative diseases more precise—once we define those groups, we can better tailor treatments for each.”

Though it labels AD-related tau, THK523 also binds non-specifically to white matter. For that reason, Villemagne's group has halted development of this ligand and switched to two other F18-labeled compounds with the same molecular scaffold. A poster by project leader Nobuyuki Okamura, Tohoku University, unveiled initial findings. Compared to THK523, the newer compounds THK5105 and THK5117 bound to white matter with lower affinity and to tau aggregates in vitro with higher affinity. In autoradiographic images of postmortem human tissue, distribution of the ligands in the brain mirrored that expected for tau pathology. Both cleared quickly from rodent brains while proving non-toxic.

In-vivo human studies have just begun. Okamura presented results on one AD patient and one healthy control who underwent THK5105 scanning. Results paralleled those for THK523, suggesting the tracer binds to tau aggregates in the brain. It was not retained in healthy control brain. Okamura expects to image 20 people in all and then decide which of the two ligands to develop further. The preferred one could be available for clinical research at several PET centers as early as this summer, he said.

“The developmental process that has gone into these tau ligands makes a convincing case that they are labeling PHF-tau,” Johnson told Alzforum. “However, the final verdict will not be in until postmortem correlation studies are done.” Johnson is currently making plans to work on both the Siemens and Japanese-developed compounds.

“Imaging tau represents the next frontier of AD neuroimaging,” Gil Rabinovici, University of California, San Francisco, told Alzforum in an e-mail. “Just as amyloid imaging has shed light on amyloid’s effects on the human brain, tau imaging would give us a much more complete picture of how the two proteins interact with the brain and with each other, and how they ultimately lead to disease.” Not only would an imaging marker help evaluate tau-targeted drugs in the future, but it might also help diagnose other tau disorders down the line, he said.—Gwyneth Dickey Zakaib

References

News Citations

Paper Citations

Small GW, Kepe V, Siddarth P, Ercoli LM, Merrill DA, Donoghue N, Bookheimer SY, Martinez J, Omalu B, Barrio JR. PET Scanning of Brain Tau in Retired National Football League Players: Preliminary Findings. Am J Geriatr Psychiatry. 2013 Jan 1;(21):138e144.
Delacourte A. Tauopathies: recent insights into old diseases. Folia Neuropathol. 2005;43(4):244-57. PubMed.

Other Citations

HAI—Amyloid Imaging in the Clinic: New Guidelines and Data

29 Jan 2013

Since the FDA approved the Aβ imaging agent florbetapir (Amyvid®) last April, academics and doctors have debated how it should be used (see ARF related news story). At that time, the Society of Nuclear Medicine and Molecular Imaging and the Alzheimer’s Association assembled an Amyloid Imaging Taskforce (AIT) to devise recommendations for clinical practice (see ARF related news story). AIT co-chair Keith Johnson presented those guidelines at the 7th Human Amyloid Imaging meeting held in Miami, Florida, 16-18 January 2013. In a nutshell, the task force concluded that patients with objectively measured cognitive problems or unusual dementia presentations would benefit from amyloid imaging, and that only dementia experts should prescribe such scans. “These guidelines are an excellent start,” said Stephen Salloway, Brown University, Providence, Rhode Island. “They are well thought out and will be useful for third-party payers and clinicians.” They were formally published January 28 in Alzheimer's & Dementia and in the Journal of Nuclear Medicine. The 13 AIT members coauthored the papers, which are freely available online. Physicians have also been asking whether amyloid imaging changes patient management or diagnosis. In Miami, researchers presented two studies that took an initial stab at addressing these questions.

The ability to detect brain amyloid by positron emission tomography has left some doctors and patients with a dilemma. Many cognitively normal people accumulate Aβ in their brains, but researchers are still unsure what that means for their future brain health. On top of that, no treatment exists to stop or reverse Aβ buildup, and it is unclear as yet whether amyloid scans improve patient care (see ARF related news story). Because of these uncertainties, some researchers have questioned if amyloid scans are even ethical. Against that backdrop, the AIT put together a set of criteria for responsible use of the technology.

The committee decided that current data support amyloid imaging in three main groups: patients with memory complaints who show measurable impairment on standard cognitive and memory tests; people diagnosed with possible AD but who have an unusual clinical presentation; and people who have progressive dementia before age 65. In all these cases, imaging can reveal if Aβ accumulation underlies the symptoms.

