Blood Cerebrospinal Fluid Barrier Function Disturbance can be Followed by β-amyloid Accumulation

Mapping Intimacies ◽

10.21203/rs.3.rs-880043/v1 ◽

2021 ◽

Author(s):

Yuji Suzuki ◽

Yukimi Nakamura ◽

Hironaka Igarashi

Keyword(s):

Cerebrospinal Fluid ◽

Water Flow ◽

Interstitial Water ◽

Therapeutic Strategies ◽

Water Dynamics ◽

Interstitial Flow ◽

Amyloid Accumulation ◽

Β Amyloid ◽

Two Indices

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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Three-year follow-up of cerebrospinal fluid tau, β-amyloid 42 and 40 concentrations in Alzheimer's disease

Neuroscience Letters ◽

10.1016/s0304-3940(00)00767-9 ◽

2000 ◽

Vol 280 (2) ◽

pp. 119-122 ◽

Cited By ~ 72

Author(s):

Tero Tapiola ◽

Tuula Pirttilä ◽

Mia Mikkonen ◽

Pankaj D. Mehta ◽

Irina Alafuzoff ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Β Amyloid

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

Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring ◽

10.1016/j.dadm.2015.11.006 ◽

2015 ◽

Vol 2 (1) ◽

pp. 27-38 ◽

Cited By ~ 19

Author(s):

Annie M. Racine ◽

Rebecca L. Koscik ◽

Christopher R. Nicholas ◽

Lindsay R. Clark ◽

Ozioma C. Okonkwo ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Amyloid Accumulation ◽

Β Amyloid

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Faculty Opinions recommendation of Ten-year follow-up survival of the Medicine, Angioplasty, or Surgery Study (MASS II): a randomized controlled clinical trial of 3 therapeutic strategies for multivessel coronary artery disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.5147956.5084054 ◽

2010 ◽

Author(s):

Johnson Francis

Keyword(s):

Coronary Artery Disease ◽

Clinical Trial ◽

Coronary Artery ◽

Therapeutic Strategies ◽

Controlled Clinical Trial ◽

Randomized Controlled Clinical Trial ◽

Multivessel Coronary Artery Disease ◽

Randomized Controlled ◽

Artery Disease

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Extremely Elevated Cerebrospinal Fluid Protein and Glucose Level in a Neonate with Hypernatremic Dehydration

Journal of Pediatric Neurology ◽

10.1055/s-0040-1708496 ◽

2020 ◽

Author(s):

Arti Maria ◽

Tapas Bandyopadhyay

Keyword(s):

Cerebrospinal Fluid ◽

Neurodevelopmental Outcome ◽

Neurological Sequelae ◽

Glucose Levels ◽

Csf Analysis ◽

First Case ◽

Time Of Admission ◽

Cerebrospinal Fluid Protein ◽

Hypernatremic Dehydration

AbstractWe describe the case of a term newborn who presented with hypernatremic dehydration on day 19 of life. The baby was otherwise hemodynamically stable with no evidence of focal or asymmetric neurological signs. The laboratory tests at the time of admission were negative except for hypernatremia and the extremely elevated levels of cerebrospinal fluid (CSF) protein (717 mg/dL) and glucose levels (97 mg/dL). The hypernatremic dehydration was corrected as per the unit protocol over 48 hours. Repeat CSF analysis done after 5 days showed normalization of the protein and glucose levels. Serial follow-up and neuroimaging showed no evidence of neurological sequelae. Unique feature of our case is this is the first case reporting such an extreme elevation of CSF protein and glucose levels that have had no bearing on neurodevelopmental outcome at 1 month and 3 months of follow-up.

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346. Eastern Equine Encephalitis and Use of Intravenous Immunoglobulin Therapy and High-Dose Steroids

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.541 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S242-S243

Author(s):

Sarah I Collens ◽

Douglas R Wilcox ◽

Shibani Mukerji ◽

Farrah J Mateen ◽

Isaac H Solomon

Keyword(s):

