The chaperone protein clusterin may serve as a cerebrospinal fluid biomarker for chronic spinal cord disorders in the dog

Chronic spinal cord dysfunction occurs in dogs as a consequence of diverse aetiologies, including long-standing spinal cord compression and insidious neurodegenerative conditions. One such neurodegenerative condition is canine degenerative myelopathy (DM), which clinically is a challenge to differentiate from other chronic spinal cord conditions. Although the clinical diagnosis of DM can be strengthened by the identification of the Sod1 mutations that are observed in affected dogs, genetic analysis alone is insufficient to provide a definitive diagnosis. There is a requirement to identify biomarkers that can differentiate conditions with a similar clinical presentation, thus facilitating patient diagnostic and management strategies. A comparison of the cerebrospinal fluid (CSF) protein gel electrophoresis profile between idiopathic epilepsy (IE) and DM identified a protein band that was more prominent in DM. This band was subsequently found to contain a multifunctional protein clusterin (apolipoprotein J) that is protective against endoplasmic reticulum (ER) stress-mediated apoptosis, oxidative stress, and also serves as an extracellular chaperone influencing protein aggregation. Western blot analysis of CSF clusterin confirmed elevated levels in DM compared to IE (p < 0.05). Analysis of spinal cord tissue from DM and control material found that clusterin expression was evident in neurons and that the clusterin mRNA levels from tissue extracts were elevated in DM compared to the control. The plasma clusterin levels was comparable between these groups. However, a comparison of clusterin CSF levels in a number of neurological conditions found that clusterin was elevated in both DM and chronic intervertebral disc disease (cIVDD) but not in meningoencephalitis and IE. These findings indicate that clusterin may potentially serve as a marker for chronic spinal cord disease in the dog; however, additional markers are required to differentiate DM from a concurrent condition such as cIVDD

The Behavioural Dysfunction Questionnaire discriminates behavioural variant frontotemporal dementia from Alzheimer's disease dementia and major depressive disorder

Background and objectives: Early-stage behavioural variant frontotemporal dementia (bvFTD) is often misdiagnosed, highlighting the need for new diagnostic instruments. Based on the revised diagnostic criteria for bvFTD, we developed the Behavioural Dysfunction Questionnaire (BDQ). In this explorative study, we aimed to determine the best scoring and analytical method for the BDQ to discriminate between bvFTD and non-bvFTD patients.Materials and methods: 34 patients with early-stage bvFTD, 56 with early-stage Alzheimer's disease dementia (ADD) and 41 with major depressive disorder (MDD) were recruited. We calculated BDQ-items with or without inclusion of a time criterion: (a) without time criterion, (b) with 10 years' time criterion (symptom presence less than 10 years), and (c) with 3 years' time criterion (symptom presentation within the first 3 years). Using these three differently calculated items, we generated six variables, i.e. 3*2 [BDQ-Global Score (BDQ-GS; domains average score); BDQ-Global Domain Score (BDQ-GDS; domains categorical score)]. Then, we performed univariate and bivariate (BDQ-GS and BDQ-GDS combined) ROC analyses.Results: Models including BDQ-GS, BDQ-GDS or both variables combined discriminated similarly between groups. In contrast, models without time criterion or with 10 years' time criterion discriminated better than models including variables with 3 years' time criterion. These models discriminated highly (AUC = 85.98-87.78) between bvFTD and MDD and bvFTD and ADD, respectively.Conclusion: BDQ-scores without any time criterion discriminated highly between early-stage bvFTD and non-bvFTD groups, which could improve the early diagnosis of bvFTD. With its standardised procedure, the BDQ is also appropriate for repeated assessments

Le Registre suisse pour la santé du cerveau - Une infrastructure nationale pour la recherche sur la maladie d’Alzheimer [The Swiss Brain Health Registry : a national infrastructure for Alzheimer's research]

The Memory Centres of several Swiss hospitals have set up a national online registry for Alzheimer's research, called www.BHR-suisse.org. This type of registry already exists in the United States (www.brainhealthregistry.org/) and the Netherlands (https://hersenonderzoek.nl/). It contributes, as do these initiating sites, to the creation of a global database of research partners <sup>b</sup> who wish to contribute by participating in studies on neurodegenerative diseases and more particularly on Alzheimer's disease. By registering, they provide a certain amount of information and become potential research partners. Researchers can then select a panel of volunteers according to the selection and exclusion criteria of their studies, contact them and include them in their studies

Disease-Related Changes in the Cerebrospinal Fluid Metabolome in Amyotrophic Lateral Sclerosis Detected by GC/TOFMS

