Scientists are becoming more nuanced in how they use amyloid scans—not just to detect the presence of Alzheimer’s pathology, but also to pinpoint disease stage. At this year’s Alzheimer’s Association International Conference, held July 13–18 in Los Angeles, researchers led by Niklas Mattsson and Oskar Hansson at Lund University, Sweden, debuted a new staging scheme. Using longitudinal data from 741 participants in the Alzheimer’s Disease Neuroimaging Initiative, including cerebrospinal fluid Aβ42 as well as PET, the researchers defined four stages of amyloid accumulation. People at stage zero had a low risk of developing plaques, but those at higher stages were likely to move to the next-higher stage within a few years, suggesting the system reflects disease progression.
- Using longitudinal PET and CSF, scientists define four stages of amyloid accumulation.
- In stage 1, plaques form in the precuneus and posterior cingulate. Global PET scans turn positive at stage 2 or 3.
- The scheme could help identify people with very early AD for research.
Their staging system differs notably from previous models derived from cross-sectional imaging and neuropathology data. It flags amyloid accumulation in the precuneus and posterior cingulate as the earliest signs of AD, long before the brain’s overall amyloid burden becomes positive on a PET scan. “If you wanted to run a very early AD trial, you could use this staging system to select participants, rather than a global amyloid cut point,” Mattsson told Alzforum.
Others agree. “This elegant approach provides critical information on how we can discern individuals in the amyloid-negative spectrum who are likely to progress to preclinical Alzheimer’s disease,” Heidi Jacobs at Massachusetts General Hospital, Boston, wrote to Alzforum (full comment below). Arthur Toga at the University of Southern California, Los Angeles, noted, “The approach could have significant utility for tracking disease progression in a clinical setting.” Mattsson and colleagues described the scheme in the July 17 JAMA Neurology.
Amyloid Staging. Longitudinal PET scans reveal regions of early (green), intermediate (blue), and late (red) amyloid accumulation. [Courtesy of Mattsson et al., ©2018 American Medical Association.]
To develop their scheme, the Lund group made use of their previous finding that CSF Aβ42 drops up to 10 years before an amyloid PET scan crosses the threshold for global positivity (Aug 2016 conference news; Palmqvist et al., 2016). These data suggested that CSF-positive people were accumulating amyloid in select brain regions. The researchers wondered if they could identify those regions of early buildup. In their initial study, CSF-positive yet whole-brain PET-negative ADNI participants indeed deposited amyloid only in specific regions, including the precuneus and posterior cingulate (Nov 2017 news).
Mattsson and colleagues extended those findings to develop a longitudinal staging system. First, they selected 641 ADNI participants who had CSF data and at least two florbetapir PET scans, and stratified them by amyloid positivity. Among this group, 288 were negative on both CSF and PET and were classified as non-accumulators; 69 were CSF-positive but PET-negative and were deemed early-stage accumulators; and 274 were positive on both—the late-stage accumulators. Ten discordant people were CSF-negative and PET-positive.
The researchers then examined longitudinal amyloid scans from the 69 early stage accumulators. They found six brain regions—the precuneus, posterior and isthmus cingulate, insula, and medial and lateral orbitofrontal cortices—where amyloid load was increasing compared to non-accumulators. Amyloid positivity in these regions, which form part of the brain’s default mode network (DMN), defined stage 1. Next, accumulation of amyloid in a large number of regions, including the parahippocampus, medial and inferior temporal lobes, inferior parietal lobe, and superior parietal, temporal, and frontal regions, marked stage 2. Most of these regions are known sites of pathology in early AD. Finally, in late-stage accumulators, amyloid piled up in precentral, postcentral, paracentral, lingual, and pericalcarine cortices. Amyloid in these regions defined stage 3 (see image above).
How did the ADNI cohort break down across these stages? For this, the researchers included another 100 ADNI volunteers who lacked CSF data but had at least two florbetapir scans, for a total of 741 participants. The full cohort comprised 304 cognitively healthy controls, 384 people with MCI, and 53 with AD dementia. Ninety-eight percent of participants fell cleanly into one of the four stages. More than half were at stage zero, three percent at stage 1, 11 percent at stage 2, and 30 percent at stage 3. The stages roughly corresponded to cognitive status, with 70 percent of controls at stage zero and 80 percent of AD patients at stage 3. Still, there were plenty of exceptions: 16 percent of controls were at stage 3, and 17 percent of AD patients were at stage zero.
