Cerebrospinal fluid ratios with Aβ
            42
            predict preclinical brain β‐amyloid accumulation

Abstract Background: Elucidation of the mechanism of β-amyloid accumulation plays an important role in therapeutic strategies for Alzheimer’s disease (AD). To elucidate the relationship between the function of the blood cerebrospinal fluid barrier (BCSFB) and the production and clearance of β-amyloid, we analyzed the changes in interstitial water flow into the CSF space from the cortex and β-amyloid accumulation in the cortex by using both [15O]H2O and [18F]flutemetamol PET over a 2-year follow-up period. Methods: Twenty-five normal older adult volunteers (13 males and 12 females, 60–81 years old) participated in this 2-year follow-up PET study. Water dynamics were analyzed using two indices in [15O]H2O PET, the influx ratio (IR) and drain rate (DR), and β-amyloid accumulation was assessed qualitatively by [18F]flutemetamol PET. Results: [15O]H2O PET examinations conducted initially and after 2 years showed no significant changes in both indices over the 2-year period (IR: 1.03 ± 0.21 and 1.02 ± 0.20, DR: 1.74 ± 0.43 and 1.67 ± 0.47, respectively). In [18F]flutemetamol PET, on the other hand, one of the 25 participants showed positive results and two showed positive changes after 2 years. In these three participants, the two indices of water dynamics showed low values at both periods (IR: 0.60 ± 0.15 and 0.60 ± 0.13, DR: 1.24 ± 0.12 and 1.11 ± 0.10). Conclusions: Our results indicated that BCSFB function disturbances could be followed by β-amyloid accumulation, because the reduced interstitial flow preceded amyloid accumulation in the positive-change subjects, and amyloid accumulation was not observed in the older adults with sufficiently high values for the two indices. In other words, adequate interstitial flow can potentially prevent amyloid accumulation. The current study confirms that disturbances in the proper clearance of β-amyloid by interstitial flow through the Virchow–Robin spaces into the CSF can play a significant role in senile plaque formation and ultimately the pathogenesis of AD. We believe that further elucidation of interstitial water flow will be the key to developing therapeutic strategies for AD, especially with regard to prevention.Trial registration: UMIN, UMIN000011939. Registered 1November 2013 - Retrospectively registered, http://www.umin.ac.jp/ctr/index.htm

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Effect of Patient-Specific Preanalytic Variables on CSF Aβ1–42 Concentrations Measured on an Automated Chemiluminescent Platform

The Journal of Applied Laboratory Medicine ◽

10.1093/jalm/jfaa145 ◽

2020 ◽

Author(s):

Jacqueline A Darrow ◽

Amanda Calabro ◽

Sara Gannon ◽

Amanze Orusakwe ◽

Rianne Esquivel ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Patient Specific ◽

Csf Biomarkers ◽

Clinical Settings ◽

Blood Contamination ◽

Gradient Effect ◽

Β Amyloid ◽

The Impact ◽

Gradient Effects

Abstract Background Cerebrospinal fluid (CSF) biomarkers are increasingly used to confirm the accuracy of a clinical diagnosis of mild cognitive impairment or dementia due to Alzheimer disease (AD). Recent evidence suggests that fully automated assays reduce the impact of some preanalytical factors on the variability of these measures. This study evaluated the effect of several preanalytical variables common in clinical settings on the variability of CSF β-amyloid 1–42 (Aβ1–42) concentrations. Methods Aβ1–42 concentrations were measured using the LUMIPULSE G1200 from both freshly collected and frozen CSF samples. Preanalytic variables examined were: (1) patient fasting prior to CSF collection, (2) blood contamination of specimens, and (3) aliquoting specimens sequentially over the course of collection (i.e., CSF gradients). Results Patient fasting did not significantly affect CSF Aβ1–42 levels. While assessing gradient effects, Aβ1–42 concentrations remained stable within the first 5 1-mL aliquots. However, there is evidence of a gradient effect toward higher concentrations over successive aliquots. Aβ1–42 levels were stable when fresh CSF samples were spiked with up to 2.5% of blood. However, in frozen CSF samples, even 0.25% blood contamination significantly decreased Aβ1–42 concentrations. Conclusions The preanalytical variables examined here do not have significant effects on Aβ1–42 concentrations if fresh samples are processed within 2 h. However, a gradient effect can be observed on Aβ1–42 concentrations after the first 5 mL of collection and blood contamination has a significant impact on Aβ1–42 concentrations once specimens have been frozen.

