Are New Cognitive Tests Ready For Preclinical Trials?
With Alzheimer’s trials starting to recruit cognitively normal and mildly impaired people at risk for Alzheimer’s dementia, researchers need tests that can detect subtle cognitive changes. Many groups are developing cognitive composites that might fit the bill. These composites generally combine those individual tests from larger established batteries that have proven most sensitive to early cognitive decline in longitudinal studies of the preclinical phase (see May 2012 news story; Nov 2012 news story; and April 2013 Webinar). Several composite measures are in the early stages of validation. At the Sixth Clinical Trials Conference on Alzheimer’s Disease (CTAD) held November 14-16 in San Diego, Dorene Rentz at Massachusetts General Hospital, Boston, described two such measures. One is in a traditional pencil-and-paper format, the other a computerized battery. Individual tests were previously shown to capture the first hints of cognitive decline and correlate with disease biomarkers. At CTAD, Rentz reported that the composites appear to be reliable. Not only do they yield similar results when taken multiple times by a given person, but scores on the computerized composite also correlate well with the paper version. The findings support the use of these measures in prevention trials, and suggest that computerized testing could replace paper versions, Rentz said.
The paper composite, formally called the Alzheimer’s Disease Cooperative Study-Preclinical Alzheimer’s Cognitive Composite (ADCS-PACC), will be the primary outcome measure in the upcoming Anti-Amyloid Treatment in Asymptomatic AD (A4) Trial. This study will enroll cognitively normal older adults with evidence of brain amyloid. The ADCS-PACC includes tests that measure learning of word lists, paragraph recall, timed executive function, and global cognition. These items were shown to track cognitive decline in the normal controls in several large longitudinal cohorts such as the Alzheimer’s Disease Neuroimaging Initiative and the Australian Imaging, Biomarkers, and Lifestyle Study. One component of the composite, the Free and Cued Selective Reminding Test, showed the most sensitivity for predicting progression to mild cognitive impairment (MCI) out of a wide range of tests evaluated in a four-year observational study (see Ferris et al., 2006; Mar 2007 Webinar; Dubois et al., 2010).
A4 study participants will take two alternating versions of the ADCS-PACC to avoid the “practice effect,” by which people often improve on repeated testing because they learn the test questions. Rentz and colleagues administered these versions one to two weeks apart to 52 cognitively normal volunteers with an average age of 71. Participants’ two scores showed a correlation of 0.94 (1.0 would be a perfect match), demonstrating that the versions are equivalent, Rentz reported.
In addition, the A4 study will deploy a computerized cognitive composite (C3) on an iPad as an exploratory outcome measure. This battery includes memory tasks such as the Face Name Associative Memory Exam, which asks participants to remember what name goes with a face. Cognitively normal people with brain amyloid perform worse on this task than do those without amyloid (see Rentz et al., 2011). Other memory measures in the composite also correlate with amyloid deposits and functional MRI changes. Some of these come from the Cogstate computerized test battery; they measure reaction time, attention, and processing speed. The researchers are developing numerous versions of the C3 so that participants will see different test questions each time they take it. So far, Rentz and colleagues have validated six versions, which have an overall test-retest coefficient of reliability of 0.83 (researchers consider scores above 0.7 to be good). C3 scores had a 0.75 correlation with those from ADCS-PACC.
The findings validate these tests for use in preclinical populations, Rentz claimed. Paul Maruff at the University of Melbourne, Australia, agreed. “The individual measures in the composite have all been shown to be sensitive to amyloid-related cognitive impairment in healthy older individuals and in MCI,” he wrote to Alzforum. “I think they are ready for use in clinical trials in this population.”
The potential of computerized tests to replace paper versions particularly interests Rentz. Tablet-based tests would have several advantages, she noted. Potentially, trial participants could take the tests at home at regular intervals. This would allow researchers to better track cognitive change over time while reducing clinic visits and keeping down costs. In addition, many of the computer tasks, such as remembering faces and names, are similar to real-world tasks and thus relevant to people’s lives, Rentz said.
