Extending the phenotypic spectrum assessed by the CDR plus NACC FTLD in genetic frontotemporal dementia.

Introduction: We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD).

Methods: Neuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD generating a new CDR plus NACC FTLD-NM scale. This was assessed in 522 mutation carriers and 310 mutation-negative controls from the Genetic Frontotemporal dementia Initiative (GENFI).

Day-to-day sleep variability with Alzheimer's biomarkers in at-risk elderly.

Introduction: Measuring day-to-day sleep variability might reveal unstable sleep-wake cycles reflecting neurodegenerative processes. We evaluated the association between Alzheimer's disease (AD) fluid biomarkers with day-to-day sleep variability.

Methods: In the PREVENT-AD cohort, 203 dementia-free participants (age: 68.

An update on the role of magnetic resonance imaging in predicting and monitoring multiple sclerosis progression.

Introduction: While magnetic resonance imaging (MRI) is established in diagnosing and monitoring disease activity in multiple sclerosis (MS), its utility in predicting and monitoring disease progression is less clear.

Areas Covered: The authors consider changing concepts in the phenotypic classification of MS, including progression independent of relapses; pathological processes underpinning progression; advances in MRI measures to assess them; how well MRI features explain and predict clinical outcomes, including models that assess disease effects on neural networks, and the potential role for machine learning.

Expert Opinion: Relapsing-remitting and progressive MS have evolved from being viewed as mutually exclusive to having considerable overlap.

Harmonization and standardization of biofluid-based biomarker measurements for AT(N) classification in Alzheimer's disease.

Unlabelled: Fluid biomarkers are currently measured in cerebrospinal fluid and blood for Alzheimer's disease diagnosis and are promising targets for drug development and for patients' follow-up in clinical trials. These biomarkers have been grouped in an unbiased research framework, the amyloid (Aβ), tau, and neurodegeneration (AT[N]) biomarker system to aid patients' early diagnosis and stratification. Metrological approaches relying on mass spectrometry have been used for the development of reference materials and reference measurement procedures.

Endo-lysosomal protein concentrations in CSF from patients with frontotemporal dementia caused by mutation.

Introduction: Increasing evidence implicates proteostatic dysfunction as an early event in the development of frontotemporal dementia (FTD). This study aimed to explore potential cerebrospinal fluid (CSF) biomarkers associated with the proteolytic systems in genetic FTD caused by mutation.

Methods: Combining solid-phase extraction and parallel reaction monitoring mass spectrometry, a panel of 47 peptides derived from 20 proteins was analyzed in CSF from 31 members of the Danish -FTD family.

AD-associated CSF biomolecular changes are attenuated in KL-VS heterozygotes.

Introduction: Dementia as an inevitable aging consequence has been challenged and underscores the need for investigations of the factors that confer resilience. We examine whether the functionally advantageous KL-VS variant of the putative aging suppressor gene attenuates age-related cognitive decline and deleterious biomolecular changes.

Methods: Trajectories of change in memory and executive function ( = 360; 2-12 visits) and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers-amyloid beta (Aβ)42, total tau (t-tau), phosphorylated tau (p-tau) ( = 112; 2-4 samplings)-were compared between KL-VS non-carriers and heterozygotes in middle-aged and older adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center studies.

Amyloid-β peptide 37, 38 and 40 individually and cooperatively inhibit amyloid-β 42 aggregation.

The pathology of Alzheimer's disease is connected to the aggregation of β-amyloid (Aβ) peptide, which exists as a number of length-variants. Truncations and extensions are found at both the N- and C-termini, relative to the most commonly studied 40- and 42-residue alloforms. Here, we investigate the aggregation of two physiologically abundant alloforms, Aβ and Aβ, as pure peptides and in mixtures with Aβ and Aβ.

Blood neurofilament light in remote settings: Alternative protocols to support sample collection in challenging pre-analytical conditions.

Introduction: This study investigated alternative pre-analytical handling of blood for neurofilament light (NfL) analysis where resources are limited.

Method: Plasma NfL was measured with single molecule array after alternative blood processing procedures: dried plasma spots (DPS), dried blood spots (DBS), and delayed 48-hour centrifugation. These were compared to standardized plasma processing (reference standard [RS]).

