Iron and Neurodegeneration in Multiple Sclerosis

Increased iron deposition might be implicated in multiple sclerosis (MS). Recent development of MRI enabled to determine brain iron levels in a quantitative manner, which has put more interest on studying the role of iron in MS. Evidence for abnormal iron homeostasis in MS comes also from analyses of iron and iron-related proteins in CSF and blood and postmortem MS brain sections. However, it is not yet clear if iron accumulation is implicated in MS pathology or merely reflects an epiphenomenon. Further interest has been generated by the idea of chronic cerebrospinal venous insufficiency that might be associated with brain iron accumulation due to a reduction in venous outflow, but its existence and etiologic role in MS are currently controversially debated. In future studies, combined approaches applying quantitative MRI together with CSF and serum analyses of iron and iron-related proteins in a clinical followup setting might help to elucidate the implication of iron accumulation in MS

Standardization of Assay Procedures for Analysis of the CSF Biomarkers Amyloid β(1-42), Tau, and Phosphorylated Tau in Alzheimer's Disease: Report of an International Workshop

Large variation in assay performance and outcomes of CSF Aβ1-42, total Tau (Tau), and phosphorylated Tau (pTau) (at amino acid 181) levels is observed between laboratories. The aim of this study was to assess the differences in assay procedures between several experienced international laboratories, as potential sources of error. 14 groups performed the Aβ42, Tau, and pTau assays according to the guidelines of the manufacturer. Differences in analytical procedures between the laboratories were monitored. At least 23 items in assay procedures were identified that varied between the laboratories, including procedures for washing, pipetting, incubation, finishing, and sample handing. In general, the inter- and intra-assay variation between the groups was generally below 10% for all three assays. We concluded that 17 international centers that use the same assays for Aβ42, Tau and pTau on a regular basis do not uniformly adhere to the procedures recommended by the manufacturer. For harmonization of intercenter results of these biomarkers standardization of protocols is highly needed

Classically and alternatively activated bone marrow derived macrophages differ in cytoskeletal functions and migration towards specific CNS cell types

<p>Abstract</p> <p>Background</p> <p>Macrophages play an important role in neuroinflammatory diseases such as multiple sclerosis (MS) and spinal cord injury (SCI), being involved in both damage and repair. The divergent effects of macrophages might be explained by their different activation status: classically activated (CA/M1), pro-inflammatory, macrophages and alternatively activated (AA/M2), growth promoting, macrophages. Little is known about the effect of macrophages with these phenotypes in the central nervous system (CNS) and how they influence pathogenesis. The aim of this study was therefore to determine the characteristics of these phenotypically different macrophages in the context of the CNS in an <it>in vitro </it>setting.</p> <p>Results</p> <p>Here we show that bone marrow derived CA and AA macrophages have a distinct migratory capacity towards medium conditioned by various cell types of the CNS. AA macrophages were preferentially attracted by the low weight (< 10 kD) fraction of neuronal conditioned medium, while CA macrophages were attracted in higher numbers by astrocyte- and oligodendrocyte conditioned medium. Intrinsic motility was twice as high in AA macrophages compared to CA macrophages. The adhesion to extracellular matrix molecules (ECM) was significantly enhanced in CA macrophages compared to control and AA macrophages. The actin cytoskeleton was differentially organized between CA and AA macrophages, possibly due to greater activity of the GTPases RhoA and Rac in CA macrophages. Phagocytosis of myelin and neuronal fragments was increased in CA macrophages compared to AA macrophages. The increase in myelin phagocytosis was associated with higher expression of CR3/MAC-1 in CA macrophages.</p> <p>Conclusion</p> <p>In conclusion, since AA macrophages are more motile and are attracted by NCM, they are prone to migrate towards neurons in the CNS. CA macrophages have a lower motility and a stronger adhesion to ECM. In neuroinflammatory diseases the restricted migration and motility of CA macrophages might limit lesion size due to bystander damage.</p

