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- Schaffer Aguzzoli, Cristiano, et al.
(författare)
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Neuropsychiatric Symptoms and Microglial Activation in Patients with Alzheimer Disease
- 2023
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Ingår i: JAMA network open. - 2574-3805. ; 6:11
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Neuropsychiatric symptoms are commonly encountered and are highly debilitating in patients with Alzheimer disease. Understanding their underpinnings has implications for identifying biomarkers and treatment for these symptoms. Objective: To evaluate whether glial markers are associated with neuropsychiatric symptoms in individuals across the Alzheimer disease continuum. Design, Setting, and Participants: This cross-sectional study was conducted from January to June 2023, leveraging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University, Canada. Recruitment was based on referrals of individuals from the community or from outpatient clinics. Exclusion criteria included active substance abuse, major surgery, recent head trauma, safety contraindications for positron emission tomography (PET) or magnetic resonance imaging, being currently enrolled in other studies, and having inadequately treated systemic conditions. Main Outcomes and Measures: All individuals underwent assessment for neuropsychiatric symptoms (Neuropsychiatry Inventory Questionnaire [NPI-Q]), and imaging for microglial activation ([11C]PBR28 PET), amyloid-β ([18F]AZD4694 PET), and tau tangles ([18F]MK6240 PET). Results: Of the 109 participants, 72 (66%) were women and 37 (34%) were men; the median age was 71.8 years (range, 38.0-86.5 years). Overall, 70 had no cognitive impairment and 39 had cognitive impairment (25 mild; 14 Alzheimer disease dementia). Amyloid-β PET positivity was present in 21 cognitively unimpaired individuals (30%) and in 31 cognitively impaired individuals (79%). The NPI-Q severity score was associated with microglial activation in the frontal, temporal, and parietal cortices (β=7.37; 95% CI, 1.34-13.41; P=.01). A leave-one-out approach revealed that irritability was the NPI-Q domain most closely associated with the presence of brain microglial activation (β=6.86; 95% CI, 1.77-11.95; P=.008). Furthermore, we found that microglia-associated irritability was associated with study partner burden measured by NPI-Q distress score (β=5.72; 95% CI, 0.33-11.10; P=.03). Conclusions and Relevance: In this cross-sectional study of 109 individuals across the AD continuum, microglial activation was associated with and a potential biomarker of neuropsychiatric symptoms in Alzheimer disease. Moreover, our findings suggest that the combination of amyloid-β- and microglia-targeted therapies could have an impact on relieving these symptoms.
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| 2. |
- Therriault, Joseph, et al.
(författare)
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Comparison of two plasma p-tau217 assays to detect and monitor Alzheimer's pathology.
- 2024
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Ingår i: EBioMedicine. - 2352-3964. ; 102
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Tidskriftsartikel (refereegranskat)abstract
- Blood-based biomarkers of Alzheimer's disease (AD) have become increasingly important as scalable tools for diagnosis and determining clinical trial eligibility. P-tau217 is the most promising due to its excellent sensitivity and specificity for AD-related pathological changes.We compared the performance of two commercially available plasma p-tau217 assays (ALZpath p-tau217 and Janssen p-tau217+) in 294 individuals cross-sectionally. Correlations with amyloid PET and tau PET were assessed, and Receiver Operating Characteristic (ROC) analyses evaluated both p-tau217 assays for identifying AD pathology.Both plasma p-tau217 assays were strongly associated with amyloid and tau PET. Furthermore, both plasma p-tau217 assays identified individuals with AD vs other neurodegenerative diseases (ALZpath AUC=0.95; Janssen AUC=0.96). Additionally, plasma p-tau217 concentrations rose with AD severity and their annual changes correlated with tau PET annual change.Both p-tau217 assays had excellent diagnostic performance for AD. Our study supports the future clinical use of commercially-available assays for p-tau217.This research is supported by the Weston Brain Institute, Canadian Institutes of Health Research (CIHR), Canadian Consortium on Neurodegeneration in Aging, the Alzheimer's Association, Brain Canada Foundation, the Fonds de Recherche du Québec - Santé and the Colin J. Adair Charitable Foundation.
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| 3. |
- Wang, Yi-Ting, et al.
(författare)
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Sex-specific modulation of amyloid-β on tau phosphorylation underlies faster tangle accumulation in females
- 2024
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Ingår i: Brain : a journal of neurology. - 1460-2156. ; 147:4, s. 1497-1510
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Tidskriftsartikel (refereegranskat)abstract
- Females are disproportionately affected by dementia due to Alzheimer's disease. Despite a similar Aβ load, females showed a higher load of neurofibrillary tangle as compared to males. Previous literature has proposed that Aβ and p-tau synergism accelerates tau tangle formation, yet the effect of biological sex in this process was overlooked. In this observational study, we examined longitudinal neuroimaging data from two cohorts, the TRIAD cohort in Canada, and the ADNI cohort in the United States. We assessed a total number of 457 participants across the clinical spectrum of AD. All participants underwent a baseline multimodal imaging assessment, including MRIs and PET scans with radioligands targeting Aβ plaques and tau tangles respectively. CSF data was also collected. Follow-up imaging assessments were conducted at the 1-year and 2-year intervals for the TRIAD cohort, and at the 1-year, 2-year and 4-year intervals for the ADNI cohort. The goal of the present study was to investigate the upstream pathological events contributing to the faster tau progression observed in females. Specifically, we assessed if the contribution of Aβ and p-tau synergism on accelerated tau tangle formation was modulated by the biological sex. We hypothesized that the cortical Aβ predisposes tau phosphorylation and tangle accumulation in a sex-specific manner. Findings from this study revealed that Aβ-positive females presented higher CSF p-tau181 concentrations as compared to Aβ-positive males in both TRIAD (P=0.04, Cohen's d=0.51) and ADNI cohort (P=0.027, Cohen's d=0.41). In addition, Aβ-positive females also presented faster NFT accumulation compared to their male counterparts (TRIAD: P=0.026, Cohen's d=0.52; ADNI: P=0.049, Cohen's d=1.14). Finally, findings from this present study unveiled that the triple interaction between female sex, Aβ and CSF p-tau181 is a significant predictor of accelerated tau accumulation at the 2-year follow-up visit (Braak I: P=0.0067, t=2.81; Braak III: P=0.017, t=2.45; Braak IV: P=0.002, t=3.17; Braak V: P=0.006, t=2.88; Braak VI: P=0.0049, t=2.93). Overall, this study reported a sex-specific modulation of cortical Aβ on tau phosphorylation, and this consequently facilitates faster NFT progression seen in female individuals over time. This presents important clinical implications suggesting the early intervention targeting Aβ plaques and tau phosphorylation may be promising therapeutic strategies for females to prevent further accumulation and spread of tau aggregates.
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