Search

Few studies can address how adulthood cognitive trajectories relate to brain health in 70-year-olds. Participants (n = 468, 49% female) from the 1946 British birth cohort underwent 18F-Florbetapir PET/MRI. Cognitive function was measured in childhood (age 8 years) and across adulthood (ages 43, 53, 60–64 and 69 years) and was examined in relation to brain health markers of β-amyloid (Aβ) status, whole brain and hippocampal volume, and white matter hyperintensity volume (WMHV). Taking into account key contributors of adult cognitive decline including childhood cognition, those with greater Aβ and WMHV at age 70 years had greater decline in word-list learning memory in the preceding 26 years, particularly after age 60. In contrast, those with smaller whole brain and hippocampal volume at age 70 years had greater decline in processing search speed, subtly manifest from age 50 years. Subtle changes in memory and processing speed spanning 26 years of adulthood were associated with markers of brain health at 70 years of age, consistent with detectable prodromal cognitive effects in early older age.

Objective: Cut-offs for high-sensitivity troponin (hs-Tn) elevations to define prognostically significant peri-operative myocardial injury (PMI) in cardiac surgery is not well-established. We evaluated the associations between peri-operative high-sensitivity troponin T (hs-TnT) elevations and 1-year all-cause mortality in patients undergoing cardiac surgery. Methods: The prognostic significance of baseline hs-TnT and various thresholds for post-operative hs-TnT elevation at different time-points on 1-year all-cause mortality following cardiac surgery were assessed after adjusting for baseline hs-TnT and EuroSCORE in a post-hoc analysis of the ERICCA trial. Results: 1206 patients met the inclusion criteria. Baseline elevation in hs-TnT >x1 99th percentile upper reference limit (URL) was significantly associated with 1-year all-cause mortality (adjusted hazard ratio 1.90, 95% confidence interval 1.15–3.13). In the subgroup with normal baseline hs-TnT (n = 517), elevation in hs-TnT at all post-operative time points was associated with higher 1-year mortality, reaching statistical significance for elevations above: ≥100 × URL at 6 h; ≥50 × URL at 12 and 24 h; ≥35 × URL at 48 h; and ≥30 × URL at 72 h post-surgery. Elevation in hs-TnT at 24 h ≥ 50 × URL had the optimal sensitivity and specificity (73% and 75% respectively). When the whole cohort of patients was analysed, including those with abnormal baseline hs-TnT (up to 10 × URL), the same threshold had optimal sensitivity and specificity (66% and 70%). Conclusions: Both baseline and post-operative hs-TnT elevations are independently associated with 1-year all-cause mortality in patients undergoing cardiac surgery. The optimal threshold to define a prognostically significant PMI in our study was ≥50 × URL elevation in hs-TnT at 24 h.

© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com, Several CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions., This study was supported in the Netherlands by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813,733050103 and 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300), the European Joint Programme—Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); V.V. and S.K. have received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 666992 (EuroPOND). E.B. was supported by the Hartstichting (PPP Allowance, 2018B011); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1); J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH); I.J.S. is supported by the Alzheimer’s Association; J.B.R. is supported by the Wellcome Trust (103838); in Spain by the Fundació Marató de TV3 (20143810 to R.S.V.); in Germany by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and by grant 779357 ‘Solve-RD’ from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Schörling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tjänarinnor, Karolinska Institutet Doctoral Funding and StratNeuro. H.Z. is a Wallenberg Scholar.

Background and ObjectivesThe goals of this work were to quantify the independent and interactive associations of β-amyloid (Aβ) and white matter hyperintensity volume (WMHV), a marker of presumed cerebrovascular disease (CVD), with rates of neurodegeneration and to examine the contributions of APOE ε4 and vascular risk measured at different stages of adulthood in cognitively normal members of the 1946 British Birth Cohort.MethodsParticipants underwent brain MRI and florbetapir-Aβ PET as part of Insight 46, an observational population-based study. Changes in whole-brain, ventricular, and hippocampal volume were directly measured from baseline and repeat volumetric T1 MRI with the boundary shift integral. Linear regression was used to test associations with baseline Aβ deposition, baseline WMHV, APOE ε4, and office-based Framingham Heart Study Cardiovascular Risk Score (FHS-CVS) and systolic blood pressure (BP) at ages 36, 53, and 69 years.ResultsThree hundred forty-six cognitively normal participants (mean [SD] age at baseline scan 70.5 [0.6] years; 48% female) had high-quality T1 MRI data from both time points (mean [SD] scan interval 2.4 [0.2] years). Being Aβ positive at baseline was associated with 0.87–mL/y faster whole-brain atrophy (95% CI 0.03, 1.72), 0.39–mL/y greater ventricular expansion (95% CI 0.16, 0.64), and 0.016–mL/y faster hippocampal atrophy (95% CI 0.004, 0.027), while each 10-mL additional WMHV at baseline was associated with 1.07–mL/y faster whole-brain atrophy (95% CI 0.47, 1.67), 0.31–mL/y greater ventricular expansion (95% CI 0.13, 0.60), and 0.014–mL/y faster hippocampal atrophy (95% CI 0.006, 0.022). These contributions were independent, and there was no evidence that Aβ and WMHV interacted in their effects. There were no independent associations of APOE ε4 with rates of neurodegeneration after adjustment for Aβ status and WMHV, no clear relationships between FHS-CVS or systolic BP and rates of neurodegeneration when assessed across the whole sample, and no evidence that FHS-CVS or systolic BP acted synergistically with Aβ.DiscussionAβ and presumed CVD have distinct and additive effects on rates of neurodegeneration in cognitively normal elderly. These findings have implications for the use of MRI measures as biomarkers of neurodegeneration and emphasize the importance of risk management and early intervention targeting both pathways.

