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Background/Objectives : Gaucher disease type 1 (GD1) is characterized by hepatosplenomegaly, thrombocytopenia, and disabling bone manifestations requiring regular MRI monitoring. The EIROS study assessed the real-world impact of velaglucerase alfa on GD1 bone disease, using MRI data collected in French clinical practice. Methods : MRIs collected retrospectively from treatment initiation and prospectively during follow-up (12-months) were analyzed centrally by a blinded expert radiologist to evaluate bone infiltration using the Bone Marrow Burden (BMB) score and a qualitative method (stable, improved or worsened for the spine and femur). Abdominal MRIs were also centrally analyzed to assess hepatosplenomegaly. Bone manifestations, hepatosplenomegaly, and hematologic parameters were analyzed from medical records. Results : MRI data were available for 20 patients: 6 treatment-naive patients and 14 patients who switched to velaglucerase alfa from another GD treatment. Interpretable MRIs for BMB scoring were available for seven patients for the spine and one patient for the femur. Qualitative assessments ( n = 18) revealed stability in spine and femur infiltration in 100.0% and 84.6% of treatment-switched patients ( n = 13), respectively, and improvements in 80.0% and 60.0% of treatment-naive patients ( n = 5), respectively; no worsening of bone infiltration was observed. Liver, spleen, and hematologic parameters improved in treatment-naive patients and remained stable in treatment-switched patients. Conclusions : The qualitative real-world data support findings from clinical trials suggesting the long-term effectiveness of velaglucerase alfa on GD1 bone manifestations. When MRI assessment by radiologists with experience of GD is not possible, a simplified qualitative assessment may be sufficient in clinical practice for monitoring bone disease progression and treatment response.

Introduction: Anti-amyloid-β (Aβ) monoclonal antibodies (mAbs) offer the promise of disease modification and are emerging treatment options in Alzheimer's disease. Anti-Aβ mAbs require brain magnetic resonance imaging (MRI) examinations to detect anti-amyloid-induced amyloid-related imaging abnormalities (ARIA), important adverse drug reactions associated with some anti-Aβ mAbs currently available in the United States and in clinical development. We present a simple rating system for ARIA-edema (ARIA-E) that can assess severity on a 3- or 5-point scale based upon a single linear measurement of the largest area of lesion, and dissemination in space, termed the 3-point Severity Scale of ARIA-E (SSAE-3) and the 5-point Severity Scale of ARIA-E (SSAE-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 ARIA-E were selected to read all cases independently. One rater was then chosen for a second read to assess intra-reader reproducibility., Results: The three raters had high agreement in identifying and grading ARIA-E. The Cohen/Fleiss kappa (κ) scores (95% confidence interval [CI]) for the inter- and intra-reader comparisons for SSAE-3 and SSAE-5 were 0.79 (0.70-1.00), 0.94 (0.94-1.00), 0.73 (0.66-1.00), and 0.90 (0.90-1.00), respectively., Discussion: Our study suggests that SSAE-3 and SSAE-5 are valid ARIA-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 anti-Aβ mAbs as a treatment option for people living with Alzheimer's disease., Highlights: A simple rating scale is needed to rate severity of amyloid-related imaging abnormalities-edema (ARIA-E) in both research and clinical settings.The 3- and 5-point Severity Scales of ARIA-E (SSAE-3/-5) have good inter- and intra-reader agreement.The SSAE-3/-5 have been used in most major Alzheimer's disease (AD) trials to date and are suitable for large-scale use in routine clinical practice, which may help support the expansion of anti-amyloid antibodies as treatment options for AD., Competing Interests: Luc Bracoud is a full‐time employee of Clario, Inc. (formerly known as Bioclinica, Inc.). Gregory Klein is a full‐time employee of and shareholder in F. Hoffmann‐La Roche Ltd. Marco Lyons is a full‐time employee of and shareholder in Roche Products Ltd. Marzia A. Scelsi is a full‐time employee of Roche Products Ltd. Jakub Wojtowicz is a full‐time employee of and shareholder in F. Hoffmann‐La Roche Ltd. Szofia Bullain is a full‐time employee of and shareholder in F. Hoffmann‐La Roche Ltd. Derk Purcell reports outside the submitted work personal fees from Biogen and provides both consultative services and image interpretation for Clario, Inc. Jochen B. Fiebach reports outside the submitted work personal fees from AbbVie, AC Immune, Artemida, Bioclinica/Clario, Biogen, BMS, Brainomix, Cerevast, Daiichi Sankyo, Eisai, F. Hoffmann‐La Roche AG, Eli Lilly, Guerbet, Ionis Pharmaceuticals, IQVIA, Janssen, Julius Clinical, jung diagnostics, Lysogene, Merck, Nicolab, Premier Research, and TauRx. Jerome Barakos provides both consultative services and image interpretation for Clario, Inc. Joyce Suhy is a full‐time employee of Clario, Inc., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Amyloid-related imaging abnormalities-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-3 > 1 versus BGTS > 3 for all readers (accuracy 0.85-0.93) 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., Competing Interests: Gregory Klein is a full‐time employee and shareholder of F. Hoffmann‐La Roche Ltd. Marzia A. Scelsi is a full‐time employee of Roche Products Ltd. Jerome Barakos provides both consultative services and image interpretation for Clario. Jochen B. Fiebach reports outside the submitted work personal fees from AbbVie, AC Immune, Artemida, Bioclinica/Clario, Biogen, BMS, Brainomix, Cerevast, Daiichi‐Sankyo, Eisai, F. Hoffmann‐La Roche AG, Eli Lilly, Guerbet, Ionis Pharmaceuticals, IQVIA, Janssen, Julius Clinical, jung diagnostics, Lysogene, Merck, Nicolab, Premier Research, and Tau Rx. Luc Bracoud is a full‐time employee of Clario. Joyce Suhy is a full‐time employee of Clario. Paul Delmar is a full‐time employee and shareholder of F. Hoffmann‐La Roche Ltd. Marco Lyons is a full‐time employee and shareholder of Roche Products Ltd. Jakub Wojtowicz is a full‐time employee and shareholder of F. Hoffmann‐La Roche Ltd. Szofia Bullain is a full‐time employee and shareholder of F. Hoffmann‐La Roche Ltd. Frederik Barkhof is supported by the NIHR Biomedical Research Centre at UCLH. He is a steering committee or iDMC member for Biogen, Merck, Roche, EISAI, and Prothena; consultant for Roche, Biogen, Merck, IXICO, Janssen, and Combinostics; has research agreements with Roche, Merck, Biogen, and GE Healthcare; and is co‐founder and shareholder of Queen Square Analytics LTD. Derk Purcell reports outside the submitted work personal fees from Biogen and provides both consultative services and image interpretation for Clario. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