The committee recommends against scanning when a clinical benefit seems unlikely. People falling into this category include those who perform within the normal range on standard neuropsychological tests, and people over age 65 who already have a clear AD diagnosis. In the former case, researchers do not know enough to tell individuals with any certainty how and when their cognition might slip; in the latter case, amyloid imaging would contribute little to their clinical workup, the committee argued.

“Physicians do not need amyloid scans for typical, garden-variety late-onset AD,” said William Klunk, University of Pittsburgh, Pennsylvania, who co-discovered PIB, sees patients, and helped advise the committee. “They need it in confusing cases, in mild cognitive impairment, and in other forms of atypical young-onset cases.”

One patient group left off the eligibility list may benefit from scans down the road, said Salloway. To researchers’ surprise, a third of ApoE4 non-carriers diagnosed clinically with mild AD turned out to be amyloid-negative in recent Phase 3 trials (see ARF related news story and ARF news story). “They may not have significant amyloid burden and may not have Alzheimer’s,” Salloway told Alzforum. At some point, it may make sense to use ApoE4 as a screening tool to decide whom to target for amyloid imaging; in other words, clarify the clinical diagnosis of mild AD in non-carriers with a scan, Salloway said.

The committee cautioned that amyloid imaging, in its current form, cannot determine the severity of a person’s dementia. It cannot be used to stage dementia in people who carry familial AD mutations, as some had suggested. The committee advises against imaging as a substitute for genetic testing when familial AD is suspected. Doctors should never prescribe a scan based solely on a family history of AD or the presence of AD risk factors, such as the ApoE4 allele, when there are no symptoms. Amyloid PET is also inappropriate for non-medical uses, such as in insurance, legal, or employment decisions.

The committee recommended that only physicians with expertise in diagnosing and treating memory disorders should order amyloid PET scans. Scan results should form part of a broader diagnostic workup—not serve as stand-alone diagnoses. AIT also advised that results be disclosed to the patient with a thorough explanation of their meaning.

One audience member wondered if primary care physicians should order the test, since a positive result could help them refer people to dementia care specialists. Christopher Rowe, University of Melbourne, Australia, who chaired this session and is part of the AIT, pointed out that a study led by Gil Rabinovici at the University of California, San Francisco, suggests scan results have little impact on patient care, arguing against broad, expensive scanning efforts at this time (see below). Additionally, Rabinovici said that widespread use of amyloid imaging could cause more harm than good if interpreted by physicians who do not understand the nuances.

These guidelines may influence not only clinicians, but also health insurers, who typically follow the Centers for Medicare & Medicaid Services’ (CMS) rules for reimbursing Medicare and Medicaid patients. A CMS panel will meet 30 January in Baltimore, Maryland, to review whether amyloid imaging improves care of dementia patients (see ARF related news story; MEDCAC meeting). The panel will later advise the CMS on reimbursement. Currently, CMS explicitly excludes coverage of all new positron emission tomography (PET) radiotracers. “The key issue is whether amyloid status changes patient management,” Johnson said. In the absence of a treatment, some see that as unlikely. “That’s the biggest threshold to cross for this technology,” said Johnson.

What does the field know about this question? Research on it is only just beginning. While scan results could, in theory, improve patient care even in the absence of a treatment, there are few data to support this idea. At HAI, Andrew Siderowf of Avid Pharmaceuticals, the maker of Amyvid, presented data published this month on one such study (see Grundman et al., 2013). It examined whether amyloid imaging changed the diagnosis, the physician’s confidence in the diagnosis, planned use of other tests, or patient treatment. The study, conducted at 19 clinical centers, included 229 people with dementia or cognitive decline whose physicians were less than 85 percent certain about their diagnoses.

Before and after amyloid imaging, physicians provided a diagnosis, an estimate of their confidence in the decision, and hypothetical plans for future diagnostic evaluation and management (the study did not track actual patient outcomes, but an upcoming Avid Phase 4 trial will). As might perhaps be expected from a study funded by the tracer’s manufacturer, Siderowf reported that the scan results did indeed influence those decisions. About half the clinicians changed their diagnosis after receiving amyloid PET results, and their diagnostic confidence rose 22 percent. For 87 percent of patients, physicians planned at least one disease management change, for instance, stopping or starting a cognitive enhancing or psychiatric medication. For patients without a complete diagnostic workup at study entry, plans for brain structural imaging, neuropsychological testing, and fluorodeoxyglucose (FDG) PET were shelved after the amyloid PET scan about 52, 65, and 91 percent of the time, respectively.

The study did not address why those other tests were abandoned, Siderowf said. “One possibility is that physicians may have decided to watch and wait rather than perform additional testing that might not provide any useful information,” he told Alzforum in an e-mail.