The changes in the cerebrospinal fluid (CSF) metabolome associated with the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) are poorly understood and earlier smaller studies have shown conflicting results. The metabolomic methodology is suitable for screening large cohorts of samples. Global metabolomics can be used for detecting changes of metabolite concentrations in samples of fluids such as CSF.Using gas chromatography coupled to mass spectrometry (GC/TOFMS) and multivariate statistical modeling, we simultaneously studied the metabolome signature of ∼120 small metabolites in the CSF of patients with ALS, stratified according to hereditary disposition and clinical subtypes of ALS in relation to controls.The study is the first to report data validated over two sub-sets of ALS vs. control patients for a large set of metabolites analyzed by GC/TOFMS. We find that patients with sporadic amyotrophic lateral sclerosis (SALS) have a heterogeneous metabolite signature in the cerebrospinal fluid, in some patients being almost identical to controls. However, familial amyotrophic lateral sclerosis (FALS) without superoxide dismutase-1 gene (SOD1) mutation is less heterogeneous than SALS. The metabolome of the cerebrospinal fluid of 17 ALS patients with a SOD1 gene mutation was found to form a separate homogeneous group. Analysis of metabolites revealed that glutamate and glutamine were reduced, in particular in patients with a familial predisposition. There are significant differences in the metabolite profile and composition among patients with FALS, SALS and patients carrying a mutation in the SOD1 gene suggesting that the neurodegenerative process in different subtypes of ALS may be partially dissimilar.Patients with a genetic predisposition to amyotrophic lateral sclerosis have a more distinct and homogeneous signature than patients with a sporadic disease

Implications for driving based on the risk of seizures after ischaemic stroke

Background: In addition to other stroke-related deficits, the risk of seizures may impact driving ability after stroke. Methods: We analysed data from a multicentre international cohort, including 4452 adults with acute ischaemic stroke and no prior seizures. We calculated the Chance of Occurrence of Seizure in the next Year (COSY) according to the SeLECT2.0 prognostic model. We considered COSY<20% safe for private and <2% for professional driving, aligning with commonly used cut-offs. Results: Seizure risks in the next year were mainly influenced by the baseline risk-stratified according to the SeLECT2.0 score and, to a lesser extent, by the poststroke seizure-free interval (SFI). Those without acute symptomatic seizures (SeLECT2.0 0-6 points) had low COSY (0.7%-11%) immediately after stroke, not requiring an SFI. In stroke survivors with acute symptomatic seizures (SeLECT2.0 3-13 points), COSY after a 3-month SFI ranged from 2% to 92%, showing substantial interindividual variability. Stroke survivors with acute symptomatic status epilepticus (SeLECT2.0 7-13 points) had the highest risk (14%-92%). Conclusions: Personalised prognostic models, such as SeLECT2.0, may offer better guidance for poststroke driving decisions than generic SFIs. Our findings provide practical tools, including a smartphone-based or web-based application, to assess seizure risks and determine appropriate SFIs for safe driving

Progress in the Treatment of Alzheimer’s Disease Is Needed – Position Statement of European Alzheimer’s Disease Consortium (EADC) Investigators

β-amyloid-targeting antibodies represent the first generation of effective causal treatment of Alzheimer’s disease (AD) and can be considered historical research milestones. Their effect sizes, side effects, implementation challenges and costs, however, have stimulated debates about their overall value. In this position statement academic clinicians of the European Alzheimer’s Disease Consortium (EADC) discuss the critical relevance of introducing these new treatments in clinical care now. Given the complexity of AD it is unlikely that molecular single-target treatments will achieve substantially larger effects than those seen with current β-amyloid-targeting antibodies. Larger effects will most likely only be achieved incrementally by continuous optimization of molecular approaches, patient selection and combinations therapies. To be successful in this regard, drug development must be informed by the use of innovative treatments in real world practice, because full understanding of all facets of novel treatments requires experience and data of real-world care beyond those of clinical trials. Regarding the antibodies under discussion we consider their effects meaningful and potential side effects manageable. We assume that the number of eventually treated patient will only be a fraction of all early AD patients due to narrow eligibility criteria and barriers of access. We strongly endorse the use of these new compound in clinical practice in selected patients with treatment documentation in registries. We understand this as a critical step in advancing the field of AD treatment, and in shaping the health care systems for the new area of molecular-targeted treatment of neurodegenerative diseases

Progress in the treatment of Alzheimer’s disease is needed – position statement of European Alzheimer’s Disease Consortium (EADC) investigators

β-amyloid-targeting antibodies represent the first generation of effective causal treatment of Alzheimer’s disease (AD) and can be considered historical research milestones. Their effect sizes, side effects, implementation challenges and costs, however, have stimulated debates about their overall value. In this position statement academic clinicians of the European Alzheimer’s Disease Consortium (EADC) discuss the critical relevance of introducing these new treatments in clinical care now. Given the complexity of AD it is unlikely that molecular single-target treatments will achieve substantially larger effects than those seen with current β-amyloid-targeting antibodies. Larger effects will most likely only be achieved incrementally by continuous optimization of molecular approaches, patient selection and combinations therapies. To be successful in this regard, drug development must be informed by the use of innovative treatments in real world practice, because full understanding of all facets of novel treatments requires experience and data of real-world care beyond those of clinical trials. Regarding the antibodies under discussion we consider their effects meaningful and potential side effects manageable. We assume that the number of eventually treated patient will only be a fraction of all early AD patients due to narrow eligibility criteria and barriers of access. We strongly endorse the use of these new compound in clinical practice in selected patients with treatment documentation in registries. We understand this as a critical step in advancing the field of AD treatment, and in shaping the health care systems for the new area of molecular-targeted treatment of neurodegenerative diseases