Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis.

In colorectal cancer patients, a high density of cytotoxic CD8+ T cells in tumors is associated with better prognosis. Using a Stat3 loss-of-function approach in two wnt/ß-catenin-dependent autochthonous models of sporadic intestinal tumorigenesis, we unravel a complex intracellular process in intestinal epithelial cells (IECs) that controls the induction of a CD8+ T cell based adaptive immune response. Elevated mitophagy in IECs causes iron(II)-accumulation in epithelial lysosomes, in turn, triggering lysosomal membrane permeabilization. Subsequent release of proteases into the cytoplasm augments MHC class I presentation and activation of CD8+ T cells via cross-dressing of dendritic cells. Thus, our findings highlight a so-far-unrecognized link between mitochondrial function, lysosomal integrity, and MHC class I presentation in IECs and suggest that therapies triggering mitophagy or inducing LMP in IECs may prove successful in shifting the balance toward anti-tumor immunity in colorectal cancer.

Perspectives on the diagnosis and management of functional cognitive disorder: An international Delphi study.

BACKGROUND: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions. METHODS: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken. RESULTS: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%-88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%-92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD. CONCLUSIONS: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions.

The West Riding Lunatic Asylum Medical Reports: the precursor of Brain?

First published in 1878, Brain: A Journal of Neurology is generally considered to be the world's first neuroscientific journal. However, this claim might be challenged since the West Riding Lunatic Asylum Medical Reports, another journal with significant neuroscientific content, was published between 1871 and 1876. Some have suggested this journal was the precursor of Brain, since it shared similar subject matter as well as editorial and authorial contributors, including James Crichton-Browne, David Ferrier and John Hughlings Jackson. To address this question, this article examines the origins, aims, structure and contents of, and some of the contributors and contributions to, the West Riding Lunatic Asylum Medical Reports and compares these elements to the first six volumes of Brain (1878-9 to 1883-4). Although the two journals did overlap in terms of some shared neuroscientific interests, Brain evidently had a broader scope and a more international authorship. Nevertheless, this analysis suggests that, through the agency of Crichton-Browne, Ferrier and Hughlings Jackson, it is appropriate to regard the West Riding Lunatic Asylum Medical Reports as not only the antecedent but also the precursor of Brain.

Using Critical Success Index or Gilbert Skill Score as composite measures of positive predictive value and sensitivity in diagnostic accuracy studies: Weather forecasting informing epilepsy research.

The Critical Success Index (CSI) and Gilbert Skill score (GS) are verification measures that are commonly used to check the accuracy of weather forecasting. In this article, we propose that they can also be used to simplify the joint interpretation of positive predictive value (PPV) and sensitivity estimates across diagnostic accuracy studies of epilepsy data. This is because CSI and GS each provide a single measure that takes the weather forecasting equivalent of PPV and sensitivity into account. We have re-analysed data from our recent systematic review of diagnostic accuracy studies of administrative epilepsy data using CSI and GS. We summarise the results and benefits of this approach.

Intracranial bruit: Charles Warlow's challenge revisited.

Over 20 years ago, Charles Warlow, the founding editor of Practical Neurology, offered a copy of his stroke textbook to anyone diagnosing an intracranial arteriovenous malformation by auscultation of the skull alone. This article examines the possible diagnostic value of intracranial bruit in terms of the 2×2 contingency table for diagnostic tests and recounts an historical case.

Combining Results of Performance-Based and Informant Test Accuracy Studies: Bayes or Boole?

BACKGROUND/AIMS: Since screening and diagnostic tests for dementia do not have perfect accuracy, >1 test is often administered when assessing patients with cognitive complaints. Use of both patient performance tests and informant questionnaires has been recommended. Combination of individual test results may be based on methods originally defined by Thomas Bayes (revision or updating of pretest probabilities to post-test probabilities given the test results) and by George Boole (application of associative "AND" or "OR" operator). This study sought to apply these methods in clinical practice. METHODS: Using the dataset of a pragmatic test accuracy study of the Six-Item Cognitive Impairment Test (6CIT) and informant Ascertain Dementia 8 (AD8), post-test probabilities for the combination were calculated using Bayes' formula and compared to Boolean "AND" combination. Combined test sensitivity and specificity was calculated using either Boolean "AND" or "OR" operator and compared to results using equations based on individual test sensitivity and specificity. RESULTS: Both Bayesian and Boolean methods produced similar improvements from pretest probability (0.288) to combined post-test probability for dementia (≈0.5). Likewise, the 2 different methods for calculating combined sensitivities and specificities gave similar results, with, as anticipated, the "AND" combination improving overall specificity (to ≈0.65) whereas the "OR" combination improved sensitivity (to ≈1.00). CONCLUSION: Combination of individual screening test results using Bayesian and Boolean methods is relatively straightforward and may add to clinicians' intuitive judgements when combining test results.

Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum.

The clinical syndromes of frontotemporal dementia are clinically and neuropathologically heterogeneous, but processes such as neuroinflammation may be common across the disease spectrum. We investigated how neuroinflammation relates to the localization of tau and TDP-43 pathology, and to the heterogeneity of clinical disease. We used PET in vivo with (i) 11C-PK-11195, a marker of activated microglia and a proxy index of neuroinflammation; and (ii) 18F-AV-1451, a radioligand with increased binding to pathologically affected regions in tauopathies and TDP-43-related disease, and which is used as a surrogate marker of non-amyloid-ß protein aggregation. We assessed 31 patients with frontotemporal dementia (10 with behavioural variant, 11 with the semantic variant and 10 with the non-fluent variant), 28 of whom underwent both 18F-AV-1451 and 11C-PK-11195 PET, and matched control subjects (14 for 18F-AV-1451 and 15 for 11C-PK-11195). We used a univariate region of interest analysis, a paired correlation analysis of the regional relationship between binding distributions of the two ligands, a principal component analysis of the spatial distributions of binding, and a multivariate analysis of the distribution of binding that explicitly controls for individual differences in ligand affinity for TDP-43 and different tau isoforms. We found significant group-wise differences in 11C-PK-11195 binding between each patient group and controls in frontotemporal regions, in both a regions-of-interest analysis and in the comparison of principal spatial components of binding. 18F-AV-1451 binding was increased in semantic variant primary progressive aphasia compared to controls in the temporal regions, and both semantic variant primary progressive aphasia and behavioural variant frontotemporal dementia differed from controls in the expression of principal spatial components of binding, across temporal and frontotemporal cortex, respectively. There was a strong positive correlation between 11C-PK-11195 and 18F-AV-1451 uptake in all disease groups, across widespread cortical regions. We confirmed this association with post-mortem quantification in 12 brains, demonstrating strong associations between the regional densities of microglia and neuropathology in FTLD-TDP (A), FTLD-TDP (C), and FTLD-Pick's. This was driven by amoeboid (activated) microglia, with no change in the density of ramified (sessile) microglia. The multivariate distribution of 11C-PK-11195 binding related better to clinical heterogeneity than did 18F-AV-1451: distinct spatial modes of neuroinflammation were associated with different frontotemporal dementia syndromes and supported accurate classification of participants. These in vivo findings indicate a close association between neuroinflammation and protein aggregation in frontotemporal dementia. The inflammatory component may be important in shaping the clinical and neuropathological patterns of the diverse clinical syndromes of frontotemporal dementia.

Functional cognitive disorder: dementia's blind spot.

An increasing proportion of cognitive difficulties are recognized to have a functional cause, the chief clinical indicator of which is internal inconsistency. When these symptoms are impairing or distressing, and not better explained by other disorders, this can be conceptualized as a cognitive variant of functional neurological disorder, termed functional cognitive disorder (FCD). FCD is likely very common in clinical practice but may be under-diagnosed. Clinicians in many settings make liberal use of the descriptive term mild cognitive impairment (MCI) for those with cognitive difficulties not impairing enough to qualify as dementia. However, MCI is an aetiology-neutral description, which therefore includes patients with a wide range of underlying causes. Consequently, a proportion of MCI cases are due to non-neurodegenerative processes, including FCD. Indeed, significant numbers of patients diagnosed with MCI do not 'convert' to dementia. The lack of diagnostic specificity for MCI 'non-progressors' is a weakness inherent in framing MCI primarily within a deterministic neurodegenerative pathway. It is recognized that depression, anxiety and behavioural changes can represent a prodrome to neurodegeneration; empirical data are required to explore whether the same might hold for subsets of individuals with FCD. Clinicians and researchers can improve study efficacy and patient outcomes by viewing MCI as a descriptive term with a wide differential diagnosis, including potentially reversible components such as FCD. We present a preliminary definition of functional neurological disorder-cognitive subtype, explain its position in relation to other cognitive diagnoses and emerging biomarkers, highlight clinical features that can lead to positive diagnosis (as opposed to a diagnosis of exclusion), and red flags that should prompt consideration of alternative diagnoses. In the research setting, positive identifiers of FCD will enhance our recognition of individuals who are not in a neurodegenerative prodrome, while greater use of this diagnosis in clinical practice will facilitate personalized interventions.

