Cerebrospinal fluid biomarkers in cardiac arrest survivors

Aim

The aim of this study was to investigate the levels of various cerebrospinal fluid (CSF) biomarkers related to neuronal damage, inflammation and amyloid β (Aβ) metabolism in patients resuscitated after an out-of-hospital cardiac arrest (CA).

Methods

CSF levels of neurofilament light protein (NFL), total tau (T-tau), hyperphosphorylated tau (P-tau), YKL-40, Aβ38, Aβ40, Aβ42, soluble amyloid precursor protein α and β (sAPPα and sAPPβ) were measured in 21 patients approximately two weeks after CA and in 21 age-matched neurologically healthy controls. The biomarker levels were also compared between patients with good and poor long-term clinical outcome according to Glasgow Outcome Scale (GOS), activities of daily living (ADL) and mini-mental state examination (MMSE), measuring neurologic function, daily functioning and cognitive function, respectively.

Results

Patients with CA had a very marked increase in the CSF levels of NFL, T-tau and YKL-40 as compared with controls. The levels were increased at about 1200, 700 and 100%, respectively. NFL and T-tau were significantly higher in patients with poor outcome according to all three outcome measures. Patients with poor outcome according to GOS and ADL had higher levels of YKL-40. Levels of Aβ38, Aβ40, Aβ42, sAPPα and sAPPβ were lower in patients with a low MMSE score. P-tau was not significantly altered.

Conclusions

Biomarkers reflecting neuronal damage and inflammation, but not so much Aβ metabolism, were significantly altered in patients after a CA, and the changes were more pronounced in the groups with poor outcome. This calls for future larger studies to determine the prognostic potential of these biomarkers.     

Lactate dehydrogenase predicts hypoxic ischaemic encephalopathy in newborn infants: a preliminary study

Background: Enzyme leakage as a result of hypoxia‐ischaemia induced cell damage in affected organs is seen together with hypoxic ischaemic encephalopathy (HIE) after perinatal asphyxia. Aim: To investigate whether plasma lactate dehydrogenase [LDH], alanine aminotransferase [ALT] and aspartate aminotransferase [AST] during the first 12 h after birth predict HIE and adverse neurodevelopment outcome in newborn term infants with intra‐partum signs of foetal distress. Methods: Enzymes were measured within 12 h post partum in newborn infants with differing degree of HIE (n = 41) and in infants with signs of foetal distress during birth (n = 205) without HIE (non‐HIE group). All infants were randomized into two groups. One group (n = 123) was used for calculation of cut off limits for the enzymes studied and the other group (n = 123) was used for calculation of the predictive value of the enzymes for detection of HIE. Results: Using ROC curves, a cut off level of 1049 U/L for [LDH] was the best predictor of HIE (sensitivity 100% and specificity 97%) but also for long term outcome after HIE. Conclusion: [LDH] is a good predictor of HIE during the first 12 h after birth. This result is of clinical interest offering a potential inexpensive and safe prognostic marker in newborn infants with perinatal asphyxia.     

Dissolution of type I collagen fibrils by gingival fibroblasts isolated from patients of various periodontitis categories

The classification of periodontitis in various disease categories, including juvenile periodontitis, rapidly progressive adult periodontitis and slowly progressive adult periodontitits is based mainly on differences in disease progresssion and age group susceptibility. Because dissolution of collagen fibers is an integral part of periodontal attachment loss, we investigated whether the clinical differences among these periodontitis/control groups are reflected in the collagen-degrading activity of gingival fibroblasts isolated from affected tissues. All fibroblast strains isolated from the 4 groups ( n =48) displayed cell-associated collagenolytic activity when seeded in contact with a reconstituted film of type I collagen fibrils. Cells from the control group ( n =14) dissolved the collagen fibril film twice as fast as those from each of the 3 disease groups (juvenile periodontitis ( n =13), rapidly progressive adult periodontitis ( n =7), and slowly progressive adult periodontitits ( n =14)). Both interleukin-1β and phorbolester accelerated the rate of dissolution 2–4-fold, but even after cytokine or phorbolester stimulation control cells were still considerably more effective in dissolving the collagen fibrils than cells from the disease groups. The observation made in this study, that dissolution of collagen fibrils by gingival fibroblasts from periodontally diseased individuals is significantly slower than by cells from healthy control subjects, challenges disease paradigm: based on a direct relationship between collagenolytic potential and disease activity.     

Longitudinal cerebrospinal fluid biomarkers over four years in mild cognitive impairment

Cerebrospinal fluid (CSF) measurements of amyloid-β42 (Aβ42), total-tau (T-tau), and phosphorylated tau (P-tau) may be used to predict future Alzheimer's disease (AD) dementia in patients with mild cognitive impairment (MCI). The precise temporal development of these biomarkers in relation to clinical progression is unclear. Earlier studies have been hampered by short follow-up. In an MCI cohort, we selected 15 patients who developed AD (MCI-AD) and 15 who remained cognitively stable during 4 years of follow-up. CSF was sampled at three serial occasions from each patient and analyzed for Aβ peptides, the soluble amyloid-β protein precursor protein fragments sAβPPα and sAβPPβ, T-tau, P-tau, and chromogranin B, which is a protein linked to regulated neuronal secretion. We also measured, for the first time in MCI patients, an extended panel of Aβ peptides by matrix-assisted-laser-desorption/ionization time-of-flight mass spectrometry (MS). Most biomarkers were surprisingly stable over the four years with coefficients of variation below or close to 10%. However, MCI-AD patients decreased in CSF AβX??? and chromogranin B concentrations, which may indicate a reduced number of functional neurons or synapses with disease progression. The MS Aβ peptide panel was more useful than any single Aβ peptide to identify MCI-AD patients already at baseline. Knowledge on these biomarkers and their trajectories may facilitate early diagnosis of AD and be useful in future clinical trials to track effects of disease modifying drugs.     

