Search

Background: Chemotherapy-induced peripheral neuropathy (CIPN), a common problem, can impair function and quality of life in patients, potentially limiting chemotherapy and adversely affecting outcomes., Methods: This trial compared investigational hand therapy intervention (Investigational) compared with a traditional occupational therapy approach (Traditional) to prevent CIPN in patients with pancreatic cancer receiving gemcitabine and albumin-bound paclitaxel containing regimens., Results: forty-nine patients were enrolled with 40 evaluable for statistical analysis (21 Investigational/19 Traditional). CIPN in the hands was reported in 6 patients (28.6%) in Investigational, and 4 (21.1%) in Traditional P = .721. Kaplan-Meier analysis showed a mean time-to-event of 76.0 days (90% CI: 68.5, 83.6), and 75.8 (90% CI: 68.5, 83.2) days respectively, P = .614. Fifteen patients in each group (78.9% Traditional, 71.4% in Investigational) were censored as they did not develop CIPN. No correlation was found between CIPN risk and age, sex, BMI, disease stage, performance status, or chemotherapy dose., Conclusion: Seventy-four percent of patients receiving gemcitabine, albumin-bound paclitaxel, and cisplatin did not develop CIPN of the hands by day 84. There was no statistical difference in time to onset of CIPN between the two groups. Early adaption of occupational therapy may prevent early onset CIPN in chemotherapy patients., Clinicaltrials.gov Identifier: NCT05374876., (© The Author(s) 2024. Published by Oxford University Press.)

Experimental cell therapies for skeletal muscle conditions have shown little success, primarily because they use committed myogenic progenitors rather than true muscle stem cells, known as satellite cells. Here we present a method to generate in vitro-derived satellite cells (idSCs) from skeletal muscle tissue. When transplanted in small numbers into mouse muscle, mouse idSCs fuse into myofibers, repopulate the satellite cell niche, self-renew, support multiple rounds of muscle regeneration and improve force production on par with freshly isolated satellite cells in damaged skeletal muscle. We compared the epigenomic and transcriptional signatures between idSCs, myoblasts and satellite cells and used these signatures to identify core signaling pathways and genes that confer idSC functionality. Finally, from human muscle biopsies, we successfully generated satellite cell-like cells in vitro. After further development, idSCs may provide a scalable source of cells for the treatment of genetic muscle disorders, trauma-induced muscle damage and age-related muscle weakness., (© 2024. The Author(s).)