If this were to happen broadly, costly amyloid scans might marginalize and over time replace other means of assessment. Indeed, at least one audience member at HAI expressed concern about the observed drop in AD diagnostic tests. “These results suggest that physicians may be overinterpreting amyloid scan results as providing a definitive diagnosis, whereas they should be treated as just one piece of the diagnostic puzzle,” said Rabinovici. “There is no evidence to suggest that these scans should substitute for the current standard of care, which includes cognitive testing and structural imaging, particularly in complex cases.” Siderowf agreed. “It is important to note that Amyvid is neither a screener for asymptomatic patients nor a stand-alone diagnostic for AD—it should be used as an adjunct to other diagnostic evaluations,” he told Alzforum.

Rabinovici presented his own study on the clinical impact of amyloid scans. He looked back at the records of 140 dementia patients from the UCSF Memory and Aging Center for whom physicians had incorporated results from FDG and Pittsburgh compound B (PIB) PET imaging. He and colleagues wanted to know if the diagnosis had changed from an Aβ to a non-Aβ disorder or vice versa, or if patients started or stopped treatment with memantine or cholinesterase inhibitors based on an amyloid scan.

Less than 10 percent of diagnoses changed. Those that did tended to side with PIB scans more than the FDG scan if the two were at odds. Though physicians altered AD symptomatic therapy in 36 percent of patients after PET scans, these adjustments did not associate with PIB or FDG results, Rabinovici said.

Siderowf's and Rabinovici's data paint different pictures of the outcome after amyloid scanning. It is difficult to directly compare these two studies because of the difference in design, noted Johnson. For one thing, the Avid study details what physicians intended to do, rather than measures they actually took, as did Rabinovici’s study. “There might be important differences between intended and observed behavior,” Johnson said. Avid’s is a multisite study. It incorporated clinicians from a wide variety of settings and backgrounds, as opposed to the single-site UCSF study, Salloway pointed out. Given that only a small proportion of patients can attend such highly specialized centers, the results of the Avid study may be more generalizable to the community, he told Alzforum. Salloway was a contributing physician in Avid’s work.

Study differences aside, the fact that physicians used scans to refine their diagnoses and modify patient treatment plans is “encouraging, and what you’d expect for a useful biomarker,” Klunk said. As these are just the first studies that look into how amyloid imaging plays out in clinical practice, neither represent the final word on its impact, he told Alzforum.—Gwyneth Dickey Zakaib

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

Paper Citations

Other Citations

External Citations

HAI—Sharper Curves: Revamping a Biomarker Staging Model

01 Feb 2013

Soon after Clifford Jack, Mayo Clinic, Rochester, Minnesota, proposed a hypothetical model showing biomarkers emerging at different stages of Alzheimer’s disease (AD), his diagram surged to the top of the Most-Popular-Slide-at-Conferences chart. All the same, scientists have been wondering how well the model will hold up. Several researchers, including Jack himself, recommended updates at the 7th Annual Human Amyloid Imaging meeting held 16-18 January in Miami, Florida. Reflecting some of the latest data on biomarkers in Alzheimer’s disease, their tweaks aim to more accurately represent the disease cascade.

Jack and colleagues published their original model in 2010 (see Jack et al., 2010, and ARF Webinar). It temporally ordered five main markers of AD. Jack proposed that Aβ changes occur first, followed by tau, alterations in brain structure, memory loss, and finally, clinical impairment. He depicted these as parallel sigmoidal curves, where biomarker change happened first rapidly, then more slowly as disease progressed (see image below).

Jack’s 2010 model of biomarkers in the AD cascade. *Image courtesy of Clifford Jack and Lancet Neurology*

As longitudinal studies begin to map the biomarker landscape more thoroughly, the model was bound to change. At HAI, for example, Victor Villemagne and Christopher Rowe from the University of Melbourne, Australia, gave an update on the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. They suggested that amyloid accumulates not just long before symptoms, but also long before changes in other biomarkers. They derived rates of Aβ accumulation for almost 200 research volunteers in AIBL who had at least three amyloid scans over three years. Some had five scans over six years. Extrapolating that rate backwards, they estimated that it took an average of 12 years to build up enough Aβ for a positive scan, and a further 19 years to reach levels seen in AD. Biomarkers such as hippocampal atrophy, gray matter shrinkage, and worsening memory appeared only about seven years before dementia onset, Rowe said.