The authors repeated the analysis with data from the Swedish BioFINDER cohort. This longitudinal biomarker study uses flutemetamol rather than florbetapir for amyloid scans. In a cross-sectional set of 306 healthy controls and 168 people with MCI, 98 percent of them fit unambiguously into one of the four stages. The percentages for each stage and cognitive group were similar to those in ADNI.
Notably, the staging patterns closely matched those seen in longitudinal PET scans from the Dominantly Inherited Alzheimer Network, where deposition occurred first in the precuneus, then in the posterior cingulate and medial orbitofrontal cortex (Feb 2018 news).
They also agree with other longitudinal PET data presented at AAIC. Michelle Farrell of Massachusetts General Hospital reported that among 265 cognitively healthy adults in the Harvard Aging Brain Study who had repeated PET scans, amyloid accumulated earliest in the precuneus, isthmus and anterior cingulate cortex, medial orbitofronal cortex, and middle and inferior temporal lobe. Likewise, Gemma Salvadó of Barcelonaβeta Brain Research Center in Barcelona, Spain, showed congruent data from the European Amyloid Imaging to Prevent Alzheimer’s Disease study. Her team developed a staging model based on PET data from 224 cognitively healthy participants in Barcelonaβeta’s Alzheimer and Families (ALFA) project, then applied it to 870 PET images from the ALFA, ADNI, ABIDE, and EMIF-AD cohorts. The first areas to accumulate plaques were the precuneus, anterior cingulate cortex, and orbitofrontal cortex.
On the other hand, the Lund group’s findings only partially overlap with cross-sectional staging schemes, including classic neuropathology data and a recent PET amyloid study from Michel Grothe and colleagues at the German Center for Neurodegenerative Diseases in Rostock (Braak and Braak, 1991; Oct 2017 news). Grothe detected the earliest amyloid deposition in neocortical regions such as the temporal lobe, parietal operculum, and anterior cingulate, but did not pick out precuneus and posterior cingulate as early sites.
“The strength of the Mattsson et al. approach is that they utilize longitudinal PET data, which can give a more dynamic picture than static states do,” Rachel Buckley at MGH wrote to Alzforum (full comment below).
Is this new staging scheme biologically meaningful? Several pieces of evidence argue that it is, Mattsson said. For one thing, the amyloid PET stages correlated with other biomarkers. People at stage 1 or higher had low CSF Aβ42 and high phospho-tau compared with controls. In those at stage 2 or higher, CSF total tau ramped up, while at stage 3 brain atrophy did. Cognitive decline began in stage 2.
Another indication that the staging system is valid is that it predicted progression. People at stage zero had a 15 percent risk of progressing to a higher stage over an average of four years, while those in stage 1 ran a 71 percent risk and stage 2, a 53 percent risk. This fast rate of progression may explain why relatively few people are found in stage 1 or 2 at any given time, the authors speculated.
A final piece of evidence is that the combined brain regions that define each stage had distinct patterns of gene expression. Using data from the Allen Human Brain Atlas, the researchers found classes of genes that were differentially expressed among the regions. They were linked to voltage-gated ion channels, neuropeptide and glutamate signaling, lipid transport, and axon guidance. The data hinted at biological factors that may underlie the selective vulnerability to amyloid accumulation of brain regions associated with different stages, Hansson said.
“The relationship to regional gene expression areas was interesting, as this may hint at the ‘why’ [of amyloid accumulation] as well as the ‘where’,” Toga wrote to Alzforum.—Madolyn Bowman Rogers
- Refining Models of Amyloid Accumulation in Alzheimer’s Disease
- Daydreaming Network Serves as Ground Zero for Aβ Deposition
- Aβ, Then Metabolism, Then Atrophy: In Familial AD, Cascade is Definitive
- PET Staging Charts Gradual Course of Amyloid Deposition in Alzheimer’s
- Palmqvist S, Mattsson N, Hansson O, Alzheimer’s Disease Neuroimaging Initiative. Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography. Brain. 2016 Apr;139(Pt 4):1226-36. Epub 2016 Mar 2 PubMed.
- Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-59. PubMed.
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