Lussier, Firoza Zubeida

AbstractBackgroundTau‐PET tracers allow for in vivo Braak staging of individuals in the Alzheimer’s disease (AD) continuum. The impact of tracers’ characteristics for Braak staging using tau‐PET remains unclear. Therefore, we performed a head‐to‐head comparison of Braak staging using first‐ and second‐generation tau‐PET tracers.MethodWe assessed 51 cognitively unimpaired (CU) and 49 cognitively impaired participants (mean [SD] age 69.4 [7.5] years) with at least two tau‐PET ligands ([18F]MK6240, [18F]AV1451, and/or [18F]RO948) at McGill University, as part of the HEAD study. We calculated standardized uptake value ratios (SUVR) in Braak‐like regions of interest (ROI) for each ligand and investigated their association using Spearman’s correlation. Thresholds defined the presence of tauopathy in each Braak ROI, which was used to assign a Braak stage to each participant. Finally, we assessed the agreement between the Braak staging provided by each tracer, both for the traditional (using separate Braak stages – 0, I, II, III, IV, V, and VI) and simplified (using joint Braak stages – 0, I‐II, III‐IV, and V‐VI) frameworks.ResultIn all Braak ROIs, we found positive correlations between the SUVR values of the three tracers (Fig. 1). The strongest correlation was between [18F]MK6240 and [18F]RO948 in Braak II (r=0.94), and the weakest between [18F]AV1451 and [18F]RO948 in VI (r=0.51). Inter‐tracer agreement regarding the latest stage of abnormality was substantial or nearly perfect between pairs of tracers but moderate between the three tracers (Fig. 2A). The simplified framework presented greater agreement compared to traditional Braak staging, except between [18F]MK6240 and [18F]RO948. At the ROI level, the lowest agreements were observed for Braak II and I‐II, when [18F]MK6240 and [18F]RO948 were compared to [18F]AV1451 (Fig. 2B‐C). [18F]AV1451 had the highest probability of overestimating the Braak stage assigned by [18F]MK6240 and by [18F]RO948, especially at earlier stages (Fig. 3).ConclusionThe ligands presented moderate to nearly perfect agreement for in vivo staging of AD severity. Off‐target binding of [18F]AV1451 to the choroid plexus might explain disagreements at early stages. Overall, slight improvements in agreements were achieved with the simplified framework, as observed in histopathological staging.

AbstractBackgroundThe newly proposed criteria by the AA working group incorporates both biological and clinical stages to characterize the progression of AD. In this study, we aim to evaluate the agreement between these two complementary systems.MethodsUsing 188 participants from McGill TRIAD and 139 from the HEAD cohorts, we categorized participants into biological (0‐4) and clinical (0‐4) stages using amyloid PET, tau PET(MK‐6240), and clinical measures as described by the working group. Participants were then stratified into three categories: congruent (clinical = biological), higher in the biological stage (clinical < biological), and higher in the clinical stage (clinical > biological). In the TRIAD cohort, we further compared these groups for age, sex, years of education, vascular burden (WMH), microglial activation (PBR scan), Astrocyte reactivity (GFAP), amyloid load, tau load, and NPI‐Q scores using Welch two‐sided t‐test with FDR multiple comparison correction.ResultsIn the TRIAD cohort, 34% of participants were congruent, 24.5% had a higher clinical stage, and 41.5% had a higher biological stage. Meanwhile in the HEAD cohort 68.2% were congruent, 20.7% had a higher clinical stage, and 17% had a higher biological stage. TRIAD participants with a higher clinical stage had lower education (P = 0.02), more neuropsychiatric symptoms (P = 0.03), and a higher vascular burden (P = 0.03) (Table 1). As expected, people with higher biological stage had more amyloid(P<0.001), tau(P<0.001), and astrocyte reactivity(P<0.001) (Table 1, Figure 2).ConclusionsOur findings highlight important discordance between clinical and biological stages, which could be partially explained by cognitive reserve. This was supported by the protective effects of educational attainment in participants with a higher biological stage. Vascular burden played a major role in the cognitive impairment of individuals with higher clinical stages. Future studies should replicate these findings in larger more representative population‐based cohorts.

AbstractBackgroundRecent studies showed that neuroinflammation plays a key role in triggering specific neuropsychiatric symptoms (NPS), such as irritability and agitation, in individuals with Alzheimer’s disease (AD). While prior studies showed an association between tau pathology and all NPS domains, the extent to which tau influences each specific NPS domain remains unclear. Here, we aim to investigate the association of tau and NPS domains in the AD continuum. We hypothesize that tau plays a comparatively greater effect on the emergence of psychotic symptoms compared to other NPS domains.MethodWe assessed 56 individuals (21 cognitively unimpaired (CU), 23 MCI, and 12 AD dementia) from the HEAD study who underwent clinical assessments with the Neuropsychiatry Inventory Questionnaire (NPI‐Q) and had positron emission tomography (PET) for amyloid‐β (Aβ) ([18F]AZD4694 or [11C]PiB), and tau tangles ([18F]MK6240) at the same visit. We selected individuals with an NPI‐Q total score ≥1. Tau SUVR values were tailored with a mask from Braak stages I‐VI, using the inferior cerebellar gray matter as reference region. Leave‐one‐out voxel wise and linear regression tested the association between each NPI‐Q domain and biomarkers accounting for age, sex, cognitive status, and study site.ResultCI individuals had significantly higher NPI‐Q score and Braak VI PET SUVR than CU individuals (Table 1). NPI‐Q score was significantly associated with tau‐PET in the periRolandic and supplementary motor cortex (Figures 1A). Linear regression showed that NPI‐Q associates with tau‐PET in the Braak stage VI (Figure 1B). Leave‐one‐out regression analysis revealed that delusions, motor disturbances, and anxiety contributed most to the association between tau‐PET and NPS (Figure 2A, C). These domains presented a higher magnitude of association compared to each other NPI‐Q domain (Figure 2B). Notably, irritability, agitation, and disinhibition exerted a negative effect to the association, emphasizing that tau may not play a role in the development of these symptoms (Figure 2A, D)ConclusionOur study supports previous evidence suggesting that irritability and agitation may not be triggered by tau, but rather by other pathological process such as neuroinflammation. These findings provide additional rationale for the therapeutics aiming to mitigate irritability and agitation in AD patients.