14 research outputs found

    Degeneration of basal and limbic networks is a core feature of behavioural variant frontotemporal dementia

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    Acknowledgment We would like to acknowledge the support of the Maxwell Computer Cluster funded by the University of Aberdeen. We also gratefully acknowledge study investigators and the generosity of study participants. Funding This study was sponsored entirely by TauRx Therapeutics Ltd (PAR1577). The Maxwell Computer Cluster is funded by the University of Aberdeen.Peer reviewedPublisher PD

    Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimerā€™s Disease : Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial

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    The supplementary material is available in the electronic version of this article: http://dx.doi.org/10.3233/JAD-170560. The study was sponsored by TauRx Therapeutics (Singapore). We thank Lon Schneider and Howard Feldman for their contribution to the Scientific Advisory Board. We gratefully acknowledge study investigators and the generosity of study participants. Authorsā€™ disclosures available online (http://j-alz.com/manuscript disclosures/17-0560r3).Peer reviewedPublisher PD

    Protocol of the Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research (CHARIOT): Prospective Readiness cOhort (PRO) SubStudy

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    The Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research (CHARIOT): Prospective Readiness cOhort (PRO) SubStudy (CPSS), sponsored by Janssen Pharmaceutical Research & Development LLC, is an Alzheimer's disease (AD) biomarker enriched observational study that began 3 July 2015 CPSS aims to identify and validate determinants of AD, alongside cognitive, functional and biological changes in older adults with or without detectable evidence of AD pathology at baseline. CPSS is a dual-site longitudinal cohort (3.5 years) assessed quarterly. Cognitively normal participants (60-85 years) were recruited across Greater London and Edinburgh. Participants are classified as high, medium (amnestic or non-amnestic) or low risk for developing mild cognitive impairment-Alzheimer's disease based on their Repeatable Battery for the Assessment of Neuropsychological Status performance at screening. Additional AD-related assessments include: a novel cognitive composite, the Global Preclinical Alzheimer's Cognitive Composite, brain MRI and positron emission tomography and cerebrospinal fluid analysis. Lifestyle, other cognitive and functional data, as well as biosamples (blood, urine, and saliva) are collected. Primarily, study analyses will evaluate longitudinal change in cognitive and functional outcomes. Annual interim analyses for descriptive data occur throughout the course of the study, although inferential statistics are conducted as required. CPSS received ethical approvals from the London-Central Research Ethics Committee (15/LO/0711) and the Administration of Radioactive Substances Advisory Committee (RPC 630/3764/33110) The study is at the forefront of global AD prevention efforts, with frequent and robust sampling of the well-characterised cohort, allowing for detection of incipient pathophysiological, cognitive and functional changes that could inform therapeutic strategies to prevent and/or delay cognitive impairment and dementia. Dissemination of results will target the scientific community, research participants, volunteer community, public, industry, regulatory authorities and policymakers. On study completion, and following a predetermined embargo period, CPSS data are planned to be made accessible for analysis to facilitate further research into the determinants of AD pathology, onset of symptomatology and progression. The CHARIOT:PRO SubStudy is registered with clinicaltrials.gov (NCT02114372). Notices of protocol modifications will be made available through this trial registry. [Abstract copyright: Ā© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

    Concentration-Dependent Activity of Hydromethylthionine on Cognitive Decline and Brain Atrophy in Mild to Moderate Alzheimerā€™s Disease

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    ACKNOWLEDGMENTS We gratefully acknowledge study investigators and the generosity of study participants. We gratefully acknowledge Professor Gordon Wilcock for critical review and commentary on drafts of the manuscript. Authorā€™s disclosures available online (https://www.j-alz.com/manuscript-disclosures/19-0772r1). SUPPLEMENTARY MATERIAL The supplementary material is available in the electronic version of this article: http://dx.doi.org/10.3233/JAD-190772. Availability of data and materials The datasets and analyses used during the current study are available from the corresponding author on reasonable request.Peer reviewedPublisher PD

    Magnetic resonance imaging measures of brain volumes across the EXPEDITION trials in mild and moderate Alzheimer's disease dementia

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    Abstract Introduction Solanezumab is a monoclonal antibody that preferentially binds soluble amyloid beta and promotes its clearance from the brain. The aim of this post hoc analysis was to assess the effect of lowā€dose solanezumab (400 mg) on global brain volume measures in patients with mild or moderate Alzheimer's disease (AD) dementia quantified using volumetric magnetic resonance imaging (vMRI) data from the EXPEDITION clinical trial program. Methods Patients with mild or moderate AD (EXPEDITION and EXPEDITION2) and mild AD (EXPEDITION3), were treated with either placebo or solanezumab (400 mg) every 4 weeks (Q4W) for 76 weeks. vMRI scans were acquired at baseline and at 80 weeks from 427 MRI facilities using a standardized imaging protocol. Whole brain volume (WBV) and ventricle volume (VV) changes were estimated at 80 weeks using either boundary shift integral (EXPEDITION and EXPEDITION2) or tensorā€based morphometry (EXPEDITION3). Results The pooled cohort used for this study consisted of participants with vMRI at baseline and week 80 across the three trials. Analyzed patient subgroups comprised full patient cohort (N = 2933), apolipoprotein E (APOE) Īµ4+ carriers (N = 1835), and patients with mild (N = 2497) or moderate AD dementia (N = 428). No significant effect (all Pā€values ā‰„.05) of treatment was observed in the pooled sample, individual trials, or subgroups of patients with mild or moderate AD or APOE Īµ4 carriers, in either WBV or VV change. Discussion Analysis of patients with mild or moderate AD dementia from baseline to 80 weeks using vMRI measures of WBV and VV changes suggested that lowā€dose solanezumab was not linked to changes in volumes at 80 weeks. Analysis of the pooled cohort did not demonstrate an effect on brain volumes with treatment. Evaluation of a higher dose of solanezumab in the preclinical stage of AD is currently being undertaken