We investigate associations between normal-appearing white matter microstructural integrity in cognitively normal ∼70-year-olds and concurrently measured brain health and cognition, demographics, genetics and life course cardiovascular health. Participants born in the same week in March 1946 (British 1946 birth cohort) underwent PET-MRI around age 70. Mean standardized normal-appearing white matter integrity metrics (fractional anisotropy, mean diffusivity, neurite density index and orientation dispersion index) were derived from diffusion MRI. Linear regression was used to test associations between normal-appearing white matter metrics and (i) concurrent measures, including whole brain volume, white matter hyperintensity volume, PET amyloid and cognition; (ii) the influence of demographic and genetic predictors, including sex, childhood cognition, education, socio-economic position and genetic risk for Alzheimer's disease ( APOE-ɛ4 ); (iii) systolic and diastolic blood pressure and cardiovascular health (Framingham Heart Study Cardiovascular Risk Score) across adulthood. Sex interactions were tested. Statistical significance included false discovery rate correction (5%). Three hundred and sixty-two participants met inclusion criteria (mean age 70, 49% female). Higher white matter hyperintensity volume was associated with lower fractional anisotropy [ b = -0.09 (95% confidence interval: -0.11, -0.06), P < 0.01], neurite density index [ b = -0.17 (-0.22, -0.12), P < 0.01] and higher mean diffusivity [ b = 0.14 (-0.10, -0.17), P < 0.01]; amyloid (in men) was associated with lower fractional anisotropy [ b = -0.04 (-0.08, -0.01), P = 0.03)] and higher mean diffusivity [ b = 0.06 (0.01, 0.11), P = 0.02]. Framingham Heart Study Cardiovascular Risk Score in later-life (age 69) was associated with normal-appearing white matter {lower fractional anisotropy [ b = -0.06 (-0.09, -0.02) P < 0.01], neurite density index [ b = -0.10 (-0.17, -0.03), P < 0.01] and higher mean diffusivity [ b = 0.09 (0.04, 0.14), P < 0.01]}. Significant sex interactions ( P < 0.05) emerged for midlife cardiovascular health (age 53) and normal-appearing white matter at 70: marginal effect plots demonstrated, in women only, normal-appearing white matter was associated with higher midlife Framingham Heart Study Cardiovascular Risk Score (lower fractional anisotropy and neurite density index), midlife systolic (lower fractional anisotropy, neurite density index and higher mean diffusivity) and diastolic (lower fractional anisotropy and neurite density index) blood pressure and greater blood pressure change between 43 and 53 years (lower fractional anisotropy and neurite density index), independently of white matter hyperintensity volume. In summary, poorer normal-appearing white matter microstructural integrity in ∼70-year-olds was associated with measures of cerebral small vessel disease, amyloid (in males) and later-life cardiovascular health, demonstrating how normal-appearing white matter can provide additional information to overt white matter disease. Our findings further show that greater 'midlife' cardiovascular risk and higher blood pressure were associated with poorer normal-appearing white matter microstructural integrity in females only, suggesting that women's brains may be more susceptible to the effects of midlife blood pressure and cardiovascular health., Competing Interests: N.C.F. has consulted for Biogen, Ionis, Eli Lilly and Roche and has served on a Data Safety Monitoring Committee for Biogen. J.M.S. has received research funding from Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly), has consulted for Roche Pharmaceuticals, Biogen, and Eli Lilly, given educational lectures sponsored by GE, Eli Lilly and Biogen, and serves on a Data Safety Monitoring Committee for Axon Neuroscience SE. C.A.L. is now a full-time employee of Roche Products Ltd and a shareholder in Hoffmann La Roche. F.B. is a steering committee or iDMC member for Biogen, Merck, Roche, EISAI and Prothena, is a consultant for Roche, Biogen, Merck, IXICO, Jansen and Combinostics, has research agreements with Merck, Biogen, GE Healthcare and Roche, and is a co-founder and shareholder of Queen Square Analytics LTD. All other authors have no conflicts of interest to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: The Centiloid scale aims to harmonize amyloid beta (Aβ) positron emission tomography (PET) measures across different analysis methods. As Centiloids were created using PET/computerized tomography (CT) data and are influenced by scanner differences, we investigated the Centiloid transformation with data from Insight 46 acquired with PET/magnetic resonanceimaging (MRI)., Methods: We transformed standardized uptake value ratios (SUVRs) from 432 florbetapir PET/MRI scans processed using whole cerebellum (WC) and white matter (WM) references, with and without partial volume correction. Gaussian-mixture-modelling-derived cutpoints for Aβ PET positivity were converted., Results: The Centiloid cutpoint was 14.2 for WC SUVRs. The relationship between WM and WC uptake differed between the calibration and testing datasets, producing implausibly low WM-based Centiloids. Linear adjustment produced a WM-based cutpoint of 18.1., Discussion: Transformation of PET/MRI florbetapir data to Centiloids is valid. However, further understanding of the effects of acquisition or biological factors on the transformation using a WM reference is needed., Highlights: Centiloid conversion of amyloid beta positron emission tomography (PET) data aims to standardize results.Centiloid values can be influenced by differences in acquisition.We converted florbetapir PET/magnetic resonance imaging data from a large birth cohort.Whole cerebellum referenced values could be reliably transformed to Centiloids.White matter referenced values may be less generalizable between datasets., Competing Interests: NCF's research group has received payment for consultancy or for conducting studies from Biogen, Eli Lilly Research Laboratories, GE Healthcare, and Roche. NCF receives no personal compensation for the aforementioned activities. JMS has received research funding from Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly); has consulted for Roche Pharmaceuticals, Biogen, Merck, and Eli Lilly; given educational lectures sponsored by GE Healthcare, Eli Lilly, and Biogen; and serves on a Data Safety Monitoring Committee for Axon Neuroscience SE. All other authors report no competing interests.Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Aging is a complex process involving transcriptomic changes associated with deterioration across multiple tissues and organs, including the brain. Recent studies using heterochronic parabiosis have shown that various aspects of aging-associated decline are modifiable or even reversible. To better understand how this occurs, we performed single-cell transcriptomic profiling of young and old mouse brains after parabiosis. For each cell type, we cataloged alterations in gene expression, molecular pathways, transcriptional networks, ligand-receptor interactions and senescence status. Our analyses identified gene signatures, demonstrating that heterochronic parabiosis regulates several hallmarks of aging in a cell-type-specific manner. Brain endothelial cells were found to be especially malleable to this intervention, exhibiting dynamic transcriptional changes that affect vascular structure and function. These findings suggest new strategies for slowing deterioration and driving regeneration in the aging brain through approaches that do not rely on disease-specific mechanisms or actions of individual circulating factors., (© 2023. The Author(s).)

