Search

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.

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.

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.

Funder: Medical Research Council, BackgroundGrip strength is an indicator of physical function with potential predictive value for health in ageing populations. We assessed whether trends in grip strength from midlife predicted later-life brain health and cognition.Methods446 participants in an ongoing British birth cohort study, the National Survey of Health and Development (NSHD), had their maximum grip strength measured at ages 53, 60-64, and 69, and subsequently underwent neuroimaging as part of a neuroscience sub-study, referred to as "Insight 46", at age 69-71. A group-based trajectory model identified latent groups of individuals in the whole NSHD cohort with below- or above-average grip strength over time, plus a reference group. Group assignment, plus standardised grip strength levels and change from midlife were each related to 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.ResultsLower grip strength from midlife was associated with smaller WBV and lower matrix reasoning scores at age 69-71, with findings consistent between analysis of individual time points and analysis of trajectory groups. There was little evidence of an association between grip strength and other cognitive test scores. Although greater declines in grip strength showed a weak association with higher WMHV at age 69-71, trends in the opposite direction were seen at individual time points with higher grip strength at ages 60-64, and 69 associated with higher WMHV.ConclusionsThis study provides preliminary evidence that maximum grip strength may have value in predicting brain health. Future work should assess to what extent age-related declines in grip strength from midlife reflect concurrent changes in brain structure.

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.

Campus recruiters play a pivotal role identifying talent and socializing students into employment. In this exploratory study, 16 recruiters participated in semistructured interviews in the business...

Traditionally holistic liberal arts undergraduates face the challenge of professional branding in the neoliberal ideology of higher education in a competitive knowledge economy. This study explores the storied career-related perceptions of undergraduates in the College of Liberal Arts at a large, state-affiliated university. Thirty-two students participated in in-depth interviews to identify prevalent themes in employability narrative construction. Transcripts were coded and analyzed according to grounded theory methodology. Findings suggest that participants construct and manage employability narratives in an iterative process of exploring, packaging, and distinguishing themselves. Participants' semantic negotiation of “liberal arts” provides a sensitizing lens for consideration of contemporary student perspectives. By ascribing meaning and value to underlying influences on career progress, exploratory student thinking offers insights for practitioners and theorists concerned for the future of liberal arts graduates.

BACKGROUND Using mobile health technology has sparked a broad engagement of data science and machine learning methods to leverage the complex, assorted amount of data for mental health purposes. Despite many studies, there is a reported underdevelopment of user engagement concepts, and the desire for high accuracy or significance has shown to lead to low explicability and irreproducibility. OBJECTIVE To overcome such reasons of poor analysis input and facilitate the reproducibility and credibility of artificial intelligence applications, we aim to explore principal characteristics of user interaction with digital mental health. METHODS We generated five latent features based on previous research, expert opinions from digital mental health, and informed by data. The features were analyzed with descriptive statistics and data visualization. We carried out two rounds of evaluations with data from 12,400 users of IntelliCare, a mental health platform with 12 apps. First, we focused to proof concept and second, we assessed reproducibility by drawing conclusion from distribution differences. User data was drawn from both research trials and public deployment on Google Play. RESULTS Our algorithms showed advantages over commonly used concepts and reproduce in our public data set with different underlying behavioral strategies. These measures relate to the distribution of a user’s allocated attention, users’ circadian behavior, their consecutive commitment to a specific strategy, and users’ interaction trajectory. Because distributions between research trial and public deployment were similar, consistency was implied regarding the underlying behavioral strategies: psychoeducation and goal setting are used as a catalyst to overcome the users’ primary obstacles, sleep hygiene is addressed most regularly, while regular self-reflective thinking is avoided. Relaxation as well as cognitive reframing have increased variance in commitment among public users, indicating the challenging nature of these apps. The relative course of users’ engagement is similar in research and public data. CONCLUSIONS We argue that deliberate, a-priori feature engineering is essential for reproducible, tangible, and explainable study analyses. Our features enable improved results as well as interpretability, providing an increased understanding of how people engage with multiple mental health apps over time. Since we based the generation of features on generic interaction, these methods are applicable to further methods of study analysis and digital health.

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.