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 low-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 tensor-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 ) ε4 + carriers ( N = 1835), and patients with mild ( N = 2497) or moderate AD dementia ( N = 428). No significant effect (all P -values ≥.05) of treatment was observed in the pooled sample, individual trials, or subgroups of patients with mild or moderate AD or APOE ε4 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 low-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., Competing Interests: Diana O. Svaldi, Ixavier A. Higgins, Karen C. Holdridge, Roy Yaari, Michael Case, Sergey Shcherbinin, and John R. Sims are all employees and minor shareholders of Eli Lilly and Company. Diana O. Svaldi has received support from Eli Lilly and Company for attending meetings and/or travel. Luc Bracoud and David Scott have nothing to report., (© 2022 Eli Lilly and Company. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The behavioural variant of frontotemporal dementia is a clinical syndrome characterized by changes in behaviour, cognition and functional ability. Although atrophy in frontal and temporal regions would appear to be a defining feature, neuroimaging studies have identified volumetric differences distributed across large parts of the cortex, giving rise to a classification into distinct neuroanatomical subtypes. Here, we extended these neuroimaging studies to examine how distributed patterns of cortical atrophy map onto brain network hubs. We used baseline structural magnetic resonance imaging data collected from 213 behavioural variant of frontotemporal dementia patients meeting consensus diagnostic criteria and having definite evidence of frontal and/or temporal lobe atrophy from a global clinical trial conducted in 70 sites in Canada, United States of America, Australia, Asia and Europe. These were compared with data from 244 healthy elderly subjects from a well-characterized cohort study. We have used statistical methods of hierarchical agglomerative clustering of 68 regional cortical and subcortical volumes (34 in each hemisphere) to determine the reproducibility of previously described neuroanatomical subtypes in a global study. We have also attempted to link the structural findings to clinical features defined systematically using well-validated clinical scales (Addenbrooke's Cognitive Examination Revised, the Mini-Mental Status Examination, the Frontotemporal Dementia Rating Scale and the Functional Assessment Questionnaire) and subscales derived from them. Whilst we can confirm that the subtypes are robust, they have limited value in explaining the clinical heterogeneity of the syndrome. We have found that a common pattern of degeneration affecting a small number of subcortical, limbic and frontal nodes within highly connected networks (most previously identified as rich club members or functional binding nodes) is shared by all the anatomical subtypes. Degeneration in these core regions is correlated with cognitive and functional impairment, but less so with behavioural impairment. These findings suggest that degeneration in highly connected basal, limbic and frontal networks is a core feature of the behavioural variant of frontotemporal dementia phenotype irrespective of neuroanatomical and clinical heterogeneity, and may underly the impairment of integration in cognition, function and behaviour responsible for the loss of insight that characterizes the syndrome., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: 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., Methods and Analysis: 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., Ethics and Dissemination: 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., Trial Registration Number: The CHARIOT:PRO SubStudy is registered with clinicaltrials.gov (NCT02114372). Notices of protocol modifications will be made available through this trial registry., Competing Interests: Competing interests: MTR was formerly employee of Janssen and is an industry consultant. GN, SB, HMA, MF, KK, ZS and NR are employees of Janssen Research & Development, LLC and own stock/stock options in the company. NK and HRB are former employees of Janssen Research & Development, LLC and both own stock/stock options in the company. JD is an employee of Janssen China Research and Development Center and owns stock/stock options in the company. LM served as principal study investigator at Imperial College of London (ICL) abd has held consultancy agreements, in the last five years, with Eli Lilly, Astra Zeneca and Takeda and is National Coordinator for the TOMMORROW, Amaranth and Generation Clinical Studies; and does not hold any agreement with any of the funders in relation to patents, products in development relevant to this study or marketed products. CR served as principal study investigator at Edinburgh University (EDI), and has served as a consultant in the last five years for: Actinogen, Biogen, Roche Pharmaceuticals and Roche Diagnostics, Eisai, Abbott Pharmaceuticals, Eli Lilly, Kyowa Kirin, Signant Health, Merck and Nutricia. He is also the Chief Investigator and Co-coordinator of IMI-EPAD which is a public-private partnership of 39 partners www.ep-ad.org. CU-M, JC, RP, GP, Cd-JL, HW and MK served as co-principal study investigators at ICL for Janssen Research & Development, LLC and all declare no conflict of interest. JC's and AM’s posts at ICL are in part supported by the NIHR NW London Applied Research Collaboration. CR, DB, MC, PG, DK, YC-S, DP, LC, KL, HM-Y, JC and AM were study investigators at ICL and declare no conflict of interest. KR served as co-principal study investigator at EDI for Janssen Research & Development, LLC and declares no conflict of interest. TW and NR-M were study investigators at EDI and declare no conflict of interest. DS and LB are employees of Bioclinica Inc. and declare no competing interests., (© 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.)