Jack showed recent data from the Mayo Clinic Study of Aging that suggests PET scans detect amyloid before FDG-PET shows irregularities in brain function or before the hippocampus shrinks measurably. Jack and colleagues conducted two or more serial PET scans, about every 16 months on average, in 213 cognitively normal adults aged 70-90 with the amyloid tracer Pittsburgh compound B (PIB). People who were initially amyloid negative turned positive at a rate of about 13 percent per year, and did so while FDG-PET and hippocampal volume stayed stable.

How do emerging data fit with the model? Jack presented a revision that will be published in the February Lancet Neurology, already available online (see Jack et al., 2013). In this version, Jack marks time—rather than disease stage—along the X axis. Why this change? It allows for person-to-person variability, said Jack. The clinical manifestation of AD pathology can differ among people with similar biomarker profiles. Cognitive impairment now appears as its own curve—or swath, to be precise. Jack and colleagues represent impairment as a green zone bounded by two lines: one to the left representing high risk of manifesting clinical symptoms with a given biomarker profile and one to the right representing a lower risk of manifesting clinical symptoms with the same biomarker profile (see image below). Risk factors such as genetics, lifestyle, cognitive reserve, and comorbid pathology influence where a person would fall within that zone at a given point in time.

Updated model, with adjusted axes and curves, reflects recent biomarker data. Image courtesy of Clifford Jack and Lancet Neurology

The updated model is different in other ways, too. Though Aβ biomarkers are still first to change, Jack and colleagues now separate out CSF Aβ and brain Aβ, with the former changing first. The group also combined 18F-fluorodeoxyglucose (FDG) PET and MRI into one curve where the previous diagram had not included FDG-PET. All markers are still represented as sigmoidal curves; however, the biomarkers that emerge later now sport a steeper final slope because their rate of change plateaus less in the dementia stages of disease. Additionally, the distance between the lines reflects how certain markers track closer together temporally.

“The model is getting closer to what we find in our data,” said Rowe. Updating the staging model is important to inform trial design in presymptomatic AD. It could help pinpoint particular time points in AD progression, determine how long trials should run, and indicate which biomarkers to track in clinical trials, he said.

At the end of his talk, Jack introduced an additional twist, which he called the "integrative model." The graph looks the same as the updated version, but reflects autopsy data showing that tau pathology appears in the brains of most middle-aged people, almost always before Aβ markers change (see Braak and Del Tredici, 2011). Current CSF analysis does not detect this kind of tau pathology, as represented by a gray bar at the bottom of the plot. Here, tau changes before Aβ, but the latter changes faster and is detectable first in the CSF.

An integrative model accounts for biomarker changes undetectable by CSF analysis. Image courtesy of Clifford Jack and Lancet Neurology

Researchers at HAI were grappling with these ideas. They wanted to know what this new model means for the pathophysiology of AD, given that many in the field have been working on the premise that Aβ pathology comes first and, indeed, precipitates tau pathology. It could be that tau deposits are a natural part of aging, Jack responded. Aβ builds up later and independently, progresses quickly, and drives tau out into the neocortex to initiate a neurodegenerative cascade.

Researchers first proposed this idea over a decade ago (see Price and Morris, 1999), but the imaging community was relatively slow to pick up the idea, said Jack. Over the years, John Morris, Washington University, St. Louis, Missouri, has repeatedly spoken about the presence of neurofibrillary tangle pathology in most people as they age, and its precipitation into Alzheimer’s once amyloid pathology arises separately (e.g., see ARF interview).

“It’s important to note that this integrative model of disease does not contradict the amyloid cascade hypothesis,” Jack told Alzforum. “Aβ still induces and transforms the propagation of tau, not the other way around.” Price and Morris’s original explanation fits the field’s current understanding of these proteins, said Villemagne. "From autosomal-dominant AD mutations, we know that overproduction of Aβ leads to tau deposition and AD,” he told Alzforum. “Mutations associated with overproduction of tau do not lead to AD.”

Rowe and Villemagne in Miami proposed a further refinement to Jack’s model. Based on the AIBL data, they argue that the Aβ curves should rise more gradually and farther to the left of the other biomarkers, which climb later and have steeper slopes. “Our data imply that Aβ deposition is a slow, protracted process that spans more than two decades,” said Rowe. “That suggests a wide therapeutic window for altering Aβ accumulation.”

While the data gave average buildup rates, people differed in their individual pace, however, and faster aggregation correlated with faster memory decline. “Even in the fastest accumulators, it looks like it still takes at least 10 years to increase from a barely positive scan to typical AD amyloid levels," Rowe said. Researchers in the Dominantly Inherited Alzheimer Network (DIAN) and the Alzheimer's Prevention Initiative find a similar two-decade Aβ buildup in early onset, familial AD carriers (see ARF related news story).