Epilepsy and prion diseases: A narrative review.

Epileptic seizures have been described as one feature of prion diseases, but are an unusual clinical presentation. The aim of this narrative Review was to summarize current knowledge of epileptic seizures in the various forms of prion diseases, from a clinical perspective. Examination of the published literature identified no systematic studies; the evidence base is largely anecdotal, consisting mainly of case studies and small case series. Hence, uncertainty prevails as to seizure frequency, semiology, treatment, and pathogenesis in prion diseases. Seizures probably occur in around 10% of sporadic cases but less frequently in iatrogenic and familial forms, with the possible exception of the E200K mutation. The literature suggests a predominance of focal motor and nonconvulsive status epilepticus. Electroencephalographic accompaniments include periodic lateralized or generalized periodic epileptiform discharges (PLEDs, GPEDs), sometimes predating the more typical periodic sharp wave complexes. There are no convincing accounts of successful antiepileptic drug therapy. The underlying mechanisms of epileptogenesis in prion diseases may include loss of cellular prion protein function (PrPc) and aggregation of abnormally folded prion protein (PrPSc). The need for systematic studies and clinical trials to expand the evidence base surrounding epilepsy and prion diseases is evident.

Free-Cog: Pragmatic Test Accuracy Study and Comparison with Mini-Addenbrooke's Cognitive Examination.

BACKGROUND/AIMS: Canonical definitions of the dementia construct encompass deficits in both cognition and function, but most screening instruments for possible dementia address only cognitive abilities. Free-Cog is a recently described brief screening instrument for dementia designed to address not only cognitive but also functional abilities. METHODS: A pragmatic test accuracy study of Free-Cog was undertaken in consecutive patients seen over 1 year in a secondary care setting. The performance of Free-Cog for diagnosis of dementia and mild cognitive impairment (MCI) was compared to that of Mini-Addenbrooke's Cognitive Examination (MACE). RESULTS: In a cohort of 141 patients (prevalence of dementia and MCI 11 and 32%, respectively) both Free-Cog and MACE were quick and easy to use and acceptable to patients. Both tests had high sensitivity (1.00) and large effect sizes (Cohen's d) for diagnosis of dementia, but Free-Cog was more specific. For diagnosis of MCI, Free-Cog lacked sensitivity (0.58) but was specific (0.81), whereas MACE was sensitive (0.91) but not specific (0.35). Weighted comparison suggested equivalence for dementia diagnosis but a net benefit for MACE regarding MCI diagnosis. CONCLUSION: Free-Cog is an acceptable and accurate test for dementia screening in a dedicated cognitive disorders clinic, but it appears less sensitive than MACE for the identification of MCI.

Accuracy of the short-form Montreal Cognitive Assessment: Systematic review and validation.