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., Competing Interests: Disclosure statement Sarah-Naomi James – Reports no disclosures, Jennifer M. Nicholas – Reports no disclosures, Kirsty Lu – Reports no disclosures, Thomas D. Parker - Supported by a Wellcome Trust Clinical Research Fellowship (200109/Z/15/Z)., Christopher A. Lane – Reports no disclosures, Ashvini Keshavan – Supported by a Wolfson Foundation Clinical Research Fellowship., Sarah E. Keuss – Reports no disclosures, Sarah M. Buchanan – Reports no disclosures, Heidi Murray-Smith – Reports no disclosures, David M. Cash – Supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK (ARUK‐PG2017‐1946),  the UCL/UCLH NIHR Biomedical Research Centre, and the UKRI Innovation Scholars: Data Science Training in Health and Bioscience (MR/V03863X/1)) - Carole H. Sudre - Supported by an MRC platform grant (EP/M020533/1) and an Alzheimer's Society Junior Fellowship (AS-JF-17-011)., Josephine Barnes – Supported by a Senior ARUK fellowship., Ian B. Malone – Reports no disclosures, Will Coath – Reports no disclosures, Marc Modat – Supported by the Leonard Wolfson Experimental Neurology Centre and an Alzheimer's Society Project Grant (AS-PG-15-025)., Andrew Wong – Reports no disclosures, Diana Kuh – Reports no disclosures, Sebastien Ourselin – Reports no disclosures, Sebastian J. Crutch - Supported by an Alzheimer's Research UK Senior Research Fellowship (ARUK-SRF2013-8)., Nick C. Fox - supported by the UCL/UCLH NIHR Biomedical Research Centre, Leonard Wolfson Experimental Neurology Centre, and the UK Dementia Research Institute at UCL., Marcus Richards – Reports no disclosures, Jonathan M. Schott - supported by the UCL/UCLH NIHR Biomedical Research Centre, UCL Hospitals Biomedical Research Centre, and Leonard Wolfson Experimental Neurology Centre. Acknowledges the EPSRC (EP/J020990/1) and European Union's Horizon 2020 research and innovation programme (Grant 666992)., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: The 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., Methods: Participants 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., Results: Three 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., Discussion: Aβ 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., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Mild parkinsonian signs (MPS) have been widely studied during the past 3 decades and proposed as a risk marker for neurodegenerative disease. This systematic review explores the epidemiology, clinical and prognostic associations, radiological features, and pathological findings associated with MPS in older adults free from neurodegenerative disease. We find that MPS as currently defined are strongly associated with increasing age and increased risk of development of Parkinson's disease (PD), all-cause dementia, disability, and death. Positive associations with later PD are found mainly in younger populations and those with other features of prodromal PD. There are currently no consistent radiological findings for MPS, and pathological studies have shown that MPS, at least in the oldest old, are often underpinned by mixed neuropathologies, including those associated with Alzheimer's disease, cerebrovascular disease, nigral neuronal loss, and Lewy bodies. Different subcategories of MPS appear to convey varying risk and specificity for PD and other outcomes. MPS overall are not specific for parkinsonian disorders and, although associated with increased risk of PD, can reflect multiple pathologies, particularly in older individuals. "Mild motor signs" appears a more appropriate term to avoid prognostic and pathological implications, and larger future studies to prospectively examine outcomes and associations of specific MPS subcategories are required. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Objective: To investigate subjective cognitive decline (SCD) in relation to β-amyloid pathology and to test for associations with anxiety, depression, objective cognition and family history of dementia in the Insight 46 study., Methods: Cognitively unimpaired ~70-year-old participants, all born in the same week in 1946 (n=460, 49% female, 18% amyloid-positive), underwent assessments including the SCD-Questionnaire (MyCog). MyCog scores were evaluated with respect to 18 F-Florbetapir-PET amyloid status (positive/negative). Associations with anxiety, depression, objective cognition (measured by the Preclinical Alzheimer Cognitive Composite, PACC) and family history of dementia were also investigated. The informant's perspective on SCD was evaluated in relation to MyCog score., Results: Anxiety (mean (SD) trait anxiety score: 4.4 (3.9)) was associated with higher MyCog scores, especially in women. MyCog scores were higher in amyloid-positive compared with amyloid-negative individuals (adjusted means (95% CIs): 5.3 (4.4 to 6.1) vs 4.3 (3.9 to 4.7), p=0.044), after accounting for differences in anxiety. PACC (mean (SD) -0.05 (0.68)) and family history of dementia (prevalence: 23.9%) were not independently associated with MyCog scores. The informant's perception of SCD was generally in accordance with that of the participant., Conclusions: This cross-sectional study demonstrates that symptoms of SCD are associated with both β-amyloid pathology, and more consistently, trait anxiety in a population-based cohort of older adults, at an age when those who are destined to develop dementia are still likely to be some years away from symptoms. This highlights the necessity of considering anxiety symptoms when assessing Alzheimer's disease pathology and SCD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Growth differentiation factor 11 (GDF11) is a transforming factor-β superfamily member that functions as a negative regulator of neurogenesis during embryonic development. However, when recombinant GDF11 (rGDF11) is administered systemically in aged mice, it promotes neurogenesis, the opposite of its role during development. The goal of the present study was to reconcile this apparent discrepancy by performing the first detailed investigation into the expression of endogenous GDF11 in the adult brain and its effects on neurogenesis. Using quantitative histological analysis, we observed that Gdf11 is most highly expressed in adult neurogenic niches and non-neurogenic regions within the hippocampus, choroid plexus, thalamus, habenula, and cerebellum. To investigate the role of endogenous GDF11 during adult hippocampal neurogenesis, we generated a tamoxifen inducible mouse that allowed us to reduce GDF11 levels. Depletion of Gdf11 during adulthood increased proliferation of neural progenitors and decreased the number of newborn neurons in the hippocampus, suggesting that endogenous GDF11 remains a negative regulator of hippocampal neurogenesis in adult mice. These findings further support the idea that circulating systemic GDF11 and endogenously expressed GDF11 in the adult brain have different target cells or mechanisms of action. Our data describe a role for GDF11-dependent signaling in adult neurogenesis that has implications for how GDF11 may be used to treat CNS disease., (© 2021. The Author(s).)