Susan Landau, University of California, Berkeley, questioned one other piece of the Jack model. She hinted that a drop in CSF Aβ does not always foreshadow brain Aβ deposition. She and colleagues examined cross-sectional data on CSF Aβ and amyloid PET with florbetapir for 374 people classified as cognitively normal, MCI, or AD in the Alzheimer's Disease Neuroimaging Initiative (ADNI). CSF and PET measures agreed as expected 80-90 percent of the time. In 20 people (three normal controls, 12 with early MCI, four with late MCI, and one with AD), however, they did not.

What explains the discordance? If CSF Aβ typically dips before amyloid deposits form in the brain, as previous data suggest (see Fagan et al., 2009), then low CSF Aβ and negative amyloid PET might occur at the same timepoint, especially in early disease stages, argued Landau. Surprisingly, she found the opposite. Among those 20 people, 13 who were either cognitively healthy or had early mild cognitive impairment (MCI) turned out to have normal CSF Aβ, yet tested positive for florbetapir. On the other hand, most of those with low CSF Aβ and normal brain scans had been diagnosed with late MCI or AD. The data go against conventional thinking and support the idea that CSF Aβ and amyloid PET measure different forms of the protein, so are not always interchangeable. “While a sample size of 20 is too small to make firm conclusions, the data hint that florbetapir might become abnormal first in some cases,” Landau said. It is also possible that the seven people with normal scans but low CSF Aβ, most of whom were diagnosed with later-stage disease, may have had another disorder, said Landau.

Agneta Nordberg, Karolinska Institute, Stockholm, agreed that Aβ measures can conflict. “Individuals with the Arctic Alzheimer's mutation are negative by PIB imaging, but have a classic CSF AD profile,” she said. “So apparently, what you measure in CSF is not identical to what you measure in brain.”

William Jagust, University of California, Berkeley, pointed out that a high proportion of those with low CSF Aβ yet no brain amyloid were ApoE4 negative. He wondered if there might be something about florbetapir binding to amyloid that is different between ApoE4 non-carriers and carriers. That is possible, said Reisa Sperling, Brigham and Women's Hospital, Boston, Massachusetts, who saw amyloid-negative ApoE4 non-carriers in the recent bapineuzumab Phase 3 trial (see ARF related news story). “It may be that the fundamental biology of amyloid deposition is a bit different in ApoE4 carriers—they accumulate more overall,” she said. It could also be that ApoE4 carriers have more vascular amyloid burden, which binds PIB easily, she noted.—Gwyneth Dickey Zakaib.

Reference:
Jack CR, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P, Wiste HJ, Weigand SD, Lesnick TG, Pankratz VS, Donohue MC, Trojanowski JQ. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013 Feb;12(2):207-16. Abstract

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Webinar Citations

News Citations

Paper Citations

Jack CR, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010 Jan;9(1):119-28. PubMed.
Jack CR, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P, Wiste HJ, Weigand SD, Lesnick TG, Pankratz VS, Donohue MC, Trojanowski JQ. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013 Feb;12(2):207-16. PubMed.
Braak H, Del Tredici K. The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol. 2011 Feb;121(2):171-81. PubMed.
Price JL, Morris JC. Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease. Ann Neurol. 1999 Mar;45(3):358-68. PubMed.
Fagan AM, Mintun MA, Shah AR, Aldea P, Roe CM, Mach RH, Marcus D, Morris JC, Holtzman DM. Cerebrospinal fluid tau and ptau(181) increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer's disease. EMBO Mol Med. 2009 Nov;1(8-9):371-80. PubMed.

Other Citations

HAI—Standardizing Amyloid PET: The Centiloid Project

01 Feb 2013

In your mind, does the word "centiloid" conjure up images of a small creature with too many legs? Instead, think centimeter yardstick, or thermometer. A centiloid is a proposed unit of measure on a unified scale for all amyloid-β imaging tracers used in positron emission tomography (PET). Alzheimer’s disease scientists use a handful of ligands in research already, and while the FDA thus far has approved only one—Amyvid®—for clinical use, other approvals appear likely. Since each tracer has its own characteristic signal strength, comparing them remains difficult. Enter, the Centiloid Project. William Klunk, University of Pittsburgh, Pennsylvania, presented the idea at the 7th Human Amyloid Imaging meeting held 16-18 January in Miami, Florida.