Introduction: Hippocampal volume (HV) and cortical thickness are commonly used imaging biomarkers in Alzheimer's disease (AD) trials, and may have utility as selection criteria for enrichment strategies. Atrophy rates of these measures, in the high-risk apolipoprotein E (APOE) ε4/ε4 homozygous AD subjects are unknown., Methods: Data from Alzheimer's Disease Neuroimaging Initiative (ADNI-1) and a tramiprosate trial were analyzed in APOE ε4/ε4 and APOE ε3/ε3 subjects with mild cognitive impairment (MCI) or mild AD. Magnetic resonance imaging (MRI) data were centrally processed using FreeSurfer; total HV and composite average cortical thickness were derived and adjusted for age, head size, and education. Volumetric changes from baseline were assessed using Boundary Shift Integral, and correlated with cognitive changes., Results: APOE ε4/ε4 MCI subjects showed significantly higher % HV atrophy and cortical thinning at 12 months (4.4%, 3.1%, n = 29) compared to APOE ε3/ε3 subjects (2.8%, 1.8%, n = 93) and similarly in mild AD (7.4%, 4.7% n = 21 vs 5.4%, 3.3% n = 29). Differences were all significant at 24 months. Over 24 months, HV atrophy and cortical thinning correlated significantly with Alzheimer's Disease Assessment Scale-Cognitive subscale worsening in APOE ε4/ε4 MCI subjects, but not in mild AD., Discussion: Correlation of volumetric measures to cognitive change in APOE ε4/ε4 subjects with early AD supports their role as efficacy biomarkers. If confirmed in a Phase 3 trial with ALZ-801 (pro-drug of tramiprosate) in APOE ε4/ε4 early AD subjects, it may allow their use as surrogate outcomes in future treatment or prevention trials in AD., Competing Interests: Dr. Susan Abushakra serves as the chief medical officer of Alzheon, Inc. and holds stock and stock options of Alzheon, Inc. Dr. Martin Tolar serves as the founder, president, and chief executive officer of Alzheon, Inc. and holds stock and stock options of Alzheon, Inc. Dr. John A. Hey serves as the chief scientific officer of Alzheon, Inc. and holds stock and stock options of Alzheon, Inc. Dr. Aidan Power serves as a vice president at Alzheon, Inc. and holds stock and stock options of Alzheon, Inc. Dr. Anton Porsteinsson receives research support from the National Institutes of Health and U.S. Department of Defense. He also receives grants from AstraZeneca, Avanir, Biogen, Biohaven, Eisai, Eli Lilly, Genentech/Roche, Janssen, Novartis, Merck, and Toyama. He receives personal fees from Acadia Pharmaceuticals, Avanir, BioXcel, Eisai, Functional Neuromodulation, Grifols, Lundbeck, Merck, Neurim Pharmaceuticals, Pfizer, Tetra Discovery Partners, and Toyama. Dr. Marwan Sabbagh receives research support from the NIH and the Keep Memory Alive Foundation. He has consulting agreements with Allergan, Biogen, Bracket, Cortexyme, Grifols, Sanofi, Neurotrope, and Roche‐Genentech. He has ownership interest in Brain Health Inc., Versanum Inc., Neurotrope Inc., and uMethod Health. Drs. Joyce Suhy, Luc Bracoud, Joel Schaerer, and David Scott serve as full‐time employees of Bioclinica Inc. and have no competing interest in Alzheon Inc., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Background: Hydromethylthionine is a potent inhibitor of pathological aggregation of tau and TDP-43 proteins., Objective: To compare hydromethylthionine treatment effects at two doses and to determine how drug exposure is related to treatment response in bvFTD., Methods: We undertook a 52-week Phase III study in 220 bvFTD patients randomized to compare hydromethylthionine at 200 mg/day and 8 mg/day (intended as a control). The principal outcomes were change on the Addenbrookes Cognitive Examination - Revised (ACE-R), the Functional Activities Questionnaire (FAQ), and whole brain volume. Secondary outcomes included Modified Clinical Global Impression of Change (Modified-CGIC). A population pharmacokinetic exposure-response analysis was undertaken in 175 of the patients with available blood samples and outcome data using a discriminatory plasma assay for the parent drug., Results: There were no significant differences between the two doses as randomized. There were steep concentration-response relationships for plasma levels in the range 0.3-0.6 ng/ml at the 8 mg/day dose on clinical and MRI outcomes. There were significant exposure-dependent differences at 8 mg/day for FAQ, Modified-CGIC, and whole brain atrophy comparing patients with plasma levels greater than 0.346 ng/ml with having minimal drug exposure. The exposure-response is biphasic with worse outcomes at the high concentrations produced by 200 mg/day., Conclusions: Hydromethylthionine has a similar concentration-response profile for effects on clinical decline and brain atrophy at the 8 mg/day dose in bvFTD as recently reported in AD. Treatment responses in bvFTD are predicted to be maximal at doses in the range 20-60 mg/day. A confirmatory placebo-controlled trial is now planned.