Objective To assess associations between head injury (HI) with loss of consciousness (LOC), ageing and markers of later‐life cerebral pathology; and to explore whether those effects may help explain subtle cognitive deficits in dementia‐free individuals. Methods Participants (n = 502, age = 69–71) from the 1946 British Birth Cohort underwent cognitive testing (subtests of Preclinical Alzheimer Cognitive Composite), 18F‐florbetapir Aβ‐PET and MR imaging. Measures include Aβ‐PET status, brain, hippocampal and white matter hyperintensity (WMH) volumes, normal appearing white matter (NAWM) microstructure, Alzheimer’s disease (AD)‐related cortical thickness, and serum neurofilament light chain (NFL). LOC HI metrics include HI occurring: (i) >15 years prior to the scan (ii) anytime up to age 71. Results Compared to those with no evidence of an LOC HI, only those reporting an LOC HI>15 years prior (16%, n = 80) performed worse on cognitive tests at age 69–71, taking into account premorbid cognition, particularly on the digit‐symbol substitution test (DSST). Smaller brain volume (BV) and adverse NAWM microstructural integrity explained 30% and 16% of the relationship between HI and DSST, respectively. We found no evidence that LOC HI was associated with Aβ load, hippocampal volume, WMH volume, AD‐related cortical thickness or NFL (all p > 0.01). Interpretation Having a LOC HI aged 50’s and younger was linked with lower later‐life cognitive function at age ~70 than expected. This may reflect a damaging but small impact of HI; explained in part by smaller BV and different microstructure pathways but not via pathology related to AD (amyloid, hippocampal volume, AD cortical thickness) or ongoing neurodegeneration (serum NFL).

BackgroundDementia is a common and devastating symptom of Parkinson’s disease (PD). Visual function and retinal structure are both emerging as potentially predictive for dementia in Parkinson’s but lack longitudinal evidence.MethodsWe prospectively examined higher order vision (skew tolerance and biological motion) and retinal thickness (spectral domain optical coherence tomography) in 100 people with PD and 29 controls, with longitudinal cognitive assessments at baseline, 18 months and 36 months. We examined whether visual and retinal baseline measures predicted longitudinal cognitive scores using linear mixed effects models and whether they predicted onset of dementia, death and frailty using time-to-outcome methods.ResultsPatients with PD with poorer baseline visual performance scored lower on a composite cognitive score (β=0.178, SE=0.05, p=0.0005) and showed greater decreases in cognition over time (β=0.024, SE=0.001, p=0.013). Poorer visual performance also predicted greater probability of dementia (χ² (1)=5.2, p=0.022) and poor outcomes (χ² (1) =10.0, p=0.002). Baseline retinal thickness of the ganglion cell–inner plexiform layer did not predict cognitive scores or change in cognition with time in PD (β=−0.013, SE=0.080, p=0.87; β=0.024, SE=0.001, p=0.12).ConclusionsIn our deeply phenotyped longitudinal cohort, visual dysfunction predicted dementia and poor outcomes in PD. Conversely, retinal thickness had less power to predict dementia. This supports mechanistic models for Parkinson’s dementia progression with onset in cortical structures and shows potential for visual tests to enable stratification for clinical trials.

Progressive multiple sclerosis (PMS) is a significant health problem with few treatments shown to slow disability progression. One challenge has been efficiently testing the pipeline of candidate therapies from preclinical studies in clinical trials. Multi-arm multi-stage (MAMS) platform trials may accelerate evaluation of new therapies compared to traditional sequential clinical trials. We describe a MAMS design in PMS, focusing on selection of interim and final outcome measures, sample size and statistical considerations.\ud \ud The UK MS Society Expert Consortium for Progression in MS Clinical Trials reviewed recent phase II and III PMS trials to inform interim and final outcome selection and design parameters. Simulations were performed to evaluate trial operating characteristics under different treatment effect, recruitment rate and sample size assumptions. People with MS formed a Patient and Public Involvement group and contributed to the trial design ensuring it would meet the needs of the MS community.\ud \ud The proposed design evaluates three experimental arms compared to a common standard of care arm in two stages. Stage 1 (interim) outcome will be whole brain atrophy on MRI at 18 months, assessed for 123 participants per arm. Treatments with sufficient evidence for slowing brain atrophy will continue to the second stage. The stage 2 (final) outcome will be time to six-month confirmed disability progression, based on a composite clinical score comprising the Expanded Disability Status Score, Timed 25-Foot Walk and 9-Hole Peg Test. To detect a hazard ratio of 0.75 for this primary final outcome with 90% power, 600 participants per arm are required. Assuming one treatment progresses to stage 2, the trial will recruit around 1,900 participants and last around 6 years. This is approximately two-thirds the size and half the time of separate two-arm phase II and III trials.\ud \ud The proposed MAMS trial design will substantially reduce duration and sample size compared to traditional clinical trials, accelerating discovery of effective treatment for PMS. The design was also well-received by people with MS. The practical and statistical principles of MAMS trial design may be applicable to other neurodegenerative conditions to facilitate efficient testing of new therapies.