The problem is that scientists cannot easily compare the results from different tracers. For example, it is known that PIB generates a stronger signal than does Amyvid, but side-by-side comparisons are rare. Most studies and clinics use either one or the other, and scientists cannot easily interpret a scan taken with one tracer relative to one taken with another.

“This [project] could really help give us a numerical scale we can all understand—like everyone having a common language,” said William Jagust, University of California, Berkeley, a member of the Centiloid Project working group.

Klunk laid out a plan for deriving this standard unit. “Imagine that different-length thermometers represent the various imaging agents—each with a shorter or longer column of mercury,” said Klunk. “We set them all to a freezing point of 0 and a boiling point of 100. That way, no matter the temperature, all thermometers will read the same.”

Here’s how that would work for amyloid imaging. Klunk and colleagues would set average minimum and maximum signal values for each tracer and then normalize them against a 0-100 scale set with a gold standard, for example, Pittsburgh compound B (PIB). For 0, they would use the median brain uptake value from 20 young controls with no amyloid accumulation. Likewise, 100 would come from the median uptake of 35 AD patients predicted to have a substantial plaque load. That range would then be divided into 100 equally spaced units defined as centiloids. (Since the 0 and 100 anchor points are median values, some scans would fall below 0 or exceed 100 centiloids.) All the scans and calculation methods would be made publicly available.

At that point, researchers or companies making amyloid imaging agents could calibrate other tracers with the PIB scale. First, to ensure that their analysis is compatible, they would download the raw public data and make sure they could recalculate the original centiloids correctly. They would then measure brain amyloid in 10 controls and 15 amyloid-positive volunteers using PIB and convert uptake values to centiloids using the already established conversion values. Within three months (to avoid significant changes over time), the same 25 subjects would undergo another scan with the second tracer to calibrate that tracer to the centiloid scale. Those raw data should also be made publicly available, suggested Klunk, so that other groups would not have to repeat the standardization.

From there, any lab group would be able to convert their own data to centiloids. They would download the public data about their tracer of choice, make sure they could recreate the calculations, and convert new data to centiloids using the common conversion values. Scientists could also apply this standardization process to calibrate different analysis methods, non-standard scanners, etc.

Not every tracer manufacturer or lab group needs to use this system, Klunk emphasized. However, studies that do use it will be comparable even if they used different amyloid PET agents or methods. That would facilitate meta-analyses. The ensuing cross-talk among labs using different tracers and methods would enable setting a clearer threshold for positive scans, a better idea of the range of Aβ deposition throughout disease, and more consistent representation of longitudinal change, suggested Klunk. Inconsistent values from different tracers and analysis methods have prevented the field from exploring these issues. “There’s a lot to be said for looking at PET amyloid data as a continuous number, rather than simply categorizing our subjects as positive and negative,” Jagust told Alzforum.

Will companies want to put in the extra time and money to join the Centiloid Project? “We are absolutely interested in participating,” said Gill Farrar of GE Healthcare Ltd., Buckinghamshire, U.K., the maker of flutemetamol. "A meta-analysis is bound to happen in the next few years when there are dozens of papers on amyloid PET imaging available. The Centiloid Project would allow researchers to normalize all those tracers into one space." Though the process of standardization could require some extra work, she said, it would allow [18F] flutemetamol to be included in that mix of comparable tracers.

Some researchers suggested there may be a few bumps along the way. “The Centiloid Project is a fabulous idea and a great initiative for the field,” said Clifford Jack, Mayo Clinic, Rochester, Minnesota. But he anticipates a complication. The field is still struggling with whether and how to use partial volume correction in amyloid PET. The process adjusts signal values depending on the estimated proportion of brain versus cerebrospinal fluid in each voxel. “There’s another layer of computational steps that have to be set in order,” said Jack. “You can’t really standardize reporting of amyloid PET data without standardizing methods for partial volume correction.”

Jagust agreed that partial volume correction, along with other sources of variation such as scanner resolution, would probably be an issue to deal with. “We are trying to tackle one thing at a time,” he told Alzforum. “This is a first pass that may get us 70-80 percent of the way there, and then we can tweak the process later.”—Gwyneth Dickey Zakaib.

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

No Available References

HAI—Aβ: First in Alzheimer’s Cascade, or Just Another Player?

