Kaj Blennow

Tau proteins in serum predict neurological outcome after hypoxic brain injury from cardiac arrest: Results of a pilot study

OBJECTIVE To conduct a pilot study to evaluate the prognostic potential of serum tau protein measurements to predict neurological outcome 6 months following resuscitation from cardiac arrest. METHODS In this retrospective observational study, we employed a new ultra sensitive digital immunoassay technology to examine serial serum samples from 25 cardiac arrest patients to examine tau release into serum as a result of brain hypoxia, and probe for its significance predicting six-month neurological outcome. Serial blood samples were obtained from resuscitated cardiac arrest survivors during their first five days in an intensive care unit, and serum total tau was measured. Cerebral function assessments were made using Cerebral Performance Categorization (CPC) at discharge from the ICU and six months later. Tau data were analyzed in the context of 6-month CPC scores. RESULTS Tau elevations ranged from modest (<10 pg/mL) to very high (hundreds of pg/mL), and exhibited unexpected bi-modal kinetics in some patients. Early tau elevations appeared within 24h of cardiac arrest, and delayed elevations appeared after 24-48 h. In patients with delayed elevations, areas under the curves of tau concentration vs. hours since cardiac arrest were highly predictive of 6-month outcome (P<0.0005). CONCLUSION High-sensitivity serum tau measurements combined with an understanding of tau release kinetics could have utility for hypoxic brain injury assessment and prediction of cerebral function outcome.

Increased CSF-BACE 1 activity is associated with ApoE-ε4 genotype in subjects with mild cognitive impairment and Alzheimer's disease

The Apolipoprotein (ApoE) epsilon 4 allele is a major genetic risk factor of Alzheimers disease, and may affect the production of amyloid beta (A beta(1-42)). Recently, we have shown that beta-secretase (BACE 1) activity can be reliably detected within the brain and human CSF. Here, we have examined an association between the ApoE genotype and CSF-levels of BACE 1 activity in Alzheimers disease and mild cognitive impairment (MCI). A total of 148 subjects were included: 60 Alzheimers disease patients, 51 MCI subjects and 37 elderly healthy controls. The CSF-levels of A beta(1-42), BACE 1 activity and BACE protein were measured in all of these subjects. The differences between ApoE-epsilon 4 carriers and ApoE-epsilon 4 non-carriers in these CSF-based measures were determined controlling for gender, age and MMSE score. The ApoE-epsilon 4 genotype was associated with increased BACE 1 activity in both Alzheimers disease (P = 0.03) and MCI (P = 0.04) subjects. Levels of A beta(1-42) were decreased in ApoE-epsilon 4 carriers in MCI (P = 0.004) but not Alzheimers disease subjects. This study is the first to demonstrate the association between ApoE-epsilon 4 and CSF-BACE 1 activity in MCI and Alzheimers disease subjects. The assessment of BACE 1 in CSF may provide a sensitive measure to detect in vivo alterations in the amyloidogenic processing potentially modified by the ApoE genotype.

Mitochondrial Function is Differentially Altered in the Basal Ganglia of Chronic Schizophrenics

In the present study, we have applied a novel strategy involving the postmortem measurement of the mitochondrial respiratory chain enzyme cytochrome-c oxidase (COX; complex IV) to identify regional changes in energy metabolism in the basal ganglia of chronic, medicated schizophrenics. COX activity was decreased in the caudate nucleus but increased in the putamen and nucleus accumbens. An increase in succinate dehydrogenase (complex II) was evident in the putamen and nucleus accumbens, but changes were not seen with NADH dehydrogenase (complex I). An analysis of interregional correlations in energy metabolism revealed several anomalies in the connections between the caudate and putamen and the globus pallidus in schizophrenics. Results provide strong evidence that changes in baseline energy metabolism in specific regions of the basal ganglia may exist in the disease. Based upon the high degree of input it receives from associative cortical areas, results suggest that a defect in the caudate may underlie certain aspects of cognitive decline in schizophrenics. In contrast, an increase in COX in the putamen, which receives extensive projections from the sensorimotor cortex, may reflect an effect of chronic neuroleptic treatment on motor function.