Other current prevention trials, such as the ones being run by the Dominantly Inherited Alzheimer Network and the Alzheimer’s Prevention Initiative, use slightly different composites that nonetheless test the same cognitive domains. All the composites also have some elements in common, which will help researchers compare results across trials. Data from these first prevention trials may show which tests are the most sensitive for tracking decline or stability, Rentz said. Maruff sees some advantage to having multiple composites. “Different groups may develop different tests, but ultimately the tests all reflect the same cognitive and clinical characteristics of the disease. It will be reassuring to the public if we can detect drug-related improvement on a variety of appropriate outcome measures, including different composites,” he wrote.—Madolyn Bowman Rogers.
- DIAN Grows, Gets Ready for Therapeutic Trials
- CTAD: Adaptive Antibody Trial to Try Bayesian Statistics
- New Frontier: Developing Outcome Measures for Pre-dementia Trials
- ADCS Prevention Instrument Project
- Ferris SH, Aisen PS, Cummings J, Galasko D, Salmon DP, Schneider L, Sano M, Whitehouse PJ, Edland S, Thal LJ, . ADCS Prevention Instrument Project: overview and initial results. Alzheimer Dis Assoc Disord. 2006 Oct-Dec;20(4 Suppl 3):S109-23. PubMed.
- Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, Delacourte A, Frisoni G, Fox NC, Galasko D, Gauthier S, Hampel H, Jicha GA, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Sarazin M, de Souza LC, Stern Y, Visser PJ, Scheltens P. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol. 2010 Nov;9(11):1118-27. PubMed.
- Rentz DM, Amariglio RE, Becker JA, Frey M, Olson LE, Frishe K, Carmasin J, Maye JE, Johnson KA, Sperling RA. Face-name associative memory performance is related to amyloid burden in normal elderly. Neuropsychologia. 2011 Jul;49(9):2776-83. PubMed.
- As AD Trials Come of Age, Will Cognitive Tests Follow Suit?
- FDA Invites Comment on Drug Testing Guidance for Early AD
- CTAD: Adaptive Antibody Trial to Try Bayesian Statistics
- DIAN Grows, Gets Ready for Therapeutic Trials
- Anti-Amyloid Treatment in Asymptomatic AD Trial
- Detecting Familial AD Ever Earlier: Subtle Memory Signs 15 Years Before
Do Tau Tracers Track Cognitive Decline in Disease?
Pathology studies show that tau tangles, unlike amyloid, track closely with the cognitive decline of Alzheimer’s disease. This has raised hope that the tau PET tracers being developed will allow researchers to stage disease, and early results do seem to bear this out, as tracer uptake correlates with the degree of cognitive impairment. But does this relationship hold true even at preclinical stages? At the Sixth Clinical Trials Conference on Alzheimer’s Disease (CTAD) held November 14–16 in San Diego, Keith Johnson at Massachusetts General Hospital, Boston, presented data showing that uptake of Eli Lilly and Company’s tau tracer T807 in the hippocampus correlated with subtle memory problems in a small number of cognitively normal elderly people. If this finding holds up in larger studies, it would imply that tau imaging could serve as an early disease biomarker.
In the same session, Mark Mintun at the Lilly subsidiary Avid Radiopharmaceuticals confirmed previous reports that AD patients with more severe dementia retain more T807 in their brains. Mintun also added to data indicating that which brain regions take up the tracer matches the typical pattern of tau deposition in AD. However, some findings did not fit the mold. Some people showed much higher binding than their level of impairment would predict, he reported. It is unclear what causes this variability, or if it will complicate the use of tau imaging. Much work remains to be done before these tracers are ready for more widespread clinical use, including confirming tau binding through autopsy studies, Mintun noted.
“It’s an exciting area,” said Ron Petersen at the Mayo Clinic in Rochester, Minnesota, who heard the talks. He plans to start using T807 in research studies in his clinic. At the same time, Petersen cautioned that researchers need more information about these agents. “We need to know about the specificity of the binding for certain isoforms or conformations of tau,” he told Alzforum. For example, in early studies the three existing classes of tau tracer appear specific for different tauopathies, suggesting they bind distinct forms of the protein (see Jan 2013 news story; Sep 2013 news story).
