Blood-Brain Barrier Breakdown in Relationship to Alzheimer and Vascular Disease.

OBJECTIVE: Blood-brain barrier (BBB) breakdown has been suggested to be an early biomarker in human cognitive impairment. However, the relationship between BBB breakdown and brain pathology, most commonly Alzheimer disease (AD) and vascular disease, is still poorly understood. The present study measured human BBB function in mild cognitive impairment (MCI) patients on 2 molecular scales, specifically BBB's permeability to water and albumin molecules. METHODS: Fifty-five elderly participants were enrolled, including 33 MCI patients and 22 controls. BBB permeability to water was measured with a new magnetic resonance imaging technique, water extraction with phase contrast arterial spin tagging. BBB permeability to albumin was determined using cerebrospinal fluid (CSF)/serum albumin ratio. Cognitive performance was assessed by domain-specific composite scores. AD pathology (including CSF Aß and ptau) and vascular risk factors were examined. RESULTS: Compared to cognitively normal subjects, BBB in MCI patients manifested an increased permeability to small molecules such as water but was no more permeable to large molecules such as albumin. BBB permeability to water was found to be related to AD markers of CSF Aß and ptau. On the other hand, BBB permeability to albumin was found to be related to vascular risk factors, especially hypercholesterolemia, but was not related to AD pathology. BBB permeability to small molecules, but not to large molecules, was found to be predictive of cognitive function. INTERPRETATION: These findings provide early evidence that BBB breakdown is related to both AD and vascular risks, but their effects can be differentiated by spatial scales. BBB permeability to small molecules has a greater impact on cognitive performance. ANN NEUROL 2021;90:227-238.

Immunological investigations of the cerebrospinal fluid in patients with recent onset psychotic disorders: A study protocol.

BACKGROUND: Though many previous studies have indicated immunological alterations in psychotic disorders, the role and prevalence of neuroinflammation is still unknown. Studies previously investigating immune related biomarkers in the cerebrospinal fluid (CSF) of these patients are mainly small studies on few markers, and many have not compared patients to healthy controls. METHODS: We will conduct a large case-control study including at least 100 patients with recent onset psychotic disorders and 100 sex- and age matched healthy controls. The cases will include patients diagnosed with a psychotic disorder according to ICD-10 (F20/F22-29) within a year prior to inclusion. We will collect both CSF, blood and fecal samples, to gain insight into possible immunological alterations. The psychopathology of all participants will thoroughly be evaluated using the SCAN interview, and multiple rating scales covering different symptom groups. All participants will partake in a detailed neurological examination, including the Neurological Evaluation Scale assessing neurological soft signs. Additionally, we will assess cognitive functioning, evaluate quality of life and level of functioning, and collect data on a broad array of possible confounders. Our primary outcomes will include CSF leucocytes, CSF/serum albumin ratio, CSF total protein, IgG index, CSF levels of IL-6 and IL-8, and presence of antineuronal autoantibodies in CSF and blood. For our secondary outcomes, exploratory analyses will be performed on a broader panel of neuroimmunological markers. All participants will be invited for a follow-up visit to assess longitudinal changes. The current study is part of a larger CSF biobank build-up for severe mental disorders (PSYCH-FLAME). DISCUSSION: This study will represent the largest investigation of CSF in patients with psychotic disorders compared to healthy controls to date. We expect the study to contribute with new, important knowledge on pathophysiological mechanisms, and to help pave the way for future investigations of individualized treatment options. TRIAL REGISTRATION: The study is approved by The Regional Committee on Health Research Ethics (Capital Region, j.no: H-16030985) and The Danish Data Protection Agency (j.no: RHP-2016-020, I-Suite no.: 04945).

Study on the timing of severe blood-brain barrier disruption using cerebrospinal fluid-serum albumin quotient in post cardiac arrest patients treated with targeted temperature management.

AIM: We aimed to evaluate the onset of severe blood-brain barrier (BBB) disruption using cerebrospinal fluid/serum albumin quotient (Qa) in cardiac arrest patients treated with target temperature management (TTM). METHODS: This was a prospective single-centre observational cohort study from October 2017 to September 2018 with the primary endpoint being the onset of severe BBB disruption, determined based on Qa in cardiac arrest patients treated with TTM. Enrolled patients were grouped according to neurologically good and poor outcomes using the cerebral performance category (CPC) at 3 months after return of spontaneous circulation (ROSC). Severe BBB disruption was evaluated using Qa measured immediately (Qa0) and at 24 h (Qa24), 48 h (Qa48), 72 h (Qa72) after ROSC. RESULTS: Of 21 patients enrolled, poor outcome group had 10 patients. Qa0 was 0.019 (0.008∼0.024) in the poor outcome group and 0.006 (0.003∼0.008) in the good outcome group (p = 0.09). Qa24 was 0.045 (0.025∼0.115) in the poor outcome group and 0.006 (0.003∼0.006) in the good outcome group (p = 0.03). Qa48 was 0.055 (0.023∼0.276) in the poor outcome group and 0.006 (0.006∼0.009) in the good outcome group (p = 0.02). Qa72 was 0.047 (0.026∼0.431) in the poor outcome group and 0.007 (0.005∼0.011) in the good outcome group (p = 0.02). CONCLUSION: Qa was significantly higher in the poor outcome group at 24 h, 48 h, and 72 h. Severe BBB disruption indicated by Qa ≥ 0.02 in poor outcome group treated with TTM occurred within the first 24 h after ROSC.

Evaluation of Cobas 8000® for the quantification of albumin and IgG in serum and cerebrospinal fluid.

According to the 2017 revised McDonald criteria, the presence of oligoclonal bands (OCB) at isoelectric focusing (IEF) is useful for the diagnosis of Multiple Sclerosis (MS), including relapsing-remitting MS and primary progressive MS. In this context, the quantification of IgG in serum and CSF is required for IEF execution (to deposit the same amount of IgG in serum and CSF), while the quantification of albumin in serum and CSF allows the calculation of the albumin quotient. We have evaluated the analytical performances of Cobas 8000® analyzer for the quantification of albumin and IgG in serum and CSF. Coefficients of variation were below 3.3% for within-run precision and below 3.1% for between-run precision. Results were similar or better than those obtained on nephelometer Immage 800® and turbidimeter SPAPLUS®. The uncertainty of quantification of IgG in CSF was 9% and that of albumin in CSF was 12%. IgG and albumin measured on Cobas 8000® in serum and CSF showed good agreement with results obtained on the nephelometer Immage 800®, including for the classification of albumin quotient and CSF IgG index as normal or pathological. Therefore, Cobas 8000® is a valuable tool for the quantification of IgG and albumin in CSF, in the context of diagnosis of MS and other inflammatory disease affecting the central nervous system.