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), 18 F-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)., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

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 ε4 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 ε4 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 ε4 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., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

We investigated whether subtle visuomotor deficits were detectable in familial and sporadic preclinical Alzheimer's disease. A circle-tracing task-with direct and indirect visual feedback, and dual-task subtraction-was completed by 31 individuals at 50% risk of familial Alzheimer's disease (19 presymptomatic mutation carriers; 12 non-carriers) and 390 cognitively normal older adults (members of the British 1946 Birth Cohort, all born during the same week; age range at assessment = 69-71 years), who also underwent β-amyloid-PET/MRI to derive amyloid status (positive/negative), whole-brain volume and white matter hyperintensity volume. We compared preclinical Alzheimer's groups against controls cross-sectionally (mutation carriers versus non-carriers; amyloid-positive versus amyloid-negative) on speed and accuracy of circle-tracing and subtraction. Mutation carriers (mean 7 years before expected onset) and amyloid-positive older adults traced disproportionately less accurately than controls when visual feedback was indirect, and were slower at dual-task subtraction. In the older adults, the same pattern of associations was found when considering amyloid burden as a continuous variable (Standardized Uptake Value Ratio). The effect of amyloid was independent of white matter hyperintensity and brain volumes, which themselves were associated with different aspects of performance: greater white matter hyperintensity volume was also associated with disproportionately poorer tracing accuracy when visual feedback was indirect, whereas larger brain volume was associated with faster tracing and faster subtraction. Mutation carriers also showed evidence of poorer tracing accuracy when visual feedback was direct. This study provides the first evidence of visuomotor integration deficits common to familial and sporadic preclinical Alzheimer's disease, which may precede the onset of clinical symptoms by several years., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: To explore the value of olfactory identification deficits as a predictor of cerebral β-amyloid status and other markers of brain health in cognitively normal adults aged ~ 70 years., Methods: Cross-sectional observational cohort study. 389 largely healthy and cognitively normal older adults were recruited from the MRC National Survey of Health and Development (1946 British Birth cohort) and investigated for olfactory identification deficits, as measured by the University of Pennsylvania Smell Identification Test. Outcome measures were imaging markers of brain health derived from 3 T MRI scanning (cortical thickness, entorhinal cortex thickness, white matter hyperintensity volumes); 18 F florbetapir amyloid-PET scanning; and cognitive testing results. Participants were assessed at a single centre between March 2015 and January 2018., Results: Mean (± SD) age was 70.6 (± 0.7) years, 50.8% were female. 64.5% had hyposmia and 2.6% anosmia. Olfaction showed no association with β-amyloid status, hippocampal volume, entorhinal cortex thickness, AD signature cortical thickness, white matter hyperintensity volume, or cognition., Conclusion and Relevance: In the early 70s, olfactory function is not a reliable predictor of a range of imaging and cognitive measures of preclinical AD. Olfactory identification deficits are not likely to be a useful means of identifying asymptomatic amyloidosis. Further studies are required to assess if change in olfaction may be a proximity marker for the development of cognitive impairment.

Satellite cells are the canonical muscle stem cells that regenerate damaged skeletal muscle. Loss of function of these cells has been linked to reduced muscle repair capacity and compromised muscle health in acute muscle injury and congenital neuromuscular diseases. To identify new pathways that can prevent loss of skeletal muscle function or enhance regenerative potential, we established an imaging-based screen capable of identifying small molecules that promote the expansion of freshly isolated satellite cells. We found several classes of receptor tyrosine kinase (RTK) inhibitors that increased freshly isolated satellite cell numbers in vitro. Further exploration of one of these compounds, the RTK inhibitor CEP-701 (also known as lestaurtinib), revealed potent activity on mouse satellite cells both in vitro and in vivo. This expansion potential was not seen upon exposure of proliferating committed myoblasts or non-myogenic fibroblasts to CEP-701. When delivered subcutaneously to acutely injured animals, CEP-701 increased both the total number of satellite cells and the rate of muscle repair, as revealed by an increased cross-sectional area of regenerating fibers. Moreover, freshly isolated satellite cells expanded ex vivo in the presence of CEP-701 displayed enhanced muscle engraftment potential upon in vivo transplantation. We provide compelling evidence that certain RTKs, and in particular RET, regulate satellite cell expansion during muscle regeneration. This study demonstrates the power of small molecule screens of even rare adult stem cell populations for identifying stem cell-targeting compounds with therapeutic potential.