Background: Cross-sectional studies in presymptomatic familial Alzheimer’s disease (FAD), have associated binding deficits with preclinical AD. How impairments in visual-short term memory (VSTM) relate to longitudinal change and proximity to expected symptom onset (EYO) is less characterized.Methods: Thirty-two FAD mutation carriers (23 presymptomatic; 9 symptomatic) carrying a mutation in either presenilin 1 or amyloid precursor protein genes and 67 healthy controls were included in an extension VSTM cross-sectional study. Forty-eight participants (23 presymptomatic carriers, 6 symptomatic and 19 healthy controls) who had at least two annual visits (median= 3), were included in the longitudinal study. Participants completed the “What was where?” relational binding task (which measures memory for object identification, localisation and object-location binding under different conditions of memory load and delay), neuropsychology assessments and genetic testing. Results: While cross-sectionally only symptomatic carriers (N=9) showed significant impairments in VSTM performance, longitudinally, presymptomatic carriers within 8.5 years of estimated symptom onset (mean=5.8 years ±SD [1.8], N=11) showed a faster rate of decline in localisation performance in long-delay conditions (4s) compared to controls: increase/year in localisation error was 6.9% greater in the high-memory load condition (p=0.008) and 7.0% greater for the low-memory load condition (p=0.043). Change in this metric preceded presymptomatic changes in traditional measures of verbal episodic memory. Symptomatic carriers had 15% faster reduction in identification performance per year compared to controls (p=0.036) and some evidence of faster increase in localisation error (6.5% increase/year; p=0.066). The earliest significant difference in VSTM performance between FAD mutation carriers (presymptomatic and symptomatic) and controls was in localisation performance, six years prior to estimated symptom onset (p=0.024). Conclusions: This longitudinal study of FAD, suggests changes in VSTM resolution, which measure precision and thus quality of recall of the memory presentation, may be sensitive markers for tracking and predicting cognitive decline in preclinical AD.

Visual short-term memory (VSTM) deficits including VSTM binding have been associated with Alzheimer's disease (AD) from preclinical to dementia stages, cross-sectionally. Yet, longitudinal investigations are lacking. The objective of this study was to evaluate VSTM function longitudinally and in relation to expected symptom onset in a cohort of familial Alzheimer's disease. Ninety-nine individuals (23 presymptomatic; 9 symptomatic and 67 controls) were included in an extension cross-sectional study and a sub-sample of 48 (23 presymptomatic carriers, 6 symptomatic and 19 controls), attending two to five visits with a median interval of 1.3 years, included in the longitudinal study. Participants completed the “What was where?” relational binding task (which measures memory for object identification, localisation and object-location binding under different conditions of memory load and delay), neuropsychology assessments and genetic testing. Compared to controls, presymptomatic carriers within 8.5 years of estimated symptom onset showed a faster rate of decline in localisation performance in long-delay conditions (4s) and in traditional neuropsychology measures of verbal episodic memory. This study represents the first longitudinal VSTM investigation and shows that changes in memory resolution may be sensitive to tracking cognitive decline in preclinical AD at least as early as changes in the more traditional verbal episodic memory tasks., Highlights • VSTM function was investigated in presymptomatic and symptomatic FAD carriers. • PMCs showed faster decline in VSTM function (target localisation) than controls. • Target localisation accuracy decreased with proximity to expected symptom onset. • “What was where?” may be sensitive to tracking preclinical cognitive decline.

Accurate, automated white matter hyperintensity (WMH) segmentations are needed for large-scale studies to understand contributions of WMH to neurological diseases. We evaluated Bayesian Model Selection (BaMoS), a hierarchical fully-unsupervised model selection framework for WMH segmentation. We compared BaMoS segmentations to semi-automated segmentations, and assessed whether they predicted longitudinal cognitive change in control, early Mild Cognitive Impairment (EMCI), late Mild Cognitive Impairment (LMCI), subjective/significant memory concern (SMC) and Alzheimer’s (AD) participants. Data were downloaded from the Alzheimer’s disease Neuroimaging Initiative (ADNI). Magnetic resonance images from 30 control and 30 AD participants were selected to incorporate multiple scanners, and were semi-automatically segmented by 4 raters and BaMoS. Segmentations were assessed using volume correlation, Dice score, and other spatial metrics. Linear mixed-effect models were fitted to 180 control, 107 SMC, 320 EMCI, 171 LMCI and 151 AD participants separately in each group, with the outcomes being cognitive change (e.g. mini-mental state examination; MMSE), and BaMoS WMH, age, sex, race and education used as predictors. There was a high level of agreement between BaMoS’ WMH segmentation volumes and a consensus of rater segmentations, with a median Dice score of 0.74 and correlation coefficient of 0.96. BaMoS WMH predicted cognitive change in: control, EMCI, and SMC groups using MMSE; LMCI using clinical dementia rating scale; and EMCI using Alzheimer’s disease assessment scale-cognitive subscale (p