Background and ObjectivesImproved biomarkers of neuroprotective treatment are needed in progressive multiple sclerosis (PMS) to facilitate more efficient phase 2 trial design. The MS-STAT randomized controlled trial supported the neuroprotective potential of high-dose simvastatin in secondary progressive MS (SPMS). Here, we analyze serum from the MS-STAT trial to assess the extent to which neurofilament light (NfL) and neurofilament heavy (NfH), both promising biomarkers of neuroaxonal injury, may act as biomarkers of simvastatin treatment in SPMS.MethodsThe MS-STAT trial randomized patients to 80 mg simvastatin or placebo. Serum was analyzed for NfL and NfH using Simoa technology. We used linear mixed models to investigate the treatment effects of simvastatin compared with placebo on NfL and NfH. Additional models examined the relationships between neurofilaments and MRI and clinical measures of disease severity.ResultsA total of 140 patients with SPMS were included. There was no evidence for a simvastatin treatment effect on NfL or NfH: compared with placebo, NfL was 1.2% lower (95% CI 10.6% lower to 9.2% higher; p = 0.820) and NfH was 0.4% lower (95% CI 18.4% lower to 21.6% higher; p = 0.969) in the simvastatin treatment group. Secondary analyses suggested that higher NfL was associated with greater subsequent whole brain atrophy, higher T2 lesion volume, and more new/enlarging T2 lesions in the previous 12 months, as well as greater physical disability. There were no significant associations between NfH and MRI or clinical variables.DiscussionWe found no evidence of a simvastatin treatment effect on serum neurofilaments. While confirmation of the neuroprotective benefits of simvastatin is awaited from the ongoing phase 3 study (NCT03387670), our results suggest that treatments capable of slowing the rate of whole brain atrophy in SPMS, such as simvastatin, may act via mechanisms largely independent of neuroaxonal injury, as quantified by NfL. This has important implications for the design of future phase 2 clinical trials in PMS.Trial Registration InformationMS-STAT: NCT00647348.Classification of EvidenceThis study provides class I evidence that simvastatin treatment does not have a large impact on either serum NfL or NfH, as quantified in this study, in SPMS.

Introduction Grip strength is an objective measure of physical function with potential predictive value for health in ageing populations. We aimed to assess whether levels and changes in grip strength from midlife predicted later-life brain health and cognition. Methods 446 participants in an ongoing British birth cohort study, the MRC National Survey of Health and Development (NSHD), had their maximum grip strength measured at ages 53, 60–64, and 69, and underwent neuroimaging as part of its neuroscience sub-study, Insight 46, at 69–71. A group-based trajectory model identified latent groups of individuals in the whole NSHD cohort with below- and above-average grip strength over time, plus a reference group. Trajectory group membership, plus standardised grip strength levels and change from age 53, were each related to MRI-derived measures of whole-brain volume (WBV) and white-matter hyperintensity volume (WMHV), plus several cognitive tests. Models were adjusted for sex, body size, head size (where appropriate), sociodemographics, and behavioural and vascular risk factors. Results Consistently below-average grip strength from midlife was associated with lower WBV and non-verbal reasoning ability at age 69–71 (e.g. low group WBV vs. reference group β = −13.38 cm^3; 95% CI = (−24.12 cm^3, −2.64 cm^3); p = 0.015). There was some accompanying evidence that above-average maximum grip strength showed a positive association with WBV, which was more pronounced in female participants (high group female WBV vs. reference group β = 18.30 cm^3; 95% CI = (1.34 cm^3, 35.29 cm^3); p = 0.034). Steeper than average declines in grip strength between 53 and 69 were additionally weakly associated with an estimated 10% higher WMHV at age 69–71 (β = 1.10, 95% CI = (1.00, 1.22); p = 0.053). Conclusion This study provides preliminary evidence that tests of maximum grip strength may have value in predicting brain health. Future work should assess how these observed differences relate to later-life negative health outcomes, and whether changes in grip strength reflect concurrent changes in brain structure and connectivity.

© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)., A key symptom of frontotemporal dementia (FTD) is difficulty interacting socially with others. Social cognition problems in FTD include impaired emotion processing and theory of mind difficulties, and whilst these have been studied extensively in sporadic FTD, few studies have investigated them in familial FTD. Facial Emotion Recognition (FER) and Faux Pas (FP) recognition tests were used to study social cognition within the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort of C9orf72, GRN, and MAPT mutation carriers. 627 participants undertook at least one of the tasks, and were separated into mutation-negative healthy controls, presymptomatic mutation carriers (split into early and late groups) and symptomatic mutation carriers. Groups were compared using a linear regression model with bootstrapping, adjusting for age, sex, education, and for the FP recognition test, language. Neural correlates of social cognition deficits were explored using a voxel-based morphometry (VBM) study. All three of the symptomatic genetic groups were impaired on both tasks with no significant difference between them. However, prior to onset, only the late presymptomatic C9orf72 mutation carriers on the FER test were impaired compared to the control group, with a subanalysis showing differences particularly in fear and sadness. The VBM analysis revealed that impaired social cognition was mainly associated with a left hemisphere predominant network of regions involving particularly the striatum, orbitofrontal cortex and insula, and to a lesser extent the inferomedial temporal lobe and other areas of the frontal lobe. In conclusion, theory of mind and emotion processing abilities are impaired in familial FTD, with early changes occurring prior to symptom onset in C9orf72 presymptomatic mutation carriers. Future work should investigate how performance changes over time, in order to gain a clearer insight into social cognitive impairment over the course of the disease.

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Supplementary Information: Additional file 1 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; Additional file 2 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; both files are available online at https://doi.org/10.1186/s13024-021-00499-4 Copyright © The Author(s) 2021. Background: A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods: A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results: When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion: In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD. This study has received support from the Swedish FTD initiative funded by the Schörling Family Foundation. This work was also funded by KTH Center for Applied Precision Medicine (KCAP) funded by the Erling-Persson Family Foundation, grants from Vetenskapsrådet Dnr 529-2014-7504, VR 2015-02926 and 2018-02754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Åhlén foundation, Demensfonden, Stohnes foundation, Gamla Tjänarinnor and Stockholm County Council ALF. Furthermore, support was received by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project, the JPND GENFI-PROX grant (2019-02248), the Dioraphte Foundation [grant numbers 09-02-00]; the Association for Frontotemporal Dementias Research Grant 2009; The Netherlands Organization for Scientific Research (NWO) (grant HCMI 056-13-018); ZonMw Memorabel (Deltaplan Dementie), (project numbers 733 050 103 and 733 050 813); JPND PreFrontAls consortium (project number 733051042). JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510. M.S. was supported by the JPND grant “GENFI-prox” (by DLR/BMBF to M. S, joint with JDR., J.vS., M.O., B.B. and C.G.). Open Access funding provided by Royal Institute of Technology.

Although APOE-ε4 carriers are at significantly higher risk of developing Alzheimer’s disease than non-carriers(1), controversial evidence suggests that APOE-ε4 might confer some advantages, explaining the survival of this gene (antagonistic pleiotropy)(2,3). In a population-based cohort born in one week in 1946 (assessed aged 69-71), we assessed differential effects of APOE-ε4 and β-amyloid pathology (quantified using (18)F-Florbetapir-PET) on visual working memory (object-location binding). In 398 cognitively normal participants, APOE-ε4 and β-amyloid had opposing effects on object identification, predicting better and poorer recall respectively. ε4-carriers also recalled locations more precisely, with a greater advantage at higher β-amyloid burden. These results provide evidence of superior visual working memory in ε4-carriers, showing that some benefits of this genotype are demonstrable in older age, even in the preclinical stages of Alzheimer’s disease.

Although APOE e4 carriers are at substantially higher risk of developing Alzheimer’s disease than noncarriers1, controversial evidence suggests that APOE e4 might confer some advantages, explaining the survival of this gene (antagonistic pleiotropy)2,3. In a population-based cohort born in one week in 1946 (assessed aged 69–71 years), we assessed differential effects of APOE e4 and β-amyloid pathology (quantified using 18F-Florbetapir-PET) on visual working memory (object–location binding). In 398 cognitively normal participants, APOE e4 and β-amyloid had opposing effects on object identification, predicting better and poorer recall, respectively. e4 carriers also recalled locations more precisely, with a greater advantage at higher β-amyloid burden. These results provide evidence of superior visual working memory in e4 carriers, showing that some benefits of this genotype are demonstrable in older age, even in the preclinical stages of Alzheimer’s disease. In a sample of about 400 cognitively normal older adults, APOE e4 genotype and β-amyloid pathology predicted better and poorer visual working memory, respectively, suggesting some benefits of e4 in older age, even in the preclinical stages of Alzheimer’s disease.

