Detection of early cerebral amyloid-b deposition by pet imaging and its downstream effects
- Autores: Gemma Salvado Blasco
- Directores de la Tesis: Juan Domingo Gispert López (dir. tes.), José Luis Molinuevo Guix (codir. tes.), Sala Llonch Roser (tut. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2021
- Idioma: inglés
- Tribunal Calificador de la Tesis: Domènec Ros Puig (presid.), Michel Grothe (secret.), Valentina Garibotto (voc.)
- Materias:
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- Resumen
Alzheimer's disease (AD) is the leading cause of dementia worldwide. This disease, however, starts decades before any clinical symptom appears with the accumulation in the brain of aggregates of two main proteins: amyloid-β (Aβ) and tau. In recent years, the appearance of in vivo biomarkers capable to track biological changes has boosted the research interest to earlier phases of the disease. With these concepts in mind, the general objective of this thesis was to investigate Aβ deposition and its downstream effects in the earliest stages of the Alzheimer's continuum. To this aim, the four studies of the thesis include participants of the ALFA (from Alzheimer and Families) cohort, who are characterized as being cognitively unimpaired, (late) middle-aged, and to be enriched in risk factors for AD. Thus, increasing the probability of incorporating participants with low-intermediate burden of Aβ.
In the first two studies of this thesis, our focus was set on the early detection of Aβ deposition using PET scans. We first used automated quantification methods, as typically done in the research setting and, second, we used visual assessment, which is more often used in the clinical context. Our results lead to the identification of quantitative thresholds for the detection of early abnormalities in amyloid PET scans significantly lower than previously proposed. We also concluded that visual inspection of Aβ PET scans is sensitive to detect and grade early Aβ deposition in the brain.
In the third study, Aβ PET images were used to investigate whether risk factors for Alzheimer's dementia promoted the deposition of insoluble, fibrillar aggregates of Aβ in the brain for similar levels of Aβ in the cerebrospinal fluid (CSF), reflecting the production/clearance rate of soluble Aβ species. We found that that the main unmodifiable risk factors for Alzheimer's dementia -older age, female sex, and APOE- ε4 allele carriership- increased deposited fibrillar Aβ for similar levels of soluble Aβ as measured in the CSF. However, while older age and female sex promoted the deposition in typical AD-related areas, thus suggesting an additive effect, APOE-ε4 allele facilitated the spread of Aβ in the entorhinal area, which has been described as an area vulnerable to tau deposition. This result suggests that APOE-ε4 allele-related mechanisms might accelerate the propagation of amyloid pathology to these areas, facilitating the spread of tau through the neocortex and thus, contributing to raise the risk of developing AD.
Finally, in our last study, we investigated Aβ-downstream effects in the earliest stages of the Alzheimer's continuum. To this aim, we analysed core and novel AD CSF biomarkers. These included: Aβ42/40 and phosphorilated tau (p-tau) as markers of Aβ and tau pathology, respectively; total tau (t-tau) and neurofilament light (NfL) as markers of neurodegeneration; neurogranin for synaptic dysfunction; glial fibrillary acidic protein (GFAP), YKL-40, soluble triggering receptor on myeloid cells 2 (sTREM2), S100b, interleukin 6 (IL-6) as glial activity biomarkers and, total α- synuclein as marker of α-synuclein pathology. We observed that, although studying participants with low Aβ load, many pathophysiological pathways, such as inflammation, were already altered. Of note, our results suggest a direct link between Aβ deposition in the brain and neurodegeneration that is independent of tau pathology.
Further, we described their direct and/or indirect associations with Aβ deposition, as well as the moderation effects of some AD risk factors on these relationships.