Introduction: We investigated whether life-course factors and neuroimaging biomarkers of Alzheimer's disease pathology predict reaction time (RT) performance in older adults., Methods: Insight 46 study participants, all born in the same week in 1946 (n = 501; ages at assessment = 69 to 71 years), completed a 2-choice RT task and amyloid beta (Aβ) positron emission tomography and MR imaging. We tested for associations between task outcomes (RT; error rate; intra-individual variability in RT) and life-course predictors including childhood cognitive ability and education. In a subsample of 406 cognitively normal participants, we investigated associations between task outcomes and biomarkers including Aβ-positivity., Results: Cognitively normal Aβ-positive participants had 10% more variable RTs than Aβ-negative participants, despite having similar mean RTs. Childhood cognitive ability and education independently predicted task performance., Discussion: This study provides novel evidence that Aβ pathology is associated with poorer consistency of RT in cognitively normal older adults, at an age when dementia prevalence is still very low., Competing Interests: Kirsty Lu reports no disclosures. Jennifer M. Nicholas reports no disclosures. Sarah‐Naomi James reports no disclosures. Thomas D. Parker is supported by a Wellcome Trust Clinical Research Fellowship (200109/Z/15/Z). Christopher A. Lane reports no disclosures. Ashvini Keshavan is supported by a Clinical Research Fellowship funded by the Wolfson Foundation. Sarah E. Keuss reports no disclosures. Sarah M. Buchanan reports no disclosures. Heidi Murray‐Smith reports no disclosures. David M. Cash is supported by an Alzheimer's Society Project Grant (AS‐PG‐205). Carole H. Sudre is supported by an Alzheimer's Society Junior Fellowship (AS‐JF‐17‐011). Ian B. Malone reports no disclosures. William Coath reports no disclosures. Andrew Wong reports no disclosures. Susie M.D. Henley reports no disclosures. Nick C. Fox is supported by the UCL/UCLH NIHR Biomedical Research Centre and the UK Dementia Research Institute at UCL. Marcus Richards reports no disclosures. Jonathan M. Schott is supported by the UCL/UCLH NIHR Biomedical Research Centre, UCL Hospitals Biomedical Research Centre, and Leonard Wolfson Experimental Neurology Centre and acknowledges the EPSRC (EP/J020990/1) and European Union's Horizon 2020 research and innovation programme (Grant 666992). Sebastian J. Crutch is supported by an Alzheimer's Research UK Senior Research Fellowship (ARUK‐SRF2013‐8)., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of the Alzheimer's Association.)

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 18 F-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., (© 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of the Alzheimer's Association.)

Importance: Midlife vascular risk burden is associated with late-life dementia. Less is known about if and how risk exposure in early adulthood influences late-life brain health., Objective: To determine the associations between vascular risk in early adulthood, midlife, and late life with late-life brain structure and pathology using measures of white matter-hyperintensity volume, β-amyloid load, and whole-brain and hippocampal volumes., Design, Setting, and Participants: This prospective longitudinal cohort study, Insight 46, is part of the Medical Research Council National Survey of Health and Development, which commenced in 1946. Participants had vascular risk factors evaluated at ages 36 years (early adulthood), 53 years (midlife), and 69 years (early late life). Participants were assessed with multimodal magnetic resonance imaging and florbetapir-amyloid positron emission tomography scans between May 2015 and January 2018 at University College London. Participants with at least 1 available imaging measure, vascular risk measurements at 1 or more points, and no dementia were included in analyses., Exposures: Office-based Framingham Heart study-cardiovascular risk scores (FHS-CVS) were derived at ages 36, 53, and 69 years using systolic blood pressure, antihypertensive medication usage, smoking, diabetic status, and body mass index. Analysis models adjusted for age at imaging, sex, APOE genotype, socioeconomic position, and, where appropriate, total intracranial volume., Main Outcomes and Measures: White matter-hyperintensity volume was generated from T1/fluid-attenuated inversion recovery scans using an automated technique and whole-brain volume and hippocampal volume were generated from automated in-house pipelines; β-amyloid status was determined using a gray matter/eroded subcortical white matter standardized uptake value ratio threshold of 0.61., Results: A total of 502 participants were assessed as part of Insight 46, and 463 participants (236 male [51.0%]) with at least 1 available imaging measure (mean [SD] age at imaging, 70.7 [0.7] years; 83 β-amyloid positive [18.2%]) who fulfilled eligibility criteria were included. Among them, FHS-CVS increased with age (36 years: median [interquartile range], 2.7% [1.5%-3.6%]; 53 years: 10.9% [6.7%-15.6%]; 69 years: 24.3% [14.9%-34.9%]). At all points, these scores were associated with smaller whole-brain volumes (36 years: β coefficient per 1% increase, -3.6 [95% CI, -7.0 to -0.3]; 53 years: -0.8 [95% CI, -1.5 to -0.08]; 69 years: -0.6 [95% CI, -1.1 to -0.2]) and higher white matter-hyperintensity volume (exponentiated coefficient: 36 years, 1.09 [95% CI, 1.01-1.18]; 53 years, 1.02 [95% CI, 1.00-1.04]; 69 years, 1.01 [95% CI, 1.00-1.02]), with largest effect sizes at age 36 years. At no point were FHS-CVS results associated with β-amyloid status., Conclusions and Relevance: Higher vascular risk is associated with smaller whole-brain volume and greater white matter-hyperintensity volume at age 69 to 71 years, with the strongest association seen with early adulthood vascular risk. There was no evidence that higher vascular risk influences amyloid deposition, at least up to age 71 years. Reducing vascular risk with appropriate interventions should be considered from early adulthood to maximize late-life brain health.