In vitro studies of autosomal dominant Alzheimer’s disease implicate longer amyloid-β peptides in disease pathogenesis; however, less is known about the behaviour of these mutations in vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-β (Aβ)42:38, Aβ42:40 and Aβ38:40 ratios between presenilin 1 (PSEN1) and amyloid precursor protein (APP) carriers. We examined the relationship between plasma and in vitro models of amyloid-β processing and tested for associations with parental age at onset. Thirty-nine participants were mutation carriers (28 PSEN1 and 11 APP). Age- and sex-adjusted models showed marked differences in plasma amyloid-β between genotypes: higher Aβ42:38 in PSEN1 versus APP (P, O’Connor et al. reveal significant differences in plasma Aβ ratios between PSEN1 and APP carriers, broadening understanding of the molecular drivers of Alzheimer’s disease. They also show associations between higher Aβ42:40 and Aβ42:38 ratios and earlier disease onset, supporting the pathogenicity of these peptide ratios.

Making predictions about the world and responding appropriately to unexpected events are essential functions of the healthy brain. In neurodegenerative disorders, such as frontotemporal dementia and Alzheimer’s disease, impaired processing of ‘surprise’ may underpin a diverse array of symptoms, particularly abnormalities of social and emotional behaviour, but is challenging to characterize. Here, we addressed this issue using a novel paradigm: music. We studied 62 patients (24 female; aged 53–88) representing major syndromes of frontotemporal dementia (behavioural variant, semantic variant primary progressive aphasia, non-fluent-agrammatic variant primary progressive aphasia) and typical amnestic Alzheimer’s disease, in relation to 33 healthy controls (18 female; aged 54–78). Participants heard famous melodies containing no deviants or one of three types of deviant note—acoustic (white-noise burst), syntactic (key-violating pitch change) or semantic (key-preserving pitch change). Using a regression model that took elementary perceptual, executive and musical competence into account, we assessed accuracy detecting melodic deviants and simultaneously recorded pupillary responses and related these to deviant surprise value (information-content) and carrier melody predictability (entropy), calculated using an unsupervised machine learning model of music. Neuroanatomical associations of deviant detection accuracy and coupling of detection to deviant surprise value were assessed using voxel-based morphometry of patients’ brain MRI. Whereas Alzheimer’s disease was associated with normal deviant detection accuracy, behavioural and semantic variant frontotemporal dementia syndromes were associated with strikingly similar profiles of impaired syntactic and semantic deviant detection accuracy and impaired behavioural and autonomic sensitivity to deviant information-content (all P, Benhamou et al. report that major dementias have distinct behavioural, autonomic and neuroanatomical profiles of musical ‘surprise’ processing. While Alzheimer’s disease patients showed normal reactivity to deviants in familiar melodies, frontotemporal dementia patients had specific impairments, suggesting that musical ‘tools’ could measure complex behavioural changes in these diseases., Graphical Abstract Graphical Abstract

Familial Alzheimer's disease (FAD) is caused by autosomal dominant mutations in the PSEN1, PSEN2 or APP genes, giving rise to considerable clinical and pathological heterogeneity in FAD. Here we investigate variability in clinical data and the type and distribution of Aβ pathologies throughout the cortical layers of different FAD mutation cases. Brain tissue from 20 FAD cases [PSEN1 pre-codon 200 (n = 10), PSEN1 post-codon 200 (n = 6), APP (n = 4)] were investigated. Frontal cortex sections were stained immunohistochemically for Aβ, and Nissl to define the cortical layers. The frequency of different amyloid-beta plaque types was graded for each cortical layer and the severity of cerebral amyloid angiopathy (CAA) was determined in cortical and leptomeningeal blood vessels. Comparisons were made between FAD mutations and APOE4 status, with associations between pathology, clinical and genetic data investigated. In this cohort, possession of an APOE4 allele was associated with increased disease duration but not with age at onset, after adjusting for mutation sub-group and sex. We found Aβ pathology to be heterogeneous between cases although Aβ load was highest in cortical layer 3 for all mutation groups and a higher Aβ load was associated with APOE4. The PSEN1 post-codon 200 group had a higher Aβ load in lower cortical layers, with a small number of this group having increased cotton wool plaque pathology in lower layers. Cotton wool plaque frequency was positively associated with the severity of CAA in the whole cohort and in the PSEN1 post-codon 200 group. Carriers of the same PSEN1 mutation can have differing patterns of Aβ deposition, potentially because of differences in risk factors. Our results highlight possible influences of APOE4 genotype, and PSEN1 mutation type on Aβ deposition, which may have effects on the clinical heterogeneity of FAD.