Introduction Cortical thickness has been proposed as a biomarker of Alzheimer's disease (AD)– related neurodegeneration, but the nature of its relationship with amyloid beta (Aβ) deposition and white matter hyperintensity volume (WMHV) in cognitively normal adults is unclear. Methods We investigated the influences of Aβ status (negative/positive) and WMHV on cortical thickness in 408 cognitively normal adults aged 69.2 to 71.9 years who underwent 18F‐Florbetapir positron emission tomography (PET) and structural magnetic resonance imaging (MRI). Two previously defined Alzheimer's disease (AD) cortical signature regions and the major cortical lobes were selected as regions of interest (ROIs) for cortical thickness. Results Higher WMHV, but not Aβ status, predicted lower cortical thickness across all participants, in all ROIs. Conversely, when Aβ‐positive participants were considered alone, higher WMHV predicted higher cortical thickness in a temporal AD‐signature region. Discussion WMHV may differentially influence cortical thickness depending on the presence or absence of Aβ, potentially reflecting different pathological mechanisms.

Alzheimer's disease has a preclinical stage when cerebral amyloid-β deposition occurs before symptoms emerge, and when amyloid-β-targeted therapies may have maximum benefits. Existing amyloid-β status measurement techniques, including amyloid PET and CSF testing, are difficult to deploy at scale, so blood biomarkers are increasingly considered for screening. We compared three different blood-based techniques-liquid chromatography-mass spectrometry measures of plasma amyloid-β, and single molecule array (Simoa) measures of plasma amyloid-β and phospho-tau181-to detect cortical 18F-florbetapir amyloid PET positivity (defined as a standardized uptake value ratio of >0.61 between a predefined cortical region of interest and eroded subcortical white matter) in dementia-free members of Insight 46, a substudy of the population-based British 1946 birth cohort. We used logistic regression models with blood biomarkers as predictors of amyloid PET status, with or without age, sex and APOE e4 carrier status as covariates. We generated receiver operating characteristics curves and quantified areas under the curves to compare the concordance of the different blood tests with amyloid PET. We determined blood test cut-off points using Youden's index, then estimated numbers needed to screen to obtain 100 amyloid PET-positive individuals. Of the 502 individuals assessed, 441 dementia-free individuals with complete data were included; 82 (18.6%) were amyloid PET-positive. The area under the curve for amyloid PET status using a base model comprising age, sex and APOE e4 carrier status was 0.695 (95% confidence interval: 0.628-0.762). The two best-performing Simoa plasma biomarkers were amyloid-β42/40 (0.620; 0.548-0.691) and phospho-tau181 (0.707; 0.646-0.768), but neither outperformed the base model. Mass spectrometry plasma measures performed significantly better than any other measure (amyloid-β1-42/1-40: 0.817; 0.770-0.864 and amyloid-β composite: 0.820; 0.775-0.866). At a cut-off point of 0.095, mass spectrometry measures of amyloid-β1-42/1-40 detected amyloid PET positivity with 86.6% sensitivity and 71.9% specificity. Without screening, to obtain 100 PET-positive individuals from a population with similar amyloid PET positivity prevalence to Insight 46, 543 PET scans would need to be performed. Screening using age, sex and APOE e4 status would require 940 individuals, of whom 266 would proceed to scan. Using mass spectrometry amyloid-β1-42/1-40 alone would reduce these numbers to 623 individuals and 243 individuals, respectively. Across a theoretical range of amyloid PET positivity prevalence of 10-50%, mass spectrometry measures of amyloid-β1-42/1-40 would consistently reduce the numbers proceeding to scans, with greater cost savings demonstrated at lower prevalence.

