Cerebral amyloid‐β load is associated with neurodegeneration and gliosis: Mediation by p‐tau and interactions with risk factors early in the Alzheimer's<i>continuum</i>

Eur J Nucl Med Mol Imaging

Milà‐Alomà

Shekari

et al. 2022

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Purpose Glial activation is one of the earliest mechanisms to be altered in Alzheimer’s disease (AD). Glial fibrillary acidic protein (GFAP) relates to reactive astrogliosis and can be measured in both cerebrospinal fluid (CSF) and blood. Plasma GFAP has been suggested to become altered earlier in AD than its CSF counterpart. Although astrocytes consume approximately half of the glucose-derived energy in the brain, the relationship between reactive astrogliosis and cerebral glucose metabolism is poorly understood. Here, we aimed to investigate the association between fluorodeoxyglucose ([18F]FDG) uptake and reactive astrogliosis, by means of GFAP quantified in both plasma and CSF for the same participants. Methods We included 314 cognitively unimpaired participants from the ALFA + cohort, 112 of whom were amyloid-β (Aβ) positive. Associations between GFAP markers and [18F]FDG uptake were studied. We also investigated whether these associations were modified by Aβ and tau status (AT stages). Results Plasma GFAP was positively associated with glucose consumption in the whole brain, while CSF GFAP associations with [18F]FDG uptake were only observed in specific smaller areas like temporal pole and superior temporal lobe. These associations persisted when accounting for biomarkers of Aβ pathology but became negative in Aβ-positive and tau-positive participants (A + T +) in similar areas of AD-related hypometabolism. Conclusions Higher astrocytic reactivity, probably in response to early AD pathological changes, is related to higher glucose consumption. With the onset of tau pathology, the observed uncoupling between astrocytic biomarkers and glucose consumption might be indicative of a failure to sustain the higher energetic demands required by reactive astrocytes.

Section: Introductionmentioning

confidence: 99%

Reactive astrogliosis is associated with higher cerebral glucose consumption in the early Alzheimer’s continuum

Eur J Nucl Med Mol Imaging

Milà‐Alomà

Shekari

et al. 2022

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“… 2 In a follow-up work, we reported that these markers were also associated with cerebral Aβ deposition as measured by PET. 3 However, the relationship between these CSF biomarkers and structural and metabolic alterations in the brain are not well understood, especially in these early phases of the disease.…”

Section: Introductionmentioning

confidence: 99%

Brain alterations in the early Alzheimer’s continuum with amyloid-β, tau, glial and neurodegeneration CSF markers

Shekari

Falcón

et al. 2022

Brain Communications

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Higher grey matter volumes/cortical thickness and fluorodeoxyglucose uptake have been consistently found in cognitively unimpaired individuals with abnormal Alzheimer’s disease biomarkers compared with those with normal biomarkers. It has been hypothesized that such transient increases may be associated with neuroinflammatory mechanisms triggered in response to early Alzheimer’s pathology. Here, we evaluated, in the earliest stages of the Alzheimer’s continuum, associations between grey matter volume and fluorodeoxyglucose uptake with CSF biomarkers of several pathophysiological mechanisms known to be altered in preclinical Alzheimer’s disease stages. We included 319 cognitively unimpaired participants from the ALFA+ cohort with available structural MRI, fluorodeoxyglucose PET and CSF biomarkers of amyloid-β and tau pathology (phosphorylated tau and total tau), synaptic dysfunction (neurogranin), neuronal and axonal injury (neurofilament light), glial activation (soluble triggering receptor on myeloid cells 2, YKL40, GFAP, interleukin-6 and S100b) and α-synuclein using the Roche NeuroToolKit. We first used the amyloid-β/tau framework to investigate differences in the neuroimaging biomarkers between preclinical Alzheimer’s disease stages. Then, we looked for associations between the neuroimaging markers and all the CSF markers. Given the non-negative nature of the concentrations of CSF biomarkers and their high collinearity, we clustered them using non-negative matrix factorization approach (components) and sought associations with the imaging markers. By groups, higher grey matter volumes were found in the amyloid-β-positive tau-negative participants with respect to the reference amyloid-β-negative tau-negative group. Both amyloid-β and tau-positive participants showed higher fluorodeoxyglucose uptake than tau-negative individuals. Using the obtained components, we observed that tau pathology accompanied by YKL-40 (astrocytic marker) was associated with higher grey matter volumes and fluorodeoxyglucose uptake in extensive brain areas. Higher grey matter volumes in key Alzheimer-related regions were also found in association with two other components characterized by a higher expression of amyloid-β in combination with different glial markers: one with higher GFAP and S100b levels (astrocytic markers) and the other one with interleukin-6 (pro-inflammatory). Notably, these components’ expression had different behaviours across amyloid-β/tau stages. Taken together, our results show that CSF amyloid-β and phosphorylated tau, in combination with different aspects of glial response, have distinctive associations with higher grey matter volumes and increased glucose metabolism in key Alzheimer-related regions. These mechanisms combine to produce transient higher grey matter volumes and fluorodeoxyglucose uptake at the earliest stages of the Alzheimer’s continuum, which may revert later on the course of the disease when neurodegeneration drives structural and metabolic cerebral changes.

“…In recent years, there has been increasing interest in investigating glial activation markers and their relationship with disease progression, as it has been suggested that inflammatory processes may have an active role in AD [4]. Previous studies proposed that some glial activation markers could be related to disease progression [7,8]. For instance, higher levels of sTREM2, a microglial activation marker [39], have been related to slower rates of Aβ accumulation and disease progression [40][41][42].…”

Section: Discussionmentioning

confidence: 99%

“…However, until recently, these biomarkers had to be measured in different platforms and using sophisticated methods, which reduced its applicability to clinical practice. Previous studies using this panel have shown alterations in some of these biomarkers in different stages and in relation to different aspects of the disease [7][8][9][10]. However, their clinical utility for predicting disease progression after accounting for core ADbiomarkers is still largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Optimal combinations of CSF biomarkers for predicting cognitive decline and clinical conversion in cognitively unimpaired participants and mild cognitive impairment patients: A multi-cohort study

Larsson

Cody

et al. 2022

Preprint

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INTRODUCTION: Our objective was determining the optimal combinations of cerebrospinal fluid (CSF) biomarkers for predicting disease progression in Alzheimer's disease (AD) and other neurodegenerative diseases. METHODS: We included 1,983 participants from three different cohorts with longitudinal cognitive and clinical data, and baseline CSF levels of Aβ42, Aβ40, p-tau, NfL, neurogranin, α-synuclein, sTREM2, GFAP, YKL-40, S100b and IL-6 (Elecsys® NeuroToolKit). RESULTS: Change of modified Preclinical Alzheimer's Cognitive Composite (mPACC) in cognitively unimpaired (CU) was best predicted by p-tau/Aβ42 alone (R2≥0.31) or together with neurofilament light ([NfL],R2=0.25), while p-tau/Aβ42 (R2≥0.19) was sufficient to accurately predict change of the Mini-Mental State Examination (MMSE) in mild cognitive impairment (MCI) patients. P-tau/Aβ42 (AUC≥0.87) and p-tau/Aβ42 with NfL (AUC≥0.75) were the best predictors of conversion to AD and all-cause dementia, respectively. DISCUSSION: P-tau/Aβ42 is sufficient for predicting progression in AD, with very high accuracy. Adding NfL improves the prediction of all-cause dementia conversion and cognitive decline.