Association of Education and Intracranial Volume With Cognitive Trajectories and Mortality Rates Across the Alzheimer Disease Continuum

OBJECTIVE: To investigate relationships of education and intracranial volume (factors related to cognitive versus brain reserve, respectively) with cognitive trajectories and mortality in individuals with biomarker-defined Alzheimer's disease (AD). METHODS: We selected 1,298 amyloid-β-positive memory clinic patients with subjective cognitive decline (SCD, n=142), mild cognitive impairment (MCI, n=274) and AD dementia (n=882) from the Amsterdam Dementia Cohort. All participants underwent baseline MRI and neuropsychological assessment, and 68% received cognitive follow-up (median=2.3 years, interquartile range=2.4). Mortality data were collected from the Central Public Administration. In the total sample and stratified by disease stage (i.e., SCD/MCI versus dementia), we examined education and intracranial volume as predictors of baseline and longitudinal cognitive performance on five cognitive domains [memory, attention, executive, language and visuospatial functions] (linear mixed models) and time-to-death (Cox proportional hazard models). Analyses were adjusted for age, sex, whole-brain gray matter atrophy and MRI field strength. RESULTS: Education and intracranial volume showed consistent positive associations with baseline cognition across disease stages. Longitudinally, we observed a relationship between higher education and faster cognitive decline among dementia patients on global cognition, memory, executive function and language (range β=-0.06-[-0.13], all p<0.05). Furthermore, in the total sample, both higher education and intracranial volume related to lower mortality risk (hazard ratio=0.84 and 0.82, respectively, p<0.05). CONCLUSIONS: In this amyloid-β-positive memory clinic sample, both reserve factors were positively associated with baseline cognition, whereas only education related to longitudinal cognition (i.e., accelerated decline among higher-educated patients with dementia). Moreover, higher education and intracranial volume both moderately attenuated overall mortality risk in AD

The effectiveness of aerobic training, cognitive behavioural therapy, and energy conservation management in treating MS-related fatigue: The design of the TREFAMS-ACE programme

Background: TREFAMS is an acronym for TReating FAtigue in Multiple Sclerosis, while ACE refers to the rehabilitation treatment methods under study, that is, Aerobic training, Cognitive behavioural therapy, and Energy conservation management. The TREFAMS-ACE research programme consists of four studies and has two main objectives: (1) to assess the effectiveness of three different rehabilitation treatment strategies in reducing fatigue and improving societal participation in patients with MS; and (2) to study the neurobiological mechanisms of action that underlie treatment effects and MS-related fatigue in general.Methods/Design: Ambulatory patients (n = 270) suffering from MS-related fatigue will be recruited to three single-blinded randomised clinical trials (RCTs). In each RCT, 90 patients will be randomly allocated to the trial-specific intervention or to a low-intensity intervention that is the same for all RCTs. This low-intensity intervention consists of three individual consultations with a specialised MS-nurse. The trial-specific interventions are Aerobic Training, Cognitive Behavioural Therapy, and Energy Conservation Management. These interventions consist of 12 individual therapist-supervised sessions with additional intervention-specific home exercises. The therapy period lasts 16 weeks. All RCTs have the same design and the same primary outcome measures: fatigue - measured with the Checklist Individual Strength, and participation - measured with the Impact on Participation and Autonomy questionnaire. Outcomes will be assessed 1 week prior to, and at 0, 8, 16, 26 and 52 weeks after randomisation. The assessors will be blinded to allocation. Pro- and anti-inflammatory cytokines in serum, salivary cortisol, physical fitness, physical activity, coping, self-efficacy, illness cognitions and other determinants will be longitudinally measured in order to study the neurobiological mechanisms of action.Discussion: The TREFAMS-ACE programme is unique in its aim to assess the effectiveness of three rehabilitation treatments. The programme will provide important insights regarding the most effective tre

Food purchasing and preparation patterns by gender during the COVID-19 lockdown in Chilean workers/Patrones de compra y preparación de alimentos según género durante la cuarentena por COVID-19 en trabajadores chilenos