Plasma neurofilament light chain level is not a biomarker of Charcot–Marie–Tooth disease progression: Results of 3-year follow-up study

Background and purpose

Charcot–Marie–Tooth disease (CMT) is a hereditary, slowly progressive neuropathy. Currently, there are no effective pharmacological treatments or sensitive disease activity biomarkers available. The aim of this study was to demonstrate the change in plasma neurofilament light chain (NfL) over time in a CMT cohort and analyse the association between CMT severity and NfL level.

Methods

Initially, 101 CMT patients and 64 controls were enrolled in the study. Repeated evaluation was performed in 73 patients and 28 controls at a 3-year interval. Disease severity assessment included clinical evaluation with CMT Neuropathy Score version 2 (CMTNSv2). Plasma NfL concentration was measured using the Simoa (single molecule array) NfL assay.

Results

Plasma NfL concentration was increased in the CMT group compared with controls (p < 0.001). Overall NfL level increased over the 3-year interval in both CMT (p = 0.012) and control (p = 0.001) groups. However, in 22 of 73 CMT patients and seven of 28 controls, the NfL level decreased from the baseline. Analysing the association between 3-year change in plasma NfL and disease severity (CMTNSv2), there was no correlation in the CMT group (r = 0.228, p = 0.052) or different CMT subgroups.

Conclusions

Our study verifies increased plasma NfL concentrations in patients with CMT compared with controls. Longitudinal 3-year data showed a variable change in NfL levels between CMT subtypes. There was no association between change in NfL over time and disease severity. These findings suggests that NfL is not a biomarker for CMT progression.     

Araceae from the Early Cretaceous of Portugal: evidence on the emergence of monocotyledons

A new species (Mayoa portugallica genus novum species novum) of highly characteristic inaperturate, striate fossil pollen is described from the Early Cretaceous (Barremian-Aptian) of Torres Vedras in the Western Portuguese Basin. Based on comparison with extant taxa, Mayoa is assigned to the tribe Spathiphylleae (subfamily Monsteroideae) of the extant monocotyledonous family Araceae. Recognition of Araceae in the Early Cretaceous is consistent with the position of this family and other Alismatales as the sister group to all other monocots except Acorus. The early occurrence is also consistent with the position of Spathiphylleae with respect to the bulk of aroid diversity. Mayoa occurs in the earliest fossil floras (from circa 110 to 120 million years ago) that contain angiosperm flowers, carpels, and stamens. The new fossil provides unequivocal evidence of monocots in early angiosperm assemblages that also include a variety of key "magnoliid" lineages (e.g., Chloranthaceae) but only a limited diversity of eudicots.     

Advances in the detection of Alzheimer's disease-use of cerebrospinal fluid biomarkers

The diagnosis of Alzheimer's disease (AD) is still made by excluding other disorders with a similar clinical picture. In addition, an analysis of symptoms and signs, blood analyses and brain imaging are the major ingredients of the clinical diagnostic work-up. However, the sensitivity of a clinical diagnosis using these instruments is unsatisfactory and disease markers with high sensitivity and specificity for AD would be a welcome supplement. Ideally, such markers should reflect the pathophysiological mechanisms of AD, that is, according to the currently predominant hypothesis mismetabolism of beta-amyloid and neurofibrillary degeneration. Among several, we have focused on three candidates that have been suggested to fulfil the requirements for biomarkers of AD: beta-amyloid42 (Abeta42), total tau (T-tau) and tau phosphorylated at various epitopes (P-tau). The cerebrospinal fluid (CSF) levels of these proteins reflect the metabolism of these proteins in the central nervous system. Only published articles using established ELISA methods for the quantification of these markers in CSF and preferably also presenting sensitivity and specificity figures have been included in this review. The number of patients included in the different studies varies; some having included only a few patients. Furthermore, diagnostic criteria vary and clinicopathological studies are scarce. However, there are some large studies, including even minor studies, and most have found reduced CSF levels of Abeta42 and increased CSF levels of T-tau in AD. The sensitivity and specificity of these measures are high for separation of AD patients from controls, but their specificity against other dementias is moderate. It increases if P-tau is added. An increasing number of studies suggest that supplementary use of these CSF markers, preferably in combination, adds to the accuracy of an AD diagnosis.     

Confusional symptomatology distinguishes early- and late-onset Alzheimer's disease

Symptoms of confusion were examined in 75 patients with Alzheimer's disease (AD). Mild confusion was found in 20, and mode-rate/severe confusion in 8 patients. Confusion was more frequent in the late-onset (26/44-59%) than in the early-onset AD group (2/31-6%) (p less than 0.0001), and patients with confusion were older (p less than 0.0001) than those without confusion. The frequency of confusion was higher in patients with ischemic heart disease (13/28-46%) than in patients without this vascular factor (10/47-21%) (p less than 0.05). An inverse relation was found between confusional symptomatology and parietal-lobe symptoms. The findings in this study suggest that a subgroup of AD patients, fulfilling the NINCDS-ADRDA criteria for probable AD, is characterized by a clinical picture of mild confusional symptomatology together with no or mild parietal-lobe symptomatology, higher age and higher frequency of ischemic heart disease. This group contrasts with the other subgroup of pure AD, which is characterized by a clinical picture of marked parietal-lobe symptomatology, almost no confusional symptomatology, lower age and lower frequency of ischemic heart disease.