INTRODUCTION: Short-form versions of the Montreal Cognitive Assessment (SF-MoCA) are increasingly used to screen for dementia in research and practice. We sought to collate evidence on the accuracy of SF-MoCAs and to externally validate these assessment tools. METHODS: We performed systematic literature searching across multidisciplinary electronic literature databases, collating information on the content and accuracy of all published SF-MoCAs. We then validated all the SF-MoCAs against clinical diagnosis using independent stroke (n = 787) and memory clinic (n = 410) data sets. RESULTS: We identified 13 different SF-MoCAs (21 studies, n = 6477 participants) with differing test content and properties. There was a pattern of high sensitivity across the range of SF-MoCA tests. In the published literature, for detection of post stroke cognitive impairment, median sensitivity across included studies: 0.88 (range: 0.70-1.00); specificity: 0.70 (0.39-0.92). In our independent validation using stroke data, median sensitivity: 0.99 (0.80-1.00); specificity: 0.40 (0.14-0.87). To detect dementia in older adults, median sensitivity: 0.88 (0.62-0.98); median specificity: 0.87 (0.07-0.98) in the literature and median sensitivity: 0.96 (range: 0.72-1.00); median specificity: 0.36 (0.14-0.86) in our validation. Horton's SF-MoCA (delayed recall, serial subtraction, and orientation) had the most favorable properties in stroke (sensitivity: 0.90, specificity: 0.87, positive predictive value [PPV]: 0.55, and negative predictive value [NPV]: 0.93), whereas Cecato's "MoCA reduced" (clock draw, animal naming, delayed recall, and orientation) performed better in the memory clinic (sensitivity: 0.72, specificity: 0.86, PPV: 0.55, and NPV: 0.93). CONCLUSIONS: There are many published SF-MoCAs. Clinicians and researchers using a SF-MoCA should be explicit about the content. For all SF-MoCA, sensitivity is high and similar to the full scale suggesting potential utility as an initial cognitive screening tool. However, choice of SF-MoCA should be informed by the clinical population to be studied.

William Barnett Warrington (1869-1919).

William Barnett Warrington (1869-1919) was a physician and physiologist working in Liverpool, United Kingdom, at the end of the 19th and beginning of the 20th centuries. His training included periods at the National Hospital for the Paralysed and Epileptic, Queen Square, London, and in the Liverpool laboratory of Charles Scott Sherrington. He investigated structural alterations in nerve cells following various nerve lesions and helped to develop laboratory facilities to support clinical practice through the Pathological Diagnosis Society of Liverpool. His clinical interests were broad, but his main focus seems to have been in disorders of the peripheral nervous system. He published many papers, encompassing descriptions of Charcot-Marie-Tooth disease, brachial plexus paralyses (possibly including neuralgic amyotrophy), and, in the context of the First World War, traumatic peripheral nerve injuries. He may have described cases of Guillain-Barré syndrome prior to the eponymous description but despite being familiar with the technique of lumbar puncture, he did not report cerebrospinal fluid findings in these patients.

Evaluating cognitive screening instruments with the "likelihood to be diagnosed or misdiagnosed" measure.

OBJECTIVES: To calculate "number needed to diagnose" (NND), "number needed to predict" (NNP), and "number needed to misdiagnose" (NNM) for cognitive screening instruments which are commonly used in suspected dementia and mild cognitive impairment, and from these to calculate a "likelihood to be diagnosed or misdiagnosed" (LDM) metric as the ratio of NNM to either NND or NNP. METHODS: Datasets from pragmatic diagnostic test accuracy studies examining four commonly used cognitive screening instruments (Mini-Mental State Examination, MMSE; Montreal Cognitive Assessment, MoCA; Mini-Addenbrooke's Cognitive Examination, MACE; Six-item Cognitive Impairment Test, 6CIT) were analysed to calculate NND, NNP, and NNM, and from these derive values for LDM. FINDINGS: Although all the tests had low NND and NNP as desired, NNM was also low. Hence, only MMSE and 6CIT achieved LDM > 1 for dementia diagnosis, and only MACE and 6CIT had LDM > 1 for diagnosis of mild cognitive impairment. CONCLUSIONS: The likelihood to be diagnosed or misdiagnosed (LDM) metric may indicate the utility or inutility of diagnostic tests for clinicians and patients. LDM values may clarify the inevitable trade-off between sensitivity and specificity and hence clinician purpose in administering the diagnostic test (minimising false negatives or false positives).

STAT3 suppresses Wnt/ß-catenin signaling during the induction phase of primary Myf5+ brown adipogenesis.