The 2018 National Institute on Aging and the Alzheimer's Association (NIA-AA) research framework recently redefined Alzheimer's disease (AD) as a biological construct, based on in vivo biomarkers reflecting key neuropathologic features. Combinations of normal/abnormal levels of three biomarker categories, based on single thresholds, form the AD signature profile that defines the biological disease state as a continuum, independent of clinical symptomatology. While single thresholds may be useful in defining the biological signature profile, we provide evidence that their use in studies with cognitive outcomes merits further consideration. Using data from the Alzheimer's Disease Neuroimaging Initiative with a focus on cortical amyloid binding, we discuss the limitations of applying the biological definition of disease status as a tool to define the increased likelihood of the onset of the Alzheimer's clinical syndrome and the effects that this may have on trial study design. We also suggest potential research objectives going forward and what the related data requirements would be., (Copyright © 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Solanezumab is a humanized monoclonal antibody that preferentially binds to soluble amyloid β and promotes its clearance from the brain in preclinical studies. The objective of this study was to assess the effect of solanezumab in slowing global and anatomically localized brain atrophy as measured by volumetric magnetic resonance imaging (MRI)., Methods: In the EXPEDITION3 phase 3 trial, participants with mild Alzheimer's disease were randomized to receive intravenous infusions of either 400 mg of solanezumab or placebo every 4 weeks for 76 weeks. Volumetric MRI scans were acquired at baseline and at 80 weeks from 275 MRI facilities using a standardized imaging protocol. A subset of 1462 patients who completed both MRI and 14-item Alzheimer's Disease Assessment Scale-Cognitive Subscale assessments at both time points were selected for analysis. Longitudinal MRI volume changes were analyzed centrally by tensor-based morphometry with a standard FreeSurfer brain parcellation. Prespecified volumetric measures, including whole brain and ventricles, along with anatomically localized regions in the temporal, parietal, and frontal lobes were evaluated in those participants., Results: Group-mean differences in brain atrophy rates were directionally consistent across a number of brain regions but small in magnitude (1.3-6.9% slowing) and not statistically significant when corrected for multiple comparisons. The annualized rates of change of the volumetric measures and the correlation of these changes with cognitive changes in placebo-treated subjects were similar to those reported previously., Discussion: In the EXPEDITION3 trial, solanezumab did not significantly slow down rates of global or anatomically localized brain atrophy. Brain volume changes and their relationship to cognition were consistent with previous reports.