The association of circulating amylin with β-amyloid in familial Alzheimer's disease.

Introduction: This study assessed the hypothesis that circulating human amylin (amyloid-forming) cross-seeds with amyloid beta (Aβ) in early Alzheimer's disease (AD).

Methods: Evidence of amylin-AD pathology interaction was tested in brains of 31 familial AD mutation carriers and 20 cognitively unaffected individuals, in cerebrospinal fluid (CSF) (98 diseased and 117 control samples) and in genetic databases. For functional testing, we genetically manipulated amylin secretion in APP/PS1 and non-APP/PS1 rats.

Risk of Transmissibility From Neurodegenerative Disease-Associated Proteins: Experimental Knowns and Unknowns.

Recent studies in animal models demonstrate that certain misfolded proteins associated with neurodegenerative diseases can support templated misfolding of cognate native proteins, to propagate across neural systems, and to therefore have some of the properties of classical prion diseases like Creutzfeldt-Jakob disease. The National Institute of Aging convened a meeting to discuss the implications of these observations for research priorities. A summary of the discussion is presented here, with a focus on limitations of current knowledge, highlighting areas that appear to require further investigation in order to guide scientific practice while minimizing potential exposure or risk in the laboratory setting.

Prevalence in Britain of abnormal prion protein in human appendices before and after exposure to the cattle BSE epizootic.

Widespread dietary exposure of the population of Britain to bovine spongiform encephalopathy (BSE) prions in the 1980s and 1990s led to the emergence of variant Creutzfeldt-Jakob Disease (vCJD) in humans. Two previous appendectomy sample surveys (Appendix-1 and -2) estimated the prevalence of abnormal prion protein (PrP) in the British population exposed to BSE to be 237 per million and 493 per million, respectively. The Appendix-3 survey was recommended to measure the prevalence of abnormal PrP in population groups thought to have been unexposed to BSE.

Cerebrospinal fluid neurofilament light concentration predicts brain atrophy and cognition in Alzheimer's disease.

Introduction: This study assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) in Alzheimer's disease (AD) diagnosis, its association with amyloid and tau pathology, as well as its potential to predict brain atrophy, cognition, and amyloid accumulation.

Methods: CSF NfL concentration was measured in 221 participants from the Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing (AIBL).

Results: CSF NfL levels as well as NfL/amyloid β (Aβ42) were significantly elevated in AD compared to healthy controls (HC; < .

Tauopathy-Associated Tau Fragment Ending at Amino Acid 224 Is Generated by Calpain-2 Cleavage.

Background: Tau aggregation in neurons and glial cells characterizes tauopathies as Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Tau proteolysis has been proposed as a trigger for tau aggregation and tau fragments have been observed in brain and cerebrospinal fluid (CSF). Our group identified a major tau cleavage at amino acid (aa) 224 in CSF; N-terminal tau fragments ending at aa 224 (N-224) were significantly increased in AD and lacked correlation to total tau (t-tau) and phosphorylated tau (p-tau) in PSP and CBD.

Cognitive Impairment Before Atrial Fibrillation-Related Ischemic Events: Neuroimaging and Prognostic Associations.

Background It is likely that a proportion of poststroke cognitive impairment is sometimes attributable to unidentified prestroke decline; prestroke cognitive function is also clinically relevant because it is associated with poor functional outcomes, including death. We investigated the radiological and prognostic associations of preexisting cognitive impairment in patients with ischemic stroke or transient ischemic attack associated with atrial fibrillation. Methods and Results We included 1102 patients from the prospective multicenter observational CROMIS-2 (Clinical Relevance of Microbleeds in Stroke 2) atrial fibrillation study.

Psychoanalytical concepts of epilepsy.

As part of the anniversary issue of Epilepsy & Behavior looking back as aspects of the history of epilepsy, this article reviews psychoanalytical concepts of the pathogenesis of seizures and the so-called epileptic personality (epileptic constitution). It addresses the question whether these theories are completely invalid or do they have insights that are worth rediscovering. Special Issue: Epilepsy & Behavior's 20th Anniversary.

The BRadykinesia Akinesia INcoordination (BRAIN) Tap Test: Capturing the Sequence Effect.