06 Feb 2013

Scientists worldwide now perform amyloid imaging on scores of research participants—from cognitively normal to demented—to figure out how Aβ buildup relates to other markers of neurodegeneration. Their findings are causing a small minority of scientists to question the amyloid cascade hypothesis anew. Does Aβ actually jumpstart a cascade that leads to neurodegeneration, or does it simply join a host of other toxic factors in wreaking havoc on the nervous system? At the 7th Human Amyloid Imaging Conference held 16-18 January in Miami, Florida, scientists presented some new data that support the latter view. They reported that other markers of neurodegeneration often precede evidence of Aβ plaques.

“AD-related neurodegeneration is probably a little more complicated than we thought it would be,” said Beth Mormino, a postdoctoral fellow from the lab of Reisa Sperling, Brigham and Women's Hospital, Boston, Massachusetts. “Not everything seems to be downstream of Aβ,” she said.

Mormino knew that as the brain ages, Aβ accumulates, the hippocampus shrinks, and episodic memory becomes worse. She wanted to know how those three things relate to each other in cognitively normal people. Does Aβ build up first? Mormino compared cross-sectional positron emission tomography (PET) scans using Pittsburgh compound B (PIB) with magnetic resonance imaging (MRI) analysis from 117 cognitively normal people, around age 73, from the Harvard Aging Brain Study. Smaller hippocampi tracked with advancing age better than did PIB status, suggesting age-related atrophy of the hippocampus can occur irrespective of amyloid accumulation. However, episodic memory had begun to fail only in those with evidence of brain amyloid. The results imply that amyloid weakens memory more than do other factors that contribute to hippocampal loss, Mormino suggested. Perhaps Aβ speeds the shrinking process or attacks a specific part of the hippocampus, she said. Alternatively, separate processes may attack the hippocampus all at once, and only when amyloid is also unleashed does memory suffer, she proposed. In any case, she proposed that Aβ is not the instigating factor in hippocampal volume loss. It is known that tau tangles accumulate in the hippocampus with age (Price and Morris, 1999), but Mormino was unable to assess the role of tau pathology in this mix of factors because tau tracers are not available just yet.

Miranka Wirth, from Bill Jagust’s lab at the University of California, Berkeley, found similar results in 72 cognitively normal people from the Berkeley Aging Cohort (BAC). Reduced hippocampal volume, impaired glucose metabolism, and thinner cortices all correlated with poorer cognitive function, regardless of PIB status. “We wouldn’t expect that based on the AD biomarker model proposed by Cliff Jack (see Jack et al., 2010, and Jack et al., 2013),” said Wirth. That model proposed a specific order of AD biomarker change, beginning with Aβ and ending with clinical decline. “We thought AD-related neurodegeneration would start with Aβ accumulation.” Aβ did seem to exert some influence, however. The relationship between the other biomarkers and cognition was stronger in those that bound more PIB. It implies that Aβ is not required to develop neurodegeneration, but aggravates existing neuronal trouble in cognitively normal older adults, Wirth told Alzforum.

Does Aβ mediate the relationship between cerebrovascular risk factors and gray matter demise in the same way? To find out, Sylvia Villeneuve, also from the Jagust lab, measured cortical thickness, hippocampal volume, and brain amyloid in 67 people from the University of Southern California Aging Brain Study. Volunteers were either cognitively healthy or had MCI, but all were at elevated risk for vascular disease. In both groups, lower HDL cholesterol (the good kind) and greater vascular burden (a higher number of risk factors, such as smoking, hypertension, diabetes, and cholesterol) correlated with thinner cortices. Low HDL cholesterol also associated with smaller hippocampi. In people with brain amyloid, those relationships were more robust, suggesting it worsened, but did not cause, the deterioration of gray matter. Thicker cortices seemed to bolster cognition against amyloid’s negative effects. “It suggests if you have a super thick cortex, amyloid will have less impact on cognition,” said Villeneuve.

While most of the talks focused on Aβ’s damage to gray matter, Kristen Kennedy, University of Texas at Dallas, looked at Aβ’s effect on white matter. Previous studies reported that human white matter connectivity degrades with age (see Kennedy and Raz, 2009), and that Aβ deposition further injures white matter tracts in mice (see Song et al., 2004). Kennedy thought amyloid might do the same in humans.

Diffusion tensor imaging (DTI) and florbetapir PET images supported that idea. In 141 healthy adults, aged 30-89, from the Dallas Lifespan Brain Study, more Aβ plaque in select regions correlated with poorer white matter integrity. For instance, amyloid in the anterior cingulate associated with damage to the nearby uncinate fasciculus (see image below). The researchers believe the DTI losses were mostly due to damaged myelin. “This study shows that Aβ is bad for connectivity,” Kennedy told Alzforum. “That suggests the peptide exerts some of its negative effects by limiting cross-talk and passage of information throughout the brain.”

