To date, limited evidence exists on the different sensitivity of MRI versus [18F]FDG-PET to detect early cerebral changes along the Alzheimer's disease (AD) continuum in Down syndrome (DS). Therefore, we aimed to characterize volume and metabolism alterations in adults with DS and compare their performance in detecting AD clinical stages.
Cross-sectional study, including 92 adults with DS from the Down-Alzheimer Barcelona Neuroimaging Initiative (34 asymptomatic without amyloid pathology [aDS A−], 20 asymptomatic with amyloid pathology [aDS A+], 12 with prodromal AD [pDS], and 26 with AD dementia [dDS]; Table 1), who underwent 3T-MRI and [18F]FDG-PET. Amyloid status in the aDS group was determined using amyloid-PET (>20 centiloids, n = 29) or CSF Aβ42/Aβ40 ratio (<0.062, Lumipulse, n = 25). Brain volume and metabolism values were extracted using the Hammers atlas, normalizing MRI volumes by total intracranial volume and PET images using the pons as reference region. We calculated standardized-β coefficients, adjusted for sex and scanner, to assess the effectiveness of MRI and PET scans in identifying stages of AD (aDS A− vs. aDS A+; aDS vs. symptomatic DS [sDS=pDS + dDS]).
Progressive brain volume loss and metabolic decline were observed along the AD continuum in DS. Compared to aDS A−, aDS A+ exhibited lower volume in multiple regions, particularly in the frontal lobe. sDS individuals showed widespread atrophy, predominantly in temporal areas (Figure 1). In contrast, no significant hypometabolism was detected in aDS A+ compared to aDS A−, but sDS individuals exhibited global hypometabolism, primarily in temporo-parietal regions (Figure 2).
Amyloid pathology in aDS individuals is linked to frontal-predominant atrophy without clear hypometabolism. In symptomatic stages, both MRI and [18F]FDG-PET revealed widespread involvement, with atrophy predominating in temporal regions and hypometabolism in temporo-parietal areas. Unlike in sporadic AD, no brain region showed greater hypometabolism than atrophy, suggesting alternative contributing factors in the general population. Our findings also suggest that MRI outperforms [18F]FDG-PET in identifying brain changes associated with AD clinical stages in DS, which has implications for early diagnosis and clinical trials.
As Alzheimer's disease studies increasingly utilize plasma biomarkers, the associations of plasma and PET biomarkers of β-amyloid (Aβ) in relation to Aβ accumulation and progression from PET A- to A+ must be better understood.
We evaluated 58 non-demented participants from ADNI and 170 from the University of Pittsburgh (UPitt) who had plasma Aβ42/Aβ40 measures and longitudinal Aβ-PET. We additionally evaluated 124 UPitt participants who had p-tau217 measures. All participants were PET A- at baseline. Plasma Aβ42/40 values were derived through either the C2N mass spectrometry-based assay (ADNI) or Simoa assay (UPitt). p-tau217 values were derived through the Janssen p-tau217+ Simoa assay. Cut-off values of 0.15 and 0.11 determined Aβ42/40 status for the ADNI and UPitt datasets, respectively, A cut-off of 0.083 pg/mL was used for p-tau217. Kaplan-Meyer survival models evaluated the association of plasma Aβ42/40 status with risk of progression to PET A+. Linear regression models, adjusting for baseline PET Aβ values, sex, age, and APOE*4 status, assessed the association of plasma Aβ42/40 values with Aβ accumulation.
Kaplan-Meyer survival analysis results showed that plasma Ab status distinctly differentiates PET A- trajectories, (Figure 1) with plasma A+ progressing to PET A+ in a median time of 4.0 years in both datasets. Only 3 (2.4%) of the 124 PET A- participants presented high p-tau217 values. Linear regression models of the continuous measures revealed that, even with the inclusion Aβ-PET and the other covariates, plasma Aβ42/40 was significantly associated with Aβ accumulation (ADNI: b=-142.29, p = 0.002; UPitt: b=-0.27, p = 0.02) (Figure 2). Plasma A+ presented significantly higher Aβ accumulation compared to plasma A-. (Figure 3)
While a better predictor of high Ab deposition than plasma Aβ42/40, p-tau217 is not elevated in PET A-. On the other hand, plasma Aβ42/40 can predict progression from PET A- to A+. This follows the notion that soluble Aβ, measured in plasma or CSF, becomes abnormal before high insoluble Aβ is detectable with PET. Therefore, plasma Aβ-positive/Aβ-PET negative identify individuals at the very early stages of Aβ deposition, at risk of progression, requiring a closer follow-up and likely to benefit the most from anti-Aβ therapy.
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