Background: The BRadykinesia Akinesia INcoordination (BRAIN) tap test is an online keyboard tapping task that has been previously validated to assess upper limb motor function in Parkinson's disease (PD).

Objectives: To develop a new parameter that detects a sequence effect and to reliably distinguish between PD patients and medication. In addition, we sought to validate a mobile version of the test for use on smartphones and tablet devices.

Neurofilament light chain as a biomarker in neurological disorders.

In the management of neurological diseases, the identification and quantification of axonal damage could allow for the improvement of diagnostic accuracy and prognostic assessment. Neurofilament light chain (NfL) is a neuronal cytoplasmic protein highly expressed in large calibre myelinated axons. Its levels increase in cerebrospinal fluid (CSF) and blood proportionally to the degree of axonal damage in a variety of neurological disorders, including inflammatory, neurodegenerative, traumatic and cerebrovascular diseases.

Novel tau fragments in cerebrospinal fluid: relation to tangle pathology and cognitive decline in Alzheimer's disease.

Tau is an axonal microtubule-binding protein. Tau pathology in brain and increased tau concentration in the cerebrospinal fluid (CSF) are hallmarks of Alzheimer's disease (AD). Most of tau in CSF is present as fragments.

Pragmatic Treatment of Stiff Person Spectrum Disorders.

Background: Stiff person spectrum disorders (SPSD) are a group of rare conditions clinically characterized by stiffness, spasms, and heightened stimulus sensitivity. They also share a spectrum of antibodies.

Methods: We reviewed the literature and our own experience with the aim of providing a practical approach to the treatment of SPSD.

Quick Flicks: Association of Paroxysmal Kinesigenic Dyskinesia and Tics.

Background: Paroxysmal kinesigenic dyskinesia (PKD) is a rare disorder characterised by brief attacks of chorea, dystonia, or mixed forms precipitated by sudden movement.

Methods: Observational study with a cohort of 14 PKD patients and genetic testing for mutations.

Results: In a series of 14 PKD patients seen in our clinic at the National Hospital of Neurology, Queen Square, from 2012-2017, we noted tics in 11 patients (79%), which stand in stark contrast to the estimated lifetime prevalence of tics estimated to reach 1%.

Magnitude and factors associated with nonadherence to antiepileptic drug treatment in Africa: A cross-sectional multisite study.

Objectives: The epilepsy treatment gap is large in low- and middle-income countries, but the reasons behind nonadherence to treatment with antiepileptic drugs (AEDs) across African countries remain unclear. We investigated the extent to which AEDs are not taken and associated factors in people with active convulsive epilepsy (ACE) identified in cross-sectional studies conducted in five African countries.

Methods: We approached 2,192 people with a confirmed diagnosis of ACE for consent to give blood voluntarily.

Author Correction: Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates.

A correction has been published and is linked to the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Mitochondrial damage and "plugging" of transport selectively in myelinated, small-diameter axons are major early events in peripheral neuroinflammation.

Background: Small-diameter, myelinated axons are selectively susceptible to dysfunction in several inflammatory PNS and CNS diseases, resulting in pain and degeneration, but the mechanism is not known.

Methods: We used in vivo confocal microscopy to compare the effects of inflammation in experimental autoimmune neuritis (EAN), a model of Guillain-Barré syndrome (GBS), on mitochondrial function and transport in large- and small-diameter axons. We have compared mitochondrial function and transport in vivo in (i) healthy axons, (ii) axons affected by experimental autoimmune neuritis, and (iii) axons in which mitochondria were focally damaged by laser induced photo-toxicity.

Impaired synaptic function is linked to cognition in Parkinson's disease.

Objective: Cognitive impairment is frequent in Parkinson's disease, but the underlying mechanisms are insufficiently understood. Because cortical metabolism is reduced in Parkinson's disease and closely associated with cognitive impairment, and CSF amyloid- species are reduced and correlate with neuropsychological performance in Parkinson's disease, and amyloid- release to interstitial fluid may be related to synaptic activity; we hypothesize that synapse dysfunction links cortical hypometabolism, reduced CSF amyloid- and presynaptic deposits of -synuclein. We expect a correlation between hypometabolism, CSF amyloid-, and the synapse related-markers CSF neurogranin and -synuclein.