ObjectiveTo investigate predictors of performance on a range of cognitive measures including the Preclinical Alzheimer Cognitive Composite (PACC) and test for associations between cognition and dementia biomarkers in Insight 46, a substudy of the Medical Research Council National Survey of Health and Development.MethodsA total of 502 individuals born in the same week in 1946 underwent cognitive assessment at age 69–71 years, including an adapted version of the PACC and a test of nonverbal reasoning. Performance was characterized with respect to sex, childhood cognitive ability, education, and socioeconomic position (SEP). In a subsample of 406 cognitively normal participants, associations were investigated between cognition and β-amyloid (Aβ) positivity (determined from Aβ-PET imaging), whole brain volumes, white matter hyperintensity volumes (WMHV), and APOE ε4.ResultsChildhood cognitive ability was strongly associated with cognitive scores including the PACC more than 60 years later, and there were independent effects of education and SEP. Sex differences were observed on every PACC subtest. In cognitively normal participants, Aβ positivity and WMHV were independently associated with lower PACC scores, and Aβ positivity was associated with poorer nonverbal reasoning. Aβ positivity and WMHV were not associated with sex, childhood cognitive ability, education, or SEP. Normative data for 339 cognitively normal Aβ-negative participants are provided.ConclusionsThis study adds to emerging evidence that subtle cognitive differences associated with Aβ deposition are detectable in older adults, at an age when dementia prevalence is very low. The independent associations of childhood cognitive ability, education, and SEP with cognitive performance at age 70 have implications for interpretation of cognitive data in later life.

Significance Traditional analysis of clinical trials precludes a mechanistic understanding of drug actions. This is further compounded by the use of outcome measures in clinical trials not directly related to the mechanism of action of the medication under study. Here, we applied structural equation models to the double-blind randomized controlled trial of simvastatin in secondary progressive multiple sclerosis to investigate causal associations that underlie treatment effects. Our results suggest that beneficial effects of simvastatin on reducing the rate of brain atrophy and slowing the deterioration of disability are independent of serum cholesterol reduction. Our work demonstrates that structural models can elucidate the statistical pathways underlying treatment effects in clinical trials of poorly understood neurodegenerative disorders, such as progressive multiple sclerosis., Understanding the mode of action of drugs is a challenge with conventional methods in clinical trials. Here, we aimed to explore whether simvastatin effects on brain atrophy and disability in secondary progressive multiple sclerosis (SPMS) are mediated by reducing cholesterol or are independent of cholesterol. We applied structural equation models to the MS-STAT trial in which 140 patients with SPMS were randomized to receive placebo or simvastatin. At baseline, after 1 and 2 years, patients underwent brain magnetic resonance imaging; their cognitive and physical disability were assessed on the block design test and Expanded Disability Status Scale (EDSS), and serum total cholesterol levels were measured. We calculated the percentage brain volume change (brain atrophy). We compared two models to select the most likely one: a cholesterol-dependent model with a cholesterol-independent model. The cholesterol-independent model was the most likely option. When we deconstructed the total treatment effect into indirect effects, which were mediated by brain atrophy, and direct effects, simvastatin had a direct effect (independent of serum cholesterol) on both the EDSS, which explained 69% of the overall treatment effect on EDSS, and brain atrophy, which, in turn, was responsible for 31% of the total treatment effect on EDSS [β = −0.037; 95% credible interval (CI) = −0.075, −0.010]. This suggests that simvastatin’s beneficial effects in MS are independent of its effect on lowering peripheral cholesterol levels, implicating a role for upstream intermediate metabolites of the cholesterol synthesis pathway. Importantly, it demonstrates that computational models can elucidate the causal architecture underlying treatment effects in clinical trials of progressive MS.

Background In view of reported associations between high adiposity, particularly in midlife and late-life dementia risk, we aimed to determine associations between body mass index (BMI), and BMI changes across adulthood and brain structure and pathology at age 69–71 years. Methods Four hundred sixty-five dementia-free participants from Insight 46, a sub-study of the British 1946 birth cohort, who had cross-sectional T1/FLAIR volumetric MRI, and florbetapir amyloid-PET imaging at age 69–71 years, were included in analyses. We quantified white matter hyperintensity volume (WMHV) using T1 and FLAIR 3D-MRI; β-amyloid (Aβ) positivity/negativity using a SUVR approach; and whole brain (WBV) and hippocampal volumes (HV) using 3D T1-MRI. We investigated the influence of BMI, and BMI changes at and between 36, 43, 53, 60–64, 69 and 71 years, on late-life WMHV, Aβ-status, WBV and mean HV. Analyses were repeated using overweight and obese status. Results At no time-point was BMI, change in BMI or overweight/obese status associated with WMHV or WBV at age 69–71 years. Decreasing BMI in the 1–2 years before imaging was associated with an increased odds of being β-amyloid positive (OR 1.45, 95% confidence interval 1.09, 1.92). There were associations between being overweight and larger mean HV at ages 60–64 (β = 0.073 ml, 95% CI 0.009, 0.137), 69 (β = 0.076 ml, 95% CI 0.012, 0.140) and 71 years (β = 0.101 ml, 95% CI 0.037, 0.165). A similar, albeit weaker, trend was seen with obese status. Conclusions Using WMHV, β-amyloid status and brain volumes as indicators of brain health, we do not find evidence to explain reported associations between midlife obesity and late-life dementia risk. Declining BMI in later life may reflect preclinical Alzheimer’s disease.

