Title: Biomarkers related to Alzheimer’s Disease in adults with Down Syndrome
Legend: Amyloid-b and tau are signature neuropathologies related to Alzheimer’s disease and can be measured using PET imaging. The figure on the left shows the trajectory of amyloid-b accumulation as a function of age in longitudinal brain imaging studies of individuals with Down syndrome. The figure on the right reveals elevated levels of tau can be detected during the early stages of amyloid accumulation (white arrows) when analysis is limited to just those individuals below the amyloid-b threshold. This information is critical for the development of future intervention trials for Alzheimer’s disease in Down syndrome.
Citations: Left Figure citation: Zammit MD, Tudorascu DL, Laymon CM, Hartley SL, Zaman SH, Ances BM, Johnson SC, Stone CK, Mathis CA, Klunk WE, Cohen AD, Handen BL, Christian BT. PET measurement of longitudinal amyloid load identifies the earliest stages of amyloid-beta accumulation during Alzheimer’s disease progression in Down syndrome. Neuroimage. 2021 Jan 7;228:117728. doi: 10.1016/j.neuroimage.2021.117728. Epub ahead of print. PMID: 33421595.
Right Figure citation: Zammit MD, Tudorascu DL, Laymon CM, Hartley SL, Ellison PA, Zaman SH, Ances BM, Johnson SC, Stone CK, Sabbagh MN, Mathis CA, Klunk WE, Cohen AD, Handen BL, Christian BT. Neurofibrillary tau depositions emerge with subthreshold cerebral beta-amyloidosis in Down syndrome. NeuroImage:Clinical, 31. 2021. doi.org/10.1016/j.nicl.2021.102740
Abstract: Left Figure: Introduction: Adults with Down syndrome (DS) are predisposed to Alzheimer’s disease (AD) and reveal early amyloid beta (Aβ) pathology in the brain. Positron emission tomography (PET) provides an in vivo measure of Aβ throughout the AD continuum. Due to the high prevalence of AD in DS, there is need for longitudinal imaging studies of Aβ to better characterize the natural history of Aβ accumulation, which will aid in the staging of this population for clinical trials aimed at AD treatment and prevention. Methods: Adults with DS (N = 79; Mean age (SD) = 42.7 (7.28) years) underwent longitudinal [C-11]Pittsburgh compound B (PiB) PET. Global Aβ burden was quantified using the amyloid load metric (AβL). Modeled PiB images were generated from the longitudinal AβL data to visualize which regions are most susceptible to Aβ accumulation in DS. AβL change was evaluated across Aβ(−), Aβ-converter, and Aβ(+) groups to assess longitudinal Aβ trajectories during different stages of AD-pathology progression. AβL change values were used to identify Aβ-accumulators within the Aβ(−) group prior to reaching the Aβ(+) threshold (previously reported as 20 AβL) which would have resulted in an Aβ-converter classification. With knowledge of trajectories of Aβ(−) accumulators, a new cutoff of Aβ(+) was derived to better identify subthreshold Aβ accumulation in DS. Estimated sample sizes necessary to detect a 25% reduction in annual Aβ change with 80% power (alpha 0.01) were determined for different groups of Aβ-status. Results: Modeled PiB images revealed the striatum, parietal cortex and precuneus as the regions with earliest detected Aβ accumulation in DS. The Aβ(−) group had a mean AβL change of 0.38 (0.58) AβL/year, while the Aβ-converter and Aβ(+) groups had change of 2.26 (0.66) and 3.16 (1.34) AβL/year, respectively. Within the Aβ(−) group, Aβ-accumulators showed no significant difference in AβL change values when compared to Aβ-converter and Aβ(+) groups. An Aβ(+) cutoff for subthreshold Aβ accumulation was derived as 13.3 AβL. The estimated sample size necessary to detect a 25% reduction in Aβ was 79 for Aβ(−) accumulators and 59 for the Aβ-converter/Aβ(+) group in DS. Conclusion: Longitudinal AβL changes were capable of distinguishing Aβ accumulators from non-accumulators in DS. Longitudinal imaging allowed for identification of subthreshold Aβ accumulation in DS during the earliest stages of AD-pathology progression. Detection of active Aβ deposition evidenced by subthreshold accumulation with longitudinal imaging can identify DS individuals at risk for AD development at an earlier stage.
Right Figure: Introduction: Adults with Down syndrome are genetically predisposed to develop Alzheimer’s disease and accumulate beta-amyloid plaques (Aβ) early in life. While Aβ has been heavily studied in Down syndrome, its relationship with neurofibrillary tau is less understood. The aim of this study was to evaluate neurofibrillary tau deposition in individuals with Down syndrome with varying levels of Aβ burden. Methods: A total of 161 adults with Down syndrome (mean age = 39.2 (8.50) years) and 40 healthy, non-Down syndrome sibling controls (43.2 (12.6) years) underwent T1w-MRI, [C-11]PiB and [F-18]AV-1451 PET scans. PET images were converted to units of standardized uptake value ratios (SUVrs). Aβ burden was calculated using the amyloid load metric (AβL); a measure of global Aβ burden that improves quantification from SUVrs by suppressing the nonspecific binding signal component and computing the specific Aβ signal from all Aβ-carrying voxels from the image. Regional tau was assessed using control-standardized AV-1451 SUVr. Control-standardized SUVrs were compared across Down syndrome groups of Aβ-negative (A-) (AβL < 13.3), subthreshold A+ (13.3 ≤ AβL < 20) and conventionally A+ (AβL ≥ 20) individuals. The subthreshold A + group was identified as having significantly higher Aβ burden compared to the A- group, but not high enough to satisfy a conventional A + classification. Results: A large-sized association that survived adjustment for chronological age, mental age (assessed using the Peabody Picture Vocabulary Test), and imaging site was observed between AβL and AV-1451 within each Braak region (p < .05). The A + group showed significantly higher AV-1451 retention across all Braak regions compared to the A- and subthreshold A + groups (p < .05). The subthreshold A + group showed significantly higher AV-1451 retention in Braak regions I-III compared to an age-matched sample from the A- group (p < .05). Discussion: These results show that even the earliest detectable Aβ accumulation in Down syndrome is accompanied by elevated tau in the early Braak stage regions. This early detection of tau can help characterize the tau accumulation phase during preclinical Alzheimer’s disease progression in Down syndrome and suggests that there may be a relatively narrow window after Aβ accumulation begins to prevent the downstream cascade of events that leads to Alzheimer’s disease.
About the Lab: Christian’s Lab is closely aligned with the PET imaging facility in the Waisman Center IDDRC Brain Imaging Laboratory. The lab’s research focuses on developing and translating novel PET methods for the study of neurodevelopment, neuropsychiatric illness and neurodegeneration with an emphasis on IDD populations. Christian is also one of the MPIs for the ABC-DS study, which is a multisite study designed to test hypotheses related to how Alzheimer’s Disease in Down syndrome may parallel sporadic Alzheimer’s Disease within an amyloid, tau, neurodegeneration AT(N) framework and to identify modifiers of risk of conversion/progression.