Background: Although hydromethylthionine is a potent tau aggregation inhibitor, no difference was found in either of two Phase III trials in mild to moderate Alzheimer's disease (AD) comparing doses in the range 150-250 mg/day with 8 mg/day intended as a control., Objective: To determine how drug exposure is related to treatment response., Methods: A sensitive plasma assay for the drug was used in a population pharmacokinetic analysis of samples from 1,162 of the 1,686 patients who participated in either of the Phase III trials with available samples and efficacy outcome data., Results: There are steep concentration-response relationships for steady state plasma levels in the range 0.3-0.8 ng/ml at the 8 mg/day dose. Using a threshold based on the lower limit of quantitation of the assay on Day 1, there are highly significant differences in cognitive decline and brain atrophy in patients with above threshold plasma levels, both for monotherapy and add-on therapy, but with effect sizes reduced by half as add-on. Plasma concentrations in the range 4-21 ng/ml produced by the high doses are not associated with any additional benefit., Conclusions: Hydromethylthionine has pharmacological activity on brain structure and function at the 8 mg/day dose as monotherapy or as add-on to symptomatic treatments. This combined with a plateau at higher doses is consistent with the lack of dose-response seen in the Phase III trials. Treatment benefit is predicted to be maximal at 16 mg/day as monotherapy. A placebo-controlled trial in mild/moderate AD is now ongoing to confirm efficacy at this dose.

Background: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation., Objectives: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD., Methods: Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error., Results: The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy., Conclusions: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis.

Background: The relationship between cerebral microbleeds (CMB) and Alzheimer's disease (AD) has not yet been clearly determined, particularly with susceptibility weight-imaging (SWI)., Objective: To evaluate the SWI sequence using 3T MRI for the detection of CMB, and its ability to differentiate elderly control subjects (CS), stable mild cognitive impairment patients (MCI-s), MCI patients progressing to AD (MCI-p), and AD patients., Methods: It was a prospective, monocentric, observational study that took place in Toulouse, France. Participants were 65 years and older, enrolled in three groups: CS, MCI, and AD. Based on the longitudinal analysis of cognitive decline, MCI subjects were retrospectively classified as MCI-s or MCI-p. Each patient had a 4-year follow-up with MRI at baseline (MRI#1) and during the fourth year (MRI#3). CMB were counted on native SWI images juxtaposed to minIP reformatted images., Results: 150 patients were enrolled: 48 CS, 25 MCI-s, 18 MCI-p, 59 AD. At MRI#1 and at MRI#3, there was no significant difference in the prevalence of CMB between groups (p = 0.75 and p = 0.87). In the MCI-p + AD group, significantly more subjects had≥4 incident CMB compared to the CS + MCI-s group (p = 0.016). In the MCI-p + AD group, the prevalence of patients with >4 CMB was significantly higher at MRI#3 than at MRI#1 (p = 0.008)., Conclusion: Using SWI, AD and MCI-p patients had developed significantly more new CMB than CS and MCI-s patients during the follow-up. Incident CMB might be suggested as a potential imaging marker of AD progression.