Despite much recent interest in music and dementia, music perception has not been widely studied across dementia syndromes using an information processing approach. Here we addressed this issue in a cohort of 30 patients representing major dementia syndromes of typical Alzheimer's disease (AD, n = 16), logopenic aphasia (LPA, an Alzheimer variant syndrome; n = 5), and progressive nonfluent aphasia (PNFA; n = 9) in relation to 19 healthy age-matched individuals. We designed a novel neuropsychological battery to assess perception of musical patterns in the dimensions of pitch and temporal information (requiring detection of notes that deviated from the established pattern based on local or global sequence features) and musical scene analysis (requiring detection of a familiar tune within polyphonic harmony). Performance on these tests was referenced to generic auditory (timbral) deviance detection and recognition of familiar tunes and adjusted for general auditory working memory performance. Relative to healthy controls, patients with AD and LPA had group-level deficits of global pitch (melody contour) processing while patients with PNFA as a group had deficits of local (interval) as well as global pitch processing. There was substantial individual variation within syndromic groups. Taking working memory performance into account, no specific deficits of musical temporal processing, timbre processing, musical scene analysis, or tune recognition were identified. The findings suggest that particular aspects of music perception such as pitch pattern analysis may open a window on the processing of information streams in major dementia syndromes. The potential selectivity of musical deficits for particular dementia syndromes and particular dimensions of processing warrants further systematic investigation.

Background Cognitive function may serve as an early indicator of prodromal Alzheimer’s disease (AD). We examined how cognitive measures over the life course are associated with the AD-related biomarkers of amyloid (Aβ) status and whole brain volume in a population-based sample free of dementia and other major neurological disorders. Methods Data were from 458 (49% female) dementia-free participants from Insight 46, a sub-study of the National Survey of Health and Development (1946 British birth cohort). At age 70–72, participants underwent 18F-Florbetapir amyloid-PET and multi-modal MRI imaging. Regression analyses and multilevel modelling examined patterns between cognitive measures (spanning age 8–69) and the neuroimaging outcomes of Aβ status (±) and whole brain volume. Results Of a range of cognitive tests, word-list learning (WLT) at age 69 was specifically associated with Aβ status at the 5% level (OR 0.75 (0.57, 0.96)). Aβ+ individuals additionally showed faster WLT decline in the 26 years preceding imaging (M1: β=-0.06 (-0.09,-0.01)). Measures of reaction time (M1: b=-0.17 (95% CI -0.27,-0.08) and search speed (M1: b=0.12 (95% CI 0.03, 0.22)) at age 60, and decline in search speed over 26 years (M1: β=0.01 (0.00,0.01)), were associated with smaller whole brain volume. These patterns remained similar after adjusting for childhood cognition, sex, education, child and adult SEP, affective problems and concurrent pathology. APOE-e4 status attenuated the association between verbal memory and Aβ. Conclusion Associations between cognitive function and neuropathology at age 70–72 appear to manifest between ages 60–69 in a population-based sample without dementia or other major neurological problems. In particular, decline in WLT is associated with Aβ+ and is partially attributed to the effects of APOE-e4; whereas level of reaction time and rate of decline of search speed are associated with smaller brain volume and are APOE-e4-independent. Our findings are consistent with evidence of cognitive changes as part of an AD prodromal syndrome in early older-age; and provide evidence that cognitive domains can differentiate underlying pathophysiology associated with AD.

BackgroundHearing impairment may be a modifiable risk factor for dementia. However, it is unclear how hearing associates with pathologies relevant to dementia in preclinical populations.MethodsData from 368 cognitively healthy individuals born during 1 week in 1946 (age range 69.2–71.9 years), who underwent structural MRI, 18F-florbetapir positron emission tomography, pure tone audiometry and cognitive testing as part of a neuroscience substudy the MRC National Survey of Health and Development were analysed. The aim of the analysis was to investigate whether pure tone audiometry performance predicted a range of cognitive and imaging outcomes relevant to dementia in older adults.ResultsThere was some evidence that poorer pure tone audiometry performance was associated with lower primary auditory cortex thickness, but no evidence that it predicted in vivo β-amyloid deposition, white matter hyperintensity volume, hippocampal volume or Alzheimer’s disease-pattern cortical thickness. A negative association between pure tone audiometry and mini-mental state examination score was observed, but this was no longer evident after excluding a test item assessing repetition of a single phrase.ConclusionPure tone audiometry performance did not predict concurrent β-amyloid deposition, small vessel disease or Alzheimer’s disease-pattern neurodegeneration, and had limited impact on cognitive function, in healthy adults aged approximately 70 years.