The basis of visual short-term memory (VSTM) impairments in preclinical Alzheimer’s disease (AD) remains unclear. Research suggests that eye movements may serve as indirect surrogates to investigate VSTM. Yet, investigations in preclinical populations are lacking. Fifty-two individuals from a familial Alzheimer’s disease (FAD) cohort (9 symptomatic carriers, 17 presymptomatic carriers and 26 controls) completed the “Object-localisation” VSTM task while an eye-tracker recorded eye movements during the stimulus presentation. VSTM function and oculomotor performance were compared between groups and their association during encoding investigated. Compared to controls, symptomatic FAD carriers showed eye movement patterns suggestive of an ineffective encoding and presymptomatic FAD carriers within 6 years of their expected age at symptom onset, were more reliant on the stimuli fixation time to achieve accuracy in the localisation of the target. Consequently, for shorter fixation times on the stimuli, presymptomatic carriers were less accurate at localising the target than controls. By contrast, the only deficits detected on behavioural VSTM function was in symptomatic individuals. Our findings provide novel evidence that encoding processes may be vulnerable and weakened in presymptomatic FAD carriers, most prominently for spatial memory, suggesting a possible explanation for the subtle VSTM impairments observed in the preclinical stages of AD.

In-vitrostudies of autosomal dominant Alzheimer’s disease (ADAD) implicate longer Aβ peptides in pathogenesis, however less is known about the behaviour of ADAD mutationsin-vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from ADAD family members who were at-risk of inheriting a mutation or were already symptomatic. We tested for differences in plasma Aβ42:38, 38:40 and 42:40 ratios betweenPresenilin1 (PSEN1)andAmyloid Precursor Protein (APP)carriers. We examined the relationship between plasma andin-vitromodels of Aβ processing and, amongPSEN1carriers, tested for associations with parental age at onset (AAO). 39 participants were mutation carriers (28PSEN1and 11APP).Age- and sex-adjusted models showed marked differences in plasma Aβ betweenAPPandPSEN1: higher Aβ42:38 inPSEN1versusAPP(pAPPversusPSEN1(pAPPandPSEN1compared to non-carriers (both pPSEN1, sex-adjusted models demonstrated negative associations between (i)Aβ42:40 (ii)Aβ42:38 and parental AAO.In-vivodifferences in Aβ processing betweenAPPandPSEN1provide insights into ADAD pathophysiology which can inform therapy development.

Background Current tasks measuring social cognition are usually ‘pen and paper’ tasks, have ceiling effects and include complicated test instructions that may be difficult to understand for those with cognitive impairment. We therefore aimed to develop a set of simple, instructionless, quantitative, tasks of emotion recognition using the methodology of eye tracking, with the subsequent aim of assessing their utility in individuals with behavioural variant frontotemporal dementia (bvFTD). Methods Using the Eyelink 1000 Plus eye tracker, 18 bvFTD and 22 controls completed tasks of simple and complex emotion recognition that involved viewing four images (one target face (simple) or pair of eyes (complex) and the others non-target) followed by a target emotion word and lastly the original four images alongside the emotion word. A dwell time change score was then calculated as the main outcome measure by subtracting the percentage dwell time for the target image before the emotion word appeared away from the percentage dwell time for the target image after the emotion word appeared. All participants also underwent a standard cognitive battery and volumetric T1-weighted magnetic resonance imaging. Results Analysis using a mixed effects model showed that the average (standard deviation) mean dwell time change score in the target interest area was 35 (27)% for the control group compared with only 4 (18)% for the bvFTD group (p p Conclusions In summary, eye tracking is a viable tool for assessing social cognition in individuals with bvFTD, being well-tolerated and able to overcome some of the problems associated with standard psychometric tasks.

© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license., Mutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting an increased CTh loss associated with age and estimated proximity to symptoms onset in GRN carriers, even before the disease onset., The authors thank all the volunteers for their participation in this study. SBE is a recipient of the Rio-Hortega post-residency grant from the Instituto de Salud Carlos III, Spain. This study was partially funded by Fundació Marató de TV3, Spain (grant no. 20143810 to RSV). The GENFI study has been supported by the Medical Research Council UK, the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, as well as other individual funding to investigators. KM has received funding from an Alzheimer’s Society PhD studentship. JDR acknowledges support from the National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research Unit and the University College London Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre, the UK Dementia Research Institute, Alzheimer’s Research UK, the Brain Research Trust and the Wolfson Foundation. JCvS was supported by the Dioraphte Foundation grant 09-02-03-00, the Association for Frontotemporal Dementias Research Grant 2009, The Netherlands Organization for Scientific Research (NWO) grant HCMI 056-13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield project. CG have received funding from JPND-Prefrontals VR Dnr 529-2014-7504, VR: 2015-02926, and 2018-02754, the Swedish FTD Initiative-Schörling Foundation, Alzheimer Foundation, Brain Foundation and Stockholm County Council ALF. DG has received support from the EU Joint Programme – Neurodegenerative Disease Research (JPND) and the Italian Ministry of Health (PreFrontALS) grant 733051042. JBR is funded by the Wellcome Trust (103838) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. MM has received funding from a Canadian Institutes of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. RV has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. EF has received funding from a CIHR grant #327387. JDR is an MRC Clinician Scientist (MR/M008525/1) and has received funding from the NIHR Rare Diseases Translational Research Collaboration (BRC149/NS/MH), the Bluefield Project and the Association for Frontotemporal Degeneration. MS was supported by a grant 779257 “Solve-RD” from the Horizon 2020 research and innovation programme.

