Imaging technologies have transformed the study of neurodegenerative diseases by giving scientists a glimpse at what is happening inside the brains of living patients. At the 66th annual meeting of the American Academy of Neurology, held 26 April to 3 May in Philadelphia, researchers touted the potential of several positron emission tomography (PET) tracers to improve diagnoses. A tau tracer under development looks promising for characterizing several types of frontotemporal lobar degeneration (FTLD), while amyloid imaging distinguishes effectively between FTLD and Alzheimer’s disease in young dementia patients, speakers said. Meanwhile, fluorodeoxyglucose (FDG) PET was confirmed once again to reveal dampened brain metabolism in people who carry one or more ApoE4 alleles, the main genetic risk factor for sporadic AD, though surprisingly, this effect occurred in people young and old, with or without amyloid deposits.
“We are in a revolutionary era of neurodegenerative disease research,” Brad Dickerson Massachusetts General Hospital, Boston, told Alzforum. “[New imaging technologies] will completely change the way we approach these diseases.”
These days the biggest buzz surrounds the potential of tau tracers, since tau pathology marks numerous neurodegenerative diseases. Several companies are developing such tracers (see Jan 2013 conference story; Aug 2013 conference story; Sep 2013 news story). At AAN, Dickerson reported preliminary results from imaging with Eli Lilly and Company’s T807 in about 15 patients with various tauopathies. These included behavioral-variant FTLD, frontotemporal aphasias, and the movement disorder progressive supranuclear palsy (PSP).
In all cases, the brain regions that T807 lit up most strongly matched the regions with the greatest atrophy and hypometabolism in that particular disease, Dickerson said. That means these three major brain imaging modalities used in living patients are aligned. In behavioral-variant FTLD patients, the frontal, insular, and anterior temporal cortices gave the strongest T807 signal, whereas Broca’s aphasia patients bound the most tracer in the inferior frontal and middle temporal gyri. These patterns correspond to the areas of greatest degeneration in each disease. Moreover, they are distinct from the profile seen in Alzheimer’s, where T807 lights up temporal regions. The findings suggest that T807 binding reflects tau deposits, but final confirmation will have to come from postmortem studies, Dickerson said.
How early in disease might a tau signal appear? Dickerson described one cognitively healthy participant who carried the tau mutation P301L, which causes frontotemporal dementia. Although the man was at least 10 years away from his expected age of symptom onset, his T807 signal was mildly elevated in the same regions of the brain that light up in symptomatic patients. The results hint that tau tracers could help identify people at preclinical disease stages.
One concern emerged from the data. Only about 40 percent of clinically diagnosed FTLD cases are tauopathies; many others are characterized instead by TDP-43 deposits. Ideally, a tau tracer would allow scientists to distinguish between these proteins. However, in this study, a participant who carried a progranulin mutation, which causes TDP-43 pathology, had an elevated T807 signal. “That was a major surprise,” Dickerson told Alzforum. This raises the question of whether T807 might react non-specifically with TDP-43; alternatively, this patient might have concurrent tau pathology. In ongoing work, Dickerson is scanning more people with different predicted pathologies to try to nail down how specific the tracer is. Eventually, he will validate in-vivo findings against autopsy results.
Despite the questionable specificity, other researchers found these results exciting. “In patients with PSP and tau mutations, the data looks very promising,” said Gil Rabinovici at the University of California, San Francisco.
A patient clinically diagnosed with Alzheimer’s was negative for amyloid imaging (left scans), but positive by FDG PET (right scans). Postmortem pathology identified the disease as corticobasal degeneration. [Image courtesy of Gil Rabinovici.]
FTLD cases can be difficult to distinguish from early onset AD. Amyloid imaging may help clinicians make this distinction, Rabinovici said in his AAN talk. Currently, many clinicians use FDG PET for differential diagnosis, because insurers such as the Centers for Medicare and Medicaid Services (CMS) reimburse for this scan. By contrast, CMS does not yet cover clinical use of amyloid imaging (see Jul 2013 news story). Many researchers believe amyloid imaging would do a better job than FDG PET of distinguishing these diseases. Rather than compare patterns of glucose use, as FDG does, amyloid tracers detect a specific, defining pathology present in AD that is typically absent in FTD. Researchers are currently gathering evidence to try to persuade the CMS to change its stance (see Oct 2013 news story).