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Concurrent Treatment with Taxifolin and Cilostazol on the Lowering of β-Amyloid Accumulation and Neurotoxicity via the Suppression of P-JAK2/P-STAT3/NF-κB/BACE1 Signaling Pathways

PLoS ONE ◽

10.1371/journal.pone.0168286 ◽

2016 ◽

Vol 11 (12) ◽

pp. e0168286 ◽

Cited By ~ 20

Author(s):

So Youn Park ◽

Hae Young Kim ◽

Hee Jeong Park ◽

Hwa Kyoung Shin ◽

Ki Whan Hong ◽

...

Keyword(s):

Signaling Pathways ◽

Concurrent Treatment ◽

Amyloid Accumulation ◽

Β Amyloid

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Visual-discrimination learning ability and β-amyloid accumulation in the dog

Neurobiology of Aging ◽

10.1016/s0197-4580(98)00084-0 ◽

1998 ◽

Vol 19 (5) ◽

pp. 415-425 ◽

Cited By ~ 116

Author(s):

E. Head ◽

H. Callahan ◽

B.A. Muggenburg ◽

C.W. Cotman ◽

N.W. Milgram

Keyword(s):

Discrimination Learning ◽

Visual Discrimination ◽

Learning Ability ◽

Visual Discrimination Learning ◽

Amyloid Accumulation ◽

Β Amyloid

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Parkin reverses intracellular β-amyloid accumulation and its negative effects on proteasome function

Journal of Neuroscience Research ◽

10.1002/jnr.22178 ◽

2009 ◽

Vol 88 (1) ◽

pp. 167-178 ◽

Cited By ~ 52

Author(s):

Kenneth M. Rosen ◽

Charbel E.-H. Moussa ◽

Han-Kyu Lee ◽

Pravir Kumar ◽

Tohru Kitada ◽

...

Keyword(s):

Negative Effects ◽

Amyloid Accumulation ◽

Β Amyloid

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Pre-therapeutic Microglia Activation and Sex Determine Therapy Effects of Chronic Immunomodulation

10.1101/2021.05.30.445761 ◽

2021 ◽

Author(s):

Gloria Biechele ◽

Tanja Blume ◽

Maximilian Deussing ◽

Benedikt Zott ◽

Yuan Shi ◽

...

Keyword(s):

Spatial Learning ◽

Microglial Activation ◽

Translocator Protein ◽

Learning Performance ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Activated Microglia ◽

Ppar Γ ◽

Amyloid Accumulation ◽

Β Amyloid

Modulation of the innate immune system is emerging as a promising therapeutic strategy against Alzheimer's disease (AD). However, determinants of a beneficial therapeutic effect are ill-understood. Thus, we investigated the potential of 18 kDa translocator protein positron-emission-tomography (TSPO-PET) for assessment of microglial activation in mouse brain before and during chronic immunomodulation. Serial TSPO-PET was performed during five months of chronic microglia modulation by stimulation of peroxisome proliferator-activated receptor (PPAR)-γ with pioglitazone in two different mouse models of AD (PS2APP, AppNL-G-F). Using mixed statistical models on longitudinal TSPO-PET data, we tested for effects of therapy and sex on treatment response. We tested correlations of baseline with longitudinal measures of TSPO-PET, and correlations between PET results with spatial learning performance and β-amyloid accumulation of individual mice. Immunohistochemistry was used to determine the molecular source of the TSPO-PET signal. Pioglitazone-treated female PS2APP and AppNL-G-F mice showed attenuation of the longitudinal increases in TSPO-PET signal when compared to vehicle controls, whereas treated male AppNL-G-F mice showed the opposite effect. Baseline TSPO-PET strongly predicted changes in microglial activation in treated mice (R=-0.874, p<0.0001) but not in vehicle controls (R=-0.356, p=0.081). Reduced TSPO-PET signal upon treatment was associated with better spatial learning and higher fibrillar β-amyloid accumulation. Immunohistochemistry confirmed activated microglia to be the source of the TSPO-PET signal (R=0.952, p<0.0001). TSPO-PET represents a sensitive biomarker for monitoring of immunomodulation and closely reflects activated microglia. Pre-therapeutic assessment of baseline microglial activation and sex are strong predictors of individual immunomodulation effects and could serve for responder stratification.

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