Thermogenic fat is a promising target for new therapies in diabetes and obesity. Understanding how thermogenic fat develops is important to develop rational strategies to treat obesity. Previously, we have shown that Tyk2 and STAT3, part of the JAK-STAT pathway, are necessary for proper development of classical brown fat. Using primary preadipocytes isolated from newborn mice we demonstrate that STAT3 is required for differentiation and robust expression of Uncoupling Protein 1 (UCP1). We also confirm that STAT3 is necessary during the early induction stage of differentiation and is dispensable during the later terminal differentiation stage. The inability of STAT3-/- preadipocytes to differentiate can be rescued using Wnt ligand secretion inhibitors when applied during the induction stage. Through chemical inhibition and RNAi, we show that it is the canonical ß-catenin pathway that is responsible for the block in differentiation; inhibition or knockdown of ß-catenin can fully rescue adipogenesis and UCP1 expression in the STAT3-/- adipocytes. During the induction stage, Wnts 1, 3a, and 10b have increased expression in the STAT3-/- adipocytes, potentially explaining the increased levels and activity of ß-catenin. Our results for the first time point towards an interaction between the JAK/STAT pathway and the Wnt/ß-catenin pathway during the early stages of in-vitro adipogenesis.

MACE for the Diagnosis of Dementia and MCI: 3-Year Pragmatic Diagnostic Test Accuracy Study.

BACKGROUND/AIMS: The Mini-Addenbrooke's Cognitive Examination (MACE) is a relatively new short cognitive screening instrument for the detection of patients with dementia and mild cognitive impairment (MCI). Few studies of the MACE have been reported hitherto. The aim of this study was to undertake a pragmatic diagnostic test accuracy study of MACE in a large cohort of patients seen in a dedicated cognitive disorders clinic. METHODS: MACE was administered to consecutive patients referred to a neurology-led Cognitive Function Clinic over the course of 3 years to assess its performance for the diagnosis of dementia and MCI using various test metrics. RESULTS: In a cohort of 599 patients, the prevalence of dementia and MCI by criterion diagnosis was 0.17 and 0.29, respectively. MACE had a high sensitivity (> 0.9) and negative predictive values (> 0.8) with large effect sizes (Cohen's d > 1) for the diagnosis of both dementia and MCI but a low specificity (< 0.5) and positive predictive values (≤0.5). CONCLUSION: MACE is an acceptable test for the assessment of cognitive complaints in a secondary care setting with good metrics for identifying cases of both dementia and MCI.

Cognitive assessment in an epilepsy clinic using the AD8 questionnaire.

OBJECTIVE: This study examined cognitive function in patients with epilepsy using the AD8 screening questionnaire to assess the frequency of, and factors associated with, cognitive impairment in these patients. METHOD: The AD8 screening questionnaire for cognitive impairment was administered to one hundred consecutive patients diagnosed with epilepsy who attended a dedicated epilepsy clinic based in a tertiary care neuroscience center. Where possible, accompanying informants also completed AD8 on behalf of the patient. RESULTS: Forty-eight percent of patients in this cohort scored above the AD8 cutoff (higher scores are considered worse) for cognitive impairment. Categorizing patient groups by AD8 score showed no difference (null hypothesis not rejected) in patient age, new or follow-up appointment, epilepsy type (partial/generalized), or treatment (monotherapy/polytherapy), but a significant difference (null hypothesis rejected) was found for disee duration, with those scoring above the AD8 cutoff having a significantly longer disease duration. There was no correlation between AD8 scores and patient age but a weak positive correlation with disease duration. AD8 questionnaires completed by informants showed a similar frequency of cognitive impairment (54%), and patient:informant AD8 scores showed substantial agreement beyond chance. CONCLUSIONS: AD8 is acceptable to patients with epilepsy and their informants for the assessment of cognitive function. In this dedicated epilepsy clinic, its use suggested a high frequency of cognitive impairment in both self-rating and informant assessments. A less sensitive, more specific cognitive screening instrument (CSI) might be more desirable in this population. Duration of epilepsy or some factor related to it may contribute to cognitive symptoms.

Toward a new STATe: the role of STATs in mitochondrial function.

Signal Transducers and Activators of Transcription (STATs) have been studied extensively and have been associated with virtually every biochemical pathway. Until recently, however, they were thought to exert these effects solely as a nuclear transcription factor. The finding that STAT3 localizes to the mitochondria and modulates respiration has opened up a new avenue through which STATs may regulate the cell. Recently, other members of the STAT family (STAT1, STAT2, STAT5, and STAT6) have also been shown to be present in the mitochondria. Coordinate regulation at the nucleus and mitochondria by these proteins places them in a unique position to drive cellular processes to achieve a specific response. This review summarizes recent findings that have led to our current understanding of how STATs influence mitochondrial function in health and disease.