Objective: To 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., Methods: A 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 ., Results: Childhood 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., Conclusions: This 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., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: The 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., Methods: Using 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., Results: Compared 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., Conclusion: These 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., Competing Interests: NCF’s research group has received payment for consultancy or for conducting studies from Biogen, Eli Lilly Research Laboratories, GE Healthcare, and Roche. NCF receives no personal compensation for the activities mentioned above. JMS has received research funding from Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly), has consulted for Roche Pharmaceuticals, Biogen, Merck and Eli Lilly, given educational lectures sponsored by GE Healthcare, Eli Lilly and Biogen, and serves on a Data Safety Monitoring Committee for Axon Neuroscience SE. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Midlife hypertension confers increased risk for cognitive impairment in late life. The sensitive period for risk exposure and extent that risk is mediated through amyloid or vascular-related mechanisms are poorly understood. We aimed to identify if, and when, blood pressure or change in blood pressure during adulthood were associated with late-life brain structure, pathology, and cognition., Methods: Participants were from Insight 46, a neuroscience substudy of the ongoing longitudinal Medical Research Council National Survey of Health and Development, a birth cohort that initially comprised 5362 individuals born throughout mainland Britain in one week in 1946. Participants aged 69-71 years received T1 and FLAIR volumetric MRI, florbetapir amyloid-PET imaging, and cognitive assessment at University College London (London, UK); all participants were dementia-free. Blood pressure measurements had been collected at ages 36, 43, 53, 60-64, and 69 years. We also calculated blood pressure change variables between ages. Primary outcome measures were white matter hyperintensity volume (WMHV) quantified from multimodal MRI using an automated method, amyloid-β positivity or negativity using a standardised uptake value ratio approach, whole-brain and hippocampal volumes quantified from 3D-T1 MRI, and a composite cognitive score-the Preclinical Alzheimer Cognitive Composite (PACC). We investigated associations between blood pressure and blood pressure changes at and between 36, 43, 53, 60-64, and 69 years of age with WMHV using generalised linear models with a gamma distribution and log link function, amyloid-β status using logistic regression, whole-brain volume and hippocampal volumes using linear regression, and PACC score using linear regression, with adjustment for potential confounders., Findings: Between May 28, 2015, and Jan 10, 2018, 502 individuals were assessed as part of Insight 46. 465 participants (238 [51%] men; mean age 70·7 years [SD 0·7]; 83 [18%] amyloid-β-positive) were included in imaging analyses. Higher systolic blood pressure (SBP) and diastolic blood pressure (DBP) at age 53 years and greater increases in SBP and DBP between 43 and 53 years were positively associated with WMHV at 69-71 years of age (increase in mean WMHV per 10 mm Hg greater SBP 7%, 95% CI 1-14, p=0·024; increase in mean WMHV per 10 mm Hg greater DBP 15%, 4-27, p=0·0057; increase in mean WMHV per one SD change in SBP 15%, 3-29, p=0·012; increase in mean WMHV per 1 SD change in DBP 15%, 3-30, p=0·017). Higher DBP at 43 years of age was associated with smaller whole-brain volume at 69-71 years of age (-6·9 mL per 10 mm Hg greater DBP, -11·9 to -1·9, p=0·0068), as were greater increases in DBP between 36 and 43 years of age (-6·5 mL per 1 SD change, -11·1 to -1·9, p=0·0054). Greater increases in SBP between 36 and 43 years of age were associated with smaller hippocampal volumes at 69-71 years of age (-0·03 mL per 1 SD change, -0·06 to -0·001, p=0·043). Neither absolute blood pressure nor change in blood pressure predicted amyloid-β status or PACC score at 69-71 years of age., Interpretation: High and increasing blood pressure from early adulthood into midlife seems to be associated with increased WMHV and smaller brain volumes at 69-71 years of age. We found no evidence that blood pressure affected cognition or cerebral amyloid-β load at this age. Blood pressure monitoring and interventions might need to start around 40 years of age to maximise late-life brain health., Funding: Alzheimer's Research UK, Medical Research Council, Dementias Platform UK, Wellcome Trust, Brain Research UK, Wolfson Foundation, Weston Brain Institute, Avid Radiopharmaceuticals., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The mammalian brain is complex, with multiple cell types performing a variety of diverse functions, but exactly how each cell type is affected in aging remains largely unknown. Here we performed a single-cell transcriptomic analysis of young and old mouse brains. We provide comprehensive datasets of aging-related genes, pathways and ligand-receptor interactions in nearly all brain cell types. Our analysis identified gene signatures that vary in a coordinated manner across cell types and gene sets that are regulated in a cell-type specific manner, even at times in opposite directions. These data reveal that aging, rather than inducing a universal program, drives a distinct transcriptional course in each cell population, and they highlight key molecular processes, including ribosome biogenesis, underlying brain aging. Overall, these large-scale datasets (accessible online at https://portals.broadinstitute.org/single&#95;cell/study/aging-mouse-brain ) provide a resource for the neuroscience community that will facilitate additional discoveries directed towards understanding and modifying the aging process.