For his part, Rabinovici compares the diagnoses made after FDG and PIB amyloid scans in patients being treated at memory clinics. Previously, he reported that amyloid imaging was more reliable between different raters than FDG PET, as well as more sensitive and equally specific, in a cohort of about 100 patients (see Rabinovici et al., 2011). In response, CMS noted that this data was promising, but lacked autopsy confirmation. At AAN, Rabinovici reported autopsy results from the first 44 patients in this cohort. Twenty-eight turned out to have had FTLD, 12 AD, 3 mixed FTLD and AD, and one had had prion disease.
Amyloid imaging correctly identified all the amyloid and mixed-pathology patients as having AD, and ruled out the prion patient. In the FTLD group, however, four patients had neuritic plaques that showed up on PIB PET scans, resulting in an AD diagnosis. Pathologists judged that these plaques were unlikely to have contributed to dementia, and called the cases FTLD. This gave amyloid imaging a sensitivity of 100 percent and a specificity of about 90 percent for distinguishing AD from FTLD. By contrast, FDG reads misclassified several AD and FTLD cases, and had an overall sensitivity of about 86 percent and specificity of 79 percent. All numbers favored amyloid imaging, but the cohort was too small to show statistical significance. Nonetheless, Rabinovici said the data indicate that amyloid imaging is at least as good as FDG PET for distinguishing FTLD and AD.
“The data definitely support the reimbursement of amyloid imaging in the FTLD versus AD scenario,” Rabinovici told Alzforum. Misdiagnosis can be harmful, because AD medications such as cholinesterase inhibitors and memantine have been found to worsen outcomes for FTLD patients in clinical trials, Rabinovici noted. However, he stressed that amyloid scans should be interpreted by experts, and only after a comprehensive clinical evaluation has been conducted. “Scans can be misinterpreted. A positive amyloid scan doesn’t rule out FTD, for example. I don’t think this technique is ready for widespread use in primary care,” he said.
While FDG PET may become passé for differential diagnosis of FTD versus AD, this technique has many other applications. At AAN, David Knopman at the Mayo Clinic in Rochester, Minnesota, reported using it to study metabolic changes in more than 800 cognitively normal adults in the Mayo Clinic Study of Aging. His data were published March 11 in Neurobiology of Aging. He found a modest decline with age in most cortical and sub-cortical brain regions. Previous studies had conflicted on this point, with some showing no age-related changes. The current study is much larger than most prior studies and used more rigorous methods, making the results more definitive, Knopman claimed.
Knopman also wanted to know how an ApoE4 allele would affect metabolism. The 209 study participants who carried at least one ApoE4 allele had lower glucose uptake than non-carriers did in the posterior cingulate, precuneus, lateral parietal, and inferior temporal regions. Intriguingly, these regions typically atrophy in AD. Knopman’s data confirm previous FDG PET findings in ApoE4 homozygotes by Eric Reiman and colleagues at Banner Alzheimer’s Institute, Phoenix, and others (see, e.g., Reiman et al., 1996; Reiman et al., 2004; Lehmann et al., 2014). The new data also extends earlier FDG PET observations on ApoE. In particular, it shows that age has no bearing. The ApoE4 effect looms as large in 30-something adults as in people in their 70s. Knopman said this surprised him. The magnitude of the drop in metabolism seen in carriers is about one-fourth of that seen in AD patients versus age-matched controls.
Notably, glucose metabolism in ApoE4 carriers was lower regardless of whether people had amyloid in their brain, agreeing with some previous data (see Dec 2012 news story). This suggests that ApoE4 may contribute to AD through some other mechanism, Knopman said. In future work, Knopman will compare FDG scans with both amyloid and tau imaging at multiple age ranges to try to gain more insight into the pathological mechanisms.
Other researchers found the results intriguing. Rabinovici wrote to Alzforum, “While ApoE4 is clearly a risk factor for amyloid aggregation, there is increasing evidence that ApoE4 also increases the risk for AD via a multitude of Aβ-independent pathways, some of which traverse the entire lifespan (see excellent review by Huang and Mucke, 2012, and interesting model proposed by Jagust and Mormino, 2011). This has major implications as the field develops strategies for AD treatment and prevention in E4 positive individuals.” (See full comment below.)—Madolyn Bowman Rogers
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