    Validation of 3ā€ and 5ā€point severity scales to assess ARIAā€E

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    Abstract INTRODUCTION Antiā€amyloidā€Ī² (AĪ²) monoclonal antibodies (mAbs) offer the promise of disease modification and are emerging treatment options in Alzheimer's disease. Antiā€AĪ² mAbs require brain magnetic resonance imaging (MRI) examinations to detect antiā€amyloidā€induced amyloidā€related imaging abnormalities (ARIA), important adverse drug reactions associated with some antiā€AĪ² mAbs currently available in the United States and in clinical development. We present a simple rating system for ARIAā€edema (ARIAā€E) that can assess severity on a 3ā€ or 5ā€point scale based upon a single linear measurement of the largest area of lesion, and dissemination in space, termed the 3ā€point Severity Scale of ARIAā€E (SSAEā€3) and the 5ā€point Severity Scale of ARIAā€E (SSAEā€5), respectively. METHODS MRI results were collected from 75 participants from the SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) studies of gantenerumab. Three neuroradiologists experienced with the detection of ARIAā€E were selected to read all cases independently. One rater was then chosen for a second read to assess intraā€reader reproducibility. RESULTS The three raters had high agreement in identifying and grading ARIAā€E. The Cohen/Fleiss kappa (Īŗ) scores (95% confidence interval [CI]) for the interā€ and intraā€reader comparisons for SSAEā€3 and SSAEā€5 were 0.79 (0.70ā€“1.00), 0.94 (0.94ā€“1.00), 0.73 (0.66ā€“1.00), and 0.90 (0.90ā€“1.00), respectively. DISCUSSION Our study suggests that SSAEā€3 and SSAEā€5 are valid ARIAā€E rating scales for use in routine clinical practice by experienced radiologists in specialized settings. The application of these scales in everyday use in clinical practice will support the expansion of antiā€AĪ² mAbs as a treatment option for people living with Alzheimer's disease. Highlights A simple rating scale is needed to rate severity of amyloidā€related imaging abnormalitiesā€“edema (ARIAā€E) in both research and clinical settings. The 3ā€ and 5ā€point Severity Scales of ARIAā€E (SSAEā€3/ā€5) have good interā€ and intraā€reader agreement. The SSAEā€3/ā€5 have been used in most major Alzheimer's disease (AD) trials to date and are suitable for largeā€scale use in routine clinical practice, which may help support the expansion of antiā€amyloid antibodies as treatment options for AD

    Measurement of brain atrophy in subcortical vascular disease: A comparison of different approaches and the impact of ischaemic lesions

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    Measurement of brain atrophy has been proposed as a surrogate marker in MS and degenerative dementias. Although cerebral small vessel disease predominantly affects white and subcortical grey matter, recent data suggest that whole brain atrophy is also a good indicator of clinical and cognitive status in this disease. Automated methods to measure atrophy are available that are accurate and reproducible in disease-free brains. However, optimal methods in small vessel disease have not been established and the impact of ischaemic lesions on different techniques has not been explored systematically. In this study, three contrasting techniques -- Statistical Parametric Mapping 5 (SPM5), SIENAX and BrainVisa -- were applied to measure cross-sectional atrophy (brain parenchymal fraction or BPF) in a large (n=143) two-centre cohort of patients with CADASIL, a genetic model of small vessel disease. All three techniques showed similar sensitivity to trends in BPF associated with age and lesion load. No single technique was particularly vulnerable to error as a result of lesions. Provided major errors in registration were excluded by visual inspection, manual correction of segmentations had a negligible impact with mean errors of 0.41% for SIENAX and 0.46% for BrainVisa. BPF correlated strongly with global cognitive function and physical disability, independent of the technique used. Correlation coefficients with the Minimental State Examination score were: BrainVisa 0.58, SIENAX 0.58, SPM5 0.60 (for all, p<0.001). These results suggest that all three methods can be applied reliably in patients with ischaemic lesions. Choice of analysis approach for this kind of clinical question will be determined by factors other than their robustness and precision, such as a desire to explore subtle localised changes using extensions of these processing tools

    Comparing ARIA-E severity scales and effects of treatment management thresholds

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    Introduction: Amyloid-related imaging abnormalitiesā€“edema (ARIA-E) is associated with anti-amyloid beta monoclonal antibody treatment. ARIA-E severity may be assessed using the Barkhof Grand Total Scale (BGTS) or the 3- or 5-point Severity Scales of ARIA-E (SSAE-3/SSAE-5). We assessed inter- and intra-reader correlations between SSAE-3/5 and BGTS. Methods: Magnetic resonance imaging scans were collected from 75 participants in the SCarlet RoAD and Marguerite RoAD studies. Three neuroradiologists reviewed scans at baseline and at follow-up. Concordance in dichotomized ARIA-E ratings was assessed for a range of BGTS thresholds. Results: SSAE-3/5 scores correlated with BGTS scores, with high inter-reader intraclass correlation coefficients across all scales. There was high agreement in dichotomized ratings for SSAE-3Ā >Ā 1Ā versus BGTSĀ >Ā 3 for all readers (accuracy 0.85ā€“0.93) and between pairs of readers. Discussion: SSAE-3/5 showed high degrees of correlation with BGTS, potentially allowing seamless transition from the BGTS to SSAE-3/5 for ARIA-E management
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