Objective: To summarise the incidental findings detected on brain imaging and blood tests during the first wave of data collection for the Insight 46 study., Design: Prospective observational sub-study of a birth cohort., Setting: Single-day assessment at a research centre in London, UK., Participants: 502 individuals were recruited from the MRC National Survey of Health and Development (NSHD), the 1946 British birth cohort, based on pre-specified eligibility criteria; mean age was 70.7 (SD: 0.7) and 49% were female., Outcome Measures: Data regarding the number and types of incidental findings were summarised as counts and percentages, and 95% confidence intervals were calculated., Results: 93.8% of participants completed a brain scan (n=471); 4.5% of scanned participants had a pre-defined reportable abnormality on brain MRI (n=21); suspected vascular malformations and suspected intracranial mass lesions were present in 1.9% (n=9) and 1.5% (n=7) respectively; suspected cerebral aneurysms were the single most common vascular abnormality, affecting 1.1% of participants (n=5), and suspected meningiomas were the most common intracranial lesion, affecting 0.6% of participants (n=3); 34.6% of participants had at least one abnormality on clinical blood tests (n=169), but few reached the prespecified threshold for urgent action (n=11)., Conclusions: In older adults, aged 69-71 years, potentially serious brain MRI findings were detected in around 5% of participants, and clinical blood test abnormalities were present in around one third of participants. Knowledge of the expected prevalence of incidental findings in the general population at this age is useful in both research and clinical settings., Competing Interests: Competing interests: NF’s research group has received payment for consultancy or for conducting studies from Avid Radiopharmaceuticals, Biogen, Eisai, Elan, Eli Lilly Research Laboratories, GE Healthcare, IXICO, Janssen, Johnson & Johnson, Lundbeck, Pfizer, Roche, Sanofi-Aventis and Wyeth Pharmaceuticals. NF receives no personal compensation for the activities mentioned above. JMS has received research funding from Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly), has consulted for Roche Pharmaceuticals, Biogen and Eli Lilly, has given educational lectures sponsored by GE, Eli Lilly and Biogen, and serves on a Data Safety Monitoring Committee for Axon Neuroscience SE., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Growth differentiation factor 11 (GDF11) belongs to the TGF-β superfamily of proteins and is closely related to myostatin. Recent findings show that GDF11 has rejuvenating properties with pronounced effects on the cardiovascular system, brain, skeletal muscle, and skeleton in mice. Several human studies were also conducted, some implicating decreasing levels of circulating GDF11 with age. To date, however, there have not been any reports on its role in human skin. This study examined the impact of GDF11 on human skin, specifically related to skin aging. The effect of recombinant GDF11 on the function of various skin cells was examined in human epidermal keratinocytes, dermal fibroblasts, melanocytes, dermal microvascular endothelial cells and 3D skin equivalents, as well as in ex vivo human skin explants. GDF11 had significant effects on the production of dermal matrix components in multiple skin models in vitro and ex vivo. In addition, it had a pronounced effect on expression of multiple skin related genes in full thickness 3D skin equivalents. This work, for the first time, demonstrates an important role for GDF11 in skin biology and a potential impact on skin health and aging., Competing Interests: The commercial affiliation with Avon Products Inc and declare that this does not alter our adherence to PLOS ONE policies on sharing data and materials.

Aging is the biggest risk factor for several neurodegenerative diseases. Parabiosis experiments have established that old mouse brains are improved by exposure to young mouse blood. Previously, our lab showed that delivery of Growth Differentiation Factor 11 (GDF11) to the bloodstream increases the number of neural stem cells and positively affects vasculature in the subventricular zone of old mice. Our new study demonstrates that GDF11 enhances hippocampal neurogenesis, improves vasculature and increases markers of neuronal activity and plasticity in the hippocampus and cortex of old mice. Our experiments also demonstrate that systemically delivered GDF11, rather than crossing the blood brain barrier, exerts at least some of its effects by acting on brain endothelial cells. Thus, by targeting the cerebral vasculature, GDF11 has a very different mechanism from that of previously studied circulating factors acting to improve central nervous system (CNS) function without entering the CNS.

Locomotion is necessary for survival in most animal species. However, injuries to the appendages mediating locomotion are common. We assess the recovery of walking in Drosophila melanogaster following leg amputation. Whereas flies pre-amputation explore open arenas in a symmetric fashion on average, foreleg amputation induces a strong turning bias away from the side of the amputation. However, we find that unbiased walking behavior returns over time in wild-type flies, while recovery is significantly impaired in proprioceptive mutants. To identify the biomechanical basis of this locomotor impairment and recovery, we then examine individual leg motion (gait) at a fine scale. A minimal mathematical model that links neurodynamics to body mechanics during walking shows that redistributing leg forces between the right and left side enables the observed recovery. Altogether, our study suggests that proprioceptive input from the intact limbs plays a crucial role in the behavioral plasticity associated with locomotor recovery after injury., (© 2016. Published by The Company of Biologists Ltd.)

Growth differentiation factor 11 (GDF11) and myostatin (or GDF8) are closely related members of the transforming growth factor β superfamily and are often perceived to serve similar or overlapping roles. Yet, despite commonalities in protein sequence, receptor utilization and signaling, accumulating evidence suggests that these 2 ligands can have distinct functions in many situations. GDF11 is essential for mammalian development and has been suggested to regulate aging of multiple tissues, whereas myostatin is a well-described negative regulator of postnatal skeletal and cardiac muscle mass and modulates metabolic processes. In this review, we discuss the biochemical regulation of GDF11 and myostatin and their functions in the heart, skeletal muscle, and brain. We also highlight recent clinical findings with respect to a potential role for GDF11 and/or myostatin in humans with heart disease. Finally, we address key outstanding questions related to GDF11 and myostatin dynamics and signaling during development, growth, and aging., (© 2016 American Heart Association, Inc.)