Appendix A. Supplementary data: The following supplementary data to this article are available online at https://ars.els-cdn.com/content/image/1-s2.0-S2213158221002862-mmc1.docx (Word document (94KB)). Copyright © 2021 The Author(s). Background: Frontotemporal dementia (FTD) is a common cause of young onset dementia, and whilst there are currently no treatments, there are several promising candidates in development and early phase trials. Comprehensive investigations of neuroimaging markers of disease progression across the full spectrum of FTD disorders are lacking and urgently needed to facilitate these trials. Objective: To investigate the comparative performance of multiple automated segmentation and registration pipelines used to quantify longitudinal whole-brain atrophy across the clinical, genetic and pathological subgroups of FTD, in order to inform upcoming trials about suitable neuroimaging-based endpoints. Methods: Seventeen fully automated techniques for extracting whole-brain atrophy measures were applied and directly compared in a cohort of 226 participants who had undergone longitudinal structural 3D T1-weighted imaging. Clinical diagnoses were behavioural variant FTD (n = 56) and primary progressive aphasia (PPA, n = 104), comprising semantic variant PPA (n = 38), non-fluent variant PPA (n = 42), logopenic variant PPA (n = 18), and PPA-not otherwise specified (n = 6). 49 of these patients had either a known pathogenic mutation or postmortem confirmation of their underlying pathology. 66 healthy controls were included for comparison. Sample size estimates to detect a 30% reduction in atrophy (80% power; 0.05 significance) were computed to explore the relative feasibility of these brain measures as surrogate markers of disease progression and their ability to detect putative disease-modifying treatment effects. Results: Multiple automated techniques showed great promise, detecting significantly increased rates of whole-brain atrophy (p

MRI-derived features of presumed cerebral small vessel disease are frequently found in Alzheimer’s disease. Influences of such markers on disease-progression measures are poorly understood. We measured markers of presumed small vessel disease (white matter hyperintensity volumes; cerebral microbleeds) on baseline images of newly enrolled individuals in the Alzheimer’s Disease Neuroimaging Initiative cohort (GO and 2) and used linear mixed models to relate these to subsequent atrophy and neuropsychological score change. We also assessed heterogeneity in white matter hyperintensity positioning within biomarker abnormality sequences, driven by the data, using the Subtype and Stage Inference algorithm. This study recruited both sexes and included: controls: [n = 159, mean(SD) age = 74(6) years]; early and late mild cognitive impairment [ns = 265 and 139, respectively, mean(SD) ages =71(7) and 72(8) years, respectively]; Alzheimer’s disease [n = 103, mean(SD) age = 75(8)] and significant memory concern [n = 72, mean(SD) age = 72(6) years]. Baseline demographic and vascular risk-factor data, and longitudinal cognitive scores (Mini-Mental State Examination; logical memory; and Trails A and B) were collected. Whole-brain and hippocampal volume change metrics were calculated. White matter hyperintensity volumes were associated with greater whole-brain and hippocampal volume changes independently of cerebral microbleeds (a doubling of baseline white matter hyperintensity was associated with an increase in atrophy rate of 0.3 ml/year for brain and 0.013 ml/year for hippocampus). Cerebral microbleeds were found in 15% of individuals and the presence of a microbleed, as opposed to none, was associated with increases in atrophy rate of 1.4 ml/year for whole brain and 0.021 ml/year for hippocampus. White matter hyperintensities were predictive of greater decline in all neuropsychological scores, while cerebral microbleeds were predictive of decline in logical memory (immediate recall) and Mini-Mental State Examination scores. We identified distinct groups with specific sequences of biomarker abnormality using continuous baseline measures and brain volume change. Four clusters were found; Group 1 showed early Alzheimer’s pathology; Group 2 showed early neurodegeneration; Group 3 had early mixed Alzheimer’s and cerebrovascular pathology; Group 4 had early neuropsychological score abnormalities. White matter hyperintensity volumes becoming abnormal was a late event for Groups 1 and 4 and an early event for 2 and 3. In summary, white matter hyperintensities and microbleeds were independently associated with progressive neurodegeneration (brain atrophy rates) and cognitive decline (change in neuropsychological scores). Mechanisms involving white matter hyperintensities and progression and microbleeds and progression may be partially separate. Distinct sequences of biomarker progression were found. White matter hyperintensity development was an early event in two sequences., Fiford et al. report that presumed small vessel disease markers (white matter hyperintensities and cerebral microbleeds) independently predict increased brain atrophy and cognitive decline. Data-driven analysis of sequences of biomarker abnormality identified distinct groups, two of which had white matter hyperintensity development as an early event., Graphical Abstract Graphical Abstract