The COVID-19 pandemic has increased the demands that workers face regarding household food-related tasks, such as grocery shopping and cooking. The literature shows that there are differences in these demands by gender, but also based on other sociodemographic characteristics, such as schooling level. The aim of this study was to compare food purchasing and preparation patterns by gender in Chilean workers, before the COVID-19 lockdown and during the first six weeks of lockdown. The study was cross-sectional, and data was collected for the first wave of a multi-country study in April 2020. The sample was composed of 317 participants who were employed during lockdown (67.8% women, mean age of 38.14). Participants answered sociodemographic questions and reported their food purchasing and preparing practices before and during lockdown. Analysis of comparison of proportions was used. On average, during lockdown, men increased their involvement in grocery shopping while women cooked more. Overall, female workers have turned to food-related tasks more often during the pandemic than male workers. This study shows the extent to which workers have changed their degree of involvement in food-related tasks, accounting for conditions such as gender roles, schooling level and working from home. These findings can inform interventions and policies that reinforce advantageous changes brought on by lockdown measures (e.g., home-cooking) to contribute to workers’ and their families’ food-related well-being during and in the aftermath of the pandemic

N-acetylaspartic acid in cerebrospinal fluid of multiple sclerosis patients determined by gas-chromatography-mass spectrometry

Background: Axonal degeneration is considered to play a major role in the development of clinical disability in multiple sclerosis (MS). N-AcetylAspartic Acid (NAA) is a neuron-specific marker constantly identified in MR-spectroscopy studies of the normal and MS brain. To our knowledge there are no studies available that evaluated NAA in cerebrospinal fluid (CSF) as a possible marker for disease severity. Objective: To evaluate CSF concentrations of NAA in MS in relation to disease phenotype, clinical measures of disability and MRI markers of disease burden. Methods: NAA concentrations were determined in CSF of 46 patients with MS (26 relapsing remitting (RRMS), 12 secondary progressive (SPMS) and 8 primary progressive (PPMS)). Prior to lumbar puncture, MS-patients underwent MRI and clinical examination, including the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC). Additionally, CSF concentrations of NAA were determined in 12 patients with other neurological diseases (OND). Results: Median CSF NAA concentration was 0.74 (IQR: 0.59-0.94) in RRMS , 0.54 (IQR: 0.35-0.73) in SPMS and 0.83 μmol/l (IQR: 0.56-1.03) in PPMS patients. SPMS patients had a significantly lower NAA concentration than RRMS patients. NAA concentrations correlated with EDSS (r = )0.37, p = 0.016), MSFC (r = 0.41, p = 0.010), normalised brain volume (r = 0.49, p = 0.001), T2 lesion load (r = )0.35, p = 0.021) and black hole lesion load (r = )0.47, p = 0.002). No differences were observed between OND (median: 0.57 IQR: 0.28-0.73) and MS patients. Conclusions: CSF NAA concentration in MS patients is related to clinical performance and MRI measures of disease burden and may therefore be an important neuron specific marker of disease severity and possibly progression

Clinical application of CSF biomarkers for Alzheimer's disease:From rationale to ratios

Biomarker testing is recommended for the accurate and timely diagnosis of Alzheimer's disease (AD). Using illustrative case narratives we consider how cerebrospinal fluid (CSF) biomarker tests may be used in different presentations of cognitive impairment to facilitate timely and differential diagnosis, improving diagnostic accuracy, providing prognostic information, and guiding personalized management in diverse scenarios. Evidence shows that (1) CSF ratios are superior to amyloid beta (Aβ)1‐42 alone; (2) concordance of CSF ratios to amyloid positron emission tomography (PET) is better than Aβ1‐42 alone; and (3) phosphorylated tau (p‐tau)/Aβ1‐42 ratio is superior to p‐tau alone. CSF biomarkers are recommended for the exclusion of AD as the underlying cause of cognitive impairment, diagnosis of AD at an early stage, differential diagnosis of AD in individuals presenting with other neuropsychiatric symptoms, accurate diagnosis of AD in an atypical presentation, and for clinical trial enrichment. HIGHLIGHTS:  : Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker testing may be underused outside specialist centers. CSF biomarkers improve diagnostic accuracy, guiding personalized management of AD. CSF ratios (amyloid beta [Aβ]1‐42/Aβ1‐40 and phosphorylated tau/Aβ1‐42) perform better than single markers. CSF ratios produce fewer false‐negative and false‐positive results than individual markers. CSF biomarkers should be included in diagnostic work‐up of AD and mild cognitive impairment due to AD