Antihypertensive Therapy Is Associated with Reduced Rate of Conversion to Alzheimer's Disease in Midregional Proatrial Natriuretic Peptide Stratified Subjects with Mild Cognitive Impairment

BACKGROUND Hypertension is a major risk factor of Alzheimers disease (AD); however, controlled studies on the effect of antihypertensive treatment on the risk of dementia are inconclusive. Therefore, a biological marker that predicts individual response to antihypertensive treatment would be of high clinical relevance. Midregional proatrial natriuretic peptide (MR-proANP), an inactive surrogate molecule of the mature atrial natriuretic peptide, is related to circulatory function and hypertension. METHODS A sample population of 134 subjects with mild cognitive impairment (MCI) was followed for up to 6 years. Multivariable Cox regression analysis was conducted to predict conversion to AD based on all relevant variables. RESULTS Baseline MR-proANP was significantly increased in the AD converter group (p < .0001). The conversion rate of patients treated with antihypertensive drugs was significantly reduced only in patients with elevated MR-proANP at baseline (p = .046). Using an optimized MR-proANP cutoff of 74 pmol/L, representing a value in the upper normal range, treatment with antihypertensive drugs reduced the conversion rate to AD by 36% (p = .035) for patients with levels >74 pmol/L. Further subgrouping by age (>/≤ 72 years at baseline) increased the positive correlation of antihypertensive treatment and MCI outcome for patients below the age of 72 years (conversion rate reduced by 74%, p = .016). CONCLUSIONS These data seem to support the notion of a potential impact of circulatory function for the prognosis of AD at a prodromal stage. The MR-proANP levels may be useful to predict the effect of antihypertensive treatment on conversion rates to AD in subjects with MCI.

Total-tau and neurofilament light in CSF reflect spinal cord ischaemia after endovascular aortic repair.

BACKGROUND Repair of extensive aortic disease may be associated with spinal cord ischaemia (SCI). Here we test if levels of cerebrospinal fluid (CSF) biomarkers for neuronal injury are altered in patients with SCI after advanced endovascular repair in extensive aortic disease. METHODS CSF was sampled for up to 48 h in ten patients undergoing endovascular aortic repair and analyzed for the axonal damage markers total-tau (T-tau) and neurofilament light (NFL). RESULTS Six of ten patients developed SCI (clinically present within 3-6 h). CSF levels of NFL increased up to 37-fold in patients with, but were stable in patients without, SCI. CSF levels of T-tau also increased in patients with SCI, but with some overlap with patients without SCI. Levels of NFL and T-tau did not increase until after the appearance of clinical signs of neurological dysfunction (12-48 h after aortic repair). CONCLUSIONS The CSF biomarkers NFL and T-tau both reflect development of SCI after endovascular aortic repair, but do not rise until after clinical signs of SCI appear. Future studies are desirable to further evaluate potential use of these biomarkers for assessment of the severity of SCI, and also to identify earlier biomarkers of SCI.

Additional file 1: Figure S1. of Ex vivo 18O-labeling mass spectrometry identifies a peripheral amyloid β clearance pathway

MALDI-TOF MS CSF Aβ peptide patterns of a patient (A) in the acute phase of BM and (B) after antibiotic treatment. (PPTX 74 kb)

Update on fluid biomarkers for concussion

Concussions are difficult to diagnose and symptoms may not appear immediately. As an accurate initial diagnosis has profound implications for the clinical management, there is an unmet need for better diagnostic tools. Fluid biomarkers for CNS injury may represent such tools. These markers are often proteins, peptides or other molecules with selective or high expression in the brain, which can be measured in the cerebrospinal fluid or blood as they leak out or get secreted into the biofluid in response to the injury. Here, we review the literature on fluid markers of neuronal, axonal and astroglial injury and response mechanisms to diagnose CNS injury upon head impact and to determine when the injurious process has resolved.