BackgroundThe human hippocampus comprises a number of interconnected histologically and functionally distinct subfields, which may be differentially influenced by cerebral pathology. Automated techniques are now available that estimate hippocampal subfield volumes using in vivo structural MRI data. To date, research investigating the influence of cerebral β-amyloid deposition-one of the earliest hypothesised changes in the pathophysiological continuum of Alzheimer's disease-on hippocampal subfield volumes in cognitively normal older individuals, has been limited.MethodsUsing cross-sectional data from 408 cognitively normal individuals born in mainland Britain (age range at time of assessment = 69.2-71.9 years) who underwent cognitive assessment, 18F-Florbetapir PET and structural MRI on the same 3 Tesla PET/MR unit (spatial resolution 1.1 x 1.1 x 1.1. mm), we investigated the influences of β-amyloid status, age at scan, and global white matter hyperintensity volume on: CA1, CA2/3, CA4, dentate gyrus, presubiculum and subiculum volumes, adjusting for sex and total intracranial volume.ResultsCompared to β-amyloid negative participants (n = 334), β-amyloid positive participants (n = 74) had lower volume of the presubiculum (3.4% smaller, p = 0.012). Despite an age range at scanning of just 2.7 years, older age at time of scanning was associated with lower CA1 (p = 0.007), CA4 (p = 0.004), dentate gyrus (p = 0.002), and subiculum (p = 0.035) volumes. There was no evidence that white matter hyperintensity volume was associated with any subfield volumes.ConclusionThese data provide evidence of differential associations in cognitively normal older adults between hippocampal subfield volumes and β-amyloid deposition and, increasing age at time of scan. The relatively selective effect of lower presubiculum volume in the β-amyloid positive group potentially suggest that the presubiculum may be an area of early and relatively specific volume loss in the pathophysiological continuum of Alzheimer's disease. Future work using higher resolution imaging will be key to exploring these findings further.

We have previously documented two patients (FOL and CLA) with posterior cortical atrophy who achieved accurate and rapid reading despite deficits in ten measures of visual processing, with two notable exceptions: (1) a measure of visual acuity, (2) a measure of visual crowding. Subsequent longitudinal investigation of these patients was carried out, involving annual tests of early visual, visuoperceptual and visuospatial processing and assessment of reading ability. Follow-up assessments identified the evolution of a particular early visual processing deficit, excessive visual crowding; this deficit has been previously implicated in forms of dyslexia. Consistent with the link between crowding and reading dysfunction, follow-up assessments also revealed deterioration in both patients' reading ability. The current findings demonstrate a neurodegenerative approach towards understanding the relationship between visual crowding and the reading system, and suggest possible mechanisms for how excessive crowding may disrupt word recognition., Highlights • Two patients demonstrate remarkably intact reading despite grave visual impairment. • Longitudinal assessments of visual function and reading ability were carried out. • Emergence of excessive crowding in central vision was observed in both patients. • Emergence of crowding was accompanied by a decline in reading ability. • Findings demonstrate a neurodegenerative approach towards acquired dyslexia.

Verbal adynamia (impaired language generation, as during conversation) has not been assessed systematically in parkinsonian disorders. We addressed this in patients with Parkinson’s dementia, progressive supranuclear palsy and corticobasal degeneration. All disease groups showed impaired verbal fluency and sentence generation versus healthy age-matched controls, after adjusting for general linguistic and executive factors. Dopaminergic stimulation in the Parkinson’s group selectively improved verbal generation versus other cognitive functions. Voxel-based morphometry identified left inferior frontal and posterior superior temporal cortical correlates of verbal generation performance. Verbal adynamia warrants further evaluation as an index of language network dysfunction and dopaminergic state in parkinsonian disorders.

