Longitudinal progression of blood biomarkers reveals a key role of astrocyte reactivity in preclinical Alzheimer’s disease

Varma, VR; An, Y; Kac, PR; Bilgel, M; Moghekar, A; Loeffler, T; Amschl, D; Troncoso, J; Blennow, K; Zetterberg, H; Ashton, NJ; Resnick, SM; Thambisetty, M

doi:10.1101/2024.01.25.24301779

Cited by 4 publications

(2 citation statements)

References 48 publications

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“…67 In light of astrocytes' importance, recent advancements in plasma GFAP assays have been introduced and evaluated in extensive imaging cohorts. 68 Although evidence suggests a potential association between elevated plasma GFAP levels and Aβ pathology, 69,70 recent findings indicate a strong negative correlation between cortical and plasma GFAP levels in both mice 71 and humans. 72 These discrepancies imply a complex relationship between plasma GFAP concentration, which is a global measure, and cortical astrocyte activation, likely influenced by peripheral tissues such as the liver or pancreas.…”

Section: Discussionmentioning

confidence: 99%

Resiliency to Alzheimer’s disease neuropathology can be distinguished from dementia using cortical astrogliosis imaging

Barsoum,

Latimer,

Nolan

et al. 2024

Preprint

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Despite the presence of significant Alzheimer's disease (AD) pathology, characterized by amyloid β (Aβ) plaques and phosphorylated tau (pTau) tangles, some cognitively normal elderly individuals do not inevitably develop dementia. These findings give rise to the notion of cognitive 'resilience', suggesting maintained cognitive function despite the presence of AD neuropathology, highlighting the influence of factors beyond classical pathology. Cortical astroglial inflammation, a ubiquitous feature of symptomatic AD, shows a strong correlation with cognitive impairment severity, potentially contributing to the diversity of clinical presentations. However, noninvasively imaging neuroinflammation, particularly astrogliosis, using MRI remains a significant challenge. Here we sought to address this challenge and to leverage multidimensional (MD) MRI, a powerful approach that combines relaxation with diffusion MR contrasts, to map cortical astrogliosis in the human brain by accessing sub-voxel information. Our goal was to test whether MD-MRI can map astroglial pathology in the cerebral cortex, and if so, whether it can distinguish cognitive resiliency from dementia in the presence of hallmark AD neuropathological changes. We adopted a multimodal approach by integrating histological and MRI analyses using human postmortem brain samples. Ex vivo cerebral cortical tissue specimens derived from three groups comprised of non-demented individuals with significant AD pathology postmortem, individuals with both AD pathology and dementia, and non-demented individuals with minimal AD pathology postmortem as controls, underwent MRI at 7 T. We acquired and processed MD-MRI, diffusion tensor, and quantitative T1 and T2 MRI data, followed by histopathological processing on slices from the same tissue. By carefully co-registering MRI and microscopy data, we performed quantitative multimodal analyses, leveraging targeted immunostaining to assess MD-MRI sensitivity and specificity towards Aβ, pTau, and glial fibrillary acidic protein (GFAP), a marker for astrogliosis. Our findings reveal a distinct MD-MRI signature of cortical astrogliosis, enabling the creation of predictive maps for cognitive resilience amid AD neuropathological changes. Multiple linear regression linked histological values to MRI changes, revealing that the MD-MRI cortical astrogliosis biomarker was significantly associated with GFAP burden (standardized β=0.658, pFDR<0.0001), but not with Aβ (standardized β=0.009, pFDR=0.913) or pTau (standardized β=-0.196, pFDR=0.051). Conversely, none of the conventional MRI parameters showed significant associations with GFAP burden in the cortex. While the extent to which pathological glial activation contributes to neuronal damage and cognitive impairment in AD is uncertain, developing a noninvasive imaging method to see its affects holds promise from a mechanistic perspective and as a potential predictor of cognitive outcomes.

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Section: Discussionmentioning

confidence: 99%

Resiliency to Alzheimer’s disease neuropathology can be distinguished from dementia using cortical astrogliosis imaging

Barsoum,

Latimer,

Nolan

et al. 2024

Preprint

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“…Plasma biomarkers are promising candidates for the early diagnosis of AD, tied to the biological β Amyloid (A) deposition, pathologic Tau (T), and Neurodegeneration (N) [ATN] framework ( 4 , 6 – 8 ). Recently, plasma glial fibrillary acidic protein (GFAP), an intermediate filament protein of astrocytes, has been demonstrated to be associated with brain amyloid status and the development of clinical AD and cognitive decline ( 9 , 10 ). Plasma neurofilament light chain (NfL), a cytoplasmic protein, is a marker of neurodegeneration associated with cognitive decline, brain atrophy, and hypometabolism ( 11 – 13 ).…”

Section: Introductionmentioning

confidence: 99%

Plasma GFAP, NfL and pTau 181 detect preclinical stages of dementia

Ingannato,

Bagnoli,

Mazzeo

et al. 2024

Front. Endocrinol.

