CSF β-amyloid and white matter damage: a new perspective on Alzheimer’s disease

ObjectiveTo assess the connection between amyloid pathology and white matter (WM) macrostructural and microstructural damage in demented patients compared with controls.MethodsEighty-five participants were recruited: 65 with newly diagnosed Alzheimer’s disease (AD), non-AD dementia or mild cognitive impairment and 20 age-matched and sex-matched healthy controls. β-amyloid1-42 (Aβ) levels were determined in cerebrospinal fluid (CSF) samples from all patients and five controls. Among patients, 42 had pathological CSF Aβ levels (Aβ(+)), while 23 had normal CSF Aβ levels (Aβ(−)). All participants underwent neurological examination, neuropsychological testing and brain MRI. We used T2-weighted scans to quantify WM lesion loads (LLs) and diffusion-weighted images to assess their microstructural substrate. Non-parametric statistical tests were used for between-group comparisons and multiple regression analyses.ResultsWe found an increased WM-LL in Aβ(+) compared with both, healthy controls (p=0.003) and Aβ(−) patients (p=0.02). Interestingly, CSF Aβ concentration was the best predictor of patients’ WM-LL (r=−0.30, p<0.05) when using age as a covariate. Lesion apparent diffusion coefficient value was higher in all patients than in controls (p=0.0001) and correlated with WM-LL (r=0.41, p=0.001). In Aβ(+), WM-LL correlated with WM microstructural damage in the left peritrigonal WM (p<0.0001).ConclusionsWM damage is crucial in AD pathogenesis. The correlation between CSF Aβ levels and WM-LL suggests a direct link between amyloid pathology and WM macrostructural and microstructural damage.

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Biological Signatures of Alzheimer’s Disease

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200228095553 ◽

2020 ◽

Vol 20 (9) ◽

pp. 770-781 ◽

Cited By ~ 12

Author(s):

Poornima Sharma ◽

Anjali Sharma ◽

Faizana Fayaz ◽

Sharad Wakode ◽

Faheem H. Pottoo

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

White Matter ◽

Senile Plaque ◽

Senile Plaques ◽

Amyloid Deposition ◽

Immune Defense ◽

Amyloid Angiopathy ◽

Microvascular Changes ◽

Β Amyloid

Alzheimer’s disease (AD) is the most prevalent and severe neurodegenerative disease affecting more than 0.024 billion people globally, more common in women as compared to men. Senile plaques and amyloid deposition are among the main causes of AD. Amyloid deposition is considered as a central event which induces the link between the production of β amyloid and vascular changes. Presence of numerous biomarkers such as cerebral amyloid angiopathy, microvascular changes, senile plaques, changes in white matter, granulovascular degeneration specifies the manifestation of AD while an aggregation of tau protein is considered as a primary marker of AD. Likewise, microvascular changes, activation of microglia (immune defense system of CNS), amyloid-beta aggregation, senile plaque and many more biomarkers are nearly found in all Alzheimer’s patients. It was seen that 70% of Alzheimer’s cases occur due to genetic factors. It has been reported in various studies that apolipoprotein E(APOE) mainly APOE4 is one of the major risk factors for the later onset of AD. Several pathological changes also occur in the white matter which include dilation of the perivascular space, loss of axons, reactive astrocytosis, oligodendrocytes and failure to drain interstitial fluid. In this review, we aim to highlight the various biological signatures associated with the AD which may further help in discovering multitargeting drug therapy.

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Activation of CREB‐mediated autophagy by thioperamide ameliorates β‐amyloid pathology and cognition in Alzheimer’s disease

Aging Cell ◽

10.1111/acel.13333 ◽

2021 ◽

Vol 20 (3) ◽

Author(s):

Jiangong Wang ◽

Bin Liu ◽

Yong Xu ◽

Meizi Yang ◽

Chaoyun Wang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Pathology ◽

Β Amyloid

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Microglial and Astrocyte priming in the APP/PS1 model of Alzheimer’s Disease: increased vulnerability to acute inflammation and cognitive deficits

10.1101/344218 ◽

2018 ◽

Cited By ~ 5

Author(s):