The analysis of clinical trials is limited to pre-specified outcomes, thereby precluding a mechanistic understanding of the treatment response. Multivariate mechanistic models can elucidate the causal chain of events by simultaneous analysis of multi-modal data that link intermediate variables to outcomes of interest. A double-blind, randomised, controlled, phase 2 clinical trial in secondary progressive multiple sclerosis (MS-STAT, NCT00647348) demonstrated that simvastatin (80mg/day) over two years reduced the brain atrophy rate and was associated with beneficial effects on cognitive and disability outcomes. Therefore, this trial offers an opportunity to apply mechanistic models to investigate the hypothesised pathways that link simvastatin to clinical outcome measures, either directly or indirectly via changes in serum total cholesterol levels and to determine which is the more likely. We re-analysed the MS-STAT trial in which 140 patients with secondary progressive multiple sclerosis were randomised (1:1) to receive placebo or simvastatin (80 mg/day). At baseline and after one and two 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). Serum total cholesterol levels were measured at each visit. We calculated the annual percentage change of brain volume loss using mixed-effects models. With multivariate mechanistic models and Bayesian mediation analyses, a cholesterol-dependent model was compared to a cholesterol-independent model. As described previously, the simvastatin group showed a slower rate of brain atrophy and clinical deterioration (as reflected by both the EDSS and the block design test) and a faster decline in serum cholesterol levels (all p

BACKGROUND: Mineralocorticoid receptor antagonist (MRA) therapy has been shown to prevent adverse left ventricular (LV) remodeling in ST-segment elevation myocardial infarction (STEMI) patients with heart failure. Whether initiating MRA therapy prior to primary percutaneous coronary intervention (PPCI) accrues additional benefit of reducing myocardial infarct size and preventing adverse LV remodeling is not known. We aimed to investigate whether MRA therapy initiated prior to reperfusion reduces myocardial infarct (MI) size and prevents adverse LV remodeling in STEMI patients. METHODS: STEMI patients presenting within 12 hours and with a proximal coronary artery occlusion with Thrombolysis In Myocardial Infarction flow grade 0 were consented and randomized to either an intravenous bolus of potassium canrenoate, followed by oral spironolactone for 3 months or matching placebo. The primary endpoint was MI size by cardiovascular magnetic resonance at 3 months. RESULTS: Sixty-seven patients completed the study. There was no significant difference in the final MI size at 3 months between the 2 groups (placebo: 17 ± 11%, MRA: 16 ± 10%, P = .574). There was also no difference in acute MI size (26 ± 16% versus 23 ± 14%, P = .425) or myocardial salvage (26 ± 12% versus 24 ± 8%, P = .456). At follow-up, there was a trend towards an improvement in LVEF (placebo: 49 ± 8%, MRA: 54 ± 11%, P = .053), and the MRA group had significantly greater percentage decrease in LVEDV (mean difference: −12.2 (95% CI −20.3 to −4.4)%, P = .003) and LVESV (mean difference: −18.2 (95% CI −30.1 to −6.3)%, P = .003). CONCLUSION: This pilot study showed no benefit of MRA therapy in reducing MI size in STEMI patients when initiated prior to reperfusion, but there was an improvement in LV remodeling at 3 months. Adequately powered studies are warranted to confirm these findings.