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BackgroundPlasma biomarkers are preferable to invasive and expensive diagnostic tools, such as neuroimaging and lumbar puncture that are gold standard in the clinical management of Alzheimer’s Disease (AD). Here, we investigated plasma Glial Fibrillary Acidic Protein (GFAP), Neurofilament Light Chain (NfL) and Phosphorylated-tau-181 (pTau 181) in AD and in its early stages: Subjective cognitive decline (SCD) and Mild cognitive impairment (MCI).Material and methodsThis study included 152 patients (42 SCD, 74 MCI and 36 AD). All patients underwent comprehensive clinical and neurological assessment. Blood samples were collected for Apolipoprotein E (APOE) genotyping and plasma biomarker (GFAP, NfL, and pTau 181) measurements. Forty-three patients (7 SCD, 27 MCI, and 9 AD) underwent a follow-up (FU) visit after 2 years, and a second plasma sample was collected. Plasma biomarker levels were detected using the Simoa SR-X technology (Quanterix Corp.). Statistical analysis was performed using SPSS software version 28 (IBM SPSS Statistics). Statistical significance was set at p < 0.05.ResultsGFAP, NfL and pTau 181 levels in plasma were lower in SCD and MCI than in AD patients. In particular, plasma GFAP levels were statistically significant different between SCD and AD (p=0.003), and between MCI and AD (p=0.032). Plasma NfL was different in SCD vs MCI (p=0.026), SCD vs AD (p<0.001), SCD vs AD FU (p<0.001), SCD FU vs AD (p=0.033), SCD FU vs AD FU (p=0.011), MCI vs AD (p=0.002), MCI FU vs AD (p=0.003), MCI FU vs AD FU (p=0.003) and MCI vs AD FU (p=0.003). Plasma pTau 181 concentration was significantly different between SCD and AD (p=0.001), MCI and AD (p=0.026), MCI FU and AD (p=0.020). In APOE ϵ4 carriers, a statistically significant increase in plasma NfL (p<0.001) and pTau 181 levels was found (p=0.014). Moreover, an association emerged between age at disease onset and plasma GFAP (p = 0.021) and pTau181 (p < 0.001) levels.Discussion and conclusionsPlasma GFAP, NfL and pTau 181 are promising biomarkers in the diagnosis of the prodromic stages and prognosis of dementia.

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Tracking neuroinflammatory biomarkers in Alzheimer’s disease: a strategy for individualized therapeutic approaches?

Lista,

Imbimbo,

Grasso

et al. 2024

J Neuroinflammation

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Background Recent trials of anti-amyloid-β (Aβ) monoclonal antibodies, including lecanemab and donanemab, in early Alzheimer disease (AD) showed that these drugs have limited clinical benefits and their use comes with a significant risk of serious adverse events. Thus, it seems crucial to explore complementary therapeutic approaches. Genome-wide association studies identified robust associations between AD and several AD risk genes related to immune response, including but not restricted to CD33 and TREM2. Here, we critically reviewed the current knowledge on candidate neuroinflammatory biomarkers and their role in characterizing the pathophysiology of AD. Main body Neuroinflammation is recognized to be a crucial and contributing component of AD pathogenesis. The fact that neuroinflammation is most likely present from earliest pre-stages of AD and co-occurs with the deposition of Aβ reinforces the need to precisely define the sequence and nature of neuroinflammatory events. Numerous clinical trials involving anti-inflammatory drugs previously yielded unfavorable outcomes in early and mild-to-moderate AD. Although the reasons behind these failures remain unclear, these may include the time and the target selected for intervention. Indeed, in our review, we observed a stage-dependent neuroinflammatory process in the AD brain. While the initial activation of glial cells counteracts early brain Aβ deposition, the downregulation in the functional state of microglia occurs at more advanced disease stages. To address this issue, personalized neuroinflammatory modulation therapy is required. The emergence of reliable blood-based neuroinflammatory biomarkers, particularly glial fibrillary acidic protein, a marker of reactive astrocytes, may facilitate the classification of AD patients based on the ATI(N) biomarker framework. This expands upon the traditional classification of Aβ (“A”), tau (“T”), and neurodegeneration (“N”), by incorporating a novel inflammatory component (“I”). Conclusions The present review outlines the current knowledge on potential neuroinflammatory biomarkers and, importantly, emphasizes the role of longitudinal analyses, which are needed to accurately monitor the dynamics of cerebral inflammation. Such a precise information on time and place will be required before anti-inflammatory therapeutic interventions can be considered for clinical evaluation. We propose that an effective anti-neuroinflammatory therapy should specifically target microglia and astrocytes, while considering the individual ATI(N) status of patients.

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Longitudinal progression of blood biomarkers reveals a key role of astrocyte reactivity in preclinical Alzheimer’s disease

Cited by 4 publications

References 48 publications

Resiliency to Alzheimer’s disease neuropathology can be distinguished from dementia using cortical astrogliosis imaging

Resiliency to Alzheimer’s disease neuropathology can be distinguished from dementia using cortical astrogliosis imaging

Plasma GFAP, NfL and pTau 181 detect preclinical stages of dementia

Tracking neuroinflammatory biomarkers in Alzheimer’s disease: a strategy for individualized therapeutic approaches?

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