Aβ and White Matter
Plaque in the anterior cingulate (light blue) leads to myelin breakdown nearby in the uncinate fasciculus. Image courtesy of Kristen Kennedy, University of Texas at Dallas

Taken together, the results present a picture that deviates slightly from the accepted amyloid cascade model. Aβ could be a partner in crime, rather than the singular mastermind behind neuron damage, said Wirth. “We all show that neurodegenerative patterns can be caused by many factors, including vascular risk, aging, and white matter damage,” she told Alzforum. “Those factors include Aβ, but it’s probably not the most prominent factor, at least in cognitively normal older subjects,” she added.

Experts batted these ideas around during discussion. “How much of our speculation about which comes first—neurodegeneration or amyloid, could be considered hot air because we’re measuring fibrillar, not soluble amyloid?” asked one commentator. That is an open question, said Victor Villemagne, University of Melbourne, Australia. “We know people have Aβ oligomers before plaque,” he said. (New Aβ oligomer ELISAs are detecting high amounts in brain tissue; see ARF related news story). Even if in-vivo imaging of those smaller aggregates is not yet possible, “we know that misprocessing of APP leads directly to Alzheimer’s disease,” so there must be some causative role for Aβ, Villemagne added.

Cliff Jack, Mayo Clinic, Rochester, Minnesota, partly agreed. “Genetic evidence is incontrovertible that an independent "Aβ-opathy" can induce or accelerate tauopathy—the reverse isn’t true,” he said. At the same time, he continued, “People are coming to this common conceptual idea of neurodegeneration independent of Aβ, including those of us at the Mayo Clinic,” he said (see ARF related news story). This kind of neurodegeneration could be tau mediated, unrelated to tau (from such factors as vascular disease), or both, he told Alzforum.

“I think this points out that we don’t really understand what aging is—it’s not as simple as just Aβ and tau,” Jagust said. Neurodegeneration happens in people without amyloid, so there must be something fundamental to systems that make them vulnerable to a whole panoply of factors, he said. “Amyloid is one, but not the only piece of the puzzle.”
Others wondered why the debate even mattered. “I think we should stop arguing about whether it’s Aβ or independent neurodegeneration—it’s both,” said Sperling. “We should find ways to work on the different processes therapeutically—we’ll probably need both Aβ and non-Aβ approaches to fix this disease.” Villemagne concurred, suggesting to Alzforum that neurodegeneration can probably arise three ways—due to Aβ alone, as a result of the peptide plus other factors, and independent of Aβ accumulation.—Gwyneth Dickey Zakaib.

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

Paper Citations

Price JL, Morris JC. Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease. Ann Neurol. 1999 Mar;45(3):358-68. PubMed.
Jack CR, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010 Jan;9(1):119-28. PubMed.
Jack CR, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P, Wiste HJ, Weigand SD, Lesnick TG, Pankratz VS, Donohue MC, Trojanowski JQ. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013 Feb;12(2):207-16. PubMed.
Kennedy KM, Raz N. Aging white matter and cognition: differential effects of regional variations in diffusion properties on memory, executive functions, and speed. Neuropsychologia. 2009 Feb;47(3):916-27. PubMed.
Song SK, Kim JH, Lin SJ, Brendza RP, Holtzman DM. Diffusion tensor imaging detects age-dependent white matter changes in a transgenic mouse model with amyloid deposition. Neurobiol Dis. 2004 Apr;15(3):640-7. PubMed.

Solanezumab Selected for Alzheimer’s A4 Prevention Trial

References

News Citations

Other Citations

Further Reading

News

HAI—Spotlight on Tau Tracers at Human Amyloid Imaging Meeting

References

News Citations

Paper Citations

Other Citations

Further Reading

Papers

News

HAI—Amyloid Imaging in the Clinic: New Guidelines and Data

Comments

Make a Comment

References

News Citations

Paper Citations

Other Citations

External Citations

Further Reading

Papers

News

HAI—Sharper Curves: Revamping a Biomarker Staging Model

Comments

Make a Comment

References

Webinar Citations

News Citations

Paper Citations

Other Citations

Further Reading

Papers

News

Webinars

HAI—Standardizing Amyloid PET: The Centiloid Project

Comments

Make a Comment

References

Further Reading

HAI—Aβ: First in Alzheimer’s Cascade, or Just Another Player?

Comments

Make a Comment

References

News Citations

Paper Citations

Other Citations

Further Reading

Papers

News

Webinars