Background Reliable biomarkers of frontotemporal dementia (FTD) are currently lacking. FTD may be associated with chronic immune dysfunction, microglial activation and raised inflammatory markers, particularly in progranulin (GRN) mutation carriers. Levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) are elevated in Alzheimer’s disease (AD), but they have not been fully explored in FTD. Methods We investigated whether cerebrospinal fluid (CSF) sTREM2 levels differ between FTD and controls, across different clinical and genetic subtypes of FTD, or between individuals with FTD due to AD versus non-AD pathology (based on CSF neurodegenerative biomarkers). We also assessed relationships between CSF sTREM2 and other CSF biomarkers (total tau [T-tau], tau phosphorylated at position threonine-181 [P-tau] and β-amyloid 1–42 [Aβ42]) and age and disease duration. Biomarker levels were measured using immunoassays in 17 healthy controls and 64 patients with FTD (behavioural variant FTD, n = 20; primary progressive aphasia, n = 44). Ten of 64 had familial FTD, with mutations in GRN (n = 3), MAPT (n = 4), or C9orf72 (n = 3). Fifteen of 64 had neurodegenerative biomarkers consistent with AD pathology (11 of whom had logopenic variant PPA). Levels were compared using multivariable linear regressions. Results CSF sTREM2 levels did not differ between FTD and controls or between clinical subgroups. However, GRN mutation carriers had higher levels than controls (mean ([SD] = 9.7 [2.9] vs. 6.8 [1.6] ng/ml; P = 0.028) and MAPT (3.9 [1.5] ng/ml; P = 0.003] or C9orf72 [4.6 [1.8] ng/ml; P = 0.006) mutation carriers. Individuals with AD-like CSF had higher sTREM2 levels than those with non-AD-like CSF (9.0 [3.6] vs. 6.9 [3.0] ng/ml; P = 0.029). CSF sTREM2 levels were associated with T-tau levels in control and FTD groups and also with P-tau in those with FTD and AD-like CSF. CSF sTREM2 levels were influenced by both age and disease duration in FTD. Conclusions Although CSF sTREM2 levels are not raised in FTD overall or in a particular clinical subtype of FTD, levels are raised in familial FTD associated with GRN mutations and in FTD syndromes due to AD pathology. Because CSF sTREM2 levels correlate with a marker of neuronal injury (T-tau), sTREM2 should be explored as a biomarker of disease intensity in future longitudinal studies of FTD.

Introduction\ud Cerebrospinal fluid (CSF) neurodegenerative markers are measured clinically to support a diagnosis of Alzheimer's disease. Several preanalytical factors may alter the CSF concentrations of amyloid β 1–42 (Aβ1–42) in particular with the potential to influence diagnosis. We aimed to determine whether routine handling of samples alters measured biomarker concentration compared with that of prompt delivery to the laboratory.\ud \ud Methods\ud Forty individuals with suspected neurodegenerative diseases underwent diagnostic lumbar punctures using a standardized technique. A sample of each patient's CSF was sent to the laboratory by four different delivery methods: (1) by courier at room temperature; (2) by courier, on ice; (3) using standard hospital portering; and (4) after quarantining for >24 hours. Aβ1–42, total tau (t‐tau), and phosphorylated tau (p‐tau) levels measured using standard enzyme‐linked immunosorbent assay techniques were compared between transfer methods.\ud \ud Results\ud There were no significant differences in Aβ1–42, t‐tau, or p‐tau concentrations measured in samples transported via the different delivery methods despite significant differences in time taken to deliver samples.\ud \ud Discussion\ud When CSF is collected in appropriate tubes, transferred at room temperature, and processed within 24 hours, neurodegenerative markers can be reliably determined.

The rationale and study design for the multicentre, randomized, controlled CONDI2/ERIC-PPCI study are discussed.

Alzheimer's disease (AD) is associated with extensive alterations in grey matter microstructure, but our ability to quantify this in vivo is limited. Neurite orientation dispersion and density imaging (NODDI) is a multi‐shell diffusion MRI technique that estimates neuritic microstructure in the form of orientation dispersion and neurite density indices (ODI/NDI). Mean values for cortical thickness, ODI, and NDI were extracted from predefined regions of interest in the cortical grey matter of 38 patients with young onset AD and 22 healthy controls. Five cortical regions associated with early atrophy in AD (entorhinal cortex, inferior temporal gyrus, middle temporal gyrus, fusiform gyrus, and precuneus) and one region relatively spared from atrophy in AD (precentral gyrus) were investigated. ODI, NDI, and cortical thickness values were compared between controls and patients for each region, and their associations with MMSE score were assessed. NDI values of all regions were significantly lower in patients. Cortical thickness measurements were significantly lower in patients in regions associated with early atrophy in AD, but not in the precentral gyrus. Decreased ODI was evident in patients in the inferior and middle temporal gyri, fusiform gyrus, and precuneus. The majority of AD‐related decreases in cortical ODI and NDI persisted following adjustment for cortical thickness, as well as each other. There was evidence in the patient group that cortical NDI was associated with MMSE performance. These data suggest distinct differences in cortical NDI and ODI occur in AD and these metrics provide pathologically relevant information beyond that of cortical thinning.