Johnson and colleagues wanted to investigate the relationship between AD pathology and the earliest signs of cognitive impairment. The researchers used T807 and Pittsburgh Compound B (PiB), which binds amyloid deposits, to scan the brains of 12 cognitively normal people whose average age was 73. Participants also took a battery of standard cognitive tests. In this cohort, the hippocampus took up the highest levels of T807, consistent with neuropathological findings that neurofibrillary tangles accumulate in this region even during normal aging. Those with the most hippocampal tau scored lowest on a test of delayed recall, the Logical Memory IIa test. These people also had the most amyloid deposits throughout the cortex, but amyloid by itself correlated only weakly with memory scores, as had been found previously (see, e.g., Dec 2008 news story; Rowe et al., 2010).
While these findings hint that tau uptake might serve as a biomarker in preclinical populations, Johnson emphasized that he is still analyzing data and that it is too early to draw firm conclusions. In ongoing work, he is testing the hypothesis that more advanced levels of impairment are associated with the spread of tau from the hippocampus into the neocortex, as described in Heiko Braak’s foundational pathology work. Johnson showed data indicating that the strength of tau binding in these areas differentiates normal elderly controls from people with mild cognitive impairment (MCI) and dementia, while uptake in the hippocampus alone does not.
Mintun also studies T807 retention in people with MCI and AD. At last July’s Alzheimer’s Association International Conference in Boston, he presented data from the first 10 people scanned with this tracer (see Jul 2013 news story). At CTAD, Mintun added results from 12 more people. The total group includes young and old controls as well as five people with MCI and nine with AD. People at more severe disease stages had dramatically higher uptake of tau tracer, which correlated with lower scores on the Mini Mental State Exam, Mintun said. The pattern matched Braak staging, with areas such as the somatosensory and occipital cortices, which are known to be spared until late in the disease, showing little retention. The new data “increases our confidence that our tracer is imaging tau deposits,” Mintun told Alzforum.
One surprise emerged from the 12 additional volunteers: Some people showed a much stronger signal than average, although their regional uptake pattern was the same. In discussions at the conference, attendees speculated that these individuals might harbor a genetic susceptibility to misfold tau. “That will be a very interesting topic for further research,” Mintun noted. One important question is whether people with abnormally high tracer retention have more accumulated tau, or simply bind the tracer more strongly, which could make it difficult to interpret tau scans. In microglial imaging studies, for example, a genetic polymorphism that increases affinity of the TPSO receptor for ligands helped scuttle development of TPSO-based glial tracers (see Apr 2012 news story).
Mintun plans to conduct longitudinal studies of people at different disease stages to see if changes in tau uptake track disease progression. In addition, he will investigate how tracer uptake correlates with other biomarkers such as tau in cerebrospinal fluid. Such data would help to validate tau tracers for use as biomarkers in clinical trials.—Madolyn Bowman Rogers.
- HAI—Spotlight on Tau Tracers at Human Amyloid Imaging Meeting
- Tau Tracer May Light Up All Tauopathies
- DC: Amyloid-Laden Brains—What Do They Mean for Healthy Seniors?
- Imaging Inflammation: Can Glial PET Tracers Make a Mark?
- Rowe CC, Ellis KA, Rimajova M, Bourgeat P, Pike KE, Jones G, Fripp J, Tochon-Danguy H, Morandeau L, O'Keefe G, Price R, Raniga P, Robins P, Acosta O, Lenzo N, Szoeke C, Salvado O, Head R, Martins R, Masters CL, Ames D, Villemagne VL. Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol Aging. 2010 Aug;31(8):1275-83. PubMed.
Growth Factor Therapy: Safe in Phase 1, Awaiting Efficacy Data
The later stages of Alzheimer’s disease are characterized by massive loss of neurons, and researchers are looking at ways to boost molecular support systems in the hope of preserving some of those cells. At the Sixth Clinical Trials Conference on Alzheimer’s Disease (CTAD) held November 14–16 in San Diego, Raymond Bartus, who runs his own biotech consulting firm, RTBioconsultants, described his earlier work for San Diego-based biotechnology company Ceregene to develop nerve growth factor (NGF) as a therapy. Ceregene was acquired by Sangamo BioSciences Inc., Richmond, California, in August 2013. Bartus and colleagues had engineered an adenovirus to deliver NGF to vulnerable cholinergic neurons. At CTAD, he presented formal results of the Phase 1 trial of the gene therapy CERE-110. The treatment appeared safe and showed some hints of stabilizing brain metabolism. A Phase 2 study started in 2009 and is still ongoing.