Genetically identical individuals display variability in their physiology, morphology, and behaviors, even when reared in essentially identical environments, but there is little mechanistic understanding of the basis of such variation. Here, we investigated whether Drosophila melanogaster displays individual-to-individual variation in locomotor behaviors. We developed a new high-throughout platform capable of measuring the exploratory behavior of hundreds of individual flies simultaneously. With this approach, we find that, during exploratory walking, individual flies exhibit significant bias in their left vs. right locomotor choices, with some flies being strongly left biased or right biased. This idiosyncrasy was present in all genotypes examined, including wild-derived populations and inbred isogenic laboratory strains. The biases of individual flies persist for their lifetime and are nonheritable: i.e., mating two left-biased individuals does not yield left-biased progeny. This locomotor handedness is uncorrelated with other asymmetries, such as the handedness of gut twisting, leg-length asymmetry, and wing-folding preference. Using transgenics and mutants, we find that the magnitude of locomotor handedness is under the control of columnar neurons within the central complex, a brain region implicated in motor planning and execution. When these neurons are silenced, exploratory laterality increases, with more extreme leftiness and rightiness. This observation intriguingly implies that the brain may be able to dynamically regulate behavioral individuality.

Quantitative genetics has primarily focused on describing genetic effects on trait means and largely ignored the effect of alternative alleles on trait variability, potentially missing an important axis of genetic variation contributing to phenotypic differences among individuals. To study the genetic effects on individual-to-individual phenotypic variability (or intragenotypic variability), we used Drosophila inbred lines and measured the spontaneous locomotor behavior of flies walking individually in Y-shaped mazes, focusing on variability in locomotor handedness, an assay optimized to measure variability. We discovered that some lines had consistently high levels of intragenotypic variability among individuals, whereas lines with low variability behaved as although they tossed a coin at each left/right turn decision. We demonstrate that the degree of variability is itself heritable. Using a genome-wide association study (GWAS) for the degree of intragenotypic variability as the phenotype across lines, we identified several genes expressed in the brain that affect variability in handedness without affecting the mean. One of these genes, Ten-a, implicates a neuropil in the central complex of the fly brain as influencing the magnitude of behavioral variability, a brain region involved in sensory integration and locomotor coordination. We validated these results using genetic deficiencies, null alleles, and inducible RNAi transgenes. Our study reveals the constellation of phenotypes that can arise from a single genotype and shows that different genetic backgrounds differ dramatically in their propensity for phenotypic variabililty. Because traditional mean-focused GWASs ignore the contribution of variability to overall phenotypic variation, current methods may miss important links between genotype and phenotype.

The α-, β-, and γ-protocadherins (Pcdhα, Pcdhβ, and Pcdhγ) comprise a large family of single-pass transmembrane proteins predominantly expressed in the nervous system. These proteins contain six cadherin-like extracellular domains, and proteolysis of Pcdhα and Pcdhγ by the γ-secretase complex releases their intracellular domains into the cytoplasm where they may function locally and/or enter the nucleus and affect gene expression. Thus, cleavage of Pcdhs may function to link intercellular contacts and intracellular signaling. Here we report that shedding of the Pcdhα extracellular domain and subsequent processing by γ-secretase require endocytosis and that Pcdhs interact with the regulator of vesicular sorting ESCRT-0 in undifferentiated cells. We also find that the accumulation of Pcdh cleavage products is regulated during development. Differentiation leads to an increase in the interactions between Pcdh proteins and a decrease in the accumulation of cleavage products. We conclude that Pcdh processing requires endocytosis and that the level of cleavage products is regulated during neuronal differentiation.

The clustered protocadherins (Pcdhs) are a large family of cadherin-like transmembrane proteins expressed in the nervous system. Stochastic expression of Pcdh genes and alternative splicing of their pre-mRNAs have the potential to generate enormous protein diversity at the cell surface of neurons. At present, the regulation and function of Pcdh proteins are largely unknown. Here, we show that Pcdhs form a heteromeric signaling complex(es), consisting of multiple Pcdh isoforms, receptor tyrosine kinases, phosphatases, and cell adhesion molecules. In particular, we find that the receptor tyrosine kinase rearranged during transformation (Ret) binds to Pcdhs in differentiated neuroblastoma cells and is required for stabilization and differentiation-induced phosphorylation of Pcdh proteins. In addition, the Ret ligand glial cell line-derived neurotrophic factor induces phosphorylation of Pcdhgamma in motor neurons and phosphorylation of Pcdhalpha and Pcdhgamma in sympathetic neurons. Conversely, Pcdh proteins are also required for the stabilization of activated Ret in neuroblastoma cells and sympathetic ganglia. Thus, Pcdhs and Ret are functional components of a phosphorylation-dependent signaling complex.

In the eukaryotic cell, a protein quality control process termed endoplasmic reticulum-associated degradation (ERAD) rids the ER of aberrant proteins and unassembled components of protein complexes that fail to reach a transport-competent state. To identify novel genes required for ERAD, we devised a rapid immunoassay to screen yeast lacking uncharacterized open reading frames that were known targets of the unfolded protein response (UPR), a cellular response that is induced when aberrant proteins accumulate in the ER. Six genes required for the efficient degradation of the Z variant of the alpha1-proteinase inhibitor (A1PiZ), a known substrate for ERAD, were identified, and analysis of other ERAD substrates in the six A1PiZ-degradation-deficient (add) mutants suggested diverse requirements for the Add proteins in ERAD. Finally, we report on bioinformatic analyses of the new Add proteins, which will lead to testable models to elucidate their activities.