Miami: When Does Amyloid Deposition Start in Familial Alzheimer’s?

Series - Human Amyloid Imaging 2012:

At the Human Amyloid Imaging Conference, held 12-13 January 2012, three speakers presented data on brain amyloid deposition in presymptomatic carriers of deterministic Alzheimer's disease mutations starting as early as their young twenties. Two datasets came from large cohorts and were similar, while one came from a small group that appears to represent an exception to the rule.

Adam Fleisher of the Banner Alzheimer’s Institute in Phoenix, Arizona, presented florbetapir pilot data of the Alzheimer’s Prevention Initiative Biomarker Project. The API-BIO aims to characterize, compare, and order the emergence of the currently available major biomarkers of AD pathogenesis in Colombian families who carry the E280A Paisa mutation in presenilin-1. This population represents the world’s largest known kindred of any AD mutation, and API is the largest study to date of autosomal-dominant AD. In preparation for multiple future clinical trials, the project is tracing back at what age each biomarker candidate—amyloid imaging, FDG-PET, MRI, fluid markers, cognition—first diverges between a carrier and their non-carrying siblings. At HAI, Fleisher presented initial data from September to December of 2011, when API colleagues in Colombia and Phoenix worked furiously to enable five successive groups of a total of 50 study participants and their relatives to travel from Medellin to Bogota to obtain visas, and then through Miami on to Phoenix for brain imaging. “For many of them, it was the first visit to Bogota, not to mention their first air travel and trip to the U.S.,” said Fleisher.

Each group stayed in Phoenix for several days before returning to Colombia. There they received a florbetapir and an FDG-PET scan. Banner staff, Avid Radiopharmaceuticals, and Cardinal Health made radioligand and scanners available through the weekend, while API staff supported the study volunteers during their stay, Fleisher said. Natalia Agudelo, a young Colombian woman who had been featured in a New York Times story, and whose father passed away of AD last year, became the first Colombian to receive a scan with florbetapir, the tracer used in this study.

The 50 participants were 18 to 60 years of age with a mean age of 32, matched for sex and education, and grouped to contain equal numbers of carriers and non-carriers. Nineteen carriers were cognitively still normal; 11 were symptomatic. Overall, the scientists saw a pattern of florbetapir uptake similar to that seen with florbetapir PET in late-onset AD cases, Fleisher told the HAI audience. When inspecting the scans visually, carriers started being positive for fibrillar amyloid in their precuneus, parietal cortex, and striatum around age 30, some 15 years before the age of mean symptomatic onset in the Paisa mutation families. Quantitative measurement of uptake across the cortex started detecting amyloid a bit earlier, around age 28. From there, uptake grew in a sigmoidal curve until age 37 to 40, and then reached a plateau as carriers entered the symptomatic stage of their disease (Fleisher et al., 2012).

Tammie Benzinger of Washington University, St. Louis, Missouri, presented data of 100 of the participants enrolled to date in the Dominantly Inherited Alzheimer Network (see ARF related news story). DIAN is the largest cohort worldwide of families with familial AD in the U.S., Australia, and the U.K., totaling more than 40 different mutations in the APP and presenilin genes. As in the case of API, the cohort is young, with a mean age of 35. Also as in API, the overall amyloid PET finding is that presymptomatic carriers have a gradual buildup of amyloid in the same brain areas as known from late-onset AD. “The carriers are different from the non-carriers in every gray matter area we tested,” Benzinger told the HAI audience (Benzinger et al., 2012)

Not all is the same between DIAN and API, nor between eFAD and LOAD, however. For one, in concordance with current thinking on LOAD, the DIAN study detects changes in FDG-PET and volumetric MRI later, not until carriers are mildly symptomatic with a 0.5 on the Clinical Dementia Rating Scale, whereas API has reported seeing subtle decrements on functional and structural imaging earlier than that (see ARF related news story). For another, there is quite a bit of variability between the studies in where amyloid first crops up—it can be the basal ganglia in some cases, the frontal lobe in others. API does not see the early striatal uptake reported in the first cases of PIB-PET in familial AD (e.g., see ARF related news story), confirming researchers' hunch that this much-discussed finding might be specific to certain mutations. DIAN sees early uptake in some areas that aren’t on the typical list of affected regions for LOAD, such as the occipital cortex and the orbital frontal lobe, Benzinger reported. At 20 to 25 years prior to expected onset, DIAN is finding PIB positivity a tad earlier than API. This could either have to do with greater sensitivity of PIB for small gray matter signals or reflect the heterogeneous mutations represented in DIAN.