Background: Leuco-methylthioninium bis(hydromethanesulfonate; LMTM), a stable reduced form of the methylthioninium moiety, acts as a selective inhibitor of tau protein aggregation both in vitro and in transgenic mouse models. Methylthioninium chloride has previously shown potential efficacy as monotherapy in patients with Alzheimer's disease. We aimed to determine whether LMTM was safe and effective in modifying disease progression in patients with mild to moderate Alzheimer's disease., Methods: We did a 15-month, randomised, controlled double-blind, parallel-group trial at 115 academic centres and private research clinics in 16 countries in Europe, North America, Asia, and Russia with patients younger than 90 years with mild to moderate Alzheimer's disease. Patients concomitantly using other medicines for Alzheimer's disease were permitted to be included because we considered it infeasible not to allow their inclusion; however, patients using medicines carrying warnings of methaemoglobinaemia were excluded because the oxidised form of methylthioninium in high doses has been shown to induce this condition. We randomly assigned participants (3:3:4) to 75 mg LMTM twice a day, 125 mg LMTM twice a day, or control (4 mg LMTM twice a day to maintain blinding with respect to urine or faecal discolouration) administered as oral tablets. We did the randomisation with an interactive web response system using 600 blocks of length ten, and stratified patients by severity of disease, global region, whether they were concomitantly using Alzheimer's disease-labelled medications, and site PET capability. Participants, their study partners (generally carers), and all assessors were masked to treatment assignment throughout the study. The coprimary outcomes were progression on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Alzheimer's Disease Co-operative Study-Activities of Daily Living Inventory (ADCS-ADL) scales from baseline assessed at week 65 in the modified intention-to-treat population. This trial is registered with Clinicaltrials.gov (NCT01689246) and the European Union Clinical Trials Registry (2012-002866-11)., Findings: Between Jan 29, 2013, and June 26, 2014, we recruited and randomly assigned 891 participants to treatment (357 to control, 268 to 75 mg LMTM twice a day, and 266 to 125 mg LMTM twice a day). The prespecified primary analyses did not show any treatment benefit at either of the doses tested for the coprimary outcomes (change in ADAS-Cog score compared with control [n=354, 6·32, 95% CI 5·31-7·34]: 75 mg LMTM twice a day [n=257] -0·02, -1·60 to 1·56, p=0·9834, 125 mg LMTM twice a day [n=250] -0·43, -2·06 to 1·20, p=0·9323; change in ADCS-ADL score compared with control [-8·22, 95% CI -9·63 to -6·82]: 75 mg LMTM twice a day -0·93, -3·12 to 1·26, p=0·8659; 125 mg LMTM twice a day -0·34, -2·61 to 1·93, p=0·9479). Gastrointestinal and urinary effects were the most common adverse events with both high doses of LMTM, and the most common causes for discontinuation. Non-clinically significant dose-dependent reductions in haemoglobin concentrations were the most common laboratory abnormality. Amyloid-related imaging abnormalities were noted in less than 1% (8/885) of participants., Interpretation: The primary analysis for this study was negative, and the results do not suggest benefit of LMTM as an add-on treatment for patients with mild to moderate Alzheimer's disease. Findings from a recently completed 18-month trial of patients with mild Alzheimer's disease will be reported soon., Funding: TauRx Therapeutics., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Importance: Early identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease-modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms., Objectives: To assess the safety of the γ-secretase inhibitor avagacestat in PDAD and to determine whether CSF biomarkers can identify this patient population prior to clinical diagnosis of dementia., Design, Setting, and Participants: A randomized, placebo-controlled phase 2 clinical trial with a parallel, untreated, nonrandomized observational cohort of CSF biomarker-negative participants was conducted May 26, 2009, to July 9, 2013, in a multicenter global population. Of 1358 outpatients screened, 263 met MCI and CSF biomarker criteria for randomization into the treatment phase. One hundred two observational cohort participants who met MCI criteria but were CSF biomarker-negative were observed during the same study period to evaluate biomarker assay sensitivity., Interventions: Oral avagacestat or placebo daily., Main Outcomes and Measure: Safety and tolerability of avagacestat., Results: Of the 263 participants in the treatment phase, 132 were randomized to avagacestat and 131 to placebo; an additional 102 participants were observed in an untreated observational cohort. Avagacestat was relatively well tolerated with low discontinuation rates (19.6%) at a dose of 50 mg/d, whereas the dose of 125 mg/d had higher discontinuation rates (43%), primarily attributable to gastrointestinal tract adverse events. Increases in nonmelanoma skin cancer and nonprogressive, reversible renal tubule effects were observed with avagacestat. Serious adverse event rates were higher with avagacestat (49 participants [37.1%]) vs placebo (31 [23.7%]), attributable to the higher incidence of nonmelanoma skin cancer. At 2 years, progression to dementia was more frequent in the PDAD cohort (30.7%) vs the observational cohort (6.5%). Brain atrophy rate in PDAD participants was approximately double that of the observational cohort. Concordance between abnormal amyloid burden on positron emission tomography and pathologic CSF was approximately 87% (κ = 0.68; 95% CI, 0.48-0.87). No significant treatment differences were observed in the avagacestat vs placebo arm in key clinical outcome measures., Conclusions and Relevance: Avagacestat did not demonstrate efficacy and was associated with adverse dose-limiting effects. This PDAD population receiving avagacestat or placebo had higher rates of clinical progression to dementia and greater brain atrophy compared with CSF biomarker-negative participants. The CSF biomarkers and amyloid positron emission tomography imaging were correlated, suggesting that either modality could be used to confirm the presence of cerebral amyloidopathy and identify PDAD., Trial Registration: clinicaltrials.gov Identifier: NCT00890890.