Dynamics and prognostic value of serum neurofilament light chain in Guillain-Barré syndrome

Background: Neurofilament light chain (NfL) is a biomarker for axonal damage in several neurological disorders. We studied the longitudinal changes in serum NfL in patients with Guillain-Barré syndrome (GBS) in relation to disease severity, electrophysiological subtype, treatment response, and prognosis. Methods: We included patients with GBS who participated in a double-blind, randomised, placebo-controlled trial that evaluated the effects of a second course of intravenous immunoglobulin (IVIg) on clinical outcomes. Serum NfL levels were measured before initiation of treatment and at one, two, four, and twelve weeks using a Simoa HD-X Analyzer. Serum NfL dynamics were analysed using linear mixed-effects models. Logistic regression was employed to determine the associations of serum NfL with clinical outcome and the prognostic value of serum NfL after correcting for known prognostic markers.Findings: NfL levels were tested in serum from 281 patients. Serum NfL dynamics were associated with disease severity and electrophysiological subtype. Strong associations were found between high levels of serum NfL at two weeks and inability to walk unaided at four weeks (OR = 1.74, 95% CI = 1.27–2.45), and high serum NfL levels at four weeks and inability to walk unaided at 26 weeks (OR = 2.79, 95% CI = 1.72–4.90). Baseline serum NfL had the most significant prognostic value for ability to walk, independent of known predictors of outcome. The time to regain ability to walk unaided was significantly longer for patients with highest serum NfL levels at baseline (p = 0.0048) and week 2 (p &lt; 0.0001). No differences in serum NfL were observed between patients that received a second IVIg course vs. IVIg and placebo.Interpretation: Serum NfL levels are associated with disease severity, axonal involvement, and poor outcome in GBS. Serum NfL potentially represents a biomarker to monitor neuronal damage in GBS and an intermediate endpoint to evaluate the effects of treatment. </p

Working memory moderates the relation between the brain-derived neurotropic factor (BDNF) and psychotherapy outcome for depression

Background: Insight into patient characteristics that predict response to treatment for major depressive disorder (MDD) may help to personalize treatment and improve outcomes. One mechanism that has been linked to the success of treatment for MDD is brain-derived neurotropic factor (BDNF). BDNF is implicated in learning and memory and may play a role in the effects of psychotherapy that involves changing cognitions and behaviors. In addition, only in individuals with low BDNF, low working memory capacity has been associated with increased symptoms of depression. However, the role of BDNF and working memory capacity in psychotherapy outcome is unclear. The aim of this study was to investigate the role of BDNF and its interaction with working memory capacity in psychotherapy outcomes for MDD. Method: Adult patients with MDD were randomized to weekly or twice weekly sessions of cognitive behavioral therapy or interpersonal psychotherapy. BDNF Val66Met polymorphism (rs6265) (n = 138) was defined and serum BDNF was quantified before (n = 138) and after psychotherapy (n = 82). Results: Baseline serum BDNF and the Val66Met polymorphism were not associated with outcome and associations did not differ between treatment conditions. Working memory capacity significantly moderated the relation between baseline serum BDNF and outcome: high serum BDNF at baseline was related to less depressive symptoms following psychotherapy in the presence of high working memory capacity, but not low working memory capacity. Discussion: These findings, if replicated, might indicate that while BDNF may not be related to psychotherapy outcomes in general, they may play a role in the presence of specific learning processes such as working memory capacity