That said, Benzinger and Fleisher agreed that their studies’ overall amyloid PET findings at this early stage match up well. DIAN contains a more heterogeneous set of patients than API, some of them having significant cerebral amyloid angiopathy along with their AD. The data are but an initial cross-sectional look thus far, and cannot be truly compared to each other yet. “We need longitudinal data, more participants, and then really drill down,” said Fleisher. Only then will scientists know which differences are real, which are large, and which are minor. Meanwhile, “whether amyloid imaging will eventually show eFAD to be substantially similar or different from LOAD remains an open and important question,” said Keith Johnson of Massachusetts General Hospital.

While most AD mutations look at least similar on amyloid PET scans, one appears to break ranks. At HAI, Agneta Nordberg of Karolinska Institutet in Stockholm, Sweden, presented data showing that the very rare so-called Arctic mutation of APP is essentially a no-show on PIB-PET scans. Known only in one Swedish family and a descendent U.S. family, this mutation causes an early onset form of AD that is clinically like sporadic AD but pathologically quite a different story. Characteristic plaques seen in postmortem LOAD with standard stains for fibrillar deposits, such as Congo red, come up negative in tissue with the Arctic mutation. At HAI, Nordberg reported that five carriers of this mutation, four of them presymptomatic, were negative for PIB retention. This means that PIB-PET matches up with postmortem pathology; hence, technically speaking, amyloid PET works, Nordberg said. More broadly, however, it means that forms of amyloid that are invisible to PIB (and presumably its 18F cousins) can cause clinically typical AD, too.

This form of AD behaved as expected in other biomarkers tested, Nordberg reported. In FDG-PET, the carriers showed the AD-typical deficit in frontoparietal, temporal, and posterior cingulate cortex; MRI revealed increasing atrophy going from cognitively normal carriers to the AD patient; and CSF markers of Aβ42 and tau/p-tau were severely abnormal, as in sporadic AD. “All biomarkers fit the picture; just fibrillar Aβ PET is aberrant with this mutation,” Nordberg said (Nordberg et al., 2012).

These data suggest, to Nordberg’s mind, that other forms of Aβ, for example, oligomers and protofibrils, can cause the pathological processes leading to AD. Other researchers agreed that this study highlights the need to develop tools to capture those other Aβ species. How many cases like these might be out there? Besides the Arctic mutation, a Japanese deletion mutation that behaves similarly has been described, as well as some isolated cases of PIB-negative LOAD. The phenomenon seems rare, but researchers don’t really know the extent of it.—Gabrielle Strobel.

This is Part 5 of a nine-part series. See also Part 1, Part 2, Part 3, Part 4, Part 6, Part 7, Part 8, Part 9. Download a PDF of the entire series.

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References

News Citations

  1. DIAN Forms Pharma Consortium, Submits Treatment Trial Grant
  2. Reeling In Biomarker Data in Young Carriers, API Rocks Staging Boat
  3. eFAD Research Surprise: In Mutation Carriers, Amyloid Starts in Striatum
  4. News Focus: 2012 Human Amyloid Imaging Conference
  5. Miami: Amyloid PET in the Clinic: What Are the Issues?
  6. Miami: Scan and Tell? Amyloid Imaging Confronts Disclosure Dilemma
  7. Miami: Can the Naked Eye Tell When a Scan Is Positive?
  8. Miami: Age and Amyloid—What Has ApoE Got to Do With It?
  9. Miami: Longitudinal Amyloid PET Data Start Converging
  10. Miami: Diagnosis and Amyloid Scan Can Be at Odds
  11. Miami: Scientists Angle for Way to Image Tangle

Paper Citations

  1. Fleisher A, Chen K, Jakimovich L, Gutierrez-Gomez M, Langbaum J, Roontiva A, Thiyyagura P, Liu X, Lee W, Ayutyanont N. Florbetapir Imaging in the World’s Largest Autosomal Dominant Early-Onset Alzheimer’s Disease Kindred: Pilot Data from the Alzheimer’s Prevention Initiative Biomarker Project. Human Amyloid Imaging Abstract. 2012 Jan 1;
  2. Benzinger T, Koeppe R, Su Y, Blazey T, Jack C, Thompson P, Saykin A, Correia S, Sperling R, Schofield P. Reference Tissue Normalization in Autosomal Dominant AD: Comparison of Cerebellar Versus Brainstem Referencing for [11C]PIB in the DIAN Cohort. Human Amyloid Imaging Abstract. 2012 Jan 1;
  3. Nordberg A, Schöll M, Wall A, Thordadottir S, Ferreira D, Bogdanovic N, Långström B, Almkvist O, Graff C. Arctic APP Mutation Carriers Show Low PIB PET Retention in the Presence of Pathological CSF Biomarkers and Reduced FDG Uptake. Human Amyloid Imaging Abstract. 2012 Jan 1;

Other Citations

  1. Download a PDF of the entire series.

External Citations

  1. New York Times story

Further Reading

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