Meanwhile, other groups are taking a different approach to modulate trophic signaling. Frank Longo and colleagues at Stanford University, Palo Alto, California, are developing small molecules that activate expression of specific growth factor receptors. These ligands have more targeted effects than native growth factors do, Longo told Alzforum. In the November 27 Journal of Neuroscience, Longo and colleagues report that one such molecule shows promise in mice that model Huntington’s disease. Another is currently in Phase 1 for Alzheimer’s disease, but not listed in clinicaltrials.gov.
Bartus and colleagues focused on cholinergic neurons because they are known to play a key role in learning and memory, degenerate in AD, and are the target of cholinesterase-inhibitor drugs approved for AD. The researchers injected CERE-110 into the nucleus basalis of Meynert, the deep-brain structure where cholinergic neurons reside (see Jan 2013 news story). Neurons then take up the DNA and begin to produce and secrete the protein. In the Phase 1, dose-ranging study, 10 AD patients each received a single injection of CERE-110, which is meant to last for the lifetime of the patient, Bartus told Alzforum. The researchers have followed the participants for nearly three years. During this time there were no adverse events that were believed to be due to the drug. Three of the patients died from unrelated causes and donated their brains for autopsy. In these samples, the researchers confirmed that the added gene was producing active protein. One indication of this was that cholinergic neurons in the vicinity of the injection sites plumped up by about 20 percent, which is a classic measure of NGF bioactivity.
There were signs the treatment preserved neuronal health, Bartus said. In AD patients, brain glucose metabolism as measured by fluorodeoxyglucose PET progressively decreases. In the Phase 1 cohort, it stayed stable over the course of the study but because of the small sample size, the researchers cannot be certain this finding is significant. Cognitive test scores declined over the two years in the treated patients, and the trial was not powered to show slowing in the rate of that decline. Bartus hopes that the ongoing placebo-controlled Phase 2 study, which is run through the Alzheimer’s Disease Cooperative Study, will answer these questions. This study enrolled 49 mild to moderate AD patients, about half of whom received CERE-110, the other half sham surgery. The trial will conclude in 2015.
One advantage of gene therapy is that it can be delivered to a targeted area of the brain, which may lessen side effects, Longo told Alzforum. On the downside, it involves surgery, and there is no practical way to modulate the dose should it become necessary later. Like conventional drugs, Longo’s small molecules can be taken orally and stopped at any time. These compounds activate only one receptor and have distinct effects from the native protein ligands. They are being developed through the biotech company PharmatrophiX, Raleigh, North Carolina, which Longo founded (see Feb 2010 news story; Apr 2010 news story).
One compound, LM11A-31, activates the p75 neurotrophin receptor. This receptor modulates binding of NGF and other neurotrophins to tyrosine kinase receptors on neurons and can also signal independently. LM11A-31 is currently in Phase 1 safety and dosage testing in young and old healthy adults. In animal models, the molecule shows potential to treat spinal cord and traumatic brain injury as well, Longo said. The Journal of Neuroscience paper describes another molecule, LM22A-4, which binds to the TrkB receptor that is normally activated by brain-derived neurotrophic factor (BDNF). First author Danielle Simmons found that in HD model mice, this agent preserved synapses in the striatum and improved some motor abilities. LM22A-4 also benefits mice that model other disorders, promoting recovery of movement after stroke, for example (see Han et al., 2012). The researchers are now developing chemical derivatives of this compound that better enter the brain, and hope to take one of these into the clinic, Longo said.—Madolyn Bowman Rogers
- Cut to the Chase: Therapies Go Directly to Central Nervous System
- Copper Mountain: Death and Trophin Receptors—New Insight, New Drugs?
- Research Brief: BDNF Data Speak Volumes, Offer Therapeutic Target
- Han J, Pollak J, Yang T, Siddiqui MR, Doyle KP, Taravosh-Lahn K, Cekanaviciute E, Han A, Goodman JZ, Jones B, Jing D, Massa SM, Longo FM, Buckwalter MS. Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke. Stroke. 2012 Jul;43(7):1918-24. PubMed.