Our aim was to evaluate the association between magnetisation transfer imaging (MTI) parameters measured 30 to 45 days after a cerebrovascular insult and post-stroke functional outcome at the same time. MTI offers the opportunity to depict subtle microstructural changes in infarcted areas. The clinical significance of the heterogeneity of brain damage within ischaemic stroke lesions is unknown. We prospectively included 58 patients with acute middle cerebral artery stroke. Diffusion-weighted imaging was performed within 12 hours after onset and the final infarct was documented by MRI with fluid-attenuated inversion recovery (FLAIR) and MTI at 30 to 45 days follow-up. We evaluated the association between MTI histogram parameters and the clinical outcome assessed by dichotomised (threshold >2) modified rankin scale (mRS) using multivariable logistic regression models adjusted on baseline characteristics. In multivariable analyses, stroke outcome was mostly driven by initial National Institutes of Health Stroke Scale (odds ratio [OR]=1.23; 95% confidence interval [CI]=1.07-1.41; p<0.01) while after adjustment of initial stroke severity magnetisation transfer ratio peak position was the only MRI parameter associated with functional status at 30 to 45 days post-stroke (OR=0.86; 95% CI=0.75-0.98; p=0.02); lower peak position values associated with higher mRS. Conversely, stroke volume measured on FLAIR sequence was not associated with stroke prognosis (p=0.87). The intensity of microstructural changes within the infarct core measured at 30 to 45 days follow-up is independently associated with the functional status evaluated at the same time. MTI and related parameters could be used as surrogate markers of treatment response in stroke clinical trials., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background and Purpose: We investigated whether hyperintensities with a diameter of at least 3, 3.5, and 4 cm and visible on at least 3 slices on diffusion-weighted imaging enables patient selection with an infarct volume of ≥15 mL., Methods: Consecutive acute stroke patients were screened for the AXIS2 trial and examined according to a standardized magnetic resonance imaging protocol in 65 sites. Diffusion-weighted lesion diameters were measured and compared with volumetric assessments., Results: Out of 238 patients, 86.2% (N=206) had infarct diameter of at least 3 cm. Volumetric assessments showed infarct volume of ≥15 mL in 157 patients. A cut-off value of 3 cm led to 96.8% sensitivity and 33.3% specificity for predicting lesion volume of ≥15 mL. Analogously, a 3.5 cm cut-off led to 96.8% sensitivity and 50.6% specificity and a 4 cm cut-off led to 91.7% sensitivity and 61.7% specificity., Conclusions: Lesion diameter measures may enable multicentric patient recruitment with a prespecified minimal infarct volume., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927836., (© 2015 American Heart Association, Inc.)

Background and Purpose: White matter hyperintensities (WMH) on MRI are a quantitative marker for sporadic cerebral small vessel disease and are highly heritable. To date, large-scale genetic studies have identified only a single locus influencing WMH burden. This might in part relate to biological heterogeneity of sporadic WMH. The current study searched for genetic modifiers of WMH volume in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a monogenic small vessel disease., Methods: We performed a genome-wide association study to identify quantitative trait loci for WMH volume by combining data from 517 CADASIL patients collected through 7 centers across Europe. WMH volumes were centrally analyzed and quantified on fluid attenuated inversion recovery images. Genotyping was performed using the Affymetrix 6.0 platform. Individuals were assigned to 2 distinct genetic clusters (cluster 1 and cluster 2) based on their genetic background., Results: Four hundred sixty-six patients entered the final genome-wide association study analysis. The phenotypic variance of WMH burden in CADASIL explained by all single nucleotide polymorphisms in cluster 1 was 0.85 (SE=0.21), suggesting a substantial genetic contribution. Using cluster 1 as derivation and cluster 2 as a validation sample, a polygenic score was significantly associated with WMH burden (P=0.001) after correction for age, sex, and vascular risk factors. No single nucleotide polymorphism reached genome-wide significance., Conclusions: We found a polygenic score to be associated with WMH volume in CADASIL subjects. Our findings suggest that multiple variants with small effects influence WMH burden in CADASIL. The identification of these variants and the biological pathways involved will provide insights into the pathophysiology of white matter disease in CADASIL and possibly small vessel disease in general.

The PERFORM MRI Project was an ancillary study of the PERFORM trial. Its aim was to investigate the potential effects of terutroban in patients with atherothrombotic disorders, in comparison to aspirin, on the evolution of magnetic resonance imaging (MRI) lesions after a recent ischemic stroke or transient ischemic attack (TIA). The change in both hypointense and hyperintense lesions on the fluid attenuated inversion recovery (FLAIR) sequence, in the total brain volume and in the hippocampal volume from baseline (M1) to the final visit (M24) was assessed as well as the number of emergent microbleeds. A total of 748 patients had their MRI examination validated both at M1 and M24 during the study. At baseline, the volume of hypointense and hyperintense lesions on FLAIR images, the total brain volume, the hippocampal volume and the number of patients with microbleeds did not differ between the two groups. During follow-up, the mean volumetric increase of lesions hypointense or hyperintense on FLAIR images (from 5 to 8 %), the mean reduction of total brain volume (−0.4 %) and of hippocampal volume (−4 %), did not differ between the two treatment arms. The same parameters analysed ipsilateral to the ischaemic lesion did not differ either between the two groups. In the terutroban group, 16.3 % of patients presented with emergent microbleeds, 10.7 % in the aspirin group; this difference was not significant. In the PERFORM study, the progression of FLAIR lesions, of cerebral or hippocampal atrophy and of microbleeds did not differ between patients treated by terutroban and those treated by aspirin.