Ana Belen Lopez-Rodriguez ◽

Edel Hennessy ◽

Carol Murray ◽

Anouchka Lewis ◽

Niamh de Barra ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Deficits ◽

Inflammasome Activation ◽

Nuclear Localisation ◽

Amyloid Pathology ◽

Model Of Alzheimer’S Disease ◽

Nlrp3 Inflammasome Activation ◽

Β Amyloid ◽

Secondary Stimulation

AbstractAlzheimer’s disease (AD) causes devastating cognitive decline and has no disease-modifying therapies. Neuroinflammation is a significant contributor to disease progression but its precise contribution remains unclear. An emerging literature indicates that secondary inflammatory insults including acute trauma and infection alter the trajectory of chronic neurodegenerative diseases and the roles of microglia and astrocytes require elucidation. The current study, using the APP/PS1 mouse model of AD, demonstrates that microglia are primed by β-amyloid pathology to induce exaggerated IL-1β responses to acute stimulation with LPS or IL-1β. Despite disease-associated NLRP3 inflammasome activation, evidenced by ASC speck formation, APP/PS1 microglial cells show neither IL-1β induction nor NFκB p65 nuclear localisation. Upon secondary stimulation with LPS or IL-1β, NFκB-p65 nuclear localisation and exaggerated pro-IL-1 induction occur. Microglial priming was also unmasked by secondary stimulation with systemic LPS leading to significant cognitive impairment in APP/PS1 mice compared to WT LPS-treated mice. Astrocytes have also recently emerged as displaying significant phenotypic heterogeneity. Here, by-passing microglial priming, and acutely challenging mice with intra-hippocampal IL-1β we demonstrate that astrocytes proximal to Aβ-plaques are also primed to produce exaggerated CCL2, CXCL1 and CXCL10 responses. Many astrocytosis-associated genes in APP/PS1 mice share these exaggerated responses to IL-1β, while others are equally induced in both strains. Collectively the data show that the amyloid-laden brain shows multiple vulnerabilities to secondary inflammatory challenge: both microglia and astrocytes are primed to produce exaggerated secondary inflammation and systemic LPS is sufficient to cause cognitive impairments relevant to delirium, selectively in animals with prior amyloid pathology.

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Unsaturated mannuronate oligosaccharide ameliorates β‐amyloid pathology through autophagy in Alzheimer’s disease cell models

Carbohydrate Polymers ◽

10.1016/j.carbpol.2020.117124 ◽

2021 ◽

Vol 251 ◽

pp. 117124

Author(s):

Decheng Bi ◽

Lijun Yao ◽

Zhijian Lin ◽

Lianli Chi ◽

Hui Li ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Models ◽

Amyloid Pathology ◽

Β Amyloid ◽

Disease Cell

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P4-590: DEEP OCCIPITAL WHITE MATTER HYPERINTENSITIES ARE ROBUSTLY RELATED TO AMYLOID PATHOLOGY AND MAY BE AN EARLY MARKER FOR ALZHEIMER'S DISEASE

Alzheimer s & Dementia ◽

10.1016/j.jalz.2019.08.138 ◽

2019 ◽

Vol 15 ◽

pp. P1548-P1549

Author(s):

Lene Pålhaugen ◽

Per Selnes ◽

Carole H. Sudre ◽

Sandra Tecelao ◽

Atle Bjornerud ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

White Matter ◽

White Matter Hyperintensities ◽

Amyloid Pathology ◽

Early Marker

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Cerebrospinal fluid A beta 1–40 peptides increase in Alzheimer’s disease and are highly correlated with phospho-tau in control individuals

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00696-1 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Sylvain Lehmann ◽

◽

Julien Dumurgier ◽

Xavier Ayrignac ◽

Cecilia Marelli ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Statistical Tests ◽

Storage Conditions ◽

Causal Link ◽

Strong Positive Correlation ◽

Amyloid Pathology ◽

Highly Correlated

Abstract Background Amyloid pathology, which is one of the characteristics of Alzheimer’s disease (AD), results from altered metabolism of the beta-amyloid (Aβ) peptide in terms of synthesis, clearance, or aggregation. A decrease in cerebrospinal fluid (CSF) level Aβ1–42 is evident in AD, and the CSF ratio Aβ42/Aβ40 has recently been identified as one of the most reliable diagnostic biomarkers of amyloid pathology. Variations in inter-individual levels of Aβ1–40 in the CSF have been observed in the past, but their origins remain unclear. In addition, the variation of Aβ40 in the context of AD studied in several studies has yielded conflicting results. Methods Here, we analyzed the levels of Aβ1–40 using multicenter data obtained on 2466 samples from six different cohorts in which CSF was collected under standardized protocols, centrifugation, and storage conditions. Tau and p-tau (181) concentrations were measured using commercially available in vitro diagnostic immunoassays. Concentrations of CSF Aβ1–42 and Aβ1–40 were measured by ELISA, xMAP technology, chemiluminescence immunoassay (CLIA), and mass spectrometry. Statistical analyses were calculated for parametric and non-parametric comparisons, linear regression, correlation, and odds ratios. The statistical tests were adjusted for the effects of covariates (age, in particular). Results Regardless of the analysis method used and the cohorts, a slight but significant age-independent increase in the levels of Aβ40 in CSF was observed in AD. We also found a strong positive correlation between the levels of Aβ1–40 and p-tau (181) in CSF, particularly in control patients. Conclusions These results indicate that an increase in the baseline level of amyloid peptides, which are associated with an increase in p-tau (181), may be a biological characteristic and possibly a risk factor for AD. Further studies will be needed to establish a causal link between increased baseline levels of Aβ40 and the development of the disease.

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