Cerebrospinal Fluid ◽

Temporal Lobe ◽

Standard Of Care ◽

High Dose ◽

High Morbidity ◽

Intravenous Immunoglobulin Therapy ◽

Eastern Equine Encephalitis ◽

Neuroanatomical Region ◽

Ivig Administration

Abstract Background Eastern equine encephalitis (EEE) is a mosquito-borne viral infection with significant neurological morbidity and mortality. The clinical presentation and patient outcomes after treatment with IVIG, high-dose steroids, or standard of care alone in EEE remains unclear. Methods A retrospective observational study of patients admitted to two tertiary academic medical centers in Boston, Massachusetts with EEE from 2005 to 2019. Results Of 17 patients (mean [SD] age, 50 [26] years; 10 (59%) male, and 16 (94%) White race), 17 patients had fever (100%), 15 had encephalopathy (88%), and 12 had headache (71%). Eleven of 14 patients with cerebrospinal fluid (CSF) cell count differential had a neutrophil predominance (mean [SD], 60.6% of white blood cells [22.8]) with an elevated protein level (mean [SD], 112 mg/dL [48.8]). Affected neuroanatomical regions included the basal ganglia (n=9/17), thalamus (n=7/17), and mesial temporal lobe (n=7/17). A total of 11 patients (65%) received IVIG; 8 (47%) received steroids. Of the patients who received IVIG, increased time from hospital admission to IVIG administration correlated with worse long-term disability as assessed by modified Rankin Score (mRS) (r=0.72, p=0.02); steroid use was not associated with mRS score. The mortality was 12%. Figure 1. Imaging Characteristics: Typical Pattern of MRI Involvement and Affected Neuroanatomical Regions in Patients with Eastern Equine Encephalitis. All images displayed are the T2-FLAIR sequence. (A) Representative images of pattern of typical neuroanatomical region involved in one patient with demonstrated involvement of the temporal lobe and pons, temporal lobe and midbrain, and basal gangial by T2-FLAIR hyperintensity (panels left to right). (B) Representative images of patients with mild (mRS 0–2), moderate (mRS 3–4), and severe (mRS 5–6) disability score at discharge. (C) Representative images of one patient over course of hospitalization at days 1, 4, and 10 after admission. (D) Quantification of neuroanatomical region involvement in initial MRI of patients with EEE as determined by T2-FLAIR hyperintensity. An area was scored as abnormal only once per patient. Figure 2. Outcomes in Patients with Eastern Equine Encephalitis. Patient disability by modified Rankin Score (mRS) of EEE patients at admission to the hospital, discharge from the hospital, and last recorded follow-up (A). Time to IVIG administration compared to mRS at discharge (B), and most recent clinical follow-up (C). Table 1. Demographics, Clinical Characteristics, and Laboratory Data in Patients with Eastern Equine Encephalitis. Abbreviations: CSF = cerebrospinal fluid, WBC = white clood count, EEG = electroencephalogram, ALT = alanine aminotransferase, AST = aspartate transaminase. Demographic data was collected for all patients with confirmed EEE. Altered mental status included any description of encephalopathy, confusion, or difficulty with attention. Seizures were defined as clinical events with a high-degree of suspicion to be true seizures, and were entirely comprised of generalized tonic-clonic seizures. Conclusion Clinicians should suspect EEE in immunocompetent patients with early subcortical neuroimaging abnormalities and CSF neutrophilic predominance. This study suggests a lower mortality than previously reported, but a high morbidity rate in EEE. IVIG as an adjunctive to standard of care may be considered early during hospitalization. Disclosures All Authors: No reported disclosures

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Association of weight change with cerebrospinal fluid biomarkers and amyloid positron emission tomography in preclinical Alzheimer’s disease

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00781-z ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Oriol Grau-Rivera ◽

◽

Irene Navalpotro-Gomez ◽

Gonzalo Sánchez-Benavides ◽

Marc Suárez-Calvet ◽

...

Keyword(s):

Positron Emission Tomography ◽

Weight Loss ◽

Cerebrospinal Fluid ◽

Weight Change ◽

Emission Tomography ◽

Link Type ◽

Preclinical Ad ◽

Positron Emission ◽

T Tau

Abstract Background Recognizing clinical manifestations heralding the development of Alzheimer’s disease (AD)-related cognitive impairment could improve the identification of individuals at higher risk of AD who may benefit from potential prevention strategies targeting preclinical population. We aim to characterize the association of body weight change with cognitive changes and AD biomarkers in cognitively unimpaired middle-aged adults. Methods This prospective cohort study included data from cognitively unimpaired adults from the ALFA study (n = 2743), a research platform focused on preclinical AD. Cognitive and anthropometric data were collected at baseline between April 2013 and November 2014. Between October 2016 and February 2020, 450 participants were visited in the context of the nested ALFA+ study and underwent cerebrospinal fluid (CSF) extraction and acquisition of positron emission tomography images with [18F]flutemetamol (FTM-PET). From these, 408 (90.1%) were included in the present study. We used data from two visits (average interval 4.1 years) to compute rates of change in weight and cognitive performance. We tested associations between these variables and between weight change and categorical and continuous measures of CSF and neuroimaging AD biomarkers obtained at follow-up. We classified participants with CSF data according to the AT (amyloid, tau) system and assessed between-group differences in weight change. Results Weight loss predicted a higher likelihood of positive FTM-PET visual read (OR 1.27, 95% CI 1.00–1.61, p = 0.049), abnormal CSF p-tau levels (OR 1.50, 95% CI 1.19–1.89, p = 0.001), and an A+T+ profile (OR 1.64, 95% CI 1.25–2.20, p = 0.001) and was greater among participants with an A+T+ profile (p < 0.01) at follow-up. Weight change was positively associated with CSF Aβ42/40 ratio (β = 0.099, p = 0.032) and negatively associated with CSF p-tau (β = − 0.141, p = 0.005), t-tau (β = − 0.147 p = 0.004) and neurogranin levels (β = − 0.158, p = 0.002). In stratified analyses, weight loss was significantly associated with higher t-tau, p-tau, neurofilament light, and neurogranin, as well as faster cognitive decline in A+ participants only. Conclusions Weight loss predicts AD CSF and PET biomarker results and may occur downstream to amyloid-β accumulation in preclinical AD, paralleling cognitive decline. Accordingly, it should be considered as an indicator of increased risk of AD-related cognitive impairment. Trial registration NCT01835717, NCT02485730, NCT02685969.

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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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