Quantitative information from magnetic resonance imaging (MRI) may substantiate clinical findings and provide additional insight into the mechanism of clinical interventions in therapeutic stroke trials. The PERFORM study is exploring the efficacy of terutroban versus aspirin for secondary prevention in patients with a history of ischemic stroke. We report on the design of an exploratory longitudinal MRI follow-up study that was performed in a subgroup of the PERFORM trial. An international multi-centre longitudinal follow-up MRI study was designed for different MR systems employing safety and efficacy readouts: new T2 lesions, new DWI lesions, whole brain volume change, hippocampal volume change, changes in tissue microstructure as depicted by mean diffusivity and fractional anisotropy, vessel patency on MR angiography, and the presence of and development of new microbleeds. A total of 1,056 patients (men and women ≥ 55 years) were included. The data analysis included 3D reformation, image registration of different contrasts, tissue segmentation, and automated lesion detection. This large international multi-centre study demonstrates how new MRI readouts can be used to provide key information on the evolution of cerebral tissue lesions and within the macrovasculature after atherothrombotic stroke in a large sample of patients.

Purpose: To achieve minimal inter-observer variability in assessment of spleen and liver volume changes using a novel MRI reading method in the context of a phase III clinical trial of a new therapy for Gaucher disease., Materials and Methods: Abdominal MRI examinations at screening and after 6 and 9 months' exposure to a novel plant-cell-derived recombinant enzyme, taliglucerase alfa, were taken in 31 patients with Gaucher disease and at least 8-fold greater than expected splenomegaly. Transverse T2, T1, and in/out-of-phase, and coronal T1 sequences were performed using standardized settings across 11 sites globally. Spleen and liver volumes were semi-automatically delineated using an automatic segmentation algorithm followed by manual correction by experienced technologists using advanced editing tools. Data of all randomized patients were then submitted for efficacy evaluation to two independent experts blinded to time-point and treatment., Results: Mean (± SD) percent variability over all time-points was 0.30% ± 0.46% for spleen and 0.53% ± 0.69% for liver using 178 spleen and liver volumes measured twice. Adjudication due to ≥ 5% variability between observers was not required., Conclusion: The measurement method was found to be precise in monitoring spleen and liver volume changes over time, with a much lower variability than traditional manual methods, supporting the accuracy of the results. Given the observed minimal variability rates among multiple readers, a single read of each volume would be sufficient., (Copyright © 2010 Elsevier Inc. All rights reserved.)

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.

Background and Purpose: Cerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage and cognitive impairment and is associated with white matter hyperintensities and cerebral microbleeds. MRI diffusion tensor imaging detects microstructural tissue damage in advanced CAA even in areas that appear normal on conventional MRI. We hypothesized that higher global mean apparent diffusion coefficient (mean ADC), reflecting a higher amount of chronic tissue disruption caused by CAA, would be independently associated with CAA-related cognitive impairment., Methods: Preintracerebral hemorrhage cognitive impairment was systematically assessed using a standardized questionnaire (IQCODE) in 49 patients. Volume of white matter hyperintensities, number of microbleeds, and mean ADC were determined from MRIs obtained within 14.0+/-22.5 days of intracerebral hemorrhage cognitive impairment. White matter hyperintensities and mean ADC were measured in the hemisphere uninvolved by intracerebral hemorrhage to avoid confounding., Results: Preintracerebral hemorrhage cognitive impairment was identified in 10 of 49 subjects. Mean ADC was the only variable associated with preintracerebral hemorrhage cognitive impairment and was elevated in those with preintracerebral hemorrhage cognitive impairment compared with those without (12.4x10(-4) versus 11.7x10(-4) mm(2)/s; P=0.03). Mean ADC positively correlated with age but not white matter hyperintensities or number of microbleeds. In logistic regression controlling for age and visible cerebral atrophy, mean ADC was independently associated with preintracerebral hemorrhage cognitive impairment (OR per 1x10(-4) mm(2)/s increase=2.45, 95% CI 1.11 to 5.40, P=0.04)., Conclusions: Mean ADC is independently associated with preintracerebral hemorrhage cognitive impairment in CAA. The lack of correlation with other MRI markers of CAA suggests that mean ADC may be sensitive to distinct aspects of CAA pathology and its tissue consequences. These results suggest that global MRI diffusion changes are sensitive to clinically relevant microstructural alterations and may be useful markers of CAA-related tissue damage.